MXPA00010685A

MXPA00010685A - Mycobacterial inhibitors

Info

Publication number: MXPA00010685A
Application number: MXPA/A/2000/010685A
Authority: MX
Inventors: Meenakshi Balganesh; Ramachandran Janakiraman; Parvinder Kaur; Santosh Nandan; Balasubramanian Venkataraman; Ethirajulu Kantharaj; Singh Ganguly Babita; Kajipalya Rangarao; Pondi Murugappan Ramanujulu; Ramamurthy Narayanan
Original assignee: Astrazeneca Ab
Priority date: 1998-05-05
Filing date: 2000-10-30
Publication date: 2002-05-09

Abstract

Use of a compound of general formula (I), wherein x is 0 or 1;R1, R2, R3 and R4 have the definitions given in the description, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in the treatment of a mycobacterial disease.

Description

MYCOBACTERIAL INHIBITORS Description of the Invention The present invention relates to compounds for use in the treatment of nacobacterial diseases, particularly those diseases caused by pathogenic icobacteria such as Mycobacterium tuberculosis, M. bovis, M. avium and M. marinum. Tuberculosis is still a major public health problem that affects almost all parts of the world. Based on tests of dermal reactivity, it is estimated that approximately one third of the population in the world, that is, 1.7 billion people are infected with? FycoJbacteriuiT. tubercul osis. Due to the availability of effective chemotherapies, this is responsible for 3 million deaths and from 8 to 10 million new cases per year remains the leading cause of death worldwide due to a single infectious agent: 26% of all deaths preventable, 7% of all deaths. According to the World Health Organization, there are 450,000 deaths per year due Ref: 124362 to tuberculosis that occurs in children under 15 years of age in underdeveloped countries, and the disease mainly affects younger, more productive adults. There are 5 first line drugs that are known to be highly effective against M. tuberculosis and 5 second line drugs that are used when one or more resistance to first line drugs is detected. The preferred form of treatment for tuberculosis is short-course chemotherapy comprising two phases. The first phase consists of a daily regimen for two months with isoniazid (300 mg), rifampicin (600 mg), pyrazinamide (3 g) and ethambutol (1.5 g). The second phase or continuation phase consists of a daily regimen for the next four months with isoniazid and rifampicin. Although the infection treated with drugs sensitive to strains of M. tuberculosis can be effectively cured with short-course chemotherapy, the proportion of the cure is very poor in many countries due to the poor attention that is reflected during long-term therapy. .

The situation is complicated by the rapid emergence of drug-resistant tuberculosis strains (MDR-TB). For example, in certain populations, the incidence of resistance to isoniazid is greater than 26% and resistance to rifampicin is approximately 15%. Before 1984, approximately 10% of the bacilli isolated from tuberculosis in patients in the United States were resistant to at least one of the mycobacterial drugs. By 1984, this increased to 52%, where more than half (32%) was resistant to more than one drug (MDT-TB). 10% of the registered cases of MDR-TB occurred in previously healthy people whose death rate - 70 to 90% - was the same as in individuals with immunosuppressed MDR-TB. The number of cases of MDR-TB has doubled since 1984 and in many of them the tuberculosis bacillus is resistant to both isoniazid and rifampicin. The median interval between the diagnosis of MDR-TB and death is only four weeks and, therefore, MDR-TB demands a response of little time between diagnosis and the start of appropriate treatment. However, MDR-TB is difficult to treat since many patients do not respond very well to second-line drugs, and the cost of alternative treatment procedures, including hospitalization and possibly surgery, increases the cost up to ten times more. than the cost of traditional treatment. Thus, there is an urgent medical need to identify new drugs with significant therapeutic activity against strains of M. tuberculosis resistant to one or several drugs and with pharmacokinetic properties that allow reducing the dose and in turn improving its benefit. According to the present invention, therefore, the use of a compound of the general formula is provided: (I) where x is 0 or 1; R1 represents a hydrogen atom, or a Ci-C2o alkyl or a mirtanyl group, or a phenyl or benzyl group optionally substituted on the aromatic ring by one or more substituents selected from the group consisting of amino, nitro, hydroxyl, carboxyl , halogen, trifluoromethyl, C?-C6 alkyl, Ci-Cβ alkoxy, C?-C6 alkoxycarbonyl, piperidyl, piperazinyl and morpholinyl, or a group (CH 2) and CONH-R 5 wherein y is an integer from 1 to 6 and R 5 represents a phenyl group optionally substituted by one or more substituents selected from the group consisting of amino, nitro, hydroxyl, carboxyl, halogen, trifluoromethyl, Ci-Cß alkyl, Ci-Cβ alkoxy, Ci-Cß alkoxycarbonyl, piperidyl, piperazil and morpholinyl; I R2 represents a hydrogen atom or a C? -C6 alkyl group, or R2 together with R3 represent a single carbon-carbon bond where x is 0, or R2 together with R4 represent a group = CH2, R3 represents an atom of hydrogen or is attached to R2 as defined above, and R4 represents a hydrogen atom or a C? -C6 alkyl group; or a C? -C10 alkylamino group optionally substituted by a di (Ci-C? alkyl) amino substituent group; or an anilino group optionally substituted on the aromatic ring by one or more substituents selected from the group consisting of amino, nitro, hydroxyl, carboxyl, halogen, trifluoromethyl, C 1 -C 6 alkyl, Ci-Cβ alkoxy, Ci-Cβ alkoxycarbonyl , piperidyl, piperazinyl and morpholinyl; or a group -SCH2CH2OH, -SCH2CH2NH2, SCH2CH2 (NH2) C02H or - SCH2CH2NHCO-R6 wherein R6 represents a C1-C10 alkyl or a C3-Cβ cycloalkyl group, or a phenyl group optionally substituted by one or more substituents selected from the group consisting of amino, nitro, hydroxyl, carboxyl, halogen, trifluoromethyl, C 1 -C 6 alkyl, Ci-Cβ alkoxy, Ci-Cβ alkoxycarbonyl, piperidyl, piperazinyl and morpholinyl; or R4 is attached to R2 as defined above; or R2, R3 and R4 together represent a phenyl group; with the conditions that: (i) R1, R3 and R4 can not simultaneously represent a hydrogen atom; (ii) when x is 0, R1 represents a 4-fluorophenyl group and R4 represents a hydrogen atom, when R2 and R3 are not together representing a carbon-carbon single bond, and (iii) when x is 0, R1 represents a 4-fluorophenyl group and R2 and R3 both represent a hydrogen atom, when R4 does not represent an anilino, 4-chloroanilino, 2,6-dichloroanilino, 3,4-dichloroanilino, 2,5-dichloroanilino, 3-chloro-4- fluoroanilino or a 4-fluoroanilino group; or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in the treatment of a mycobacterial disease, in particular tuberculosis. In the context of the present specification, unless otherwise indicated, an alkyl group (substituent) or an alkyl portion in an alkoxy or an alkoxycarbonyl substituent group may be linear or branched. Preferably R1 in the formula (I) represents a hydrogen atom or a C1-C15 radical; more preferably a C 1 -C 10 alkyl or mirtanyl group, or a phenyl or benzyl group optionally substituted on the aromatic ring by one to four, particularly one or two, substituents selected from amino, nitro, hydroxyl, carboxyl, halogen (eg example, fluorine, chlorine or bromine), trifluoromethyl, C 1 -C 4 alkyl (for example, methyl, ethyl, propyl, isopropyl or butyl), C 1 -C 6 alkoxy (for example, methoxy, ethoxy, propoxy, or butoxyl), C 1 -C 4 alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl), piperidyl, piperazinyl and morpholinyl; or a group (CH2) and CONH-R5 wherein y is an integer 1, 2, 3 or 4 and R5 represents a phenyl group optionally substituted by one to four, particularly one or two, substituents selected from amino, nitro, hydroxyl, carboxyl, halogen (for example, fluorine, chlorine or bromine), trifluoromethyl, C 1 -C 4 alkyl (for example, methyl, ethyl, propyl, isopropyl or butyl), C 1 -C 4 alkoxy (for example, methoxy, ethoxy, propoxyl, or butoxyl), C 1 -C 4 alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl), piperidyl, piperazinyl and morpholinyl.

