JP2006182755A - Treatment of latent tuberculosis - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a medicine for treating latent tuberculosis. <P>SOLUTION: The compound useful for producing a medicine for treating latent tuberculosis is selected from 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(3,5-difluorophenyl)-4-dimethylamino-1-phenylbutan-2-ol, 1-(6-bromo-2-methoxyquinolin-3-yl)-4-2-naphthalen-1-yl-1-phenylbutan-2-ol, 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,5-difluorophenyl)-4-dimethylamino-1-phenylbutan-2-ol, their physiologically acceptable acid or base addition salts, N-oxides, tautomers and stereochemical isomers. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

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

BACKGROUND OF THE INVENTION Mycobacterium tuberculosis causes more than 2 million deaths per year and is the leading cause of death in people infected with HIV ¹ (Non-Patent Document 1). Regardless of decades of TB (TB) control program, about 2 billion people are asymptomatically infected with Mycobacterium tuberculosis. About 10% of these humans are at risk of developing active TB during their lifetime ² (Non-Patent Document 2). The global pandemic of TB is fueled by HIV infection of TB patients and an increase in multi-drug resistant TB strains (MDR-TB). Reactivation of latent TB is a high risk factor for disease onset and causes 32% of deaths in HIV-infected patients ¹ (Non-patent Document 1). In order to control the TB epidemic, what is needed is to find new drugs that can kill dormancy or latent gonococci. Dormant TB can be reactivated by several factors such as suppression of host immunity through the use of immunosuppressive agents such as antibodies to tumor necrosis factor α or interferon-γ and can cause disease. In the case of HIV positive patients, the only prophylactic treatment available for latent TB is rifampicin, a pyrazine amide 2 to 3 month regimen ( ^3,4 ). Reference 4). The effectiveness of treatment regimen is not yet clear, and the length of treatment is an important constraint in a more limited environment. Thus, there is a strong need to identify new drugs that can serve as chemopreventive drugs for patients with latent TB bacilli. Tuberculosis enters into healthy humans by inhalation; they are phagocytosed by lung alveolar macrophages. This leads to a potent immune response and the formation of granuloma consisting of macrophages infected with M. tuberculosis surrounded by T cells. After 6-8 weeks, the host immune response causes deposition in peripheral cheese-like material having a certain extracellular bacilli surrounded by a layer of dead and macrophages, epitheloid cells and lymphoid tissues of infected cells by necrosis ⁵ (Non-patent document 5). In healthy humans, most of the mycobacteria are killed in these environments, but a small percentage of gonococci still survive and appear to exist in a non-replicating, hypometabolic state, such as isoniazid. it is resistant to killing by the TB drug ⁶ (non-Patent Document 6). These bacilli can remain in a modified physiological environment even during the lifetime of a human being without showing the clinical symptoms of the disease. However, at 10%, these latent gonococci can reactivate and cause disease. One hypothesis for the emergence of these surviving bacteria is the pathophysiological environment in human lesions: reduced oxygen tension, nutrient limitation and acidic pH ⁷ (Non-Patent Document 7). These factors have been regarded as making these bacteria phenotypically resistant to major anti-mycobacterial drugs ⁷ (Non-Patent Document 7).

U.S. Patent No. 6,057,031 describes substituted quinoline derivatives useful for the treatment of mycobacterial diseases. The document discloses the antimycobacterial properties of substituted quinoline derivatives against sensitive susceptible mycobacteria strains, but does not describe their activity against latent, dormant, surviving mycobacteria.
International Publication No. 2004/011436 Pamphlet Corbett, E .; 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 .; & Raviglione, M .; C. Consensus statement. Global burden of tuberculosis: estimated incident, prevalence, and mortality by county. WHO Global Survey and Monitoring Project. JAMA 282, 1999, 677-686. Am J Respir. Crit Care Med 161, 2000, S221-S247. Halsey, N .; A. et al. Cho, Randomized trial of isoniazid versus rifampicin and pyrazinamide for prevention of tuberculosis HIV-1 infection. Lancet 351, 1998, 786-792. Mitchison, D.M. A. & Coates, A.C. R. Authors, Predictive in vitro models of the sterilizing activity of anti-tuberculosis drugs. Curr. Pharm. Des 10, 2004, 3285-3295. Karakousis, P.A. C. et al. Written by Dormanty phenotype displayed by extracellular Mycobacterium tuberculosis within the artificial granulomas in mice. J Exp. Med. 200, 2004, 647-657. Gomez, J .; E. & McKinney, J.A. D. Author, M.C. tuberculosis persistence, latency, and drug tolerance. Tubeculosis. (Edinb.) 84, 2004, 29-44.

  This time, we have the sterilization of the compounds of Patent Document 1, especially the compounds of the formulas (Ia) and (Ib) defined below, and are effective in killing dormant mycobacteria, especially human tuberculosis, It has been found that it can be used for the treatment of latent TB. They will therefore greatly strengthen the arsenal to fight TB.

Figure Legend: Dormant M. cerevisiae assayed by luciferase count. Effect of various drugs on R. bovis (RLU: relative luminescence units) (bacteria were suspended in drug-free medium for 5 days after anaerobic life for 7 days).
FIG. 2A): Dormant Effect of various drugs on Bovis (CFU: colony forming unit) (reports CFU determined 2 days after anaerobic life).
FIG. 2B): Dormant Effect of various drugs on Bovis (CFU: colony forming unit) (reports CFU determined 5 days after anaerobic life).
Figure 3: Effects of various drugs on dormant M. tuberculosis (Wayne model).

The present invention thus relates to the 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

[Where:
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 the formula

A group, wherein 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 and include N to which they are attached, optionally alkyl, halo, haloalkyl, Pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, which may be substituted with hydroxy, alkyloxy, amino, mono- or dialkylamino, alkylthio, alkyloxyalkyl, alkylthioalkyl and pyrimidinyl Forming 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-
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 the group ═N—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; A cyclic saturated hydrocarbon group having 3 to 6 carbon atoms bonded to a linear or branched saturated hydrocarbon group having 1 carbon atom; wherein each carbon atom is optionally halo, hydroxy, Can be substituted with alkyloxy or oxo;
Ar is an allocyclic ring selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, and each allocyclic ring can be optionally substituted by 1, 2 or 3 substituents, 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 That;
Het is a monocyclic heterocycle selected from the group of N-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; Or quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo [1,4] dioxinyl or benzo [1, 3] is 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 1-6 where one or more carbon atoms are substituted with one or more halo-atoms A linear or branched saturated hydrocarbon group having 3 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 present 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 present invention.

