Saturated nitrogen and N-acylated heterocycles potentiating the activity of an active antibiotic against Mycobacteria

Abstract

The present invention concerns a compound of general formula (I): ##STR00001##
in which n=0 or 1, R1 represents an optionally substituted alkyl chain, in particular substituted alkyl chain, in particular substituted with fluorine, X is chosen from N and CH, and R2 is chosen from optionally substituted phenyl and benzyl, wherein the heterocycles having 6 vertices comprise one, two or three nitrogen atoms. The present invention also concerns the use of this compound as a medicament, in particular in the treatment of bacterial and mycobacterial infections such as tuberculosis in combination with an antibiotic that is active against bacteria and/or mycobacteria, said compound potentiating the activity of said antibiotic.

Claims

1. A compound of formula (I): ##STR00091## in which: n is 0 or 1; R1 is selected from the group consisting of CH.sub.2CF.sub.3 and CH.sub.2CH.sub.2CF.sub.3; X is N or CH; R2 is selected from the group consisting of phenyl, benzyl, phenyl substituted by linear or branched C1-C4 alkyl, benzyl substituted by linear or branched C1-C4 alkyl, phenyl substituted by linear or branched C1-C4 alkyl substituted by fluorine, benzyl substituted by linear or branched C1-C4 alkyl substituted by fluorine, phenyl substituted by one or more substituent selected from Cl, F, CF.sub.3, OCH.sub.3, and OH, and a six-membered heterocycle comprising one, two or three nitrogen atoms.

2. The compound according to claim 1, wherein n is 1.

3. The compound according to claim 1, wherein R1 is CH.sub.2CF.sub.3.

4. The compound according to claim 1, wherein X is CH.

5. The compound according to claim 1, wherein R2 is phenyl or benzyl.

6. The compound according to claim 1, wherein R2 is phenyl substituted in meta position relative to the bond to X by a substituent selected from Cl, F, CF.sub.3 and OCH.sub.3.

7. The compound according to claim 1, wherein R2 is phenyl substituted by fluorine.

8. The compound according to claim 1, wherein R2 is phenyl substituted by fluorine in para position relative to the bond to X.

9. The compound according to claim 1, wherein R2 is selected from: ##STR00092##

10. The compound according to claim 1, which is selected from the group consisting of: ##STR00093## ##STR00094## ##STR00095## ##STR00096## ##STR00097##

11. A method of treatment of tuberculosis, leprosy and atypical mycobacterial infections comprising administering to a patient in need thereof an effective amount of a compound of claim 1.

12. A pharmaceutical composition comprising as active ingredient a compound of claim 1 and a pharmaceutically acceptable excipient.

13. The pharmaceutical composition of claim 12 further comprising an antibiotic active against bacteria and/or mycobacteria.

14. The pharmaceutical composition of claim 12 further comprising an antibiotic activatable via the EthA pathway.

15. The pharmaceutical composition of claim 12 further comprising an antibiotic selected from the thioamide family.

16. The pharmaceutical composition of claim 12 further comprising ethionamide or prothionamide.

17. A method of treatment of tuberculosis, leprosy and atypical mycobacterial infections comprising administering to a patient in need thereof an effective amount of a compound of claim 1 and an effective amount of an antibiotic activatable via the EthA pathway.

18. A method of treatment of mycobacterial infections comprising administering to a patient in need thereof an effective amount of claim 1.

19. The compound according to claim 3, wherein n is 1.

20. The compound according to claim 19, wherein X is CH.

Description

EXPERIMENTAL SECTION

(1) Synthesis Process(es)

(2) Nuclear magnetic resonance spectra (NMR).sup.1H and .sup.13C were performed at ambient temperature on a Bruker DPX 300 spectrometer at 300 MHz. The chemical shifts are expressed in parts per million (ppm). The assignments were performed using .sup.1H and .sup.13C one-dimensional (1D) or two-dimensional (2D) HSQC-COSY experiments. Mass spectra were performed on an LCMS Waters Alliance Micromass ZQ 2000 system. The commercial reagents and solvents were used without ulterior purification.

