HK1113795B

HK1113795B - Quinoline derivatives and their use as mycobacterial inhibitors

Info

Publication number: HK1113795B
Application number: HK08103990.6A
Authority: HK
Inventors: Jérôme Emile Georges Guillemont; Jozef Frans Elisabetha Van Gestel; Marc Gaston Venet; Koenraad Jozef Lodewijk Marcel Andries; Imre Christian Francis Csoka; Laurence Françoise Bernadette Decrane; Daniel F. J. Vernier; Frank Christopher Odds
Original assignee: Janssen Pharmaceutica N.V.
Priority date: 2002-07-25
Filing date: 2008-04-09
Publication date: 2012-11-30

Description

Quinoline derivatives and their use as mycobacterial inhibitors

The present application is a divisional application of patent application No. 03817713.7 entitled "quinoline derivatives and their use as mycobacterial inhibitors".

The present invention relates to novel substituted quinoline derivatives useful in the treatment of: mycobacterial diseases, in particular diseases caused by pathogenic mycobacteria such as mycobacterium tuberculosis (mycobacterium tuberculosis), mycobacterium bovis (m.bovis), mycobacterium avium (m.avium) and mycobacterium marinum (m.marinum).

Background

Mycobacterium tuberculosis is Tuberculosis (TB), a worldwide pathogen of serious and potentially fatal infection. Estimated by the world health organization, over eight million people become infected with TB each year, and two million people die of tuberculosis each year. In the last 10 years, TB cases have grown by 20% worldwide, placing a tremendous burden on most poor countries. If these trends continue, the incidence of TB will increase by 41% over the next 20 years. TB has been located after AIDS for 50 years since the introduction of effective chemotherapy as the leading cause of infection in adult deaths in the world. The epidemic of TB is complicated by the increasing trend towards multidrug resistant strains, and the lethal symbiosis with HIV. People who are HIV positive and infected with TB have a 30-fold higher probability of developing active TB than people who are HIV negative, and TB is responsible for one death in every 3 HIV/AIDS patients worldwide.

Existing methods for treating tuberculosis all involve the combined use of multiple therapeutic agents. For example, the recommended treatment regimen by U.S. public Health Service is a combination of isoniazid, rifampin and pyrazinamide for 2 months of treatment, followed by another 4 months of treatment with isoniazid and rifampin alone. In patients infected with HIV, these drugs continue for an additional 7 months. For patients infected with multidrug resistant strains of mycobacterium tuberculosis, therapeutic agents such as ethambutol, streptomycin, kanamycin, amikacin, capreomycin, ethionamide, cycloserine, ciprofloxacin and ofloxacin are added to the combination therapy. There is no therapeutic agent that is clinically effective in treating tuberculosis, nor is there any combination of therapeutic agents that provides a therapeutic potential for a duration of less than 6 months.

There is a great medical need for new drugs that improve current treatments by enabling the adoption of treatment regimens that improve patient and donor compliance. Shorter treatment regimens and regimens that require less supervision are the best ways to achieve this goal. When 4 drugs are administered together, most of the benefit from treatment is achieved in the first 2 months, which is a booster or bactericidal period; the bacterial burden is greatly reduced and the patient becomes non-infectious. A 4-6 month continuation or sterilization period is required to eliminate persistent bacilli and minimize the risk of relapse. An effective sterilizing agent that shortens treatment to 2 months or less would be extremely beneficial. There is also a need for drugs that improve compliance by requiring less supervision. Clearly, a compound that both shortens the overall treatment length and reduces the frequency of administration would provide the greatest benefit.

The epidemic of TB is complicated by the increasing incidence of multidrug resistant strains or MDR-TB. Worldwide, up to 4% of all cases are considered MDR-TB, i.e. those that tolerate the most potent drugs-standard 4 drugs, isoniazid and rifampicin. MDR-TB is fatal when untreated and cannot be adequately treated by standard therapy, so treatment requires 2 years of "second line medication. These drugs are often toxic, expensive and marginally effective. In the absence of effective treatment, patients with infectious MDR-TB continue to transmit the disease, resulting in infection with a new strain of MDR-TB. There is a great medical need for new drugs with new mechanisms of action, possibly exhibiting activity against MDR strains.

It is an object of the present invention to provide novel compounds, in particular substituted quinoline derivatives, which have mycobacterial growth inhibiting properties and are therefore useful in the treatment of mycobacterial diseases, in particular diseases caused by pathogenic mycobacteria such as mycobacterium tuberculosis, mycobacterium bovis, mycobacterium avium and mycobacterium marinum.

Substituted quinoline compounds have been disclosed in US5,965,572 (usa) for the treatment of antibiotic resistant infections and substituted quinoline compounds that inhibit the growth of bacterial microorganisms are disclosed in WO 00/34265. None of these publications disclose the substituted quinoline derivatives of the present invention.

Summary of The Invention

The present invention relates to novel substituted quinoline derivatives of formula (Ia) or (Ib)

A pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a tautomeric form thereof and a N-oxide form thereof, wherein:

R¹is hydrogen, halo, haloalkyl, cyano, hydroxy, Ar, Het, alkyl, alkoxy, alkylthio, alkoxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl;

p is an integer equal to 0, 1, 2, 3 or 4;

R²is hydrogen, hydroxy, mercapto, alkoxy, alkoxyalkoxy, alkylthio, mono-or di (alkyl) amino or a group of formulaWherein Y is CH₂O, S, NH or N-alkyl;

R³is alkyl, Ar-alkyl, Het or Het-alkyl;

q is an integer equal to 0, 1, 2, 3 or 4;

R⁴and R⁵Each independently is hydrogen, alkyl or benzyl; or

R⁴And R⁵Together with the N to which they are attached may form a group selected from: pyrrolidinyl, 2H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, imidazolidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl, and thiomorpholinyl, which groups may be optionally substituted with alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, mono-or dialkylamino, alkylthio, alkoxyalkyl, alkylthioalkyl, and pyrimidinyl;

R⁶is hydrogen, halogen, haloalkyl, hydroxy, Ar, alkyl, alkoxy, alkylthio, alkoxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar) alkyl; or

Two R⁶The groups may together form a divalent group of formula ═ C —;

r is an integer equal to 0, 1, 2, 3, 4 or 5; and is

R⁷Is hydrogen, alkyl, Ar or Het;

R⁸is hydrogen or alkyl;

R⁹is an oxo group; or

R⁸And R⁹Together form a group which is N-CH-,

alkyl is a straight or branched chain 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 straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms; wherein each carbon atom may be optionally substituted by halogen, hydroxy, alkoxy or oxo;

ar is a carbocyclic ring selected from: phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each of which is optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from hydroxy, halogen, cyano, nitro, amino, mono-or dialkylamino, alkyl, haloalkyl, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, aminocarbonyl, morpholinyl, and mono-or dialkylaminocarbonyl;

het is a monocyclic heterocycle selected from: n-phenoxypiperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocycle selected from: quinolyl, quinoxalyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2, 3-dihydrobenzo [1, 4] dioxinyl, or benzo [1, 3] dioxolyl; each of said monocyclic and bicyclic heterocycles may optionally be substituted on carbon by 1, 2 or 3 substituents selected from halo, hydroxy, alkyl or alkoxy;

halogen is a substituent selected from fluorine, chlorine, bromine and iodine, and

haloalkyl is a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radical having 3 to 6 carbon atoms, wherein one or more carbon atoms are substituted by one or more halogen atoms.

The compounds of the formulae (Ia) and (Ib) are interrelated in that, for example, R is⁹A compound of formula (Ib) which is oxo is wherein R²Tautomeric equivalents of compounds of formula (Ia) that are hydroxy groups (keto-enol tautomerism).

Detailed Description

In the present application, alkyl is a straight or branched chain 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 straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms; wherein each carbon atom may be optionally substituted with halo, hydroxy, alkoxy or oxo. The alkyl group is preferably a methyl, ethyl or cyclohexylmethyl group.

In the present application, Ar is a carbocyclic ring selected from: phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each of which is optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from hydroxy, halogen, cyano, nitro, amino, mono-or dialkylamino, alkyl, haloalkyl, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, aminocarbonyl, morpholinyl, and mono-or dialkylaminocarbonyl. Ar is preferably naphthyl or phenyl, each optionally substituted with 1 or 2 halogen substituents.

In the present application, Het is a monocyclic heterocycle selected from: n-phenoxypiperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocycle selected from: quinolyl, quinoxalyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2, 3-dihydrobenzo [1, 4] dioxinyl, or benzo [1, 3] dioxolyl; each of said monocyclic and bicyclic heterocycles may optionally be substituted on carbon by 1, 2 or 3 substituents selected from halo, hydroxy, alkyl or alkoxy.

In the present application, halogen is a substituent selected from the group consisting of fluorine, chlorine, bromine and iodine, and haloalkyl is a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms, wherein one or more carbon atoms are substituted with one or more halogen atoms. Halogen is preferably bromine, fluorine or chlorine, and haloalkyl is preferably trifluoromethyl.