Compounds according to formulas (Ia) and (Ib) are, for example, tautomeric equivalents of compounds according to formula (Ia), wherein a compound according to formula (Ib) having R ⁹ equal to oxo has R ² equal to hydroxy are mutually related (keto-enol tautomerism).

  Within the framework of this 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 this application, Ar is an allocyclic ring selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each optionally substituted by 1, 2 or 3 substituents, Substituents are independently hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono- or dialkylaminocarbonyl. Selected from the group. Preferably, Ar is naphthyl or phenyl, each optionally substituted with 1 or 2 halo substituents.

  Within the framework of this application, Het is a monocycle selected from the group of N-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl. Or a 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 is optionally 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 this 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 with one or more halo-atoms. It 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. Preferably, halo is bromo, fluoro or chloro, preferably haloalkyl is polyhaloC _1-6 alkyl, which is mono- or polyhalo substituted C _1-6 alkyl, eg one or more fluoro atoms Defined as, for example, difluoromethyl or trifluoromethyl, 1,1-difluoro-ethyl, and the like. If more than one halogen atom is attached to an alkyl group within the definition of polyhaloC _1-6 alkyl, they can be the same or different.

In the definition of Het, or when R ⁴ and R ⁵ are taken together, all possible isomers of the heterocyclic ring are included, for example pyrrolyl comprises 1H-pyrrolyl and 2H-pyrrolyl.

Ar or Het (see eg R ³ ) mentioned in the definition of substituents of compounds of formula (Ia) or (Ib) mentioned above or hereinafter is any ring carbon Alternatively, it can also be bonded to the remainder of the molecule of formula (Ia) or (Ib) via a heteroatom as appropriate. Thus, for example, when Het is imidazolyl, it can be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, and the like.

  A line drawn from a substituent into the ring system indicates that the bond can be attached to any suitable ring atom.

When two vicinal R ⁶ groups together form a divalent group of the formula —CH═CH—CH═CH—, this means that the two vicinal R ⁶ groups are linked to the phenyl to which they are attached. It means forming naphthyl together with a ring.

  For therapeutic use, the salt of the compound of formula (Ia) or (Ib) is such that the counterion is pharmaceutically acceptable. However, pharmaceutically unacceptable acid and base salts may also find use, for example, in the manufacture or purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or unacceptable, are included within the scope of the present invention.

  The pharmaceutically acceptable addition salts referred to above or hereinafter comprise the therapeutically active non-toxic acid addition salts that can be formed by the compounds of formula (Ia) or (Ib). Shall. The latter forms the base in the form of an inorganic acid such as hydrohalic acid such as hydrochloric acid or hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid or the like; 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, treatment with an alkali can convert the salt form to the free base form.

  Compounds of formula (Ia) or (Ib) containing acidic protons can be converted to their therapeutically active non-toxic metal or amine addition salt forms by treatment with suitable organic and inorganic bases. . Suitable base salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts, such as lithium, sodium, potassium, magnesium, calcium salts, 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, 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, treatment with an acid can convert the salt form to the free acid form.

  The term addition salt also includes the hydrate and solvent addition forms that a compound of formula (Ia) or (Ib) can form. Examples of such forms are eg hydrates, alcoholates and the like.

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

  As used hereinbefore or hereinafter, the term “stereochemical isomer” refers to compounds of formula (Ia) and (Ib) and their N-oxides, addition salts or physiologically functional derivatives. Define all possible stereoisomers that you may have. Unless otherwise stated or indicated, the chemical name of a compound refers to a mixture of all possible stereochemical isomers containing all diastereomers and enantiomers of the underlying molecular structure. In particular, the stereogenic center can have an R- or S-configuration; substituents on a divalent cyclic (partially) saturated group can have either a cis- or trans-configuration. A compound containing a double bond may have E (entgengen) or Z (zusammen) -stereochemistry at the double bond. The terms cis, trans, R, S, E and Z are well known to those skilled in the art. The stereochemical isomers of the compounds of formula (Ia) and (Ib) are clearly intended to be included within the scope of the present invention.

  According to the CAS nomenclature agreement, if there are two known absolute configuration stereogenic centers in a molecule, the lowest numbered chiral center, the R or S descriptor in the reference center (descriptor) ) Is specified (based on 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 and [R * , R *] indicates the center having the same chirality, and [R *, S *] indicates the center having the same chirality. For example, when the lowest numbered chiral center in the molecule has the S configuration and the second center is R, the stereographic character is defined as S- [R *, S *]. When “α” and “β” are used: the position of the highest priority substituent on the asymmetric carbon atom in the ring system with the lowest ring number is always “α” in the mean plane, which is always determined by the ring system. It ’s in the position. The position of the highest priority substituent on another asymmetric carbon atom in the ring system relative to the position of the highest priority substituent on the reference atom is when 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 that the form is substantially free of other isomers, ie less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably 5% Less than, more preferably less than 2% and most preferably less than 1%. Thus, when a compound of formula (I) is defined as, for example, (αS, βR), this means that the compound is substantially free of (αR, βS) isomers.

  Compounds of formula (Ia) and (Ib) can be synthesized in the form of a racemic mixture of enantiomers, which can be separated from each other according to resolution methods known in the art. Racemic compounds of formula (Ia) and (Ib) can be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. 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 a stereospecific manufacturing method. These methods will advantageously use enantiomerically pure starting materials.