The group R1 especially represents a hydrogen atom, or a C4-C6alkyl (eg, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl) or a mirtanyl group, or a phenyl group substituted by a substituent group piperidyl, or a group (CH2) and CONH-R5 wherein y is 1 or 2 and R5 represents a phenyl group substituted by a piperidyl substituent group. Preferably R 2 represents a hydrogen atom or a C 1 -C 4 alkyl, particularly the methyl group, or R 2 together with R 3 represent a single carbon-carbon bond where x is 0, or R 2 together with R 3 represent a group = CH 2 . R 4 preferably represents a hydrogen atom or a C 1 -C 4 alkyl group (for example methyl, ethyl, propyl or butyl); or a C2-C? alkylamino group or optionally substituted by a di (Ci-Cß alkyl) amino, especially the substituent group di (C 1 -C 4 alkyl) amino; or an anilino group optionally substituted on the aromatic ring by one to four, particularly one or two, substituents selected from amino, nitro, hydroxyl, carboxyl, halogen (eg, fluorine, chlorine or bromine), trifluoromethyl, alkyl C C 4 (for example, methyl, ethyl, propyl, isopropyl or butyl), C 1 -C 4 alkoxy (for example, methoxy, ethoxy, propoxy, or butoxyl), C 1 -C 4 alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl), piperidyl, piperazinyl and morpholinyl; or a group -SCH2CH2OH, -SCH2CH2NH2, -SCH2CH2 (NH2) C02H or -SCH2CH2NHCO-R6 wherein- R6 represents a C5-C10 alkyl or a C3-C6 cycloalkyl group, or a phenyl group optionally substituted by one or more selected substituents from the group consisting of amino, nitro, hydroxyl, carboxyl, halogen halogen (eg, fluorine, chlorine or bromine), trifluoromethyl, C 1 -C 4 alkyl (eg, methyl, ethyl, propyl, isopropyl or butyl), C3-Cβ alkoxy (e.g., propoxyl, butoxy, pentoxy or hexyloxy), C? -C4 alkoxycarbon (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl), piperidyl, piperazinyl and morpholinyl; or R4 is attached to R2 as defined above. It is more preferred that R4 represents a hydrogen atom, a methyl or ethyl group, a C2-C alkylamino group or optionally substituted by a di (C2-C4 alkyl) amino substituent group, an anilino group substituted by a piperidyl substituent group, -SCH2CH2OH, -SCH2CH2NH2, -SCH2CH2 (NH2) C02H or -SCH2CH2NHCO -R6 wherein R6 represents a C7 alkyl, cyclopropyl, cyclopentyl or cyclohexyl group or a phenyl group substituted by a nitrogen, C1-C4 alkyl or an alkoxyl substituent group C3-Cß, or R4 is attached to R2 as defined above. Particularly preferred compounds of the formula (I) include: l-Decylpyrrolidin-2, 5-one, l-nonylpiperidin-2,6-dione. 2- ((6,6-dimethylbicyclo [3.1.1] hepta-2-yl) methyl) isoindol-1,3-dione, 1- (6,6-dimethylbicyclo [3,1,1] hepta- 3-yl) methyl) -3-methy1-3-pyrrolin-2, 5-dione, 3-methyl-1-nonyl-3-pyrrolin-2, 5-dione, 3-methylene-l-nonylpyrrolidin-2, 5 -dione, 3-methyl-1-octyl-3-pyrrolin-2, 5-dione, 3-methylene-1-octy-pyrrolidin-2, 5-dione, (4- (3-methyl-1,2,5-dioxo-3-pyrrolinyl) ) phenyl) piperidine, l-octyl-3-pyrrolin-2, 5-dione, l-decyl-3-pyrrolin-2, 5-dione, l-nonyl-3-pyrrolin-2, 5-dione, l-butyl -3-pyrrolin-2, 5-dione, l-hexyl-3-pyrrolin-2, 5-dione, 1- (4-piperrodylphenyl) -3-pyrrolin-2, 5-dione, 1- (octyl-3-) (octylamino) -pyrrolidin-2, 5-dione, l-decyl-3- (decylamino) pyrrolidin-2, 5-dione, 3- (octylamino) -3-pyrrolidin-2, 5-dione, 3- (heptylamino) nonylpyrrolidin-2, 5-dione, l-nonyl-3- (nonylamino) pyrrolidin-2, 5-dione, l-nonyl-3- (octylamino) pyrrolidin-2, 5-dione, 2-amino-3- acid ( 3-methyl-l-nonyl-2, 5-dioxo-pyrrolidin-3-ylthio) propanoic acid, 2-amino-3- (3-methyl-l-octyl-2, 5-dioxo-pyrrolidin-3-i) ltio) propanoic acid, 2-amino-3- (l-octyl-2, 5-dioxo-pyrrolidin-3-ylthio) propanoic acid, 3-methyl-l-octylpyrrolidin-2, 5-dione, 3-meti1-1- nonylpyrrolidin-2, 5-dione, 2- (2, 5-dioxopyrrolidinyl) -N- (4-piperidylphenyl) ethanamide, 2- (2,5-dioxopyrrolidinyl) -N- (4-piperidylphenyl) propanamide, 3-ethyl-l-nonylpyrrolidin-2, 5-dione, 3- (2-aminoethylthio) -l-nonylpyrrolidin-2, 5-dione, 2-ethyl-N- (2- (1-nonyl-2, 5-dioxopyrrolidin-3-ylthio) ethyl) hexanamide, cyclopropyl-N- (2 - (1-nonyl-2, 5-dioxopyrrolidin-3-ylthio) ethyl) formamide, (4-butylphenyl) -N- (2- (1-nonyl-2, 5-dioxopyrrolidin-3-ylthio) ethyl) formamide, (4-hexyloxyphenyl) -N- (2- (1-nonyl-2, 5-dioxopyrrolidin-3-ylthio) ethyl) formamide, (4-methylphenyl) -N- (2- (1-nonyl-2, 5- dioxopyrrolidin-3-ylthio) ethyl) formamide, (4- (tert-butyl) phenyl-N- (2- (l-nonyl-2,5-dioxopyrrolidin-3-ylthio) ethyl) formamide, cyclopentyl-N- (2 - (1-nonyl-2, 5-dioxopyrrolidin-3-ylthio) ethyl) formamide, ethane, cyclohexyl-N- (2- (1-nonyl-2, 5-dioxopyrrolidin-3-ylthio) ethyl) formamide, (4 -nitrophenyl) -N- (2- (1-nonyl-2, 5-dioxopyrrolidin-3-ylthio) ethyl) formamide, 3- ((2- (dibutylamino) ethyl) amino) -l-nonylpyrrolidin-2, 5- diona, 3- ((2- ( diethylamino) ethyl) amino) -l-nonylpyrrolidin-2, 5-dione, l-nonyl-3-. { (4-piperidinylphenyl) amino) pyrrolidin-2, 5-dione, 3- (hydroxyethylthio) -3-methyl-1-nonylpyrrolidin-2,5-dione, 3- (2-aminoethylthio) -3-methyl-1-nonylpyrrolidin-2, 5-dione, and 3-methy1-1-octy1-3- (octylamino) pyrrolidin-2, .5-dione. The compounds of the formula (I) are known compounds or can be prepared using conventional techniques. The compounds of the formula (I) can, if desired, be converted to a pharmaceutically acceptable salt or solvate thereof, preferably an addition salt of an acid such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p-toluenesulfonate, or an alkali metal salt such as sodium or potassium salt. Certain compounds of the formula (I) are capable of existing in stereoisomeric forms. It should be understood that the invention encompasses all geometrical and optical isomers of the compounds of the formula (I) and mixtures thereof including branches. Tautomers and mixtures thereof also form an aspect of the present invention. The compounds of the formula (I) are advantageous because they possess bactericidal activity against mycobacteria, particularly pathogenic mycobacteria such as Ayycobacteriujp tubercul osis, M. bovis, M. avi um and M. Mari num. According to another aspect, the invention provides a method for treating a patient suffering from, or at risk for, a mycobacterial disease, comprising administering to the patient a therapeutically effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined above. The compounds of the formula (I) and the pharmaceutically acceptable salts and solvates thereof may be used on their own but generally be administered in the form of a pharmaceutical composition wherein the compounds / salt / solvate of the formula (I) (active ingredient ) are in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