(3) General Flow Diagram of the Synthetic Process(es) for Piperidino and Pyrrolidino Derivatives:

(4) ##STR00009##
Protocol:

(5) The LDA (solution at 2M in THF/heptane/ethyl benzene, 3.3 mmole 1.1 eq) was added with 5 mL anhydrous THF in a flask previously oven-dried and put under argon. The solution was cooled to 78 C. The N-Boc-4-piperidone (or N-Boc-3-pyrrolidinone) (3 mmol, 1 eq) dissolved in 5 mL THF was added drop-wise, then the reaction medium was agitated for 20 minutes at 78 C. The N-phenyl-trifluoromethane-sulphonimide (3.3 mmol, 1.1 eq) dissolved in 5 mL THF was added. The solution was agitated 2 h at 0 C. and then evaporated. The residue was dissolved in a mixture of cyclohexane/AcOEt 9:1 and then filtrated on alumina. The product (triflate) was used in the next step without purification. In a flask containing the triflate (1 eq) and put under argon, one added the boronic acid (1.1 eq), LiCl (3 eq), the 2N solution of Na.sub.2CO.sub.3 (1.4 eq), the DME (0.34 M) and the tetrakis(triphenylphosphine)palladium (0.05 eq). The solution was heated between 1 h and 16 h under reflux and then evaporated. The residue was taken up in AcOEt and then washed once using water and once using a solution saturated with NaCl. The organic phase was dried and then evaporated. The residue was taken up in AcOEt and then filtrated on sintered glass. The solvent was evaporated, then the product was purified using chromatography on silica gel (cyclohexane/AcOEt).

(6) The unsaturated derivative (1 eq) was dissolved in ethanol (0.1M) with PtO.sub.2 (0.1 eq) or Pd/C (0.1 eq). The reaction mixture was put under hydrogen and agitated at ambient temperature until the input product has disappeared. The solution was filtrated on celite, then evaporated.

(7) Or: the unsaturated derivative (1 eq) was dissolved in methanol (0.1M) with ammonium formate (5 eq) and Pd/C (10% by mass). The reaction mixture was heated under reflux until the input product disappeared. The solution was filtrated on celite and then evaporated.

(8) The protected amine (1 eq.) was added in a flask with dioxane (1 M), then a solution of HCl 4N in dioxane (5 eq) was added. The solution was agitated 1 h at ambient temperature, then evaporated. The residue was taken over in light petroleum and then filtrated on sintered glass.

(9) The acid (1.3 eq) was activated using EDCl (1.3 eq) and HOBt (0.4 eq) in DMF (0.25 M) in the presence of DEIA (4 eq) and then the amine (1 eq) was added. The solution was agitated 3 h at ambient temperature and then evaporated. The residue was dissolved in AcOEt and then washed twice using saturated NaHCO.sub.3, twice using HCl 1N and once using saturated NaCl. The organic phase was dried on MgSO.sub.4 and then evaporated. The residue was purified using preparative HPLC.

(10) General Flow Diagram of the Synthetic Process(es) for Piperazines:

(11) ##STR00010##
Protocol:

(12) The acid (1.3 eq) was activated using EDCl (1.3 eq) and HOBt (0.4 eq) in DMF (0.25 M) in the presence of DIEA (4 eq), then the commercially available piperazine (1 eq) was added. The solution was agitated 3 h at ambient temperature, then evaporated. The residue was dissolved in AcOEt, then washed twice using saturated NaHCO.sub.3, twice using HCl 1N and once using saturated NaCl. The organic phase was dried on MgSO.sub.4 then evaporated. The residue was purified using preparative HPLC.

(13) BDM_44647

(14) 4-phenylpiperidine is commercially available. Only the coupling was performed.

(15) ##STR00011##

(16) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.36-7.31 (m, 2H), 7.25-7.21 (m, 3H), 4.78-4.71 (m, 1H), 3.99-3.93 (m, 1H), 3.22-3.12 (m, 1H), 2.84-2.48 (m, 6H), 1.96-1.86 (m, 2H), 1.72-1.56 (m, 2H). MS [M+H].sup.+ m/z 286.