The present invention preferably relates to compounds of the formulae (Ia) and (Ib) as defined below, in which:

R¹is hydrogen, halo, cyano, Ar, Het, alkyl and alkoxy;

p is an integer equal to 0, 1, 2, 3 or 4;

R²is hydrogen, hydroxy, alkoxy, alkoxyalkoxy, alkylthio or a group of the formulaWherein Y is O;

R³is alkyl, Ar-alkyl or Het;

q is an integer equal to 0, 1, 2 or 3;

R⁴and R⁵Each independently is hydrogen, alkyl or benzyl; or

R⁴And R⁵Together with the N to which they are attached may form a group selected from: pyrrolidinyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyrazinyl, morpholinyl and thiomorpholinyl, which groups may be optionally substituted with alkyl and pyrimidinyl;

R⁶is hydrogen, halogen or alkyl; or

Two R⁶The groups may together form a divalent group of formula ═ C —;

r is an integer equal to 1; and is

R⁷Is hydrogen;

R⁸is hydrogen or alkyl;

R⁹is an oxo group; or

R⁸And R⁹Together form a group which is N-CH-,

alkyl is a straight or branched chain 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 straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms; wherein each carbon atom may be optionally substituted with halogen or hydroxy;

ar is a carbocyclic ring selected from: phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each of which is optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from the group consisting of halogen, haloalkyl, cyano, alkoxy, and morpholinyl;

het is a monocyclic heterocycle selected from: n-phenoxypiperidinyl, furanyl, thienyl, pyridinyl, pyrimidinyl; or a bicyclic heterocycle selected from: benzothienyl, 2, 3-dihydrobenzo [1, 4] dioxinyl or benzo [1, 3] dioxolyl; each of said monocyclic and bicyclic heterocycles may be optionally substituted on carbon by 1, 2 or 3 alkyl substituents; and is

Halogen is a substituent selected from fluorine, chlorine and bromine.

For the compounds of formulae (Ia) and (Ib), R¹Preferably hydrogen, halogen, Ar, alkyl or alkoxy. R¹More preferably a halogen. R¹Most preferably bromine.

p is preferably equal to 1.

R²Preferably hydrogen, alkoxy or alkylthio. R²Alkoxy groups are preferred. R²Methoxy is most preferred.

R³Preferably naphthyl, phenyl or thienyl, each of which is optionally substituted with 1 or 2 substituents, preferably halogen or haloalkyl, most preferably halogen. R³More preferably naphthyl or phenyl. R³Most preferred is naphthyl.

q is preferably equal to 0, 1 or 2. q is more preferably equal to 1.

Preferably, R⁴And R⁵Each independently hydrogen or alkyl, more preferably hydrogen, methyl or ethyl, most preferably methyl.

Preferably, R⁴And R⁵Together with the N to which they are attached form a group selected from: imidazolyl, triazolyl, piperidinyl, piperazinyl and thiomorpholinyl, said radicals optionally being substituted by alkyl, halogen, haloalkyl, hydroxy, alkoxyAlkylthio, alkoxyalkyl or alkylthioalkyl, preferably by alkyl, most preferably by methyl or ethyl.

R⁶Preferably hydrogen, alkyl or halogen. R⁶Most preferably hydrogen. r is preferably 0, 1 or 2. R⁷Preferably hydrogen or methyl.

For compounds of formula (Ib) only, preferably, R⁸Is alkyl, preferably methyl, and R⁹Is oxygen.

A group of interesting compounds are compounds of formula (Ia) as defined below, the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof and the N-oxide form thereof, wherein R is¹Is hydrogen, halogen, Ar, alkyl or alkoxy, p ═ 1, R²Is hydrogen, alkoxy or alkylthio, R³Is naphthyl, phenyl or thienyl, each of which is optionally substituted with 1 or 2 substituents selected from halogen and haloalkyl, q ═ 0, 1, 2 or 3, R⁴And R⁵Each independently is hydrogen or alkyl, or R⁴And R⁵Together with the N to which they are attached form a group selected from: imidazolyl, triazolyl, piperidinyl, piperazinyl and thiomorpholinyl, R⁶Is hydrogen, alkyl or halogen, R is equal to 0 or 1, and R is⁷Is hydrogen.

The most preferred compounds of the invention are:

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; and

o 1- (6-bromo-2-methoxy-quinolin-3-yl) -4-dimethylamino-2- (3-fluoro-phenyl) -1-phenyl-butan-2-ol,

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

Pharmaceutically acceptable acid addition salts are defined as therapeutically active non-toxic acid addition salt forms which the compounds of formula (Ia) and (Ib) of the present invention are capable of forming. Such acid addition salts may be obtained by treating the compounds of formulae (Ia) and (Ib) in base form with a suitable acid, for example an inorganic acid, such as hydrohalic acids, in particular hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; organic acids such as acetic acid, glycolic acid, propionic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, and pamoic acid (pamoic acid).

The compounds of formulae (Ia) and (Ib) containing an acidic proton may also be converted into therapeutically active non-toxic base addition salt forms thereof by treatment with suitable organic and inorganic bases. Suitable base addition salt forms include, for example, the ammonium salts, the alkali and alkaline earth metal salts, especially the lithium, sodium, potassium, magnesium and calcium salts, salts with organic bases such as benzathine (benzathine), N-methyl-D-glucamine, hybr-amine, and salts with amino acids such as arginine and lysine.

Likewise, the acid or base addition salt forms can be converted to the free form by treatment with a suitable base or acid.

The term addition salt as used herein also includes solvates which the compounds of formula (Ia) and (Ib) and salts thereof are able to form. Such solvates include, for example, hydrates and alcoholates.

The term "stereoisomeric forms" as used herein defines all possible isomeric forms which the compounds of formula (Ia) and (Ib) may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound refers to the mixture of all possible stereoisomeric forms, said compounds containing all diastereomers and enantiomers of the basic molecular structure. More specifically, the stereogenic center may have the R-or S-configuration; the substituents on the divalent cyclic (partially) saturated groups may have either the cis-or trans-configuration. It is clear that stereochemically isomeric forms of the compounds of formula (Ia) and (Ib) are included within the scope of the present invention.

According to the CAS-nomenclature convention, when two stereogenic centers of known absolute configuration are present in a molecule, then the least numbered chiral center-the reference center, is designated as the R or S descriptor (according to Cahn-Ingold-Prelog ordering principles). The configuration of the second stereogenic center is represented by relative descriptors [ R, R ] or [ R, S ], wherein the reference centers are always represented by R, and [ R, R ] represent centers having the same chirality and [ R, S ] represent centers of different chirality. For example, if the least numbered chiral center in a molecule has an S configuration and the second center is an R configuration, the stereodescriptor will be described as S- [ R, S ]. If "α" and "β" are used: the position of the most preferred substituent on the asymmetric carbon atom having the smallest ring number in the ring system is always in the "alpha" position of the average plane defined by the ring system. The position of the most preferred substituent on the other asymmetric carbon atom in the ring system relative to the position of the most preferred substituent on the reference atom is designated: it is named "α" if it is on the same side of the mean plane determined by the ring system, or "β" if it is on the other side of the mean plane determined by the ring system.

The compounds of formulae (Ia) and (Ib) and certain intermediate compounds always have at least two stereogenic centers in their structures, which can lead to at least 4 stereochemically different structures.

Tautomeric forms of the compounds of formulae (Ia) and (Ib) include compounds of formulae (Ia) and (Ib) in which the enol group is converted to a keto group (keto-enol tautomerism).

N-oxide forms of the compounds of formulae (Ia) and (Ib) include compounds of formulae (Ia) and (Ib) in which one or more nitrogen atoms are oxidized to the so-called N-oxides, particularly N-oxides in which the nitrogen of the amine group is oxidized.

The compounds of formula (Ia) and (Ib), as prepared by the methods described below, may be synthesized as racemic mixtures of enantiomers which can be separated from each other by resolution methods known in the art. Racemic compounds of formula (Ia) and (Ib) can be converted into the corresponding diastereomeric salt forms by treatment with a suitable chiral acid. The diastereomeric salt forms can then be separated, for example, by selective or fractional crystallization, and the enantiomers liberated therefrom with a base. Another method of separating the enantiomeric forms of the compounds of formula (Ia) and (Ib) involves liquid chromatography using a chiral stationary phase. The pure stereochemically isomeric forms may also be prepared from the appropriate starting materials in the corresponding pure stereochemically isomeric forms, provided that the reaction proceeds stereospecifically. Preferably, if a particular stereoisomer is desired, said compound is synthesized by stereospecific methods of preparation. These processes will advantageously employ enantiomerically pure starting materials.

The invention also includes derivative compounds (often referred to as "prodrugs") of the pharmacologically active compounds of the invention that degrade in vivo to produce the compounds of the invention. Prodrugs are generally (but not always) less potent at the target receptor than the compound into which they are degraded. Prodrugs are particularly useful when the desired compound has chemical or physical properties that make it difficult or inefficient to administer. For example, the desired compound may only have very poor solubility, it may cross the mucosal epithelium very weakly, or it may have an undesirably short plasma half-life. For further discussion of Prodrugs see Stella, V.J. et al, "Prodrugs", Drug delivery systems, 1985, pp.112-176, and Drugs, 1985, 29, pp.455-473.