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

  N-oxide forms of the compounds according to formulas (Ia) and (Ib) include compounds of the formulas (Ia) and (Ib) in which one or several tertiary nitrogen atoms are oxidized to the so-called N-oxide. It shall be

  Compounds of formula (Ia) and (Ib) can be converted to the corresponding N-oxide form according to methods known in the art for converting trivalent nitrogen to its N-oxide form. The N-oxidation reaction can generally be carried out by reacting the starting materials of formula (Ia) and (Ib) with a suitable organic or inorganic peroxide. 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 peroxy acids such as benzene carboperoxo Acid or halo-substituted benzene carboperoxo acids such as 3-chlorobenzene carboperoxo acid, peroxoalkanoic acids such as peroxoacetic acid, alkyl hydroperoxides such as t. Butyl hydro-peroxide can be included. 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 present invention also comprises derivatized compounds of pharmacologically active compounds according to the present invention (usually referred to as “prodrugs”), which decompose in vivo to give the compounds according to the present invention. Prodrugs are usually (but not necessarily) of lower potency at the target receptor than the compounds they degrade to give. 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 slightly soluble, it may be less transported across the mucosal epithelium, or it may have an undesirably short plasma half-life. For further discussion of prodrugs, see Stella, V. et al. J. et al. et al. "Prodrugs", Drug Delivery Systems, 1985, pp. 112-176 and Drugs, 29, 1985, pp. 455-473.

Prodrug forms of pharmacologically active compounds according to the invention generally comprise compounds according to formulas (Ia) and (Ib) having an esterified or amidated acid group, their pharmaceutically acceptable acids or bases Addition salts, their stereochemical isomers, their tautomers and their N-oxide forms. Included in such esterified acid groups is a group of formula —COOR ^x , where R ^x is C _1-6 alkyl, phenyl, benzyl or the following groups:

It is one of. 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.

  Compounds according to the invention having amino groups can be derivatized with ketones or aldehydes, such as formaldehyde, to form Mannich bases. This base will be hydrolyzed with first order kinetics in aqueous solution.

  Whenever used herein, the term “compound of formula (Ia) or (Ib)” refers to their pharmaceutically acceptable acid or base addition salts, their N-oxide forms, their Tautomers or stereochemical isomers thereof are also included. Of particular interest are stereochemically pure compounds of formula (Ia) or (Ib).

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 the formula

Where 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 taken} together and including N to which they are attached include pyrrolidinyl, imidazolyl, triazolyl, piperidinyl, Can form a group selected from the group of piperazinyl, pyrazinyl, morpholinyl and thiomorpholinyl, each ring system can optionally be substituted with alkyl or pyrimidinyl;
R ⁶ is hydrogen, halo or alkyl; or two vicinal R ⁶ groups taken together form the formula —CH═CH—CH═CH—
A divalent group of
r is an integer equal to 1;
R ⁷ is hydrogen;
R ⁸ is hydrogen or alkyl;
R ⁹ is oxo; or R ⁸ and R ⁹ together form the group ═N—CH═CH—;
Whether the 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; A cyclic saturated hydrocarbon group having 3 to 6 carbon atoms bonded to a linear or branched saturated hydrocarbon group having 1 carbon atom; wherein each carbon atom is optionally halo or hydroxy Can be substituted;
Ar is an allocyclic ring selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, and each allocyclic ring can be optionally substituted with 1, 2 or 3 substituents, each substituent being Independently selected from the group of halo, haloalkyl, cyano, alkyloxy and morpholinyl;
Het is a monocyclic heterocycle selected from the group of N-phenoxypiperidinyl, piperidinyl, furanyl, thienyl, pyridinyl, pyrimidinyl; or benzothienyl, 2,3-dihydrobenzo [1,4] dioxinyl or benzo A bicyclic heterocycle selected from the group [1,3] dioxolyl; each monocyclic and bicyclic heterocycle is optionally substituted with 1, 2 or 3 alkyl or Ar-carbonyl substituents. And relates to the use as defined above of a compound of formula (Ia) or (Ib), wherein halo is a substituent selected from the group of fluoro, chloro and bromo.

In a second interesting embodiment, the compound of formula (Ia) or (Ib) or any subgroup thereof mentioned as an interesting embodiment above is 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 embodiment, the compound of formula (Ia) or (Ib) or any subgroup thereof mentioned as an interesting embodiment above is a compound of formula (Ia) wherein p is equal to 1 and R ¹ is different from hydrogen. And (Ib).

In a fourth interesting embodiment, the compound of formula (Ia) or (Ib) or any subgroup thereof mentioned as an interesting embodiment above is wherein R ² is hydrogen, alkyloxy or alkylthio; preferably R ² Are compounds according to formulas (Ia) and (Ib) wherein R ² is alkyloxy, in particular C _1-4 alkyloxy; more preferably 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 compound of formula (Ia) or (Ib) or any subgroup thereof mentioned above as an interesting embodiment is wherein R ³ is optionally substituted with 1 or 2 substituents, respectively. Naphthyl, phenyl or thienyl, the substituent is preferably halo or haloalkyl, most preferably halo; preferably R ³ is each optionally substituted with halo, preferably 3-fluoro Compounds according to formulas (Ia) and (Ib) wherein R ³ is naphthyl or phenyl; most preferably R ³ is naphthyl.

  In a sixth interesting aspect, the compound of formula (Ia) or (Ib) or any subgroup thereof mentioned as an interesting aspect above has q equal to zero, 1 or 2; Equal compounds according to formulas (Ia) and (Ib).

In a seventh interesting embodiment, the compounds of formula (Ia) or (Ib) or any of their subgroups mentioned above as interesting embodiments are such that R ⁴ and R ⁵ are each independently hydrogen or alkyl, in particular hydrogen Or C _1-4 alkyl, more particularly C _1-4 alkyl; compounds according to formulas (Ia) and (Ib), 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 embodiment, the compound of formula (Ia) or (Ib) or any subgroup thereof referred to above as an interesting embodiment is the N ⁴ where R ⁴ and R ⁵ are taken together and to which they are attached. Can be optionally substituted with alkyl, halo, haloalkyl, hydroxy, alkyloxy, alkylthio, alkyloxyalkyl or alkylthioalkyl, preferably substituted with alkyl, most preferably substituted with methyl or ethyl A compound according to formula (Ia) and (Ib) which forms a group selected from the group of imidazolyl, triazolyl, piperidinyl, piperazinyl and thiomorpholinyl.