Depending on the mode of administration, the pharmaceutical composition preferably comprises from 0.55 to 99% w (percent by weight), more preferably from 0.10 to 70%, of active ingredient, and, from 1 to 99.95% w, more preferably from 30 to 99.90. %, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight are based on the total composition. The pharmaceutical composition may additionally contain another anti-tubercular agent and / or other variety of ingredients known in the art, for example, a lubricant, a stabilizing agent, a buffering agent, an emulsifying agent, a viscosity regulating agent, a surfactant, a preservative, flavoring or coloring. The daily dose of the compound of the formula (I) administered, of course, varies with the compound employed, the mode of administration, the desired treatment and the indicated mycobacterial disease. However, in general, satisfactory results can be obtained when the compound of the formula (I) is administered in a daily dose not exceeding 1 g, for example, in the proportion of 10 to 50 mg / kg of body weight.

The compounds of the formula (I) can be administered systematically, for example by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions. The present invention will now be explained with reference to the following illustrative examples.

Example 1 1-decylpyrrolidin-2, 5-dione Succinimide (0.1M) is dissolved in dry dimethylformamide which has been treated with sodium hydride (0.1M) at a temperature of 0 ° C. Nonyl bromide (0.1M) and la. The reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is concentrated in vacuo and the residue is extracted into ethyl acetate. The ethyl acetate layer is washed with water, dried over sodium sulfate and concentrated in vacuo. The residue obtained is chromatographed on silica gel to obtain the desired product. 1HNMR: d 0.75 (3H, t), 1.10-1.20 (12H, m), 1.35-1.45 (2H, m), 2.55 (4H, s), 3.35 (2H, dd).

Example 2 l-nonylpiperidin-2,6-dione The procedure of Example 1 is repeated except that gluta iride replaces succinimide. 1HNMR: d (0.9 (3H, t), 1.2-1.3 (12H, m), 1.4-1.5 (2H, m), 1.9 (2H, p), 2.6 (4H, t), 3.7 (2H, dd).

Example 3 2- ((6,6-dimethylbicyclo [3,1,1] hepta-2-yl) methyl) isoindol-1,3-dione A solution of eftalic anhydride (0.1M) in pyridine (20 ml) is treated with (-) -cis-mirtanylamine (0.1M). The reaction mixture is heated at 90 ° C for six hours. The reaction mixture is concentrated in vacuo and the residue is extracted into ethyl acetate. The ethyl acetate layer is washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulfate and finally concentrated in vacuo. The residue obtained is chromatographed on silica gel to obtain the desired product. 1HNMR: d 0.85 (ΔH, d), 1.2 (6H, d), 1.5-1.65 (2H, m), 1.80-2.05 (4H, m), 2.27-2.35. (ÍH, m), 2.45-2.60 (ÍH, m), 3.60-3.75 (2H,), 7.65-7.70 (2H, m), 7.78-7.85 (2H, m).

Example 4 1- ((6,6-dimethylbicyclo [3,1,1] hepta-3-yl) methyl) -3-methyl-3-pyrrolidine-2,5-dione A solution of citraconic anhydride (0.1M) in pyridine (20 ml) is treated with (-) - cis-mirtanylamine (0.1M). The reaction mixture is heated at 90 ° C for six hours. The reaction mixture is concentrated in vacuo and the residue is extracted into ethyl acetate. The ethyl acetate layer is washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulfate and finally concentrated in vacuo. The residue obtained is chromatographed on silica gel to obtain the desired product. ^ NMR: d 0.65 (ÍH, d), 1.0 (6H, d), 1.25-1.37) ÍH,), 1.55-1.80 (5H, m), 1.9 (3H, s), 2.08-2.25 (2H,), 3.15-3.40 (2H, m), 6.0 (ÍH, s).