Prodrugs of the pharmacologically active compounds of the present invention are generally compounds of formulae (Ia) and (Ib) having an acid group which is esterified or amidated, the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof and the N-oxide forms thereof. Such esterified acid groups include those of the formula-COOR^xA group shown in the formula, wherein R^xIs C_1-6Alkyl, phenyl, benzyl or one of the following groups:

amidated groups include the formula-CONR^yR^zA group shown in the formula, wherein R^yIs H, C_1-6Alkyl, phenyl or benzyl, and R^zis-OH, H, C_1-6Alkyl, phenyl or benzyl.

The compounds of the present invention having an amino group can be derivatized with a ketone or aldehyde, such as formaldehyde, to form a Mannich base. The base is hydrolyzed in aqueous solution with first order kinetics.

The compounds of the present invention surprisingly show suitability for the treatment of mycobacterial diseases, in particular diseases caused by pathogenic mycobacteria such as mycobacterium tuberculosis, mycobacterium bovis, mycobacterium avium and mycobacterium marinum. The invention therefore also relates to compounds of formulae (Ia) and (Ib), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof and the N-oxide forms thereof for use as medicaments.

The invention also relates to compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the invention as an active ingredient. The compounds of the present invention may be formulated into various pharmaceutical forms for administration. Suitable compositions which may be mentioned are all compositions for the systemic administration of drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unit dosage form particularly suitable for oral or parenteral administration by injection. For example, in preparing the compositions in oral dosage form, any of the conventional pharmaceutical media may be employed, such as water, glycols, oils, alcohols, and the like for oral liquid preparations such as suspensions, syrups, elixirs, emulsions, and solutions; or for powders, pills, capsules and tablets, the pharmaceutical media are solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral unit dosage form in which case solid pharmaceutical carriers are obviously employed. For compositions for parenteral administration, the carrier will usually comprise at least a major proportion of sterile water, and may also include other components, for example to facilitate dissolution. For example, injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline 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 converted into liquid form preparations immediately prior to use.

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

The pharmaceutical compositions of the present invention may also contain various other components known in the art, such as lubricants, stabilizers, buffers, emulsifiers, viscosity modifiers, surfactants, preservatives, flavoring agents, or coloring agents.

It is particularly advantageous to formulate the above pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. As used herein, unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, alkyl groups, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof. The daily dosage of the compounds of the invention will, of course, vary with the compound employed, the mode of administration, the desired treatment and the mycobacterial indication. However, satisfactory results are generally obtained when the compounds of the invention are administered in a daily dose of not more than 1 gram, for example 10-50mg/kg body weight.

Furthermore, the present invention relates to the use of compounds of formula (Ia) and (Ib), their pharmaceutically acceptable acid or base addition salts, their stereochemically isomeric forms, their tautomeric forms and their N-oxide forms as well as pharmaceutical compositions thereof for the manufacture of a medicament for the treatment of mycobacterial diseases.

Thus, in another aspect, the invention provides a method of treating a patient suffering from, or at risk of, mycobacterial disease, comprising administering to said patient a therapeutically effective amount of a compound or pharmaceutical composition of the invention.

General preparation

The compounds of the invention can generally be prepared by successive steps, each of which is known to those skilled in the art.

In particular, the compounds of formula (Ia) may be prepared by: the intermediate compound of formula (II) was reacted with the intermediate compound of formula (III) in a mixture of DIPA and THF using BuLi according to reaction scheme (1) below:

reaction scheme 1

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

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

reaction scheme 2

Wherein all variables are as defined in formulas (Ia) and (Ib). Reaction scheme (2) comprises a step (a) wherein an appropriately substituted aniline is reacted with a suitable acid chloride such as 3-phenylpropanoyl chloride, 3-fluorophenylpropionyl chloride or p-chlorophenylpropionyl chloride in the presence of a suitable base such as triethylamine and a suitable reaction inert solvent such as dichloromethane or 1, 2-dichloroethane. The reaction can be conveniently carried out at room temperature to reflux temperature. In a next step (b), the adduct obtained in step (a) is reacted with phosphorus oxychloride (POCl)₃) In the presence of N, N-dimethylformamide (Vilsmeier-Haack formylation followed by cyclization). The reaction can be conveniently carried out at room temperature to reflux temperature. In the next step (c), R is introduced by the following reaction³Particular R being alkoxy or alkylthio³-a group: reacting the intermediate compound obtained in step (b) with a compound X-Alk, wherein X ═ S or O, and Alk is alkyl as defined in formulae (Ia) and (Ib).

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

Reaction scheme 3

Obviously, in the above and below reactions, the reaction product may be isolated from the reaction medium and, if desired, further purified according to methods generally known in the art, such as extraction, crystallization and chromatography. It is also clear that the reaction products present in more than one enantiomeric form can be separated from their mixtures by known techniques, in particular preparative chromatography, for example preparative HPLC. The compounds of formula (Ia) and (Ib) can generally be separated into their isomeric forms.

The (III) intermediate compounds are commercially available compounds or can be prepared according to conventional reaction methods generally known in the art. For example, the compound of formula (III-a) as defined below can be prepared according to the following reaction scheme (4): wherein R is³Is substituted by s substituents R¹⁰Substituted Ar, wherein each R¹⁰Independently selected from hydroxy, halogen, cyano, nitro, amino, mono-or dialkylamino, alkyl, haloalkyl, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, aminocarbonyl, morpholinyl and mono-or dialkylaminocarbonyl, and s is an integer equal to 0, 1, 2 or 3:

reaction scheme 4

Reaction scheme (4) includes a step (a) in which an appropriately substituted phenyl group is reacted with a suitable acid chloride such as 3-chloropropionyl chloride or 4-chlorobutyryl chloride in a suitable Lewis acid such as AlCl₃、FeCl₃、SnCl₄、TiCl₄Or ZnCl₂And a suitable reaction-inert solvent the Friedel-Craft reaction is carried out in the presence of stereo dichloromethane or 1, 2-dichloroethane. The reaction can be conveniently carried out at room temperature to reflux temperature. In the next step (b), an amino group (-NR) is introduced by the following reaction⁴R⁵): will be atReacting the intermediate compound obtained in step (a) with a primary or secondary amine.

The following examples illustrate the invention but do not limit it.

Examples section

For certain compounds, the absolute stereochemical configuration of the carbon atoms in which the stereoisomers are produced is not experimentally determined. In these cases, the first isolated stereochemically isomeric form is referred to as "a" and the second isolated stereochemically isomeric form is referred to as "B", without further indication of the actual stereochemical configuration. However, the "a" and "B" isomeric forms can be unambiguously characterized by those skilled in the art using methods known in the art, such as X-ray diffraction. The separation method is described in detail below.

Hereinafter, "DMF" is defined as N, N-dimethylformamide, "DIPE" is defined as diisopropyl ether, and "THF" is defined as tetrahydrofuran.

A. Preparation of intermediate compounds

Example A1

Preparation of intermediate Compound 1

Phenylpropionyl chloride (0.488mol) was added dropwise to 4-bromoaniline (0.407mol) in Et at room temperature₃N (70ml) and CH₂Cl₂(700ml) and the mixture was stirred at room temperature overnight. The mixture was poured into water and concentrated NH₄In OH, with CH₂Cl₂And (4) extracting. The organic layer was dried (MgSO₄) Filtered and the solvent evaporated. The residue was crystallized from diethyl ether. The residue (119.67g) was taken up in CH₂Cl₂And washed with HCl 1N. The organic layer was dried (MgSO₄) Filtering, mixingThe solvent is evaporated. Yield: 107.67g of intermediate compound 1.

Preparation of intermediate Compound 9

Thus, using the same procedure as for intermediate compound 1, but using 4-methyl phenylpropanoyl chloride, intermediate compound 9 was prepared.

Example A2

Preparation of intermediate Compound 2

The reaction was carried out 2 times. Adding POCl at 10 deg.C₃(1.225mol) was added dropwise to DMF (0.525 mol). Intermediate compound 1 (prepared according to a1) (0.175mol) was then added at room temperature. The mixture was stirred at 80 ℃ overnight, poured onto ice and washed with CH₂Cl₂And (4) extracting. The organic layer was dried (MgSO₄) Filtered and the solvent evaporated. The product was used without further purification. Yield: (77.62 g; yield 67%).

Preparation of intermediate Compound 10

Thus, intermediate compound 10 was prepared from intermediate compound 9 (prepared according to a1) following the same procedure as intermediate compound 2.

Example A3

Preparation of intermediate Compound 3

Intermediate Compound 2 (prepared according to A2) (0.233mol) in CH₃A mixture of ONa (30%) in methanol (222.32ml) and methanol (776ml) was stirred and refluxed overnight, then poured onto ice and treated with CH₂Cl₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue was purified by chromatography on a silica gel column (eluent: CH)₂Cl₂Cyclohexane 20/80, then 100/0; 20-45 μm). The pure fractions were collected and the solvent was evaporated. Yield: 25g of intermediate compound 3 (yield 33%; mp.84 ℃) was a white powder.