In a ninth interesting embodiment, the compound of formula (Ia) or (Ib) or any subgroup thereof mentioned as an interesting embodiment above is wherein 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 embodiment, the compound of formula (Ia) or (Ib) or any subgroup thereof mentioned above as an interesting embodiment is according to formula (Ia) and (Ib) wherein r is 1 or 2 A compound.

In an interesting embodiment of the eleventh, the compounds or any subgroup thereof as mentioned hereinbefore as interesting embodiment are the above formula (Ia) or (Ib), R ⁷ is hydrogen or methyl; preferably R ⁷ is hydrogen Compounds according to certain formulas (Ia) and (Ib).

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

  In a thirteenth interesting embodiment, the compound of formula (Ia) or (Ib) or any subgroup thereof mentioned as an interesting embodiment above is a compound according to formula (Ia), its pharmaceutically acceptable 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 are 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 optionally substituted with 1 or 2 substituents selected from the group; q = 0, 1, 2 or 3; R ⁴ and R ⁵ are each independently hydrogen Or an alkyl or a group selected from the group of imidazolyl, triazolyl, piperidinyl, piperazinyl and thiomorpholinyl, including N to which R ⁴ and R ⁵ are joined and bonded together; 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 mentioned above as an interesting embodiment, 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-quinoline ethanol -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-quinoline ethanol -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: compounds 12, 71, 174, 75, 172 and 79, described below in Tables 1-6, in particular compounds 12, 71, 174 and 75, more particularly compound 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 -Α- [2- (Dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-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-quinoline ethanol, a pharmaceutically acceptable acid or base addition salt thereof, N-oxide or a stereochemical isomer thereof; or 6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinoline ethanol or a pharmacy thereof Acceptable acid addition salts; or 6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinoline ethanol or its stereochemical isomerism Or 6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinoline ethanol or Or (αS, βR) -6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinoline ethanol and (αR , ΒS) -6-Bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol or a pharmaceutically acceptable acid addition thereof Salts or mixtures of stereochemical isomers thereof, 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-quinoline ethanol, 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-quinoline ethanol, which is 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 formulas (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 sequence of steps, each of which is known to the skilled worker.

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

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

  The same reaction method can be used to synthesize the compound of formula (Ib).

  The starting materials and intermediate compounds of formula (II) and (III) are compounds that are commercially available or can be prepared according to conventional 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) in which 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, A suitably 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 carried out conveniently at a temperature in the range of 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 carried out conveniently at a temperature in the range of room temperature to reflux temperature. In the next step (c), the intermediate compound obtained in step (b) is reacted with a compound H—C—C _1-6 alkyl wherein X is S or O, so that R ² is, for example, C _1-6 A specific R ² — group which is an alkyloxy or C _1-6 alkylthio group is introduced.

  Intermediate compounds according to formula (II-b) can be prepared according to the following reaction scheme (3), in which the substituted indole-2,3-dione is converted to sodium hydroxide as in sodium hydroxide in the first step (a). Reacting 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 the reaction such as diphenyl ether. Decarboxylate at high temperature.

  It will be appreciated that in the reactions described above and below, 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 evident that reaction products which exist in more than one enantiomeric form can be isolated from their mixtures by known methods, in particular by preparative chromatography, for example by preparative HPLC. Typically, compounds of formula (I) can be separated into their isomers.

Intermediate compounds of formula (III) are compounds that are commercially available or can be prepared according to conventional 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 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) in which a suitable Lewis acid, for example AlCl ₃ , FeCl ₃ , SnCl ₄ , TiCl ₄ or ZnCl ₂ and a suitable solvent inert to the reaction. A suitably substituted Ar, in particular a suitably substituted phenyl, in the presence of methylene chloride or ethylene dichloride, for example by a Friedel-Craft reaction, suitable acyl chlorides such as 3-chloropropionyl chloride or 4-chlorobutyryl chloride. React with. The reaction can be carried out conveniently at a temperature in the range of room temperature to reflux temperature. In the next step (b), an amino group (—NR ₄ R ₅ ) is introduced by reacting the intermediate compound obtained in step (a) with a primary or secondary amine.

  For the interpretation of the present invention, latent TB, dormant TB or persistence TB are the same.

  As already described above, compounds of formula (Ia) and (Ib) can be used for the treatment of latent TB. The exact dosage and frequency of administration of the compound will depend on the particular compound of formula (Ia) and (Ib) used, the particular condition being treated, as well known to those skilled in the art. Depending on the severity of the condition, age of the particular patient, weight, sex, diet, time of administration and general physical conditions, mode of administration and other medications the patient may be taking. It is further apparent that the effective daily dose can be reduced or increased depending on the response of the patient being treated and / or depending on the evaluation of the physician prescribing the 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 a variety of pharmaceutical forms for administration purposes. Suitable compositions can include all compositions commonly used for systemically administering drugs. For the preparation of a pharmaceutical composition, an effective amount of a particular compound, optionally in the form of an addition salt, is combined in an intimate mixture with a pharmaceutically acceptable carrier, and The carrier may take a wide variety of forms depending on the form of preparation desired for administration. Desirably these pharmaceutical compositions are in unit dosage forms suitable for administration, particularly by oral or parenteral injection. For example, in the preparation of compositions in oral dosage forms, water, glycols, oils in the case of oral liquid preparations such as any conventional pharmaceutical media such as suspensions, syrups, elixirs, emulsions and solutions. Or in the case of powders, pills, capsules and tablets, solid carriers such as starches, sugars, kaolins, diluents, lubricants, binders, disintegrants and the like can be used. Because of their ease of administration, tablets and capsules provide the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise at least a majority of sterile water, but can contain other ingredients, for example, to aid solubility. For example, an injectable solution can be prepared in which the carrier comprises saline, glucose solution or a mixture of saline and glucose solution. Injectable suspensions can also be prepared, in which case suitable liquid carriers, suspending agents and the like can be employed. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations.

  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 30-99.9% 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-regulating agents, surfactants, preservatives, flavoring agents or coloring agents. Can be contained.