(17) BDM_44648

(18) 4-phenylpiperidine is commercially available. Only the coupling was performed.

(19) ##STR00012##

(20) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.36-7.31 (m, 2H), 7.25-7.20 (m, 3H), 4.78-4.72 (m, 1H), 3.99-3.92 (m, 1H), 3.19-3.09 (m, 1H), 2.81-2.60 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 2.29-2.16 (m, 2H), 1.97-1.87 (m, 4H), 1.70-1.54 (m, 2H). MS [M+H].sup.+ m/z 300.

(21) BDM_44808

(22) ##STR00013##

(23) .sup.1H NMR (CDCl.sub.3) 7.34-7.28 (m, 2H), 6.97-6.94 (m, 3H), 3.83-3.80 (m, 2H), 3.67-3.64 (m, 2H), 3.24-3.17 (m, 4H), 2.68-2.49 (m, 4H). MS [M+H].sup.+ m/z 287.

(24) BDM_44809

(25) ##STR00014##

(26) .sup.1H NMR (CDCl.sub.3) 7.34-7.28 (m, 2H), 6.97-6.94 (m, 3H), 3.82-3.79 (m, 2H), 3.65-3.62 (m, 2H), 3.22-3.16 (m, 4H), 2.48 (t, J=7.2 Hz, 2H), 2.31-2.15 (m, 2H), 2.03-1.92 (m, 2H). MS [M+H].sup.+ m/z 301.

(27) BDM_70666

(28) ##STR00015##

(29) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.27-7.20 (m, 2H), 7.16-7.03 (m, 2H), 4.79-4.73 (m, 1H), 3.98-3.93 (m, 1H), 3.24-3.08 (m, 2H), 2.74-2.48 (m, 5H), 1.95-1.86 (m, 2H), 1.74-1.63 (m, 2H). MS [M+H].sup.+ m/z 304.

(30) BDM_70531

(31) ##STR00016##

(32) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.27-7.20 (m, 2H), 7.16-7.02 (m, 2H), 4.79-4.74 (m, 1H), 3.99-3.94 (m, 1H), 3.24-3.09 (m, 2H), 2.75-2.49 (m, 5H), 1.95-1.86 (m, 2H), 1.75-1.59 (m, 2H). MS [M+H].sup.+ m/z 304.

(33) BDM_44751

(34) ##STR00017##

(35) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.33-7.19 (m, 2H), 7.06-7.00 (m, 2H), 4.77-4.72 (m, 1H), 3.98-3.92 (m, 1H), 3.21-3.11 (m, 1H), 2.83-2.49 (m, 6H), 1.94-1.86 (m, 2H), 1.68-1.46 (m, 2H).

(36) .sup.13C NMR (CD.sub.2Cl.sub.2) 167.64, 161.45 (d, J=244 Hz), 141.20, 127.42 (q, J=274 Hz), 128.16 (d, J=8 Hz), 115.11 (d, J=21 Hz), 45.83, 42.40, 41.91, 33.81, 32.96, 29.53 (q, J=29 Hz), 25.79. MS [M+H].sup.+ m/z 304.

(37) BDM_71148

(38) ##STR00018##

(39) .sup.1H NMR (CD.sub.2Cl.sub.2) 6.69 (t, J=8.7 Hz, 2H), 4.78-4.72 (m, 1H), 3.98-3.92 (m, 1H), 3.27-3.10 (m, 2H), 2.68-2.48 (m, 5H), 2.07-1.90 (m, 2H), 1.82-1.74 (m, 2H). MS [M+H].sup.+ m/z 340.

(40) BDM_44819

(41) ##STR00019##

(42) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.04-6.98 (m, 2H), 6.95-6.90 (m, 2H), 3.79-3.75 (m, 2H), 3.64-3.61 (m, 2H), 3.14-3.07 (m, 4H), 2.61-2.46 (m, 4H). MS [M+H].sup.+ m/z 305.