Preparation of intermediate Compound 11

Thus, intermediate compound 11 was prepared from intermediate compound 10 (prepared according to a2) following the same procedure as intermediate compound 3.

Example A4

Preparation of intermediate Compound 4

A mixture of intermediate compound 2 (prepared according to A2) (0.045mol) in a solution of NaOEt 21% in ethanol (50ml) and ethanol (150ml) was stirred and refluxed for 12 hours. The mixture was poured onto ice and combined with CH₂Cl₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. Yield: 15.2g of intermediate compound 4 (98%).

Example A5

Preparation of intermediate Compound 5

A mixture of 5-bromo-1H-indole-2, 3-dione (0.28mol) in NaOH3N (650ml) was stirred and heated at 80 ℃ for 30 minutes, then cooled to room temperature. Phenylpropanal (0.28mol) was added and the mixture was stirred and refluxed overnight. The mixture was allowed to cool to room temperature and acidified with HOAc until pH 5. Filtering off the precipitate with H₂O washed and dried (vacuum). Yield: 50g of intermediate compound 5 (52%).

Example A6

Preparation of intermediate Compound 6

A mixture of intermediate compound 5 (prepared according to A5) (0.035mol) in diphenyl ether (100ml) was stirred and heated at 300 ℃ for 8 h and then cooled to room temperature. This operation was performed 4 times. The four mixtures were combined and then purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH100/0, then 99/1). The pure fractions were collected and the solvent was evaporated. Yield: 25.6g of intermediate compound 6 (61%).

Example A7

Preparation of intermediate Compounds 7 and 8

Intermediate 7 ═ (a)

Intermediate 8 ═ (B)

nBuLi1.6M (0.13mol) was added dropwise to a mixture of N- (1-methylethyl) -2-propylamine (0.13mol) in THF (300ml) at-10 ℃ under a stream of nitrogen. The mixture was stirred at-10 ℃ for 20 minutes and then cooled to-70 ℃. A solution of intermediate compound 3 (prepared according to A3) (0.1mol) in THF (300ml) was added dropwise. The mixture was stirred at-70 ℃ for 45 minutes. A solution of 2- (3-oxo-3-phenylpropyl) -1H-isoindole-1, 3(2H) -dione (0.13mol) in THF (300ml) is added dropwise. Stirring the mixture at-70 deg.C for 1 hr, cooling to-40 deg.C, stirring at-40 deg.C for 2 hr, and adding H₂O was hydrolyzed at-40 ℃ and extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (40g) was purified by column chromatography on silica gel (eluent: cyclohexane/EtOAc 85/15). Two fractions were collected and the solvent was evaporated. Yield: 1.8g of intermediate compound 7 (3%) and 5.3g of intermediate compound 8 (9%).

Example A8

Preparation of intermediate Compounds 12 and 13

Intermediate 12 intermediate 13

A mixture of aluminium chloride (34.3g, 0.257mol) and 3-chloropropionyl chloride (29.7g, 0.234mol) in dichloroethane (150ml) was stirred at 0 ℃. A solution of naphthalene (30g, 0.234mol) in dichloroethane (50ml) was added. The mixture was stirred at 5 ℃ for 2 hours and poured into water. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (56g) was purified by column chromatography on silica gel (eluent: cyclohexane/CH)₂Cl₂: 60/40, respectively; 20-45 μm). Two fractions were collected and the solvent was evaporated to give intermediate compound 12(31 g; yield 61%) as an oil. The second fraction (14g) was taken up in DIPE to give intermediate compound 13(8.2 g; yield 16%; mp.68 ℃) as a pale yellow solid.

Example A9

Preparation of intermediate Compound 14

Intermediate 14

A mixture of intermediate compound 12 (prepared according to A8) (3 g; 0.0137mol), N-benzylmethylamine (2 ml; 0.0150mol) in acetonitrile (100ml) was stirred at 80 for 2 hours. Water was added at Room Temperature (RT). By CH₂Cl₂The mixture is extracted. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (6g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂MeOH: 97/3, respectively; 20-45 μm) to yield BB1(4.2 g; quantitative yield) as an oil, intermediate compound 14 was obtained.

Example A10

Preparation of intermediate Compound 15

A mixture of 3, 5-difluoroacetophenone (commercially available) (25 g; 0.16mol), diethylamine hydrochloride (52 g; 0.64mol), paraformaldehyde (19 g; 0.63mol) in concentrated hydrochloric acid (5ml) and ethanol (300ml) was stirred at 80 ℃ for 16 h. The mixture was evaporated to dryness and the residue was taken up in HCl3N (50 ml). The mixture was washed with Et₂O (3X 30ml) extraction. Collecting the organic layer with K₂CO₃Basification (10% aqueous solution). The organic layer was washed with MgSO₄Dried and evaporated. The product, intermediate compound 15, was used in the next step without further purification (23.7 g; yield: 69%) as an oil.

B. Preparation of the Final Compounds

Example B1

Preparation of the final Compounds 1, 2, 3 and 4

Compound 1(A1)

Compound 2(A2)

Compound 3(A)

Compound 4(B)

nBuLi1.6M (0.067mol) was slowly added to a solution of N- (1-methylethyl) -2-propylamine (0.067mol) in THF (100ml) at-20 ℃ under a stream of nitrogen. The mixture was cooled to-70 ℃. A solution of intermediate compound 3 (prepared according to A3) (0.122mol) in THF (200ml) was added slowly. The mixture was stirred at-70 ℃ for 30 minutes. A solution of 3- (dimethylamino) -1-phenyl-1-propanone (0.146mol) in THF (100ml) was added slowly. The mixture was stirred at-70 ℃ for 1 hour, then hydrolyzed with ice water at-30 ℃ and extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (67g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 99/1/0.1; 20-45 μm). Two fractions were collected and the solvent was evaporated. Fraction 1(7.2g) was crystallized from DIPE. The precipitate was filtered off and dried. Yield: 6.5g of diastereomer A (final compound 3) (mp.172 ℃ C.) (10%) as a white solid. Fraction 2(13g) was crystallized from 2-propanone and diethyl ether. The precipitate was filtered off and dried. Yield: 11g diastereomer B (final compound 4) (mp.170 ℃ C.) (17%) as a white solid. A portion of the fraction of final compound 3 (4g) was separated into its enantiomers by column chromatography (eluent: hexane/2-propanol 99.9/0.1; column: CHIRACEL OD). Two pure fractions were collected and their solvents were evaporated. The residue was crystallized from pentane. The precipitate was filtered off and dried. Yield: 0.7g of enantiomer A1 (final compound 1) (mp.194 ℃ C.) and 0.6g of enantiomer A2 (final compound 1)Compound 2) (mp.191 ℃) as a white solid.

Example B2

Preparation of the final Compounds 5 and 6

Compound 5(A)

Compound 6(B)

nBuLi1.6M (0.048mol) was slowly added to a solution of N- (1-methylethyl) -2-propylamine (0.048mol) in THF (70ml) at-20 ℃. The mixture was cooled to-70 ℃ again. A solution of intermediate compound 4 (prepared according to A4) (0.044mol) in THF (150ml) was added slowly. The mixture was stirred at-70 ℃ for 30 minutes. A solution of 3- (dimethylamino) -1-phenyl-1-propanone (0.053mol) in THF (100ml) was added slowly. The mixture was stirred at-70 ℃ for 1 hour, then hydrolyzed with ice water at-30 ℃ and extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (23.5g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 99.5/0.5/0.1; 15-40 μm). Two pure fractions were collected and their solvents were evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried. Yield: 0.7g of the final compound 5 (3%) (mp.162 ℃ C.) as a white solid, and 1g of the final compound 6 (5%) (mp.74 ℃ C.) as a white solid.

Example B3

Preparation of Final Compounds 7 and 8

Compound 7(A)

Compound 8(B)

nBuLi (1.6M) (0.070mol) was added dropwise to a solution of N- (1-methylethyl) -2-propylamine (0.070mol) in THF (70ml) at-30 ℃ under a stream of nitrogen. The mixture was stirred at-20 ℃ for 30 minutes and then cooled to-70 ℃. A solution of intermediate compound 6 (prepared according to A6) (0.046mol) in THF (130ml) was added dropwise. The mixture was stirred at-70 ℃ for 45 minutes. A solution of 3- (dimethylamino) -1-phenyl-1-propanone (0.056mol) in THF (100ml) was added dropwise. The mixture was stirred at-70 ℃ for 2h, hydrolyzed with ice water and extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (23.6g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 99/1/0.1; 15-40 μm). Two pure fractions were collected and their solvents were evaporated. Fraction 1(4g) was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 1.7g of final compound 7(mp.98 ℃ C.) (7.6%). Fraction 2(3.5g) was crystallized from diethyl ether/EtOAc. The precipitate was filtered off and dried. Yield: 2.2g of the final compound 8(mp.180 ℃ C.) (9.8%) as a white solid.