  It is especially advantageous to prepare the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. As used herein, dosage unit form refers to physically separated units suitable as a single dosage, each unit being a predetermined amount of active ingredient calculated to produce the desired therapeutic effect. Together with the necessary pharmaceutical carrier. Examples of such unit dosage forms are tablets (including chopped or coated tablets), capsules, pills, powder packages, wafers, suppositories, injectable solutions or suspensions, etc., as well as multiple of them separated is there. The daily dosage of the compounds according to the invention will of course vary with the compound used, the mode of administration, the desired treatment and the applied mycobacterial disease. In general, however, administration of a compound according to the invention at a daily dosage not exceeding 1 or 2 grams per kg body weight, for example in the range of 10-50 mg, will give satisfactory results.

Experimental Part As already described above, the compounds of formula (Ia) and (Ib) and their preparation are described in WO 2004/011436, the description of which is incorporated herein by reference. It becomes contents.

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

  When “A” and “B” are stereoisomeric mixtures, they can be further separated, and the respective first fractions isolated thereby will be referred to as “A1” and “B1”, respectively, Are referred to as “A2” and “B2,” respectively, and no further reference is made to the actual stereochemical configuration. However, using methods known in the art such as X-ray diffraction, one skilled in the art can clearly characterize the “A1, A2” and “B1, B2” isomers. .

  The present compounds (see Tables 1 to 6) are numbered according to the compounds of WO 2004/011436 and can be prepared according to the method described in WO 2004/011436. . The example numbers in the table below refer to the example numbers in the pamphlet of International Publication No. 2004/011436, indicating that the compound can be produced 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

Benzenepropanoyl chloride (0.488 mol) is added dropwise at room temperature to a solution of 4-bromobenzenamine (0.407 mol) in Et ₃ N (70 ml) and CH ₂ Cl ₂ (700 ml) 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 was 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. POCl ₃ (1.225 mol) was added dropwise at 10 ° C. to N, 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

A mixture of CH ₃ ONa (30%) in methanol (222.32 ml) and intermediate compound 2 (prepared according to A2) (0.233 mol) in methanol (776 ml) was stirred and refluxed overnight, then on ice Poured and extracted with CH ₂ Cl ₂ . The organic layer was separated, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH ₂ Cl ₂ / cyclohexane 20/80 and then 100/0; 20-45 μm). The pure fractions were collected and the solvent was evaporated. Yield: 25 g of intermediate compound 3 as white powder (Yield = 33%; mp 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 1.6M (0.05 mol) at −20 ° C. under N ₂ flow. 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 ° C. for 3 hours, hydrolyzed with ice water at −30 ° C. 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, yielding 3 g of fraction 1 and 4.4 g of fraction 2. Fractions 1 and 2 were crystallized separately from DIPE. The precipitate was filtered and dried, 2.2 g of diastereoisomer A final compound 14 (yield: 9%; melting point 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 (eluent: hexane / EtOH; 99.95 / 0.05) to give the corresponding enantiomer. 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 enantiomer A2 (final compound 13) as a white solid (melting point 120 ° C., [α] _D ²⁰ = + 167.60 ^° (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 enantiomer B1 and 78.8 mg enantiomer B2. Enantiomer B1 was purified by column chromatography over silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH; 99/1 / 0.1; 15-40 μm). One fraction was collected and the solvent was evaporated. Yield: 57 mg of enantiomer B1 (final compound 12a) ([α] _D ²⁰ = −42.56 ^° (c = 0.336 g / 100 ml in DMF)). Enantiomer B2 was purified by column chromatography over silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH; 99/1 / 0.1; 15-40 μm). One fraction was collected and the solvent was evaporated. Yield: 53 mg of enantiomer B2 (final compound 13a) ([α] _D ²⁰ = + 43.55 ^° (c = 0.349 g / 100 ml in DMF)).

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

A. Study of effect of final compound 12 in killing dormant Mycobacterium bovis Bacterial strains and medium Mycobacterium bovis BCG was obtained from Tibotec Virco (TB0087- (Belgium), plasmid pSMT1. M. bovis BCG (a kind donation from Dr. Kris Huygen ⁸ in Pasteur Institute, Brussels) expressing the luciferase gene above, Medbrook 7H9 medium (Difco, BD1310 with 0.05% Tween-80 (Sigma) ) In the logarithmic phase for 3 to 4 days before the start of the experiment.

For growth medium preparation: 4.7 g of Middlebrook powder is dissolved in 895 ml of distilled water, 5 ml of glycerol, 200 μl of Tween 80 is added and autoclaved at 121 ° C. for 15 minutes. Once cooled to 45 ° C., 100 ml of Middlebrook OADC enrichment medium is aseptically added to the medium. Store at 4 ° C for up to 1 month. All media is pre-incubated for 2 days at 37 ° C. and examined for contamination. Strains M. expressing the luciferase gene For Bovis BCG (BCG-pSMT1), add 50 μg / ml hygromycin.
I. Research dormancy assay using Mycobacterium bovis BCG 500 μl of Mycobacterium bovis BCG stock stock was added to 100 ml of Middlebrook 7H9 broth with supplements in 250 ml of sterile Duran bin with magnetic stir bar . Incubation was carried out on a magnetic stirrer at 37 ° C. for 7 days (500 rpm). A 5 ml aliquot (OD _{600 nm} = 0.5-0.8) of the log phase culture was transferred into a 15 ml screw-caped falcon tube. Various drugs were added to individual tubes at a final concentration of 10 μg / ml. After the 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 individual drugs and the start of anaerobic life in the jar was carried out very quickly as previously described ⁹ . The jar was 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). Cells were washed twice with 7H9 medium to remove drug and resuspended in drug-free medium. CFUs of treated and untreated cultures were determined by plating on days 0, 2 and 5 to assess bactericidal activity.
II. M. expressing the luciferase gene on plasmid pSMT1 Study dormancy assay using Bovis BCG 500 μl of Mycobacterium bovis BCG luciferase (pSMT1) stock bacteria was added to 100 ml of Middlebrook 7H9 broth with supplements in 250 ml of sterile Duran bin with a magnetic stir bar. Incubation was carried out on a magnetic stirrer at 37 ° C. for 7 days (500 rpm). A 5 ml aliquot (OD _{600 nm} = 0.5-0.8) of the log phase culture was transferred into a 15 ml screw-cap falcon tube. Various drugs 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) ⁹ very quickly as previously described. An anaerobic gas generating wrap was used to obtain an anaerobic condition in the jar, and an anaerobic strip was used to monitor the anaerobic condition. The jar was 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). Cells were washed twice with 7H9 medium to remove drug and resuspended in drug-free medium. After washing, 250 μl of dormant M.P. Bovis BCG luciferase (pSMT1) was added to 5 different microplates (day 0-5). All samples in the microplate were diluted in medium (5-fold dilution) and reincubated at 37 ° C. until 0-5 days. 40 μl of sample and dilution was added to 140 μl of PBS. 20 μl of luciferase substrate (1% n-decylaldehyde in ethanol) was added. Every day from 0 to 5 days, luminescence was measured for 10 seconds (using a Luminoskan Ascent Labsystems with injector) to follow the growth of viable bacteria.