Example 5 3-methyl-l-nonyl-3-pyrrolin-2, 5-dione A solution of citraconic anhydride (0.1M) in pyridine (20 ml) is treated with nonilamine (0.1M). The reaction mixture is heated at 90 ° C for six hours. The reaction mixture is concentrated in vacuo and the residue is extracted into ethyl acetate. The ethyl acetate layer is washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulfate and finally concentrated in vacuo. The residue obtained is chromatographed on silica gel to obtain the desired product. ^ NMR: d 0.8 (3H, t), 1.15-1.30 (12H,), 1.4-1.55 (2H, m), 2.05 (3H, s), 3.4 (2H, dd), 6.25 (ÍH, s).

Example 6 3-methylene-l-nonylpyrrolidin-2, 5-dione A solution of itaconic anhydride (0.1M) in pyridine (20 ml) is treated with nonilamine (0.1M). The reaction mixture is heated at 90 ° C for six hours. The reaction mixture is concentrated in vacuo and the residue is extracted into ethyl acetate. The ethyl acetate layer is washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulfate and finally concentrated in vacuo. The residue obtained is chromatographed on silica gel to obtain the desired product.

Example 7 3-methyl-l-octyl-3-pyrrolidin-2, 5-dione A solution of citraconic anhydride (0.1M) in pyridine (20 ml) is treated with octylamine (0.1M). The reaction mixture is heated at 90 ° C for six hours. The reaction mixture is concentrated in vacuo and the residue is extracted into ethyl acetate. The ethyl acetate layer is washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulfate and finally concentrated in vacuo. The residue obtained is chromatographed on silica gel to obtain the desired product. 1HNMR: d 0.85 (3H, t), 1.15-1.30 (12H, m), 1.45-1.60 (2H, m), 2.05 (2H, s), 3.45 (2H, dd), 6.27 (HH, s).

Example 8 3-methylene-1-octylpyrrolidine-2, 5-dione A solution of itaconic anhydride (0.1M) in pyridine (20 ml) is treated with octylamine (0.1M). The reaction mixture is heated at 90 ° C for six hours. The reaction mixture is concentrated in vacuo and the residue is extracted into ethyl acetate. The ethyl acetate layer is washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulfate and finally concentrated in vacuo. The residue obtained is chromatographed on silica gel to obtain the desired product. 1HNMR: d 0.85 (3H, t), 1.20- 1.35 (10H, m), 1.50-1.65 (2H, m), 3.3 82H, s), 3.55 (2H, dd), 5.6 (ÍH, s), 6.35 ( ÍH, s).

Example 9 (4- (3-methyl-2, 5-dioxo-3-pyrrolinyl) phenyl) piperidine A solution of citraconic anhydride (0.1M) in pyridine (20 ml) is treated with 4- (1-piperidyl) aniline (0.1M). The reaction mixture is heated at 90 ° C for six hours. The reaction mixture is concentrated in vacuo and the residue is extracted into ethyl acetate. The ethyl acetate layer is washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulfate and finally concentrated in vacuo. The residue obtained is chromatographed on silica gel to obtain the desired product. 1HNMR: d 1.5-1.75 (6H, m), 2.12 (3H, s), 3.18 (4H, t), 6.4 (ÍH, br s), 6.95 (2H, d), 7.1 (2H, d).

Example 10 1-octyl-2-pyrrolin-2, 5-dione To a solution of maleic anhydride (0.1M) in acetone (150 ml), maintained at 0 ° C, octylamine (0.1M) is added dropwise over a period of 15 minutes. The reaction mixture is heated at 90 ° C for six hours. The reaction mixture is stirred for a further period of one hour, and the crystalline white N-octyl maleimic acid which separates is dried and filtered. A mixture of maleic N-octyl acid (0.1M) and sodium acetate (0.1M) in acetic anhydride (150 ml) is heated in a steam bath for two hours. The acetic anhydride is removed under vacuum and the residual liquid product is taken up in ethyl acetate, washed with water, dried with sodium sulfate and concentrated to give a viscous liquid. Purification by flash gas chromatography (10% ethyl acetate in petroleum ether) yields the desired product. 1HNMR: d 0.82 (3H, t), 1.15-1.4 (10H, m), 1.48-1.6 (2H, m), 3.45 (2H, dd), 6.65 (2H, s).

Example 11 l-decyl-3-pyrrolidin-2,5-dione The procedure of Example 10 is repeated using decylamine instead of octylamine. 1HNMR: d 0.85 (3H, t), 1.15-1.30 (14H,), 1.50-1.60 (2H,), 3.47 (2H, dd), 6.65 (2H, s).

Example 12 l-nonyl-3-pyrrolin-2, 5-dione The procedure of Example 10 is repeated using nonilamine instead of octylamine. 1HNMR: d 0.85 (3H, t), 1.15-1.35 (12H, m), 1.5-1.6 (2H, m), 3.45 (2H, t), 6.65 (HH, s).

Example 13 l-Butyl-3-pyrrolin-2, 5-dione O The procedure of Example 10 is repeated using butylamine instead of octylamine. 1HNMR: d 0.9 (3H, t), 1.25 (2H, m), 1.6 (2H, m), 3.5 (2H, dd), 6.65 (2H, s).

Example 14 l-hexyl-3-pyrrolin-2, 5-dione The procedure of Example 10 is repeated using hexylamine instead of octylamine. 1HNMR: d 0.85 (3H, t), 1.2-1.35 (6H, m), 1.45-1.60 (2H, m), 3.45 (2H, dd), 6.65 (2H, s).

Example 15 1- (4-piperidylphenyl) -3-pyrrolin-2, 5-dione The procedure of Example 10 is repeated using 4- (piperidyl) aniline in place of octylamine. 1H MR: d 1.5-1.65 (6H,), 3.0-3.12 (4H, m), 6.80 (2H, s), 6.95 (2H, d), 7.1 (2H, d).

Example 16 1- (Octyl-3- (octylamino) -pyrrolidin-2,5-dione A mixture of N-octyl maleimide (0.01M) prepared as described in Example 10 above, octylamine (0.01M), triethylamine [catalytic, 0.1 equivalent] in acetonitrile (25 ml). it is stirred for 24 hours at room temperature. The acetonitrile is removed under vacuum to provide a residual liquid product which is subjected to flash chromatography (25% ethyl acetate in petroleum ether) to yield a white solid as the desired product. XHNMR: d 0.8 (6H, t), 1.15-1.35 (20H, m), 1.45-1.65 (4H, m), 1.7 (HH, s), 2.45-2.65 (3H, m), 2.88 (HH, dd) , 3.25 (2H, dd), 3.7 (ÍH, dd).