Example B4

Preparation of Final Compound 9

A mixture of intermediate compound 8 (prepared according to A7) (0.009mol) and hydrazine (0.01mol) in ethanol (70ml) was stirred and refluxed for 1 hour. The solvent was evaporated to dryness. Dissolving the residue in CH₂Cl₂In (1). The organic solution is treated with K₂CO₃Washed 10% and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (5g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 97/3/0.1; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 2.6g of the final compound 9(mp.204 ℃ C.) (62%) areLight yellow solid.

Example B5

Preparation of Final Compound 10

Reacting CH at room temperature₃I (0.0033mol) was added to a solution of the final compound 4 (prepared according to B1) (0.003mol) in 2-propanone (15 ml). The precipitate was filtered off and dried. Yield: 1.2g of the final compound 10(mp.198 ℃ C.) (62%) as a pale yellow solid.

Example B6

Preparation of Final Compound 11

3-Chloroperbenzoic acid (0.0069mol) was added to CH at room temperature₂Cl₂(35ml) is added dropwise to the final compound 4 (prepared according to B1) (0.0069mol) in CH₂Cl₂(35ml) in water. The mixture was stirred at room temperature for 1 hour with K₂CO₃Washed 10% and dried (MgSO)₄) Filtered and the solvent evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 1.8g of the final compound 11(mp.208 ℃ C.) are white solids.

Example B7

Preparation of the final Compounds 12, 13, 14 and 15

Compound 12(A1)

Compound 13(A2)

Compound 14(A)

Compound 15(B)

nBuLi1.6M (0.05mol) was slowly added to a solution of N- (1-methylethyl) -2-propylamine (0.05mol) in THF (80ml) at-20 ℃ under a stream of nitrogen. The mixture was stirred at-20 ℃ for 15 minutes and then cooled to-70 ℃. A solution of intermediate compound 3 (prepared according to A3) (0.046mol) in THF (150ml) was added slowly. The mixture was stirred at-70 ℃ for 30 minutes. A solution of 0.055mol3- (dimethylamino) -1- (1-naphthyl) -1-propanone in THF (120ml) was added slowly. The mixture was stirred at-70 ℃ for 3 hours, hydrolyzed with ice water at-30 ℃ and extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (29g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH/NH₄OH; 99.5/0.5/0.1; 15-35 μm). Two fractions were collected and the solvent was evaporated. Yield: 3g fraction 1 and 4.4g fraction 2. Fractions 1 and 2 were each crystallized from DIPE. The precipitate was filtered off and dried, yield: 2.2g of diastereomer A final compound 14 (yield: 9%; mp.210 ℃ C.) as a white solid, and 4g of diastereomer B final compound 15 (yield: 16%; mp.244 ℃ C.) as a white solid. To obtain the corresponding enantiomer, diastereomer A (final compound 14) was purified by chromatography on chiral silica gel (eluent: hexane// EtOH; 99.95/0.05). Two fractions were collected and the solvent was evaporated. Yield: 0.233g of enantiomer A1 (final compound 12) (mp.118 ℃ C.) as a white solid, and 0.287g of enantiomer A2 (final compound 13) (mp.120 ℃ C.) as a white solid.

Example B8

Preparation of final Compounds 67, 68, 110 and 111

Compound 68(B)

Final Compound 110

(A1)

Final Compound 111

(A2)

nBuLi1.6M (0.067mol) was slowly added to a solution of N- (1-methylethyl) -2-propylamine (0.0104mol) in THF (50ml) at-20 ℃ under a stream of nitrogen. The mixture was cooled to-70 ℃. A solution of intermediate compound 3 (prepared according to A3) (0.0087mol) in THF (50ml) was added slowly. The mixture was stirred at-70 ℃ for 30 minutes. A solution of 3- (dimethylamino) -1- (2, 5-difluorophenyl) -1-propanone (0.0122mol) in THF (20ml) was added slowly. The mixture was stirred at-70 ℃ for 1 hour, then hydrolyzed with ice water at-30 ℃ and extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (6.3g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 98/2/0.2; 20-45 μm). Two pure fractions were collected and their solvents were evaporated. Fraction 1(1.2g) from Et₂Crystallizing in O. The precipitate was filtered off and dried. Yield: 0.63g of diastereomer a (final compound 67) (mp.60 ℃; yield ═ 13%) as a white solid. Fraction 2(1g) was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 0.64g of diastereomer B (final compound 68) (mp.208 ℃; yield 14%). 0.63g of diastereomer A was purified by chiral AD (eluent: heptane/iPrOH 99.95/0.05). Two fractions were collected, which corresponded to the A1 enantiomer (final compound 110, 0.13 g; mp167 ℃) as a white solid and the A2 enantiomer (final compound 111, 0.086g) as an oil.

Example B9

Preparation of final Compounds 38, 39, 108 and 109

Compound 38(A)

Compound 39(B)

Compound 108(A1)

Compound 109(A2)

nBuLi1.6M (0.04mol) was slowly added to a solution of N- (1-methylethyl) -2-propylamine (0.04mol) in THF (50ml) at-20 ℃ under a stream of nitrogen. The mixture was cooled to-70 ℃. A solution of intermediate compound 3 (prepared according to a 3) (0.037mol) in THF (100ml) was added slowly. The mixture was stirred at-70 ℃ for 30 minutes. A solution of 3- (dimethylamino) -1- (3-fluorophenyl) -1-propanone (0.044mol) in THF (50ml) was added slowly. The mixture was stirred at-70 ℃ for 1 hour, then hydrolyzed with ice water at-30 ℃ and extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (20g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 99.5/0.5/0.1; 15-40 μm). Three pure fractions were collected and the solvent was evaporated. Fraction 1(2.8g) was crystallized from DIPE. The precipitate was filtered off and dried. Yield: 1.45g (7%) of diastereomer A (final compound 38) (mp.198 ℃ C.) are white solids. Fraction 2(3.4g) was crystallized from DIPE. The precipitate was filtered off and dried. Yield: 1.55g (8%) of diastereomer B (final compound 39) (mp.207 ℃ C.) are white solids. A fraction (1g) of part of the final compound 38 was separated into its enantiomers by chiral chromatography (eluent: hexane/2-propanol 99.9/0.1; column: CHIRACEL OD). Two pure fractions were collected and their solvents were evaporated. The residue was crystallized from pentane. The precipitate was filtered off and dried. Yield: 0.3g of enantiomer A1 (final compound 108) (mp.160 ℃ C.) is a white solid, and 0.26g of enantiomer A2 (final compound 109) (mp.156 ℃ C.) is a white solid.

Example B10

Preparation of the final Compounds 71 and 72

Compound 71(A)

Compound 72(B)

nBuLi1.6M (0.0042mol) was slowly added to a solution of N- (1-methylethyl) -2-propylamine (0.0042mol) in THF (20ml) at-20 ℃ under a stream of nitrogen. The mixture was cooled to-70 ℃. A solution of intermediate compound 9 (prepared according to A1) (0.0038mol) in THF (50ml) was added slowly. The mixture was stirred at-70 ℃ for 30 minutes. A solution of 3- (dimethylamino) -1- (1-naphthyl) -1-propanone (0.0059mol) in THF (20ml) was added slowly. The mixture was stirred at-70 ℃ for 1 hour, then hydrolyzed with ice water at-30 ℃ and extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (2.2g) was purified by chromatography on a silica gel column (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 99/1/0.1; 15-40 μm). Two pure fractions were collected and their solvents were evaporated. Fraction 1(0.17g) from Et₂Crystallizing in O. The precipitate was filtered off and dried. Yield: 0.05g of diastereomer a (final compound 71) (mp.174 ℃; yield ═ 3%) as a white solid. Fraction 2(0.27g) was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 0.053g of diastereomer B (final compound 72) (mp.178 ℃; yield 4%) as a white solid.

Example B11

Preparation of Final Compound 99

Compound 99(A1)

3-Chloroperbenzoic acid (0.0036mol) in CH at room temperature₂Cl₂(10ml) was added dropwise to the final compound 12 (enantiomer A1) (prepared according to B7) (0.0069mol) in CH₂Cl₂(35ml) in water.The mixture was stirred at room temperature for 1 hour with K₂CO₃And (5) washing by 10%. Drying (MgSO)₄) Filtered and the solvent evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 0.16g of the final compound 99(mp.218 ℃; yield ═ 78%) as a white solid.

Example B12

Preparation of Final Compound 110

nBuLi1.6M (0.0075mol) was slowly added to a solution of N- (1-methylethyl) -2-propylamine (0.0075mol) in THF (30ml) at-20 ℃ under a stream of nitrogen. The mixture was cooled to-70 ℃. A solution of intermediate compound 3 (prepared according to A3) (0.0062mol) in THF (20ml) was added slowly. The mixture was stirred at-70 ℃ for 30 minutes. A solution of 0.0075mol of intermediate compound 14 (prepared according to example A9) in THF (10ml) was added slowly. The mixture was stirred at-70 ℃ for 90 min, then hydrolyzed with ice water at-30 ℃ and extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (3g) was purified by column chromatography on silica gel (eluent: cyclohexane/EtOAc 90/10; 15-40 μm). The final compound 110(1.5 g; yield 38%) was obtained as an oil.