Results and Discussion An in vitro dormancy model of dormancy has been developed based on Wayne's oxygen-depleted method of forming dormant bacteria ^9,10 . In Wayne's model, mycobacteria settle to the bottom of the flask, so they form an oxygen gradient, creating an anaerobic condition at the bottom of the flask. This transition to hypoxia makes mycobacteria dormant, which leads to upregulated expression of several genes including isocitrate lyase 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 the case of aerobic respiration. The energy of the reduced substrate creates an electrochemical gradient.

In this experiment, the application of Wayne's model was used in an experimental configuration that included the use of a gaspak anaerobic jar that depleted oxygen indoors by a chemical reaction ⁹ . A lid containing the catalyst is attached to the gas package. A gas foil foil cover containing a substance that produces hydrogen and CO ₂ is placed in a jar with a bacterial culture. Open the cover and pipet 10 ml of tap water into it. When the jar is closed (the lid is tightened tightly), the generated hydrogen combines with oxygen and forms water through the catalyst. This gradually depletes the oxygen present in the room, 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 color change in the indicator strip indicates that proper atmospheric conditions have been achieved.

For rapid analysis of the effects of compounds on dormant bacteria, M. elegans transformed with luciferase constructs. Bovis BCG was used. M.M. Bovis BCG has been used in previous experiments as a surrogate to mimic dormancy in whole mycobacteria and specifically in Mycobacterium tuberculosis ^11,12 . Luciferase reporter strains have been used very frequently to assess bacterial viability ^13,14 . E. The reporter plasmid pSMT1, which is a shuttle vector containing E. coli and mycobacterial origins of replication, was used for M. Transform bovis BCG ⁸ . Luminescent genes (lux A and B) from Vibro harveyi are under the control of the BCG hsp60 promoter and produce light in the presence of ATP or flavin mononucleotide (FMNH ₂ ). Dead cells are unable to produce these cofactors, thus corresponding to a decrease in luminescence.

In this dormancy assay, the activity of the final compound 12 and the activities of other drugs including metronidazole and isoniazid were analyzed. Dormant bacteria are not killed by isoniazid and are somewhat resistant to rifampicin but are susceptible to killing by metronidazole, an antibiotic for anaerobic pathogens ^15,16 . Isoniazid acts as initial bactericides, although its activity is limited to killing of replicating bacilli, do not have significant sterilized active to 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 the viability of the bacteria was assessed by luciferase count. As shown in FIG. 1, isoniazid has no effect on these dormant bacteria, these bacteria have almost similar growth characteristics compared to the standard and show a dormant or non-replicating state of the cultured bacilli. Indicated. In contrast, metronidazole was clearly effective in killing dormant bacilli over a period of time, reducing it by 2 log ₁₀ compared to the standard. The final compound 12 affects the survival of dormant bacteria in a concentration dependent manner. In the final compound 12 at a concentration of 10 μg / ml, there was an approximately 4-log ₁₀ reduction in bacterial survival compared to the untreated standard. For 0.1 and 1 μg / ml compounds, the killing of the corresponding dormant bacteria was about 0.5 log ₁₀ and 2 log ₁₀ respectively.

To correlate the effect of the final compound 12 on bacterial killing by relative luminescence units (RLU / ml) to colony forming units (CFU / ml), bacterial accounts were also measured on 7H10 plates. A similar ratio of RLU units to CFU counts was observed after plating 2 and 4 day samples on 7H10 plates. The decrease in CFU counts compared to the untreated standard counts indicates viability of about 4, 2.3 and 0 for 2 days at 10 μg / ml, 1 μg / ml and 0.1 μg / ml of final compound 12, respectively. .5 log ₁₀ and a decrease of about 6, 4.7 and 1.1 log _{10 on the} 5th day. FIG. 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 the concentration of ATP in these cells is very low, which is characteristic of the metabolic state of dormant bacilli. It has been shown ⁸ .

The activity of the final compound 12 against dormant (non-proliferating) mycobacteria is a very important finding that it fights against tuberculosis by eradicating the disease in patients at risk of developing TB. Because it will help.
B. Study of effect of final compound 12 in killing dormant human Mycobacterium tuberculosis according to Wayne dormancy model * Bacterial strain and medium Mycobacterium tuberculosis (H37RV) was cultured in Middlebrook medium with 0.05% Tween .