Example 17 l-decyl-3- (decylamino) pyrrolidin-2, 5-dione A mixture of N-decyl maleimide (0.01M) prepared as described in Example 11 above, decylamine (0.01M), triethylamine [catalytic, 0.1 equivalent] in acetonitrile (25 ml) is stirred for 24 hours at room temperature. The acetonitrile is removed under vacuum to provide a residual liquid product which is subjected to flash chromatography (25% ethyl acetate in petroleum ether) to yield a white solid as the desired product. 1HNMR: d 0.8 (6H, t), 1.15-1.35 (24H, m), 1.45-1.65 (4H, m), 1.7 (IH, s), 2.45-2.65 (3H, m), 2.88 (IH, dd) , 3.25 (2H, dd), 3.71 (ÍH, dd).

Example 18 3- (octylamino) -3-pyrrolidin-2, 5-dione OR A mixture of maleimide (0.01M), octylamide (0.01M), triethylamine [catalytic, 0.1 equivalent] in acetonitrile (25 ml) is stirred for 24 hours at room temperature. The acetonitrile is removed under vacuum to provide a residual liquid product which is subjected to flash chromatography (25% ethyl acetate in petroleum ether) to yield a white solid as the desired product. 1HNMR: d 0.85 (3H, t), 1.15-1.35 (10H, m), 1.42-1.55 (2H, m), 2.50-2.70 (3H,), 2.90 (HH, dd), 2.80 (iH, dd).

Example 19 3- (Heptilamino) -l-nonylpyrrolidin-2,5-dione A mixture of N-decyl maleimide (0.01M) prepared as described in Example 12 above, heptylamine (0.01M), triethylamine [catalytic, 0.1 equivalent] in acetonitrile (25 ml) is stirred for 24 hours at room temperature. The acetonitrile is removed under vacuum to provide a residual liquid product which is subjected to flash chromatography (25% ethyl acetate in petroleum ether) to yield a white solid as the desired product.

Example 20 l-nonyl-3- (nonylamino) pyrrolidin-2, 5-dione A mixture of N-decyl maleimide (0.01M) prepared as described in Example 12 above, nonilamine (0.01M), triethylamine [catalytic, 0.1 equivalent] in acetonitrile (25 ml) is stirred for 24 hours at room temperature. The acetonitrile is removed under vacuum to provide a residual liquid product which is subjected to flash chromatography (25% ethyl acetate in petroleum ether) to yield a white solid as the desired product. XHNMR: d 0.85 (6H, t), 1.15- 1.38 (24H, m), 1.40-1.55 (4H,), 1.70 (HH, br s), 2.45- 2.70 (3H, m), 2.85 (HH, dd) , 3.45 (2H, dd), 3.70 (ÍH, dd).

Example 21 l-nonyl-3- (octylamino) pyrrolidin-2, 5-dione A mixture of N-decyl maleimide (0.01M) prepared as described in Example 12 above, octylamine (0.01M), triethylamine [catalytic, 0.1 equivalent] in acetonitrile (25 ml) is stirred for 24 hours at room temperature. The acetonitrile is removed under vacuum to provide a residual liquid product which is subjected to flash chromatography (25% ethyl acetate in petroleum ether) to yield a white solid as the desired product. 1HNMR: d 0.8-0.9 (6H, m), 1.18-1.30 (20H, m), 1.35-1.60 (4H, m), 2.5-2.6 (3H, m), 2.7-3.0 (5H, m), 3.45 ( 2H, dd).

Example 22 2-Amino-3- (3-methyl-1-nonyl-2, 5-dioxo-pyrrolidin-3-ylthio) propanoic acid DL-cysteine (0.0067M) is dissolved in potassium acetate (50 mM) and the resulting solution is slowly added to the N-nonyl itaconimide (0.004M) prepared as described in Example 6 above. The reaction mixture is then dissolved in dimethylformamide with gentle stirring and triethylamine is added. The stirring continues for at least four hours at room temperature. The progress of the reaction is monitored by reverse phase by thin layer chromatography using 75% methanol in the aqueous system. The formation of the desired product is detected by the reaction with ninhydrin.

EXAMPLE 23 2-Amino-3- (3-methyl-1-octyl-2, 5-dioxo-pyrrolidin-3-ylthio) propanoic acid The procedure according to Example 22 is repeated using the imide of Example 8 above. 1HNMR: d 0.85 (3H, t), 1.15-1.32 (10H, m), 1.3 (3H, d), 1.4-1.52 (2H, m), 2.65-2.85 (2H, m), 3.00-3.30 (2H, m), 3.42 (2H, t), 3.85 (ÍH, dd).

Example 24 2-Amino-3- (1-octyl-2,5-dioxo-pyrrolidin-3-i thio) propanoic acid OR The process according to Example 22 is prepared using the imide of Example 10 above.

Example 25 3-methyl-l-octylpyrrolidin-2,5-dione O \ * ~~ N - (CH2)? CH, w O 10% palladium added in carbon catalyst (5% by weight) to a solution of N-nonyl citraconimide (0.02M) which is stirred and prepared as described in Example 5 above in methanol (100 ml). Hydrogen gas in bubbles is added to this solution for three hours. The solution is then filtered over celite and concentrated in vacuo. Chromatography on silica gel provides the desired product. 1HNMR: d 0.85 (3H, t), 1. 15-1.3 (10H, m), 1.3 (3H, d), 1.47-1.60 (2H, m), 2.28 (1H, dd), 2.77-2.95 (2H, m), 3.45 (2H, dd).

Example 26 3-methyl-l-nonylpyrrolidin-2, 5-dione The procedure of Example 25 is repeated using instead N-octyl citraconimide prepared as described in Example 7 above. 1HNMR: d 0.85 (3H, t), 1.15-1.3 (12H,), 1.3 (3H, d), 1.47-1.60 (2H, m), 2.28 (HI, dd), 2.77-2.95 (2H, m), 3.45 (2H, dd).

Example 27 2- (2,5-dioxopyrrolidinyl) -N- (4-piperidylphenyl) ethanamide A solution of glycine hydrochloride benzyl ether 80.1 M) in diethyl ether is treated with triethylamine (0.11 mM) and then with succinic anhydride (0.11 mM). The reaction mixture is stirred at room temperature for two hours and then divided between 10% aqueous hydrochloric acid and ethyl acetate. The ethyl acetate layer is separated, dried over sodium sulfate and concentrated in vacuo to give a yellow oil.