(43) BDM_44820

(44) ##STR00020##

(45) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.04-6.98 (m, 2H), 6.94-6.89 (m, 2H), 3.77-3.74 (m, 2H), 3.62-3.59 (m, 2H), 3.12-3.06 (m, 4H), 2.45 (t, J=7.2 Hz, 2H), 2.25-2.15 (m, 2H), 1.97-1.87 (m, 2H). MS [M+H].sup.+ m/z 319.

(46) BDM_70669

(47) ##STR00021##

(48) .sup.1H NMR (CD.sub.2Cl.sub.2) 6.99-6.82 (m, 3H), 3.79-3.76 (m, 2H), 3.64-3.61 (m, 2H), 3.05-2.99 (m, 4H), 2.67-2.48 (m, 4H). MS [M+H].sup.+ m/z 323.

(49) BDM_70534

(50) ##STR00022##

(51) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.41-7.39 (m, 1H), 7.32-7.17 (m, 3H), 4.80-4.75 (m, 1H), 3.99-3.94 (m, 1H), 3.35-3.17 (m, 2H), 2.76-2.49 (m, 5H), 1.99-1.89 (m, 2H), 1.66-1.53 (m, 2H). MS [M+H].sup.+ m/z 320.

(52) BDM_70668

(53) ##STR00023##

(54) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.32-7.21 (m, 3H), 7.15-7.13 (m, 1H), 4.78-4.72 (m, 1H), 3.98-3.93 (m, 1H), 3.21-3.11 (m, 1H), 2.83-2.48 (m, 6H), 1.95-1.87 (m, 2H), 1.69-1.52 (m, 2H). MS [M+H].sup.+ m/z 320.

(55) BDM_70535

(56) ##STR00024##

(57) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.33-7.30 (m, 2H), 7.20-7.17 (m, 2H), 4.78-4.71 (m, 1H), 3.99-3.92 (m, 1H), 3.21-3.11 (m, 1H), 2.82-2.48 (m, 6H), 1.94-1.86 (m, 2H), 1.67-1.51 (m, 2H). MS [M+H].sup.+ m/z 320.

(58) BDM_44811

(59) ##STR00025##

(60) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.28-7.23 (m, 2H), 6.91-6.86 (m, 2H), 3.78-3.75 (m, 2H), 3.64-3.61 (m, 2H), 3.20-3.13 (m, 4H), 2.67-2.46 (m, 4H). MS [M+H].sup.+ m/z 321.

(61) BDM_44812

(62) ##STR00026##

(63) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.27-7.22 (m, 2H), 6.91-6.86 (m, 2H), 3.77-3.74 (m, 2H), 3.62-3.59 (m, 2H), 3.18-3.12 (m, 4H), 2.45 (t, J=7.2 Hz, 2H), 2.31-2.15 (m, 2H), 1.97-1.87 (m, 2H). MS [M+H].sup.+ m/z 335.

(64) BDM_70716

(65) ##STR00027##

(66) .sup.1H NMR (CDCl.sub.3) 7.39 (d, J=8.3 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.04 (dd, J=8.3 Hz, J=2.0 Hz, 1H), 4.82-4.77 (m, 1H), 4.00-3.94 (m, 1H), 3.21-3.12 (m, 1H), 2.79-2.48 (m, 6H), 1.96-1.88 (m, 2H), 1.67-1.51 (m, 2H).

(67) .sup.13C NMR (CDCl.sub.3) 167.99, 145.10, 132.60, 130.58, 128.84, 127.11 (q, J=275 Hz), 126.11, 45.74, 42.40, 41.90, 33.48, 32.53, 29.69 (q, J=29 Hz), 25.95. MS [M+H].sup.+ m/z 354.

(68) BDM_70536

(69) ##STR00028##

(70) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.68 (d, J=4.5 Hz, 1H), 7.58 (t, J=4.5 Hz, 1H), 7.46 (d, J=4.5 Hz, 1H), 7.37 (t, J=4.5 Hz, 1H), 4.81-4.77 (m, 1H), 4.00-3.97 (m, 1H), 3.23-3.17 (m, 2H), 2.73-2.52 (m, 5H), 1.92-1.85 (m, 2H), 1.75-1.68 (m, 2H). MS [M+H].sup.+ m/z 354.