Example B13

Preparation of Final Compounds 111 and 112

Final Compound 111(A)

Final Compound 112(B)

To a solution of derivative 111(1.5g, 0.0023mol) in dichloromethane (30ml) was added 1-chloroethyl chloroformate (0.25ml, 0.0023mol) at room temperature under a nitrogen atmosphere. The mixture was stirred at 80 ℃ for 1 hour. The solvent was evaporated and methanol (15ml) was added. The mixture was stirred and refluxed for 30 minutes. After evaporation, the residue (1.49g) was purified by silica gel column chromatography (15-40 μm). The first fraction collected was crystallized from DIPE to yield (0.168 g; mp.204 ℃; yield ═ 13%) of the final compound 111 as the a diastereomer. The second fraction collected corresponded to final compound 112 as the B diastereomer (0.298 g; mp.225 ℃; yield ═ 23%).

Example B14

Preparation of the final Compounds 113 and 114

Final Compound 113

(A)

Final Compounds 114

(B)

nBuLi1.6M (3.5 ml; 0.0056mol) was slowly added to a solution of N- (1-methylethyl) -2-propylamine (770. mu.l; 0.0055mol) in THF (20ml) at-20 ℃ under a stream of nitrogen. The mixture was cooled to-70 ℃. A solution of intermediate compound 3 (prepared according to A3) (1.5 g; 0.0047mol) in THF (20ml) was added slowly. The mixture was stirred at-70 ℃ for 30 minutes. A solution of intermediate compound 15(1 g; 0.0047mol) in THF (10ml) was added slowly. The mixture was stirred at-70 ℃ for 3 hours, then hydrolyzed with ice water at-30 ℃ and extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (2.8g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 99/1/0.1; 15-40 μm). Two pure fractions were collected and their solvents were evaporated. Fraction 1(0.149g) was crystallized from DIPE to give the final compoundSubstance 113(0.14 g; mp.185 ℃; yield ═ 6%) as a white powder. Fraction 2(0.14g) from Et₂Crystallization in O gave the final compound 114(0.14 g; mp.210 ℃; yield ═ 6%) as a white powder.

Example B15

Preparation of the final Compounds 115, 116, 117 and 118

Final compound 115(A diastereomer)

Final compound 116(A diastereomer)

Final compound 117(A1 enantiomer)

Final compound 118(A2 enantiomer)

nBuLi1.6M (4.6 ml; 0.0074mol) was slowly added to a solution of N- (1-methylethyl) -2-propylamine (1 ml; 0.0071 mol) in THF (20ml) at-20 ℃ under a stream of nitrogen. The mixture was cooled to-70 ℃. A solution of intermediate compound 15 (prepared according to A10) (2 g; 0.0061mol) in THF (10ml) was added slowly. The mixture was stirred at-70 ℃ for 30 minutes. A solution of 3- (dimethylamino) -1- (3, 5-difluorophenyl) -1-propanone (prepared according to A10) (2 g; 0.0094mol) in THF (15ml) was added slowly. The mixture was stirred at-70 ℃ for 2 hours and then at-30 ℃ with 10% NH₄Aqueous Cl was hydrolyzed and extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (4.5g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/iPrOH/NH₄OH 99.5/0.5/0.05; 15-40 μm). Two pure fractions were collected and their solvents were evaporated. Fraction 1(0.67 g; yield ═ 20%) was crystallized from DIPE to give final compound 115(0.29 g; mp.192 ℃ c; yield ═ 9%) as a white powder. Fraction 2(0.46g) from Et₂Crystallization in O afforded final compound 116(0.22 g; mp.224 ℃; yield 7%),as a white powder. The final compounds 116 and 117 (enantiomers) were isolated from 0.1g of the final compound 115 via CHIRACEL OD (eluent: heptane/iPrOH 99.9/0.1; 15-40 μm). Two fractions were collected from Et₂Crystallization in O afforded final compound 116(0.05 g; mp.161 ℃; yield: 100%) as a white powder, and final compound 117(0.043 g; mp.158 ℃; yield: 98%) as a white powder.

The following final compounds were prepared according to the above procedure:

a table 1:

table 2:

compound numbering

Example numbering

R¹

R²

R³

R⁴

R⁵

Physical data (salt/melting point) and stereochemistry

18

B1

Br

OCH₃

Phenyl radical

CH₂CH₃

Oxalate salt (2: 3); (A) (ii) a 230 deg.C

19

B1

Br

OCH₃

Phenyl radical

CH₂CH₃

Oxalate salts (2:3), (B);

compound numbering

Example numbering

R¹

R²

R³

R⁴

R⁵

Physical data (salt/melting point) and stereochemistry

150℃

44

B4

Br

OCH₃

Phenyl radical

H

(A)；190℃

9

B4

Br

OCH₃

Phenyl radical

H

(B)；204℃

141

B7

Br

OCH₃

2-naphthyl radical

CH₃

CH₂CH₃

(A)；188℃

142

B7

Br

OCH₃

2-naphthyl radical

CH₃

CH₂CH₃

(B)；202℃

230

B12

Br

OCH₃

1-naphthyl radical

CH₃

Benzyl radical

Oil/oil

147

B7

Br

OCH₃

1-naphthyl radical

CH₃

CH₂CH₃

(A)；168℃

148

B7

Br

OCH₃

1-naphthyl radical

CH₃

CH₂CH₃

(B)；212℃

56

B13

Br

OCH₃

1-naphthyl radical

CH₃

H

(A)；204℃

214

B13

Br

OCH₃

1-naphthyl radical

CH₃

H

(B)；225℃

Table 3:

compound numbering	Example numbering	R³	L	Stereochemistry and melting Point
					47	B1	Phenyl radical	1-piperidinyl radical	(A)；190℃
48	B1	Phenyl radical	1-piperidinyl radical	(B)；210℃
					128	B1	2-naphthyl radical	1-piperidinyl radical	(A)；254℃
129	B1	2-naphthyl radical	1-piperidinyl radical	(B)；212℃
					49	B1	Phenyl radical	1-imidazolyl	(A)；216℃
50	B1	Phenyl radical	1-imidazolyl	(B)；230℃
					51	B1	Phenyl radical	1- (4-methyl) piperazinyl	(A)；150℃
52	B1	Phenyl radical	1- (4-methyl) piperazinyl	(B)；230℃
					53	B1	Phenyl radical	1- (1, 2, 4-triazolyl)	(A)；180℃

Table 4:

compound numbering	Example numbering	R³	Q	L	Stereochemistry and melting Point
						61	B1	Phenyl radical	0	N(CH₃)₂	(A)；220℃
62	B1	Phenyl radical	0	N(CH₃)₂	(B)；194℃
						63	B1	Phenyl radical	2	N(CH₃)₂	(A)；150℃
64	B1	Phenyl radical	2	N(CH₃)₂	(B)；220℃
						125	B7	2-naphthyl radical	2	N(CH₃)₂	(A)；229℃
126	B7	2-naphthyl radical	2	N(CH₃)₂	(B)；214℃
						65	B1	Phenyl radical	3	N(CH₃)₂	(A)；130℃

Compound numbering	Example numbering	R³	Q	L	Stereochemistry and melting Point
						66	B1	Phenyl radical	3	N(CH₃)₂	(B)；170℃
132	B7	2-naphthyl radical	2	Pyrrolidinyl radical	(A)；227℃
						133	B7	2-naphthyl radical	2	Pyrrolidinyl radical	(B)；222℃
161	B7	2-naphthyl radical	2	Morpholinyl radical	(B)；234℃

186	B7	1-naphthyl radical	2	N(CH₃)₂	(A)；187℃
						190	B7	2-naphthyl radical	3	N(CH₃)₂	(A)；170℃
191	B7	2-naphthyl radical	3	N(CH₃)₂	(B)；145℃
						192	B7	2-naphthyl radical	2	N(CH₂CH₃)₂	(A)；90℃
193	B7	2-naphthyl radical	2	N(CH₂CH₃)₂	(B)；202℃
						194	B7	1-naphthyl radical	2	Pyrrolidinyl radical	(B)；206℃
197	B7	1-naphthyl radical	3	N(CH₃)₂	(A)；160℃
						198	B7	2-naphthyl radical	2	Morpholinyl radical	(A)；215℃
199	B7	1-naphthyl radical	2	N(CH₂CH₃)₂	(A)；185℃
						210	B7	1-naphthyl radical	2	Morpholinyl radical	(B)；222℃
211	B7	1-naphthyl radical	2	Morpholinyl radical	(A)；184℃

Table 5:

compound numbering	Example numbering	R³	R⁸	R⁹	Stereochemistry and melting Point
						106	B1	Phenyl radical	CH₃	＝O	(A)；224℃
107	B1	Phenyl radical	CH₃	＝O	(B)；180℃
						138	B7	1-naphthyl radical	H	＝O	(A1)；>260℃

Table 6:

C. pharmacological examples

C.1. In vitro method for testing compounds against mycobacterium tuberculosis

Plate sterile 96-well plastic microtiter plates were filled with 100. mu.l Middlebrook (1X) broth. Stock solutions of compounds (10 × final test concentration) were then added to a series of duplicate wells in column 2 in a volume of 25 μ l to assess the effect of compounds on bacterial growth. In microtiter plates, serial quintupling dilutions were performed directly from column 2 to column 11 using a custom-made robotic system (zymark corp., Hopkinton, MA). Pipette tips were changed after each 3 dilutions to minimize pipetting errors for highly hydrophobic compounds. Untreated control samples with (column 1) and without (column 12) inoculum were included in each microtiter plate. Mycobacterium tuberculosis (strain H37 RV) at about 5000 CFU/well was added to the wells at rows A to H except column 12 in a volume of 100. mu.l (in Middlebrook (1X)) broth medium. The same volume of broth without inoculum was added to the wells of rows a to H of column 12. The cultures were incubated at 37 ℃ for 7 days under a humid atmosphere (incubators with open gas valves and continuous ventilation). Resazurin (1: 5) was added to all wells in a volume of 20. mu.l 6 days after inoculation and one day before the end of incubation, and the plates were incubated at 37 ℃ for another 24 hours. On day 7, bacterial growth was quantitatively determined by fluorometry.