This oil is dissolved in acetic anhydride (20 ml) containing sodium acetate (0.1 mM) and heated to 90 ° C for three hours. The reaction mixture is cooled, poured into water and extracted three times with ethyl acetate. The ethyl acetate layer is separated, dried over sodium sulfate and concentrated in vacuo to give a yellow oil. Chromatography on silica gel produces succinyl glycine benzyl ester. 10% palladium added in carbon catalyst (5% by weight) to a solution of succinoyl benzyl ester (0.009M) in methanol (50 ml) under stirring. Hydrogen gas in bubbles is added to this solution for three hours. The solution is then filtered over celite and concentrated in vacuo to give the corresponding acid as a white solid. A solution of the acid (0.1 mM9 in dry dichloromethane is cooled to 0 ° C and treated with dimethylformamide (0.1 mM) followed by oxalyl chloride (0.1 mM) The cold bath is removed and the reaction mixture is refluxed for one hour, then 4- (piperidyl) aniline (0.01 mM) is added to the reaction mixture and this solution is stirred for two hours at room temperature, then the reaction is diluted with dichloromethane, washed with aqueous sodium bicarbonate. The organic layer is dried over sodium sulfate and concentrated in vacuo, the residue obtained is subjected to chromatography to obtain the desired product: 1 H NMR: d 1.5-1.7 (6H, m), 2.8 (4H, s) ), 3.10 (4H, t), 4.3 (2H, s), 6.85 (2H, d), 7.30 (2H, d), 7.42 (ÍH, br s).

Example 28 2- (2,5-dioxopyrrolidinyl) -M- (4-piperidylphenyl) propanamide The process according to Example 27 is prepared using β-alanine benzyl ester hydrochloride instead. ^ NMR: d 1.50-1.85 (6H, m), 2.65-2.80 (6H, m), 3.05 (4H, t), 3.9 (2H, t), 6.85 (2H, d), 7.35 (2H, d), 7.4-7.5 (ÍH, br s).

EXAMPLE 29 3-Ethyl-l-nonylpyrrolidine-2,5-dione A solution of succinimide (15.15 mM) in tetrahydrofuran (15 ml) containing phosphorus hexamethyl triamide at -78 ° C is treated with a solution of lithium diisopropylamide (30.30 mM) in tetrahydrofuran 825 ml). This solution is stirred at -78 ° C for one hour and then treated with ethyl iodide (15.90 mM). The reaction mixture is stirred at -78 ° C for 30 minutes, warmed to room temperature and quenched with aqueous ammonium chloride. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (3 x 25 ml). The combined organic layers are washed with 10% aqueous sodium thiosulfate, brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel affords pure 3-ethyl succinimide. A solution of 3-ethyl succinimide (4.72 mM) in dimethylformamide (10 ml) is treated with sodium hydride (5.20 mM) and nonyl bromide (5.20 mM). The reaction mixture is stirred at room temperature for two hours and then quenched with saturated aqueous ammonium chloride. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (3 x 25 ml). The combined organic layers are washed with 10% sodium thiosulfate, brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel provides the desired product, 3. ethyl-N-nonyl succinimide. 1H MR: d 0.8 (3H, t), 0.9 (3H, t), 1.15-1.35 (12H, m), 1.45-1.65 (3H, m), 1.80-1.95 (HH, m), 2.35 (HH, dd), 2.6-2.95 (2H, m), 3.45 (2H, dd).

EXAMPLE 30 3- (2-Aminoethylthio) -l-nonylpyrrolidin-2,5-dione) A mixture of N-nonyl maleimide (0.01M) is prepared as described in Example 12 above, mercapto ethylamine (0.01M) and triethylamine (0.001M) in acetonitrile (50 ml) are stirred for 24 hours at room temperature. The acetonitrile is evaporated in vacuo and the residue obtained is triturated with ethyl acetate (25 ml). The resulting suspension is filtered and the solid is washed with ethyl acetate. The solid is then dried and characterized as the desired product, N-nonyl, 3-, ercapto ethylamino maleimide. XHNMR: d 0.85 (3H, t), 1.15-1.35 (12H, m), 1.45-1.55 (2H, m), 2.55 (2H, dd), 3.1-3.3 (2H, m), 3.35-3.50 (4H, m), 4.1 (ÍH, dd), 7.5-7.9 (2H, wide).

Example 31 2-ethyl-N- (2- (l-nonyl-2,5-dioxopyrrolidin-3-ylthio) ethyl) hexanamide N-nonyl, 3-mercapto ethylamino maleimide is prepared (0.5 mM) as described in Example 30 above in 2 ml of dichloromethane and treated with one equivalent of triethanolamine and one equivalent of 2-ethylhexanoyl chloride. The reaction mixture is stirred for five hours. The dichloromethane is then evaporated to give a residue which is added to a solution of saturated sodium bicarbonate (2 ml) with stirring for 30 minutes. The ethyl acetate layer is then separated and concentrated to produce the desired effect.

Example 32 Cyclopropyl-N- (2- (1-nonyl-2,5-dioxopyrrolidin-3-ylthio) ethyl) formamide The procedure of Example 31 is repeated using mbio cyclopropanecarbonyl chloride.

Example 33 (4-Butylphenyl) -N-2- (1-nonyl-2,5-dioxopyrrolidin-3-ylthio) ethyl) formamide The procedure of Example 31 is repeated using instead 4-butylbenzoyl chloride.

Example 34 (4-hexyloxyphenyl) -N- (2- (1-nonyl-2, 5-diocopyrrolidin-3-ylthio) ethyl) formamide The procedure of Example 31 is repeated using 4-hexyloxybenzoyl chloride instead.

Example 35 (4-methylphenyl) -N- (2- (l-nonyl-2m5-dioxopyrrolidin-3-ylthio) ethyl) formamide The procedure of Example 31 is repeated using 4-methylbenzoyl chloride instead.

Example 36 (4- (tert-butyl) phenyl-N- (2- (1-nonyl-2, 5-dioxopyrrolidin-3-ylthio) ethyl) formamide The procedure of Example 31 is repeated using instead 4-tert-butylbenzoyl chloride.

Example 37 Cyclopentyl-N- (2- (1-2, 5-dioxopyrrolidin-3-ylthio) ethyl) formamide, ethane The procedure of Example 31 is repeated using the cyclopentanecarbonyl chloride instead.

Example 38 Cyclohexyl-N- (2- (1-nonyl-2,5-dioxopyrrolidin-1-thio) ethyl) formamide The procedure of Example 31 is repeated using cyclohexanecarbonyl chloride instead.

Example 39 (4-nitrophenyl) -N- (2- (1-nonyl-2, 5-dioxopyrrolidin-3-ylthio) ethyl) formamide The procedure of Example 31 is repeated using the 4-nitrobenzoyl chloride.

Example 40 3- ((2- (dibutylamino) ethyl) amino) -1-nonylpyrrolidin-2,5-dione N-Nonyl maleimide (0.02 mM) is prepared as described in Example 12 above in 2 ml of acetonitrile which is treated with one equivalent of triethylamine and one equivalent of N, N-dibutylenediamine. The reaction mixture is stirred for six hours and then the acetonitrile is evaporated. The obtained residue is treated with a cold aqueous hydrochloric acid solution and ethyl acetate, with stirring for one hour. The ethyl acetate layer is then separated and concentrated to give the desired product.