(71) BDM_70546

(72) ##STR00029##

(73) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.51-7.46 (m, 4H), 4.80-4.75 (m, 1H), 4.01-3.95 (m, 1H), 3.23-3.14 (m, 1H), 2.93-2.82 (m, 1H), 2.74-2.50 (m, 5H), 1.99-1.90 (m, 2H), 1.74-1.57 (m, 2H).

(74) .sup.13C NMR (CD.sub.2Cl.sub.2) 167.72, 146.30, 130.56 (q, J=32 Hz), 130.37, 129.09, 127.44 (q, J=275 Hz), 124.35 (q, J=275 Hz), 123.51 (q, J=4 Hz), 123.25 (q, J=4 Hz), 45.73, 42.48, 42.29, 33.46, 32.63, 29.52 (q, J=28 Hz), 25.83. MS [M+H].sup.+ m/z 354.

(75) BDM_70667

(76) ##STR00030##

(77) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.61 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 4.80-4.74 (m, 1H), 4.01-3.95 (m, 1H), 3.23-3.13 (m, 1H), 2.92-2.82 (m, 1H), 2.73-2.48 (m, 5H), 1.98-1.89 (m, 2H), 1.73-1.61 (m, 2H). MS [M+H].sup.+ m/z 354.

(78) BDM_70665

(79) ##STR00031##

(80) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.19-7.09 (m, 4H), 4.80-4.74 (m, 1H), 4.00-3.94 (m, 1H), 3.23-3.14 (m, 1H), 3.06-2.95 (m, 1H), 2.74-2.47 (m, 5H), 2.38 (s, 3H), 1.88-1.80 (m, 2H), 1.71-1.54 (m, 2H). MS [M+H].sup.+ m/z 300.

(81) BDM_70664

(82) ##STR00032##

(83) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.23-7.20 (m, 1H), 7.06-7.01 (m, 3H), 4.77-4.71 (m, 1H), 3.98-3.92 (m, 1H), 3.20-3.11 (m, 1H), 2.79-2.46 (m, 6H), 2.33 (s, 3H), 1.94-1.85 (m, 2H), 1.71-1.53 (m, 2H). MS [M+H].sup.+ m/z 300.

(84) BDM_70663

(85) ##STR00033##

(86) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.16-7.10 (m, 4H), 4.77-4.70 (m, 1H), 3.97-3.91 (m, 1H), 3.20-3.10 (m, 1H), 3.06-2.95 (m, 1H), 2.77-2.47 (m, 5H), 2.33 (s, 3H), 1.93-1.85 (m, 2H), 1.69-1.51 (m, 2H). MS [M+H].sup.+ m/z 300.

(87) BDM_70540

(88) ##STR00034##

(89) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.25-7.15 (m, 2H), 6.98-6.91 (m, 2H), 4.78-4.72 (m, 1H), 3.97-3.92 (m, 1H), 3.86 (s, 3H), 3.28-3.14 (m, 2H), 2.75-2.47 (m, 5H), 1.94-1.84 (m, 2H), 1.69-1.54 (m, 2H).

(90) .sup.13C NMR (CD.sub.2Cl.sub.2) 167.59, 156.89, 133.37, 127.49 (q, J=275 Hz), 127.18, 126.35, 120.56, 110.44, 55.23, 46.16, 42.73, 35.54, 32.31, 31.48, 29.59 (q, J=29 Hz), 25.81. MS [M+H].sup.+ m/z 316.

(91) BDM_70538

(92) ##STR00035##

(93) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.27-7.22 (m, 1H), 6.83-6.76 (m, 3H), 4.78-4.71 (m, 1H), 3.99-3.92 (m, 1H), 3.80 (s, 3H), 3.20-3.11 (m, 1H), 2.81-2.47 (m, 6H), 1.95-1.87 (m, 2H), 1.71-1.54 (m, 2H). MS [M+H].sup.+ m/z 316

(94) BDM_70537

(95) ##STR00036##

(96) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.17-7.14 (m, 2H), 6.89-6.86 (m, 2H), 4.76-4.71 (m, 1H), 3.97-3.92 (m, 1H), 3.79 (s, 3H), 3.20-3.11 (m, 1H), 2.74-2.50 (m, 6H), 1.93-1.86 (m, 2H), 1.63-1.55 (m, 2H).