Fluorescence was read in a computer controlled fluorometer (Spectramax Gemini EM, molecular devices) at an excitation wavelength of 530nm and an emission wavelength of 590 nm. Percent growth inhibition achieved by the compounds was calculated according to standard methods and MIC data (representing IC90 in micrograms/ml) was calculated. The results are shown in Table 5.

C.2.Antibacterial activity of test compound against mycobacterium smegmatis (m. smegmatis) ATCC607 Sexual in vitro method

The plate was filled with 180 μ l of sterile deionized water supplemented with 0.25% BSA in a sterile 96-well plastic microtiter plate. Stock solutions of compounds (7.8 × final test concentration) were then added to a series of duplicate wells in column 2 in a volume of 45 μ l to assess the effect of compounds on bacterial growth. In microtiter plates, serial five-fold dilutions (45 μ Ι in 180 μ Ι) were made directly from column 2 to column 11 using a custom-made robotic system (zymark corp., Hopkinton, MA). Pipette tips were changed after each 3 dilutions to minimize pipetting errors for highly hydrophobic compounds. Untreated control samples with (column 1) and without (column 12) inoculum were included in each microtiter plate. About 250 CFU/well of bacterial inoculum was added to the wells in rows A to H except column 12 in a volume of 100. mu.l (in 2.8X Mueller-Hinton broth). The same volume of broth without inoculum was added to the wells of rows a to H of column 12. The cultures were incubated at 37 ℃ for 7 days under a humid atmosphere (incubators with open gas valves and continuous ventilation). Bacterial growth was quantified by fluorometry 2 days after inoculation and at the end of the culture. Alamar Blue (10X) was therefore added to all wells in a volume of 20. mu.l and incubated for a further 2 hours at 50 ℃.

Fluorescence was read in a computer-controlled fluorometer (Cytofluor, Biosearch) at an excitation wavelength of 530nm and an emission wavelength of 590 nm. The percent growth inhibition achieved by the compounds was calculated according to standard methods. pIC₅₀Defined as the concentration that inhibits bacterial growth by 50%. The results obtained are shown in Table 5.

TABLE 5: compounds of the invention against Mycobacterium tuberculosis (MIC) and Mycobacterium smegmatis (pIC)₅₀) Results of in vitro screening

Compound numbering	MIC	pIC50
			118	0.01	9.1
174	0.06	6.8
			12	0.07	8.7
115	0.07	8.6
			69	0.13	8.5
71	0.14	8.5
			113	0.27	8.6
5	0.33	7.8
			32	0.33	7.4
109	0.33	8.2
			16	0.34	6.8
37	0.34	7.9
			67	0.34	8.6
110	0.34	8.5
			164	0.36	7.9
183	0.36	8.3
			208	0.38	7.9
98	0.51	7.9
			216	0.85	8.0
26	1.00	7.2
			22	1.11	7.2
203	1.15	8.0
			28	1.41	7.3
30	1.46	7.8
			179	1.48	7.0
135	1.50	7.4
			91	1.51	7.5
188	1.60	7.2
			24	1.62	7.2
63	1.64	6.7
			65	1.69	5.7
66	1.69	4.7
			17	1.71	6.5
111	1.71	6.4
			117	1.71	6.7
196	1.71	6.6
			75	1.74	7.9
76	1.74	5.9
			45	1.76	8.0
46	1.76	6.4

Compound numbering	MIC	pIC₅₀
			227	1.76	7.5

94	1.77	7.9
			225	1.80	6.6
35	1.82	6.8
			190	1.85	6.5
191	1.85	6.5
			80	2.11	7.1
102	2.21	6.5
			121	2.21	5.9
165	2.26	6.6
			79	2.43	7.2
15	2.78	6.5
			72	3.59	6.9
180	373	6.6
			82	3.90	7.1
205	4.56	7.2
			36	5.40	6.4
103	5.54	5.9
			192	5.98	6.5
44	6.01	5.9
			64	6.54	5.8
19	672	6.5
			195	6.82	6.5
52	7.06	6.4
			172	7.30	5.7
31	7.31	5.8
			134	7.52	6.5
92	7.55	6.5
			83	7.78	5.8
62	7.79	5.9
			27	7.97	5.9
6	8.23	5.8
			33	8.27	6.0
38	8.30	7.9
			39	8.30	6.1
181	8.30	6.9
			182	8.30	6.3
41	8.51	5.9
			215	8.52	6.2
220	8.52	5.3
			116	8.58	6.6
138	8.58	6.6
			47	8.65	6.5
48	8.65	5.8
			84	8.76	7.0

Compound numbering	MIC	pIC₅₀
			85	8.76	5.9
23	8.79	6.4
			14	8.80	6.8
218	8.80	6.6
			228	8.80	5.1

77	8.93	7.2
			141	9.03	7.3
142	9.03	6.2
			226	9.03	5.5
99	9.06	7.9
			101	9.06	5.8
212	9.08	6.0
			206	9.09	6.5
204	9.14	5.4
			197	9.25	6.6
162	9.28	7.0
			193	9.47	5.6
176	9.50	6.8
			156	9.68	5.3
201	9.77	5.7
			175	10.19	6.5
119	10.20	7.8
			10	10.26	5.6
18	10.60	6.7
			152	10.93	5.8
147	11.36	7.4
			151	13.76	5.0
86	16.02	6.9
			21	16.17	5.4
58	16.49	6.8
			136	16.81	6.2
95	16.87	6.9
			125	18.01	4.4
97	20.17	5.9
			25	20.36	5.2
96	21.24	6.2
			40	21.38	4.7
73	23.49	8.0
			8	23.83	5.7
127	25.26	6.9
			189	25.43	5.5
57	25.77	5.4
			222	30.35	8.0
93	35.31	4.8
			9	37.92	4.5

Compound numbering	MIC	pIC₅₀
			61	39.04	4.5
229	40.09	7.1
			87	40.23	5.0
120	40.60	5.9
			20	40.63	5.9
11	41.42	4.6
			81	42.14	5.4
137	42.23	4.6
			219	42.69	5.8

56	43.01	7.2
			114	43.01	5.9
167	43.01	5.5
			13	44.13	6.7
107	44.13	5.8
			217	44.13	6.9
221	44.13	6.5
			224	44.13	4.9
42	44.34	6.3
			43	44.34	4.4
131	44.45	6.9
			29	44.46	5.9
78	44.76	5.8
			55	44.77	5.1
88	45.40	6.8
			100	45.40	7.1
34	45.66	5.1
			170	46.19	5.6
171	46.19	4.3
			163	46.51	5.9
129	47.31	4.7
			132	47.31	4.4
194	47.31	4.9
			199	47.47	6.5
7	47.54	4.6
			207	48.05	5.2
149	48.50	5.1
			202	48.98	4.8
130	50.32	5.3
			143	50.39	6.9
70	52.35	5.8
			144	52.46	7.0
157	52.46	5.6
			49	52.85	5.4
50	52.85	5.0
			53	52.94	5.1

Compound numbering	MIC	pIC₅₀
			54	52.94	4.1
112	54.15	5.5
			123	54.75	4.2
124	54.75	5.3
			153	54.77	5.3
106	55.55	6.2
			126	56.96	5.2
148	56.96	4.9
			186	56.96	4.5
173	57.85	4.7
			187	57.85	4.0
122	58.16	4.8
			74	59.00	6.5

89	59.06	6.4
			90	59.06	5.3
128	59.56	4.0
			133	59.56	5.1
145	59.56	5.3
			146	59.56	4.8
139	59.76	4.1
			140	59.76	5.8
158	59.76	5.3
			223	60.56	5.7
161	61.16	4.0
			198	61.16	4.3
210	61.16	6.1
			211	61.16	4.1
150	63.44	5.7
			155	67.45	4.9
166	67.45	4.1
			200	67.47	4.9
209	67.47	4.0
			177	67.65	4.0
178	67.65	4.5
			154	68.95	4.9
1	Not measured	7.3
			2	Not measured	6.8
3	Not measured	6.7
			4	Not measured	5.7
51	Not measured	5.8
			59	Not measured	5.1
60	Not measured	5.6
			68	Not measured	6.4
104	Not measured	6.6
			105	Not measured	6.0