Example 41 3- ((2- (diethylamino) ethyl) amino) -1-nonylpyrrolidin-2,5-dione The procedure of Example 40 is repeated using 3-diethylamino-1-methylpropylamine instead.

Example 42 l-nonyl-3- ((4-piperidinylphenyl) amino) pyrrolidin-2, 5-dione The procedure of Example 40 is repeated using 4- (piperidyl) aniline instead.

Example 43 3- (Hydrocytlthio) -3-methyl-1-nonylpyrrolidin-2, 5-dione A solution of N-nonyl citraconimide (0.5 mM) is prepared as described in Example 5 above in dimethylformamide (10 ml) and treated with triethylamine (0.5 mM) and then 2-mercaptoethanol is added dropwise. (0.5 mM). The progress of the reaction is monitored by thin layer chromatography and when the initial material is no longer detected the reaction mixture is concentrated in vacuo. The residue obtained is dissolved in ethyl acetate, washed with water and dried over sodium sulfate. Purification by chromatography produces the desired product.

Example 44 3- (2-Aminoethylthio) -3-methyl-1-nonylpyrrolidin-2, 5-dione The procedure of Example 43 is repeated using 2-mercaptoethylamine instead.

Example 45 3-methyl-l-octyl-3- (octylamino) pyrrolidin-2, 5-dione A solution of N-octyl citraconimide is prepared (0.223g, 1 mM) as described in Example 7 above in acetonitrile (2 ml) and treated with triethylamine (0.14 ml, 1 mM) and then with octylamine (0.165 ml, 1 mM) which is added dropwise. The progress of the reaction is monitored by thin layer chromatography and when the initial material is no longer detected the reaction mixture is concentrated in vacuo. The remaining residue is dissolved in ethyl acetate, washed with water and dried over sodium sulfate. Purification by chromatography produces the desired effect. 1HNMR: d 0.8 (6H, t), 1.10-1.28 (20H, m), 1.3 (3H, s), 1.32-1.58 (4H, m), 2.25-2.48 (2H, m), 2.50 & 2.80 (2H, Abq), 3.42 (2H, dd).

Example 46 Each of the compounds of Examples 1 to 45 was evaluated for bactericidal activity against M. tuberculosis by analyzing its minimum inhibitory concentration (MIC) in the "BACTEC" system (registered trademark) developed by Becton-Dockinson Diagnostic Instrument Systems, Sparks, USA, which is based on a radiometric principle where carbon dioxide is released by catabolism of the C14-palmitate that is detected spectrophotometrically and is counted in arbitrary units of measurement that are referred to as units of the growth index ( Gl).

Thus, the routes of "BACTEC" are inoculated with 0.1 ml of M. tuberculosis (final bacterial concentration, 1 x 105 colony forming units per ml) and 0.1 ml of the component of analysis in a variety of concentrations. Gl values are monitored up to a value of > 30 obtained for the 1: 100 dilution control. For the purpose of this analysis, MIC is defined as the minimum concentration of analysis that is performed at > 95% inhibition of the culture compared to the undiluted control, when the control enriches a Gl value of 999. The determination of the endpoint (> 99% inhibition) is based on a conventional resistance of 1% cut, in where the organism is considered resistant to a particular concentration of the test compound if the growth of more than 1% of the bacterial population is observed. Thus, a comparison is made between the growth of the organism in the presence of a pre-determined concentration of the analysis compound and the growth of the same organism diluted in 1_100 in the absence of any test compound. The change in Gl values (? GI) is used to determine the susceptibility of the organism endpoint of the test compound. If the? GI of control 1: 100 is greater than? GI in the presence of the test compound, then the concentration of the test compound is considered to be bactericidal (> 99% inhibition) of the organism. The MIC of the compounds of Examples 1 to 46 was determined for the following strains of M. tuberculosis.

H37Rv, H37Ta, A clinical isolate susceptible to isoniazid, rifampicin, ethambutol and streptomycin [E: 22/95; Estonia], Clinical Isolation Resistant to Isoniazid and Rifampicin [H: 44/95, Honduras], Clinical Isolation Resistant to Isoniazid and Streptomycin "S: 150/96, Sweden], Clinical Isolation Resistant to Isoniazid , rifampicin and streptomycin [AA: 063; Ethiopia], Three clinical isolates resistant to isoniazid, rifampicin, streptomycin and ethambutol [P: 24/95; Estonia, S: 39/95; Nepal, S: 42/95; China, H: 1005/94; Honduras], and appear in all cases to be less than or equal to 20 μg / ml. Accordingly, the compounds of Examples 1 to 46 demonstrate a bactericidal activity effective against the above strains of M. tuberculosis which include strains resistant to one or more drugs.

It is noted that in relation to this date, the best known method for the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. The use of a compound of the general formula where x is 0 or 1; R1 represents a hydrogen atom, or a C?-C2o alkyl or a mirtanyl group, or a phenyl or benzyl group optionally substituted on the aromatic ring by one or more substituents selected from the group consisting of amino, nitro, hydroxyl, carboxyl, halogen, trifluoromethyl, C?-C6 alkyl, C?-C6 alkoxy, C?-C6 alkoxycarbonyl, piperidyl, piperazinyl and morpholinyl, or a group (CH 2) and CONH-R 5 where y is an integer from 1 to 6 and R 5 represents a phenyl group optionally substituted by one or more substituents selected from the group consisting of amino, nitro, hydroxyl, carboxyl, halogen, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl , piperidyl, piperazinyl and morpholinyl; I R2 represents a hydrogen atom or a C? -C6 alkyl group, or R2 together with R3 represent a single carbon-carbon bond where x is 0, or R2 together with R4 represent a group = CH2, R3 represents an atom of hydrogen or is attached to R2 as defined above, and R4 represents a hydrogen atom or a Ci-Cß alkyl group,; or an Ci-Cio alkylamino group optionally substituted by a di (Ci-Cß) alkylamino substituent group; or an anilino group optionally substituted on the aromatic ring by one or more substituents selected from the group consisting of amino, nitro, hydroxyl, carboxyl, halogen, trifluoromethyl, C?-C6 alkyl, Ci-Cß alkoxy, C alco alkoxycarbonyl C6, piperidyl, piperanizil and morpholinyl; or a group -SCH2CH2OH, -SCH2CH2NH2 SCH2CH2 (NH2) C02H or -SCH2CH2NHCO-R6 wherein R6 represents a C1-C10 alkyl or a C3-C3 cycloalkyl group, or a phenyl group optionally substituted by one or more substituents selected from a group consisting of amino, nitro, hydroxyl, carboxyl, halogen, trifluoromethyl, C 1 -C 6 alkyl, Ci-Cβ alkoxy, C 1 -C 6 alkoxycarbonyl, piperidyl, piperazinyl and morpholinyl; or R4 is attached to R2 as defined above; or R2, R3 and R4 together represent a phenyl group; with the conditions that: (i) RX, R2, R3 and R4 can not simultaneously represent a hydrogen atom; (ii) when x is 0, R1 represents a 4-fluorophenyl group and R4 represents a hydrogen atom, when R2 and R3 are not together representing a carbon-carbon single bond, and (iii) when x is 0, R1 represents a 4-fluorophenyl group and R2 and R3 both represent a hydrogen atom, when R4 does not represent an anilino, 4-chloroanilino, 2,6-dichloroanilino, 3,4-dichloroanilino, 2,5-dichloroanilino, 3-chloro-4- fluoroanilino or a 4-fluoroanilino group; or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in the treatment of a mycobacterial disease.