(97) .sup.13C NMR (CD.sub.2Cl.sub.2) 168.38, 158.58, 138.06, 127.49 (q, J=275 Hz), 127.56, 113.81, 55.16, 45.97, 42.53, 41.76, 34.06, 33.12, 29.56 (q, J=29 Hz), 25.80. MS [M+H].sup.+ m/z 316.

(98) BDM_70539

(99) ##STR00037##

(100) .sup.1H NMR (MeOD) 7.08 (dd, J=7.6 Hz, J=1.5 Hz, 1H), 7.00 (td, J=7.6 Hz, J=1.7 Hz, 1H), 6.80-6.74 (m, 2H), 4.71-4.64 (m, 1H), 4.09-4.02 (m, 1H), 3.27-3.15 (m, 2H), 2.80-2.70 (m, 3H), 2.58-2.47 (m, 2H), 1.96-1.83 (m, 2H), 1.74-1.53 (m, 2H). MS [M+H].sup.+ m/z 302.

(101) BDM_45572

(102) ##STR00038##

(103) .sup.1H NMR (MeOD) 7.04 (d, J=8.7 Hz, 2H), 6.72 (d, J=8.7 Hz, 2H), 4.67-4.61 (m, 1H), 4.04-3.98 (m, 1H), 3.21-3.12 (m, 1H), 2.75-2.66 (m, 4H), 2.58-2.46 (m, 2H), 1.89-1.79 (m, 2H), 1.67-1.44 (m, 2H). MS [M+H].sup.+ m/z 302.

(104) BDM_70542

(105) ##STR00039##

(106) .sup.1H NMR (CD.sub.2Cl.sub.2) 8.52 (d, J=6.1 Hz, 2H), 7.16 (d, J=6.1 Hz, 2H), 4.80-4.73 (m, 1H), 4.01-3.93 (m, 1H), 3.22-3.13 (m, 1H), 2.84-2.48 (m, 6H), 1.98-1.89 (m, 2H), 1.71-1.54 (m, 2H). MS [M+H].sup.+ m/z 287.

(107) BDM_70670

(108) 4-benzylpiperidine is commercially available. Only the coupling was performed.

(109) ##STR00040##

(110) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.33-7.28 (m, 2H), 7.24-7.16 (m, 3H), 4.59-4.51 (m, 1H), 3.82-3.77 (m, 1H), 3.02-2.92 (m, 1H), 2.59-2.47 (m, 7H), 1.85-1.67 (m, 3H), 1.24-1.07 (m, 2H).

(111) MS [M+H].sup.+ m/z 300. BDM_70719

(112) ##STR00041##

(113) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.35-7.26 (m, 5H), 3.61 (t, J=5.1 Hz, 2H), 3.54 (s, 2H), 3.45 (t, J=5.1 Hz, 2H), 2.61-2.41 (m, 8H). MS [M+H].sup.+ m/z 301.

(114) BDM_70717

(115) ##STR00042##

(116) .sup.1H NMR (CDCl.sub.3) 7.24-7.18 (m, 2H), 7.07-7.00 (m, 2H), 4-09-3.99 (m, 0.5H), 3.91-3.81 (m, 1H), 3.72-3.64 (m, 0.5H), 3.60-3.31 (m, 3H), 2.61-2.50 (m, 4H), 2.46-2.27 (m, 1H), 2.16-1.95 (m, 1H). MS [M+H].sup.+ m/z 290.

(117) BDM_44810

(118) ##STR00043##

(119) .sup.1H NMR (CDCl.sub.3) 7.34-7.28 (m, 2H), 6.97-6.90 (m, 3H), 3.80 (t, J=5.1 Hz, 2H), 3.66 (t, J=5.1 Hz, 2H), 3.22-3.15 (m, 4H), 2.42-2.37 (m, 2H), 1.70-1.53 (m, 3H), 0.95 (d, J=6.3 Hz, 6H). MS [M+H].sup.+ m/z 261.