For the preparation of Middlebrook 7H9 broth (1X) (BD 271310) with supplements: 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 15 ° C. at 15 ° C. Autoclave for minutes. Once cooled to 45 ° C., 100 ml of Middlebrook OADC Accumulation Medium (BD 211886) is aseptically added to the medium. Store at 4 ° C for up to 1 month. All media is pre-incubated for 2 days at 37 ° C. and examined for contamination.
* Wayne L. G. et al. Written; Infection and Immunity 64 (6), 1996, 2062-2069
Research dormancy assay using Mycobacterium tuberculosis (H37RV) 1000 μl of Mycobacterium tuberculosis stock (previously culture) was added to 100 ml of Middlebrook 7H9 broth with supplements in 250 ml of sterile Duran bin with magnetic stir bar . Incubation was carried out on a magnetic stirrer at 37 ° C. for 7 days (500 rpm). A 17 ml aliquot of the log phase culture (calculated OD _600nm = 0.01) was transferred into a 25 ml tube. The tube was tightly closed with a cap having a rubber septum and incubated on a magnetic stir plate to produce an anaerobic life due to oxygen depletion. Agitation in the tube was performed using 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 life (methylene blue (1.5 mg / liter) turned colorless). After 14 days, various drugs (final concentrations of 100, 10, 1 and 0.1 μg / ml) were added to individual tubes. Metronidazole was added as a standard for killing dormant bacteria (added at the 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 collected by low speed centrifugation (2000 rpm for 10 minutes). Cells were washed twice with 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 and bactericidal activity was assessed.

Results and discussion:
A Wayne dormancy model is used to show the effect of the final compound 12 on dormant bacteria (see FIG. 3). As already indicated above, it is an in vitro oxygen depletion model, which initiates a dormant response in bacteria ^18-23 . In the Wayne model, bacterial cultures are subjected to gradual oxygen depletion by incubation in a stirred closed tube. With the slow transition of the aerobically growing bacteria to the anaerobic state, the culture can adapt and survive more anaerobically by moving down to the state of anaerobic persistence. The Wayne model is a well-characterized in vitro model for dormancy.

In the final compound 12 at a concentration of 10 μg / ml, more than a 2 log ₁₀ reduction in dormant bacteria was observed, as was also the case with moxifloxacin and rifampicin. Isoniazid has no effect on dormant bacteria, but the standard compound, metranidazole, showed excellent efficacy.
Reference literature list Corbett, E .; 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 .; & Raviglione, M .; C. Consensus statement. Global burden of tuberculosis: estimated incident, prevalence, and mortality by county. WHO Global Survey 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 ATS Board of Directors, July 1999. This is a joint statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC). This statement was endorsed by the Council of the Infectious Diseases Society of America (IDSA), September 1999, and the department of this statement. Am J Respir. Crit Care Med 161, 2000, S221-S247.
4). Halsey, N .; A. et al. Cho, Randomized trial of isoniazid versus rifampicin and pyrazinamide for prevention of tuberculosis HIV-1 infection. Lancet 351, 1998, 786-792.
5. Mitchison, D.M. A. & Coates, A.C. R. Authors, Predictive in vitro models of the sterilizing activity of anti-tuberculosis drugs. Curr. Pharm. Des 10, 2004, 3285-3295.
6). Karakousis, P.A. C. et al. Written by Dormanty phenotype displayed by extracellular Mycobacterium tuberculosis within the artificial granulomas in mice. J Exp. Med. 200, 2004, 647-657.
7). Gomez, J .; E. & McKinney, J.A. D. Author, M.C. tuberculosis persistence, latency, and drug tolerance. Tubeculosis. (Edinb.) 84, 2004, 29-44.
8). Snewin, V.M. A. et al. Author, of of Immunity to mycobacterial infectivity with luciferase reporter constructs. Infect. Immun. 67, 1999, 4586-4593.
9. Stover, C.I. K. et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis, Nature 405, 2000, 962-966.
10. Wayne, L.M. G. By Synchronized replication of Mycobacterium tuberculosis. Infect. Immun. 17, 1977, 528-530.
11. Boon, C.I. & Dick, T .; Author, Mycobacterium bovis BCG response regulator essential for hypoxic dormancy. J. et al. Bacteriol. 184, 2002, 6760-6767.
12 Hutter, B.M. & Dick, T .; Written, Up-regulation of narX, encoding a putative 'fused nitrate reductase' in analogy dormant mycobacterium bovis BCG. FEMS Microbiol. Lett. 178, 1999, 63-69.
13. Andrew, P.M. W. & Roberts, I.C. S. Written, Construction of a bioluminescent mycobacterium and its use for assay of anticobacterial agents. J Clin. Microbiol. 31, 1993, 2251-2254.
14 Hickey, M .; J. et al. et al. Author, Luciferase in vivo expression technology: use of recombinant mycobacterial reporter strains to evaluation of antibacterial activity in mice. Antimicrob. Agents Chemother. 40, 1996, 400-407.
15. Wayne, L.M. G. & Sramek, H .; A. By Metronazole is bacterial to dormant cells of Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 38, 1994, 2054-2058.
16. Wayne, L.M. G. Author, Dormancy of Mycobacterium tuberculosis and latency of disease. Eur. J Clin Microbiol. Infect. Dis 13, 1994, 908-914.
17. Lalande, V.M. , Truffot-Pernot, C.I. , Packard-Mouulin, A .; Grosset, J .; & Ji, B. Author, Powerful bacterial activity of sparfloxacin (AT-4140) against mycobacterium tuberculosis in mice. Antimicrob. Agents Chemother. 37, 1993, 407-413.
18. Zhang, Y. et al. Written by Persistent and Dormant tubercle bacilli and latent tuberculosis. Front Biosci. 9, 2004, 1136-1156.
19. Boon, C.I. & Dick, T .; Author, Mycobacterium bovis BCG response regulator essential for hypoxic dormancy. J Bacteriol. 184, 2002, 6760-6767.
20. Peh, H .; L. Toh, A .; , Murugasu-Oei, B .; & Dick, T .; In Vitro activities of mitomycin C against growing and hypoxic dominant tuberculi. Antimicrob. Agents Chemother. 45, 2001, 2403-2404.
21. Hutter, B.M. & Dick, T .; Written, Increased alanine dehydrogenase activity duty dormancy in Mycobacterium smegmatis. FEMS Microbiol. Lett. 167, 1998, 7-11.
22. Wayne, L.M. G. & Hayes, L .; G. By An in vitro model for sequential study of shiftdown of Mycobacterium tuberculosis through two stages of non-replicating persistence. Infect. Immun. 64, 1996, 2062-2069.
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Dormant M. assayed by luciferase count. The graph which shows the effect of the various chemical | medical agents to Bovis. Dormant M.M. The graph which shows the effect of the various chemical | medical agents to Bovis. Dormant M.M. The graph which shows the effect of the various chemical | medical agents to Bovis. The graph which shows the effect of the various chemical | medical agent to dormant human tuberculosis bacteria.