2. The use according to claim 1, characterized in that R 1 represents a hydrogen atom, C 4 -C 6 alkyl, or mirtanyl group, or a phenyl group substituted by a piperidyl substituent group, or a group (CH 2) and CONH-R 5 in where y is 1 or 2 and R 5 represents a phenyl group substituted by a piperidyl substituent group.

3. The use according to claim 1 or claim 2, characterized in that R2 together with R3 represent a carbon-carbon single bond where x is 0, or R2 together with R4 represent a group = CH2.

4. The use according to any one of claims 1 to 3, characterized in that R4 represents a hydrogen atom or a methyl or ethyl group, a C2-C alkylamino group or optionally substituted by a di (C2-C4 alkyl) substituent group. amino, an anilino group substituted by a piperidyl substituent group, -SCH2CH2OH, -SCH2CH2NH2, -SCH2CH2 (NH2) C02H or -SCH2CH2NHCO -R6 wherein R6 represents a C7 alkyl, cyclopropyl, cyclopentyl or cyclohexyl group or a substituted phenyl group by a nitrogen, C 1 -C 4 alkyl or a C 3 -C β alkoxyl substituent group, or R 4 is attached to R 2 as defined in claim 1.

5. The use according to claim 1, characterized in that the compound of the formula (I) is selected from: l-Decylpyrrolidin-2, 5-one, l-nonylpiperidin-2,6-dione. 2- ((6,6-dimethylbicyclo [3, 1, 1] hepta-2-yl) methyl) isoindol-1,3-dione, 1- ((6,6-dimethylbicyclo [3, 1, 1] hepta- 3-yl) methyl) -3-methy1-3-pyrrolin-2, 5-dione, 3-met il-1 -nonyl-3-pyr rolin-2, 5-dione, 3-met ilen-l-nonylpyrrolidin- 2, 5-dione, 3-met il-1-octyl-3-pyrrolin-2, 5-dione, 3-methylene-l-octylpyrrolidin-2, 5-dione, (4- (3-methyl-2, 5- dioxo-3-pyrrolinyl) phenyl) piperidine, l-octyl-3-pyrrolin-2, 5-dione, l-decyl-3-pyrrolin-2, 5-dione, l-nonyl-3-pyrrolin-2, 5- dione, l-butyl-3-pyrrolin-2, 5-dione, l-hexyl-3-pyrrolin-2, 5-dione, 1- (4-piperodylphenyl) -3-pyrrolin-2, 5-dione, 1- (octyl-3- (octylamino) -pyrrolidin-2, 5-dione, l-decyl-3- (decylamino) pyrrolidin-2, 5-dione, 3- (octylamino) -3-pyrrolidin-2, 5-dione, 3- (Heptilamino) nonylpyrrolidin-2,5-dione, l-nonyl-3- (nonylamino) pyrrolidin-2, 5-dione, l-nonyl-3- (octylamino) pyrrolidin-2, 5-dione, 2- amino-3- (3-methyl-l-nonyl-2, 5-dioxo-pyrrolidin-3-ylthio) propanoic acid, 2-amino-3- (3-methyl-l-octyl-2, 5-dioxo-pyrrole) idin-3-ylthio) propanoic acid, 2-amino-3- (l-octyl-2, 5-dioxo-pyrrolidin-3-ylthio) propanoic acid, 3-methyl-1-octylpyrrolidin-2, 5-dione, 3- methy1-1-nonylpyrrolidin-2, 5-dione, 2- (2,5-dioxopyrrolidinyl) -N- (4-piperidylphenyl) ethanamide, 2- (2,5-dioxopyrrolidinyl) -N- (4-piperidylphenyl) propanamide, 3-ethyl-1-noni-pyrrolidin-2, 5-dione, 3- (2-aminoethylthio) -l-nonylpyrrolidin-2,5-dione , 2-ethyl-N- (2- (l-nonyl-2, 5-dioxopyrrolidin-3-ylthio) ethyl) hexanamide, cyclopropyl-N- (2- (l-nonyl-2, 5-dioxopyrrolidin-3-ylthio ) ethyl) formamide, (4-butylphenyl) -N- (2- (1-nonyl-2, 5-dioxopyrrolidin-3-ylthio) ethyl) formamide, (4-hexyloxyphenyl) -N- (2- (1-nonyl -2, 5-dioxopyrrolidin-3-ylthio) ethyl) formamide, (4-methylphenyl) -N- (2- (1-nonyl-2, 5-dioxopyrrolidin-3-ylthio) ethyl) formamide, (4- (tert. -butyl) phenyl-N- (2- (1-nonyl-2, 5-dioxopyrrolidin-3-ylthio) ethyl) formamide, cyclopentyl-N- (2- (1-nonyl-2, 5-dioxopyrrolidin-3-ylthio ) ethyl) formamide, ethane, cyclohexyl-N- (2- (1-nonyl-2, 5-dioxopyrrolidin-3-ylthio) ethyl) formamide, (4-nitrophenyl) -N- (2- (1-nonyl-2) , 5-dioxopyrrolidin-3-ylthio) ethyl) formamide, 3- ((2- (dibutylamino) ethyl) amino) -l-nonylpyrrolidin-2,5-dione, 3- ((2- (diethylamino) ethyl) amino) -l-nonylpyrrolidin-2, 5-dione, l-nonyl-3- ((4-piperidinylphenyl) amino) pyrrolidin-2, 5-dione, 3- (hydroxyethylthio) -3-methyl-l-nonylpyrrolidin-2,5-dione, 3- (2-aminoethylthio) -3-methyl-1-nonylpyrrolidin-2, 5-dione, and 3-methyl-1-octyl-3- (octylamino) pyrrolidin-2, 5-dione.

6. The use according to any of the preceding claims, characterized in that the mycobacterial disease is tuberculosis.

7. A method for treating a patient suffering from, or at risk of, a mycobacterial disease, characterized in that it comprises administering to a patient a therapeutically effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof , as defined in claim 1.