(120) BDM_44813

(121) ##STR00044##

(122) .sup.1H NMR (CDCl.sub.3) 7.26-7.22 (m, 2H), 6.91-6.86 (m, 2H), 3.74 (t, J=5.1 Hz, 2H), 3.63 (t, J=5.1 Hz, 2H), 3.18-3.11 (m, 4H), 2.39-2.34 (m, 2H), 1.67-1.49 (m, 3H), 0.95 (d, J=6.3 Hz, 6H). MS [M+H].sup.+ m/z 295.

(123) BDM_44821

(124) ##STR00045##

(125) .sup.1H NMR (CDCl.sub.3) 7.04-6.98 (m, 2H), 6.94-6.90 (m, 2H), 3.74 (t, J=5.1 Hz, 2H), 3.63 (t, J=5.1 Hz, 2H), 3.12-3.05 (m, 4H), 2.39-2.34 (m, 2H), 1.64-1.49 (m, 3H), 0.95 (d, J=6.6 Hz, 6H). MS [M+H].sup.+ m/z 279.

(126) BDM_44649

(127) 4-phenylpiperidine is commercially available. Only the coupling was performed.

(128) ##STR00046##

(129) .sup.1H NMR (CD.sub.2Cl.sub.2) 7.36-7.31 (m, 2H), 7.25-7.20 (m, 3H), 4.77-4.73 (m, 1H), 4.02-3.98 (m, 1H), 3.18-3.09 (m, 1H), 2.81-2.71 (m, 1H), 2.66-2.57 (m, 1H), 2.39-2.34 (m, 2H), 1.94-1.85 (m, 2H), 1.69-1.51 (m, 5H), 0.95 (d, J=6.4 Hz, 6H). MS [M+H].sup.+ m/z 260.

(130) Evaluation of the Compounds' Activity

(131) Potentiation of Ethionamide Cell Test

(132) The test used made it possible to ascertain that these compounds were capable of potentiating the bactericide activity of ethionamide on M. tuberculosis alone. This test was a High Content Screening (HCS) or dense content screening test. HCS tests were performed on cell cultures that enable certain phenotypic features of a microorganism (e.g. a bacterium) in a given environment to be studied. The phenotypic changes observed can range from the increase (or decrease) of the production of certain marked proteins to the modification of the morphology of the microorganism under consideration. The method is described in the following publication: Ethionamide Boosters: Synthesis, Biological Activity, and Structure-Activity Relationships of a Series of 1,2,4-Oxadiazole EthR Inhibitors, M. Flipo et al., Journal of Medicinal Chemistry, 2011, 54(8), 2994-3010.

(133) This test aims to determine the ligand concentration necessary to potentiate ten times the activity of ethionamide (ETH).

(134) To measure the ligand concentration necessary for potentiating ten times the activity of ETH, a constant concentration of ethionamide (0.1 g/mL corresponding to 1/10 of its CMI.sub.99) was chosen. By varying the ligand concentration, the concentration necessary to inhibit 50% of the bacterial growth, i.e. the concentration necessary to potentiate ten times the activity of ethionamide, was determined. This concentration was denoted EC.sub.50.

(135) Measurement of the Solubility

(136) 40 L of a solution at 10 mM in DMSO of the sample was added to 1.96 mL MeOH or PBS at pH 7.4. The samples were then agitated during 24 h at RT, centrifuged during 5 min and then filtrated on filters of 0.45 m size. 20 L of each solution were then added to 180 L MeOH and then analyzed by LC-MS. The solubility was determined as ratio of the surfaces of the mass signals PBS/MeOH.

(137) Measured Biological Activities

(138) The tables I to Ill hereafter summarize the formulas of the inventive compounds tested as well as the values of the EC.sub.50 experimentally measured according to the aforementioned protocol.

(139) TABLE-US-00001 TABLE I EC.sub.50 Solubility ID_structure R2 X n R1 (M) (g/mL) BDM_44647 CH 1 CH.sub.2CF.sub.3 0.0008 50.4 BDM_44648 CH 1 (CH.sub.2).sub.2CF.sub.3 <0.01 42.9 BDM_44751 CH 1 CH.sub.2CF.sub.3 0.001 51.9 BDM_70717 0 CH 0 CH.sub.2CF.sub.3 0.009 ND
With reference to the results of Table I, one observes that a CH.sub.2CF.sub.3 group affords a greater potentiating activity of ethionamide without negatively affecting the compound's solubility. The results show that for a same radical R1 and a same radical R2, the potentiating activity of the inventive compounds was improved when n=1.

(140) TABLE-US-00002 TABLE II EC.sub.50 ID_structure R2 X n R1 (M) BDM_44810 N 1 (CH.sub.2)isopropyl 0.06 BDM_44813 N 1 (CH.sub.2)isopropyl 0.1 BDM_44821 N 1 (CH.sub.2)isopropyl 0.1 BDM_44649 CH 1 (CH.sub.2)isopropyl 0.06

(141) Table III hereafter summarizes the activities expressed in EC.sub.50 for all the inventive compounds tested.

(142) TABLE-US-00003 TABLE III EC.sub.50 ID_structure R2 X n R1 (M) BDM_44647 CH 1 CH.sub.2CF.sub.3 0.0008 BDM_44648 CH 1 (CH.sub.2).sub.2CF.sub.3 <0.01 BDM_44649 CH 1 (CH.sub.2)isopropyl 0.06 BDM_44808 N 1 CH.sub.2CF.sub.3 0.01 BDM_44809 N 1 (CH.sub.2).sub.2CF.sub.3 0.07 BDM_70666 0 CH 1 CH.sub.2CF.sub.3 0.001 BDM_70531 CH 1 CH.sub.2CF.sub.3 0.0008 BDM_44751 CH 1 CH.sub.2CF.sub.3 0.001 BDM_71148 CH 1 CH.sub.2CF.sub.3 0.001 BDM_44819 N 1 CH.sub.2CF.sub.3 0.027 BDM_44820 N 1 (CH.sub.2).sub.2CF.sub.3 0.14 BDM_70669 N 1 CH.sub.2CF.sub.3 0.021 BDM_70534 CH 1 CH.sub.2CF.sub.3 0.11 BDM_70668 CH 1 CH.sub.2CF.sub.3 0.0005 BDM_70535 CH 1 CH.sub.2CF.sub.3 0.12 BDM_44811 0 N 1 CH.sub.2CF.sub.3 0.010 BDM_44812 N 1 (CH.sub.2).sub.2CF.sub.3 <0.02 BDM_70716 CH 1 CH.sub.2CF.sub.3 0.025 BDM_70536 CH 1 CH.sub.2CF.sub.3 0.770 BDM_70546 CH 1 CH.sub.2CF.sub.3 0.001 BDM_70667 CH 1 CH.sub.2CF.sub.3 0.3 BDM_70665 CH 1 CH.sub.2CF.sub.3 0.035 BDM_70664 CH 1 CH.sub.2CF.sub.3 0.001 BDM_70663 CH 1 CH.sub.2CF.sub.3 0.026 BDM_70540 CH 1 CH.sub.2CF.sub.3 0.14 BDM_70538 0 CH 1 CH.sub.2CF.sub.3 0.14 BDM_70537 CH 1 CH.sub.2CF.sub.3 0.002 BDM_70539 CH 1 CH.sub.2CF.sub.3 ND BDM_45572 CH 1 CH.sub.2CF.sub.3 0.28 BDM_70542 CH 1 CH.sub.2CF.sub.3 0.33 BDM_70670 CH 1 CH.sub.2CF.sub.3 0.054 BDM_70719 N 1 CH.sub.2CF.sub.3 1.1 BDM_44810 N 1 (CH.sub.2)isopropyl 0.06 BDM_44813 N 1 (CH.sub.2)isopropyl 0.1 BDM_44821 N 1 (CH.sub.2)isopropyl 0.1 BDM_70717 0 CH 0 CH.sub.2CF.sub.3 0.009