Compound numbering	MIC	pIC50
			108	Not measured	7.0

Claims

1. Use of a compound for the manufacture of a medicament for the treatment of a mycobacterium tuberculosis infection, wherein the compound is of formula (Ia) or formula (Ib)

R¹is hydrogen, halogen, cyano, Ar, H8t, alkyl or alkoxy;

p is an integer equal to 0, 1, 2, 3 or 4;

R²is hydrogen, hydroxy, alkoxy, alkoxyalkoxy, alkylthio, mono-or di (alkyl) amino or a group of formula

Wherein Y is O;

R³is alkyl, Ar-alkyl, Het or Het-alkyl;

q is an integer equal to 0, 1, 2, 3 or 4;

R⁴and R⁵Each independently is hydrogen, alkyl or benzyl; or

R⁶is hydrogen, halogen, Ar, alkyl or alkoxy; or

Two R⁶The groups may together form a divalent group of formula ═ C —;

r is an integer equal to 0, 1, 2, 3, 4 or 5; and is

R⁷Is hydrogen;

R⁸is hydrogen or alkyl;

R⁹is an oxo group;

2. Use according to claim 1, characterized in that

R¹Is hydrogen, halo, cyano, Ar, Het, alkyl and alkoxy;

p is an integer equal to 0, 1, 2, 3 or 4;

R²is hydrogen, hydroxy, alkoxy, alkoxyalkoxy, alkylthio or a group of the formula

Wherein Y is O;

R³is alkyl, Ar-alkyl or Het;

q is an integer equal to 0, 1, 2 or 3;

R⁴and R⁵Each independently is hydrogen, alkyl or benzyl; or

R⁶is hydrogen, halogen or alkyl; or

Two R⁶The groups may together form a divalent group of formula ═ C —;

r is an integer equal to 1; and is

R⁷Is hydrogen;

R⁸is hydrogen or alkyl;

R⁹is an oxo group;

Halogen is a substituent selected from fluorine, chlorine and bromine.

3. Use according to claim 1 or 2, wherein R⁶Is hydrogen, alkyl or halogen.

4. The use of claim 3, wherein R⁶Is hydrogen.

5. Use according to any one of the preceding claims wherein R¹Is hydrogen, halogen, Ar, alkyl or alkoxy.

6. The use of claim 5, wherein R¹Is a halogen.

7. Use according to any one of the preceding claims, wherein p is equal to 1.

8. Use according to any one of the preceding claims wherein R²Is hydrogen, alkoxy or alkylthio.

9. The use of claim 8, wherein R²Is an alkoxy group.

10. Use according to any one of the preceding claims wherein R³Is naphthyl, phenyl or thienyl, each of which may be optionally substituted with 1 or 2 substituents.

11. The use of claim 10, wherein R³Is naphthyl or phenyl.

12. The use of claim 11, wherein R³Is naphthyl.

13. The use of any one of claims 1-9, wherein R³Is Ar-alkyl.

14. Use according to any one of the preceding claims wherein q is equal to 0, 1 or 2.

15. The use of claim 14, wherein q is equal to 1.

16. Use according to any one of claims 1 to 13, wherein q is equal to 3.

17. Use according to any one of the preceding claims wherein R⁴And R⁵Each independently hydrogen or alkyl.

18. The use of claim 17, wherein R⁴And R⁵Each independently is methyl.

19. Use according to any one of the preceding claims wherein R⁷Is hydrogen or methyl.

20. Use according to any one of the preceding claims wherein r is 0, 1 or 2.

21. Use according to any one of claims 1 to 3, characterized in that, independently of one another, R¹Is hydrogen, halogen, Ar, alkyl or alkoxy, p ═ 1, R²Is hydrogen, alkoxy or alkylthio, R³Is naphthyl, phenyl or thienyl, each of which is optionally substituted with 1 or 2 substituents selected from halogen and haloalkyl, q 0, 1, 2 or 3, R⁴And R⁵Each independently is hydrogen or alkyl, or R⁴And R⁵Together with the N to which they are attached form a group selected from: imidazolyl, triazolyl, piperidinyl, piperazinyl and thiomorpholineRadical, R⁶Is hydrogen, alkyl or halogen, R is equal to 0 or 1, and R is⁷Is hydrogen.

22. Use according to claim 21, characterized in that, independently of one another, R¹Is bromine, R²Is alkoxy, R³Is naphthyl or phenyl, q ═ 1, R⁴And R⁵Each independently is hydrogen, methyl or ethyl, and R⁶Is hydrogen.

23. The use of any one of claims 1 to 22 wherein the compound is a compound of formula (Ia).

24. Use of a compound which degrades in vivo to produce a compound according to any one of claims 1 to 23 in the manufacture of a medicament for the treatment of a mycobacterium tuberculosis infection.

25. Use according to claim 1, characterized in that said compound is

26. The use of claim 1, wherein the compound is a compound of formula (Ia) which may be represented by the following formula

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

27. The use of claim 1, wherein the compound is a compound of formula (Ia) which may be represented by the following formula

Or a pharmaceutically acceptable acid or base addition salt thereof.

28. The use of claim 1, wherein the compound is a compound of formula (Ia) which may be represented by the following formula

Or a pharmaceutically acceptable acid addition salt thereof.

29. The use of claim 1, wherein the compound is a compound of formula (Ia) which may be represented by the following formula

Or a stereochemically isomeric form thereof.

30. The use of claim 1, wherein the compound is a compound of formula (Ia) which may be represented by the following formula

Or an N-oxide thereof.

31. The use of claim 1, wherein the compound is a compound of formula (Ia) which may be represented by the following formula

32. Use according to claim 26, wherein said compound is diastereomer a, a pharmaceutically acceptable acid or base addition salt or a stereochemically isomeric form thereof, having a melting point of 210 ℃.

33. Use according to claim 26, wherein said compound is diastereomer a, which exhibits the greatest numerical pIC in the mycobacterium smegmatis assay relative to another diastereomer B of the same formula₅₀Value, or a pharmaceutically acceptable acid or base addition salt or a stereochemically isomeric form of said diastereomer a.

34. Use according to claim 32 or 33, wherein the compound is in the form of an enantiomer that exhibits a minimum numerical MIC value in a mycobacterium tuberculosis assay relative to another enantiomer of the same formula, or a pharmaceutically acceptable acid or base addition salt of said enantiomer.

35. Use according to claim 34, wherein the compound is in the form of an enantiomer that exhibits a minimum numerical MIC value in a mycobacterium tuberculosis assay, relative to another enantiomeric form of the same formula, or a pharmaceutically acceptable acid addition salt of said enantiomeric form.

36. Use according to claim 34, wherein the compound is in an enantiomeric form which exhibits the lowest numerical MIC value in a mycobacterium tuberculosis assay relative to another enantiomeric form of the same.

37. The use of claim 32 or 33, wherein the compound is an enantiomer obtainable by chiral chromatographic separation of a compound as claimed in claim 32 or 33, or a pharmaceutically acceptable acid addition salt of said enantiomer.

38. Use according to claim 37, wherein said compound is an enantiomer which exhibits the lowest numerical MIC value in a mycobacterium tuberculosis assay, relative to the other enantiomer of the same formula, or a pharmaceutically acceptable acid addition salt of said enantiomer.

39. Use according to claim 32 or 33, wherein the compound is in the form of an enantiomer that exhibits the greatest numerical pIC in a m.smegmatis assay relative to another enantiomer of the same formula₅₀A pharmaceutically acceptable acid or base addition salt of a compound of formula (I), or of said enantiomeric form.

40. The compound of claim 39, wherein the compound is in an enantiomeric form that exhibits the greatest numerical pIC in a Mycobacterium smegmatis assay relative to another enantiomeric form of the same formula₅₀A pharmaceutically acceptable acid addition salt of a compound of formula (I), or of said enantiomeric form.

41. The compound of claim 39, wherein said compound is in the form of an enantiomer relative to the congenerAnother enantiomeric form of the same, which exhibits the greatest numerical pIC in a Mycobacterium smegmatis assay₅₀The value is obtained.

42. The use as claimed in claim 1, wherein the compound is a pharmaceutically acceptable acid addition salt of the enantiomer obtainable by chiral chromatographic separation of diastereomer a, having a melting point of 210 ℃ and having the formula

Wherein the enantiomer exhibits the lowest MIC value in a Mycobacterium tuberculosis assay relative to the other enantiomer of the same formula.

43. A compound having the formula

Wherein

R¹Is hydrogen, halo, cyano, Ar, Het, alkyl or alkoxy;

p is an integer equal to 0, 1, 2, 3 or 4;

R⁶is hydrogen, halogen, Ar, alkyl or alkoxy; or

Two R⁶The groups may together form a divalent group of formula ═ C —;

r is an integer equal to 0, 1, 2, 3, 4 or 5;

x is S or O,

alk is an alkyl group;

alkyl is a straight or branched chain 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 straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms;

wherein each carbon atom may be optionally substituted with halo, hydroxy, alkoxy or oxo.

44. The compound of claim 43, wherein X ═ O.

45. The compound of claim 44, wherein the compound is a compound having the formula