Claims (26)

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
[Where:
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 the formula
A group, wherein 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 and include N to which they are attached, optionally alkyl, halo, haloalkyl, Pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, which may be substituted with hydroxy, alkyloxy, amino, mono- or dialkylamino, alkylthio, alkyloxyalkyl, alkylthioalkyl and pyrimidinyl Forming 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-
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 the group ═N—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 carbon atoms; wherein each carbon atom is optionally Can be substituted with halo, hydroxy, alkyloxy or oxo;
Ar is an allocyclic ring selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, and each allocyclic ring can be optionally substituted by 1, 2 or 3 substituents, 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 That;
Het is a monocyclic heterocycle selected from the group of N-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; Or quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo [1,4] dioxinyl or benzo [1, 3] is 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 1-6 where one or more carbon atoms are substituted with one or more halo-atoms A linear or branched saturated hydrocarbon group having 3 or 6 carbon atoms or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms]
Use that is a pharmaceutically acceptable acid or base addition salt thereof, an N-oxide thereof, a tautomer thereof or a stereochemical isomer thereof. 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 the formula
Where 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 taken} together and including N to which they are attached include pyrrolidinyl, imidazolyl, triazolyl, piperidinyl, Can form a group selected from the group of piperazinyl, pyrazinyl, morpholinyl and thiomorpholinyl, each ring system can optionally be substituted with alkyl or pyrimidinyl;
R ⁶ is hydrogen, halo or alkyl; or two vicinal R ⁶ groups taken together form the formula —CH═CH—CH═CH—
A divalent group of
r is an integer equal to 1;
R ⁷ is hydrogen;
R ⁸ is hydrogen or alkyl;
R ⁹ is oxo; or R ⁸ and R ⁹ together form the group ═N—CH═CH—;
Whether the 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 carbon atoms; wherein each carbon atom is optionally Can be substituted with halo or hydroxy;
Ar is an allocyclic ring selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, and each allocyclic ring can be optionally substituted with 1, 2 or 3 substituents, each substituent being Independently selected from the group of halo, haloalkyl, cyano, alkyloxy and morpholinyl;
Het is a monocyclic heterocycle selected from the group of N-phenoxypiperidinyl, piperidinyl, furanyl, thienyl, pyridinyl, pyrimidinyl; or benzothienyl, 2,3-dihydrobenzo [1,4] dioxinyl or benzo A bicyclic heterocycle selected from the group [1,3] dioxolyl; each monocyclic and bicyclic heterocycle is optionally substituted with 1, 2 or 3 alkyl or Ar-carbonyl substituents. And the halo is a substituent selected from the group of fluoro, chloro and bromo. Use according to claim 1 or 2, wherein in formula (Ia) or (Ib), R ¹ is hydrogen, halo, Ar, alkyl or alkyloxy. Use according to claim 3, wherein R ¹ is halo.   Use according to any one of claims 1 to 4, wherein in formula (Ia) or (Ib), p is equal to 1. In the formula (Ia) or (Ib), using R ² is hydrogen, according to any one of claims 1-5 alkyloxy or alkylthio. Use according to claim 6, wherein R ² is alkyloxy. In formula (Ia) or (Ib), each R ³ is naphthyl, phenyl or thienyl optionally substituted with one or two substituents selected from the group of halo and haloalkyl. Use according to any one of 7. Use according to claim 8, wherein R ³ is naphthyl.   10. Use according to any one of claims 1 to 9, wherein q is equal to 1 in formula (Ia) or (Ib). In formula (Ia) or (Ib), R ⁴ and R ⁵ are each independently hydrogen or alkyl, or R ⁴ and R ^{5 taken} together and include N to which they are attached, imidazolyl, Use according to any one of claims 1 to 10 forming a group selected from the group of triazolyl, piperidinyl, piperazinyl and thiomorpholinyl. Use according to claim 11, wherein in formula (Ia) or (Ib), R ⁴ and R ⁵ are each independently hydrogen or alkyl. Use according to claim 12, wherein R ⁴ and R ⁵ are C _1-4 alkyl. Use according to any one of claims 1 to 13, wherein in formula (Ia) or (Ib) R ⁶ is hydrogen, alkyl or halo. Use according to claim 13, wherein R ⁶ is hydrogen.   16. Use according to any one of claims 1 to 15, wherein r is equal to 1 in formula (Ia) or (Ib). Use according to any one of claims 1 to 16, wherein in formula (Ia) or (Ib) R ⁷ is hydrogen. 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 optionally substituted with 1 or 2 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 taken} together and including N to which they are attached form a group selected from the group of imidazolyl, triazolyl, piperidinyl, piperazinyl and thiomorpholinyl Use according to claim 1, wherein R ⁶ is hydrogen, alkyl or halo; r is equal to 1 and R ⁷ is hydrogen. 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;
According to claim 1, characterized in that they are selected from the group consisting of their pharmaceutically acceptable acid or base addition salts, their N-oxides, their tautomers or their stereochemical isomers use. The compound is 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-quinoline corresponding to 6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinoline ethanol -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 20. Use according to claim 19, selected from the group consisting of tautomers thereof, or their stereochemical isomers. The compound is 6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinoline ethanol, a pharmaceutically acceptable acid or base addition salt thereof , Its N-oxide or its stereochemical isomer. The compound is 6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinoline ethanol or a pharmaceutically acceptable acid addition salt thereof. Use according to claim 21. Use according to claim 21, wherein the compound is 6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinoline ethanol or a stereochemical isomer thereof. . Use according to claim 21, wherein the compound is 6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinoline ethanol or its N-oxide form. The compound is (αS, βR) -6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinoline ethanol or a pharmaceutically acceptable salt thereof. Use according to claim 21 which is the resulting acid addition salt. Use according to claim 25, wherein the compound is (αS, βR) -6-bromo-α- [2- (dimethylamino) ethyl] -2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol.