2-homopiperazine-1-yl-4H-1,3-benzothiazine-4-one derivatives and process for the preparation of 2-(homo)piperazine 1,3-benzothiazine-4-one hydrochlorides

Abstract

2-homopiperazine-1-yl-4H-1, 3-bensothiazine-4-one derivatives of formula (I) are provided. They are useful in the treatment of bacterial infections, in particular tuberculosis, buruli ulcer and leprosy. A process for the preparation of 2-(homo)piperazine 1, 3-benzothiazine-4-one hydrochlorides is also provided.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: ##STR00012## wherein n is 2; R.sup.1 is a linear, branched or cyclic C.sub.3-12 alkyl group, a linear, branched or cyclic C.sub.3-12 alkenyl group, a linear, branched or cyclic C.sub.3-12 alkynyl group, all of which may be substituted with halogen, and wherein one or two CH.sub.2-groups may be substituted with O or S, or ##STR00013## wherein X is a linear or branched C.sub.1-6 alkyl group, a linear or branched C.sub.1-6 alkenyl group, or a linear or branched C.sub.1-6 alkynyl group; Y is a direct bond, O, S, NH, NMe, NEt, or NPr; Z is a direct bond, or a linear or branched C.sub.1-3 alkyl group; Q is cyclopentyl, cyclohexyl, cycloheptyl, phenyl, or naphtyl, which may be substituted with 1-3 substituents selected from halogen, a linear or branched C.sub.1-3 alkoxy group, a linear or branched C.sub.1-3 alkenyloxy group, a linear or branched C.sub.1-3 alkynyloxy group, mono-, di or trifluoromethyl; and R.sup.2 is NO.sub.2 or NHOH.

2. The compound according to claim 1, wherein R.sup.1 is a linear, branched or cyclic C.sub.3-12 alkyl group, which may substituted with halogen, and wherein one or two CH.sub.2-groups may be substituted with O or S.

3. The compound according to claim 1, wherein n is 2, R.sup.1 is a linear or cyclic C.sub.4-9 alkyl group, and R.sup.2 is NO.sub.2.

4. The compound according to claim 1, which is a hydrochloride salt of formula (Ia): ##STR00014## wherein n, R.sup.1 and R.sup.2 are as defined in claim 1.

5. A method for treating a bacterial infection, the method comprising administering to a subject in need thereof a compound according to claim 1 or a pharmaceutically acceptable salt thereof, thereby treating said bacterial infection in said subject.

6. A pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable excipient.

7. The compound of claim 1, wherein R.sup.2 is NO.sub.2.

8. The method according to claim 5, wherein the bacterial infection is a mycobacterial infection.

9. The method according to claim 8, wherein the mycobacterial infection causes a disease selected from the group consisting of tuberculosis, buruli ulcer and leprosy.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) In a first aspect, the present invention provides a one-pot synthesis for the preparation of 2-piperazine and 2-homopiperazine 1,3-benzothiazine-4-one hydrochlorides of general formula (Ia). The term homopiperazine is synonymous with the term diazepan and can be used interchangeably.

(2) As the process of the present invention is a one-pot-synthesis, it is unnecessary to isolate and purify the intermediates which may be difficult and usually lowers the yield of the final product.

(3) The process according to the invention comprises the following steps: (1) reacting a substituted 2-chloro-5-(trifluoromethyl)benzoyl chloride of formula (II) with a thiocyanate salt M-SCN; (2) reacting the resulting substituted 2-chloro-5-(trifluoromethyl)benzoyl isothiocyanate without isolation with a substituted piperazine or homopiperazine of formula (III); (3) acidifying the resulting 2-piperazine or 2-homopiperazine 1,3-benzothiazine-4-one with hydrochloric acid to obtain a compound of formula (Ia).

(4) ##STR00010##

(5) In this scheme, n, R.sup.1, M, and R.sup.2 are as defined above. Preferred embodiments of R.sup.1 and R.sup.2 are those which are described below in relation to the compounds of the invention.

(6) The compounds wherein R.sup.2 is NHOH may be obtained by reducing the corresponding compound of formula (Ia) wherein R.sup.2 is NO.sub.2 in a manner known to the skilled person.

(7) The hydrochlorides of general formula (Ia) which are obtained in the process of the present invention may be converted into the corresponding compounds of general formula (I), i.e. into the free base form or other pharmaceutically acceptable salts thereof, by standard methods which are known to the skilled person. In particular, the free base may conveniently be obtained by reaction of the hydrochloride salt with sodium carbonate.

(8) The process of the present invention, is preferably carried out in an organic solvent, preferably THF or acetone, most preferably THF.

(9) Hereinafter, a particularly preferred embodiment of the process according to the invention is described:

(10) In the first reaction step, a solution of a substituted 2-chloro-5-(trifluoromethyl)benzoyl chloride in THF, preferably 2-chloro-3-nitro-5-(trifluoromethyl)benzoyl chloride, is added to a solution of the thiocyanate salt M-SCN at a temperature of 10 C. to +30 C., preferably 5 to +20 C.

(11) In this step, the thiocyanate salt. M-SCN is preferably used in a molar ratio of from 1 to 3, more preferably of from 1 to 1.4, based on the compound of formula (II).

(12) Following the reaction of the thiocyanate salt with the substituted 2-chloro-5-(trifluoromethyl)benzoyl chloride so as to obtain the corresponding 2-chloro-5-(trifluoromethyl)benzoyl isothiocyanate, the precipitated, white, solid alkali/ammonium chloride is removed by filtration.

(13) In the second reaction step, a freshly distilled substituted piperazine or homopiperazine in THF is added dropwise to the substituted 2-chloro-5-(trifluoromethyl)benzoyl isothiocyanate mother liquid at a temperature of 10 C. to +75 C., preferably between 0 to +50 C. The free base of the 2-piperazine or 2-homopiperazine 1,3-benzothiazine-4-one precipitates as a solid from the reaction mixture during storage at a temperature of between 0 C. to +30 C., preferably at +25 C., for 0.5 to 3 hours.

(14) The substituted piperazine or homopiperazine is used in a molar ratio of 1 to 5, preferably in a molar ratio of 1 to 2, based on the compound of formula (IT).

(15) In the final acidification step, the obtained reaction mixture is treated with a solution of HCl in water or an organic solvent, preferably methanol, ethanol, isopropanol or ethyl acetate, thereby converting the free base into the hydrochloride salt. The hydrochloride salt precipitates from the reaction mixture, and is obtained with high yield and purity.

(16) Preferably, HCl is used in a concentration of 5%, and is added in an amount so as to adjust the pH to about 2. The mixture is cooled over night, preferably at a temperature of 4 C. The precipitated 2-piperazine or 2-homopiperazine 1,3-benzothiazine-4-one hydrochloride is filtered off, and subsequently washed with a small amount of an organic solvent, preferably acetone.

(17) In a second embodiment, the present invention is directed to novel 2-piperazine-1-yl-4H-1,3-benzothiazine-4-one derivatives of formula (I) and their pharmaceutically acceptable salts, in particular to the hydrochloride salts of the compounds of formula (I):

(18) ##STR00011##
wherein n, R.sup.1, and R.sup.2 are as defined above.

(19) In a preferred embodiment, R.sup.1 is a linear, branched or cyclic C.sub.3-12 alkyl group which may be substituted with halogen and wherein one or two CH.sub.2-groups may be substituted with O or S. In a more preferred embodiment, R.sup.1 is a linear, branched or cyclic C.sub.3-12 alkyl group, wherein one CH.sub.2-group may be substituted with O. In an even more preferred embodiment, R.sup.1 is a linear, branched or cyclic C.sub.4-9 alkyl group, wherein one CH.sub.2 group may be substituted with O. In the most preferred embodiment, R.sup.1 is a linear or cyclic C.sub.4-9 alkyl group.

(20) In a particularly preferred embodiment of the compounds of formula (I), R.sup.1 is a linear or cyclic C.sub.4-9 alkyl group and R.sup.2 is NO.sub.2.

(21) The compounds of formula (I) may be in the form of their free bases or their pharmaceutically acceptable salts, including their hydrochlorides, sulfates, nitrates, methanesulfonates, benzenesulfonates, oxalates, maleates, phosphates, malates, tartrates, fumarates and salicylates, preferably their hydrochlorides and sulfates. The hydrochlorides are particularly preferred.

(22) The compounds of the formula (I) according to the invention exhibit strong antibacterial activity, especially against mycobacteria with minimal inhibitory concentrations (MIC) in the range of 0.2-1 ng/ml for M. tuberculosis H37Rv, determined by the resazurin reduction method (J. C. Palomino, A. Martin, M. Camacho, H. Guerra, J. Swings, F. Portaels, Antimicrob, Agents Chemother., 2002, 46, 2720-2722). In particular, the compounds according to the invention demonstrate a high level of selectivity for mycobacteria and related actinobacteria, so that they are expected to be associated with fewer adverse effects.

(23) Thus, the compounds of the invention are useful for the treatment of mycobacterial infections, and even other actinobacterial infections such as diphtheria or nocardiosis, in humans and in animals. They are especially potent in the treatment of tuberculosis, buruli ulcer and leprosy.

(24) Pharmaceutical compositions comprising the compounds according to the invention may be prepared in a manner known to the skilled person, e.g. by mixing with commonly used excipients and tableletting.

(25) The present invention will hereinafter be described in more detail by way of the following non-limiting examples.

EXAMPLES

(26) Chemicals and solvents were purchased from Alfa-Aesar (GB) or from Aldrich Co. (Sigma-Aldrich Company, St-Louis, US). They were used without additional purification.

(27) Melting points were determined according to the EP procedure and are uncorrected (Electrothermal 9001, GB).

(28) The molecular formula was analysed (Carlo-Erba 5500, Italy).

(29) NMR spectra were determined with a Varian Unity Plus 300 (USA). Shifts for .sup.1H NMR are reported in ppm downfield from TMS ().

(30) Mass spectra were obtained using a Finnigan SSQ-700 (USA) instrument with direct injection.

(31) Reactions and purity of compounds were controlled by TLC using Silicagel 60 F.sub.254 aluminium sheets (Merck Co, Germany).

Example 1

2-[4-(Cyclohexylmethyl)-1,4-diazepan-1-yl]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one Hydrochloride

(32) (Compound 1)

(33) A solution of 5.0 g (17.3 mmol) fresh 2-chloro-3-nitro-5-(trifluoromethyl)benzoyl chloride in 25 ml of THF was added to a solution of 1.45 g (19.0 mmol) NH.sub.4SCN in 25 ml of THE within 5 rain at room temperature. The reaction mixture was stored for 10 min at room temperature, and the white solid (NH.sub.4Cl) was quickly removed by filtration, and washed with 5 ml THF. A solution of 3.40 g (17.3 mmol) of distilled 1-(cyclohexylmethyl)-1,4-diazepane in 25 THF was added dropwise to the mother liquid within 5 min at room temperature and a yellow solid formed. The reaction mixture was stored for 1 hour at room temperature, and subsequently treated with 5% HCl solution in MeOH until a pH of 2 was reached. The mixture was cooled to 4 C. overnight. Light yellow 2-[4-(cyclohexylmethyl)-1,4-diazepan-1-yl]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one was filtered off and washed with a small volume of acetone.

(34) The product was recrystallized from an appropriate solvent, such as EtOH.

(35) Yield: 67%

(36) mp: 269-271 C. (EtOH)

(37) MS (m/z): 470 (M.sup.+)

(38) .sup.1H NMR (DMSO-d.sub.6): 10.93 (1H, broad s, NH), 8.80 and 8.86 (two 1H, two s, 2CH), 4.60 and 4.32 (2H, broad s, NCH.sub.2), 3.78 (2H, broad s, NHCH.sub.2), 3.16 (2H, broad s, NCH.sub.2), 3.18 (2H, broad s, NCH.sub.2), 2.96 (2H, broad s, CH.sub.2), 2.12 (2H, broad s, NCH.sub.2), 1.86 (2H, broad s, CH.sub.2), 1.74 and 1.55 (11H, 2 m. HC(CH.sub.2).sub.5) ppm

(39) Anal. for C.sub.21H.sub.25F.sub.3N.sub.4O.sub.3SHCl:

(40) Calc.: C, 49.75; H, 5.17; N, 11.05.

(41) Found: C, 49.64; H, 5.14; N, 11.14.

(42) The following compounds were obtained by conducting the process of Example 1, except for using the appropriate (homo)piperazine derivative.

Example 2

8-Nitro-2-(4-pentyl-1,4-diazepan-1-yl)-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one Hydrochloride

(43) (Compound 2)

(44) Yield: 59%

(45) mp: 246-248 C. (EtOH)

(46) MS (m/z): 444 (M.sup.+)

(47) .sup.1H NMR (DMSO-d.sub.6): 10.89 (1H, broad s, NH), 8.82 and 8.86 (two 1H, two s, 2CH), 0.76-4.62 (21H, several very broad s, CH.sub.2 and CH.sub.3) ppm

(48) Anal. for C.sub.19H.sub.23F.sub.3N.sub.4O.sub.3SHCl:

(49) Calc.: C, 47.45; H, 5.29; N, 11.32.

(50) Found: C, 47.47; H, 5.26; N, 11.30.

Example 3

2-(4-Hexyl-1,4-diazepan-1-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one Hydrochloride

(51) (Compound 3)

(52) Yield: 63%

(53) mp: 249-251 C. (EtOH)

(54) MS (m/z): 458 (M.sup.+)

(55) .sup.1H NMR (DMSO-d.sub.6): 10.92 (1H, broad s, NH), 8.81 and 8.87 (two 1H, two s, 2CH), 4.64 and 4.21 (2H, broad d, NHCH.sub.2), 3.92 (2H, broad s, NCH.sub.2), 3.65 (2H, broad s, NCH.sub.2), 3.06 (2H, broad s, NCH.sub.2, 2.32 (2H, broad s, NCH.sub.2), 1.76 (2H, broad s, CH.sub.2), 1.35 (6H, broad s, (CH.sub.2).sub.3) and 0.94 (2H, broad s, CH.sub.2) ppm

(56) Anal. for C.sub.20H.sub.25F.sub.3N.sub.4O.sub.3SHCl:

(57) Calc.: C, 48.53; H, 5.29; N, 11.32.

(58) Found: C, 48.59; H, 5.23; N, 11.27.

Example 4

2-[4-(2-Cyclohexylethyl)-1,4-diazepan-1-yl]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one Hydrochloride

(59) (Compound 4)

(60) Yield: 60%

(61) mp: 274-277 C. (EtOH)

(62) MS (m/z): 484 (M.sup.+)

(63) .sup.1H NMR (DMSO-d.sub.6): 10.86 (1H, broad s, NH), 8.82 and 8.86 (two 1H, two s, 2CH), 0.91-4.65 (25H, several very broad s, 12 CH.sub.2 and CH) ppm

(64) Anal. for C.sub.22H.sub.27F.sub.3N.sub.4O.sub.3SHCl:

(65) Calc.: C, 50.72; H, 5.42; N, 10.75.

(66) Found: C, 50.75; H, 5.59; N. 10.59.

Example 5

2-(4-Heptyl-1,4-diazepan-1-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one Hydrochloride

(67) (Compound 5)

(68) Yield: 67%

(69) mp: 256-258 C. (EtOH)

(70) MS (m/z): 472 (M.sup.+)

(71) .sup.1H NMR (DMSO-d.sub.6): 10.85 (1H, broad s, NH), 8.81 and 8.87 (two 1H, two s, 2CH), 1.12-4.68 (25H, several very broad s, 11 CH.sub.2 and CH.sub.3) ppm

(72) Anal. for C.sub.21H.sub.27F.sub.3N.sub.4O.sub.1SHCl:

(73) Calc.: C, 49.55; H, 5.54; N, 11.01.

(74) Found: C, 49.47; H, 5.50; N, 11.09.

Example 6

2-(4-Cyclohexyl-1,4-diazepan-1-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one Hydrochloride

(75) (Compound 6)

(76) Yield: 64%

(77) mp: 290-293 C. (EtOH/H.sub.2O)

(78) MS (m/z):456 (M.sup.+)

(79) .sup.1H NMR (DMSO-d.sub.6): 10.89 (1H, broad s, NH), 8.82 and 8.87 (two 1H, two s, 2CH), 0.87-4.65 (21H, several very broad s, 10 CH.sub.2 and CH) ppm

(80) Anal. for C.sub.20H.sub.24F.sub.3N.sub.4O.sub.3SHCl:

(81) Calc.: C, 48.73; H, 4.91; N, 11.37.

(82) Found: C, 48.66; H, 4.94; N, 11.42.

Example 7

8-Nitro-2-[4-(2-phenylethyl)-1,4-diazepan-1-yl]-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one Hydrochloride

(83) (Compound 7)

(84) Yield: 58%

(85) mp 264-267 C. (EtOH/H.sub.2O)

(86) MS (m/z): 478 (M.sup.+)

(87) .sup.1H NMR (DMSO-d.sub.6): 11.32 (1H, broad s, NH), 8.98 and 8.89 (two 1H, two s, 2CH), 7.21-7.43 (5H, m, C.sub.6H.sub.5), 4.60 and 4.34 (2H, broad d, NHCH.sub.2), 4.01 (2H, broad s, NCH.sub.2), 3.65 (2H, broad s, NCH.sub.2), 3.32 (2H, broad s, NCH.sub.2), 3.13 (2H, broad s, CH.sub.2), 2.61 (2H, broad s, CH.sub.2), 2.40 (2H, broad s, NHCH.sub.2) ppm

(88) Anal. for C.sub.22H.sub.21F.sub.3N.sub.4O.sub.3SHCl:

(89) Calc.: C, 51.31; H, 4.31; N, 10.88.

(90) Found: C, 51.37; H, 4.37; N, 10.93.

Example 8

Synthesis of 2-[4-(cyclohexylmethyl)piperazin-1-yl]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one Hydrochloride Hydrochloride (PBTZ169HCl)

(91) (Compound 8)

(92) Yield: 78%

(93) mp: 296-297 C. (EtOH/H.sub.2O)

(94) MS (m/z): 456 (M.sup.+)

(95) .sup.1H NMR (DMSO-d.sub.6): 11.13 (1H, broad s, NH), 8.86 and 8.76 (two 1H, two s, 2CH), 4.64 (2H, broad s, NHCH.sub.2), 3.94 (2H, broad s, NHCH.sub.2), 3.18 (2H, broad s, NCH.sub.2), 3.18 (2H, broad s, NCH.sub.2), 2.96 (2H, broad s, CH.sub.2), 1.75 and 1.53 (11H, 2 m, HC(CH.sub.2).sub.5) ppm

(96) Anal. for C.sub.20H.sub.23F.sub.3N.sub.4O.sub.3SHCl:

(97) Calc.: C, 48.73; H, 4.91; N, 11.37.

(98) Found: C, 48.79; H, 4.85; N, 11.46.

(99) The following compounds in the form of light yellow crystals were obtained in the same manner as Example 8.

Example 9

2-[4-(2-Cyclohexylethyl)piperazin-1-yl]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one Hydrochloride

(100) (Compound 9)

(101) Yield: 76.7%

(102) mp: 271-273 C. (EtOH/H.sub.2O)

(103) MS (m/z): 470 (M.sup.+)

(104) .sup.1H NMR (DMSO-d.sub.6): 11.13 (1H, broad s, NH), 8.86 and 8.76 (two 1H, two s, 2CH), 3.91 (4H, broad s, N(CH.sub.2).sub.2), 2.51 (4H, broad s, N(CH.sub.2).sub.2), 2.36 (2H, t, CH.sub.2), 1.70-0.85 (13H, 4 broad m, CH.sub.2CH(C.sub.5H.sub.10)) ppm.

(105) Anal. for C.sub.21H.sub.25F.sub.3N.sub.4O.sub.3SHCl:

(106) Calc.: C, 49.75; H, 5.17; N, 11.05.

(107) Found: C, 49.63; H, 5.11; N, 11.20.

Example 10

2-(4-Heptylpiperazin-1-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one Hydrochloride

(108) (Compound 10)

(109) Yield: 68%

(110) mp: 254-256 C. (EtOH/H.sub.2O)

(111) MS (m/z): 458 (M.sup.+)

(112) .sup.1H NMR (DMSO-d.sub.6): 11.01 (1H, broad s, NH), 8.85 and 8.76 (two 1H, two 2CH), 3.90 (4H, broad s, N(CH.sub.2).sub.2), 2.52 (4H, broad s, N(CH.sub.2).sub.2), 2.33 (3H, t, CH), 1.43 (2H, broad m, CH.sub.2), 1.28 (8H, broad m, 4CH.sub.2) 0.86 (3H, t, CH.sub.3) ppm

(113) Anal. for C.sub.20H.sub.25F.sub.3N.sub.4O.sub.3SHCl:

(114) Calc.: C, 48.53; H, 5.29; N, 11.32.

(115) Found: C, 48.61; H, 5.22; N, 11.18.

Example 11

8-Nitro-2-[4-(4-phenoxybutyl)piperazin-1-yl]-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one Hydrochloride

(116) (Compound 11)

(117) Yield: 74%

(118) mp: 256-258 C. (EtOH)

(119) MS (m/z): 508 (M.sup.+)

(120) .sup.1H NMR (DMSO-d.sub.6): 10.93 (1H, broad s, NH), 8.91 and 8.80 (two 1H, two s, 2CH), 7.29 (2H, t, 2CH), 6.93 (3H, d, 3CH), 4.03 (2H, t, OCH.sub.2), 3.65 (2H, d, 2CH), 3.19 (4H, broad m, N(CH.sub.2).sub.2), 1.94 and 1.79 (4H, 2 broad m, 2CH.sub.2) ppm

(121) Anal. for C.sub.23H.sub.23F.sub.3N.sub.4O.sub.4SHCl:

(122) Calc.: C, 50.69; H, 4.44; N, 10.28.

(123) Found: C, 50.47; H, 4.32; N, 10.16.

Example 12

2-(4-[3-(4-Fluorophenoxy)propyl]piperazin-1-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one Hydrochloride

(124) (Compound 12)

(125) Yield: 77%

(126) mp: 261-2637 C. (ethanol)

(127) MS (m/z): 512 (M.sup.+)

(128) .sup.1H NMR (DMSO-d.sub.6): 10.97 (1H, broad s, NH), 8.85 and 8.76 (two 1H, two s, 2CH), 7.11 (2H, t, 2CH), 6.94 (2H, m, 2CH), 4.12 (2H, t, OCH.sub.2), 3.85 (4H, broad s, N(CH.sub.2).sub.2), 2.52 (4H, broad s, N(CH.sub.2).sub.2), 2.48 (2H, m, CH.sub.2), 1.83 (2H, q, CH.sub.2) ppm

(129) Anal. for C.sub.22H.sub.20F.sub.4N.sub.4O.sub.4SHCl:

(130) Calc.: C, 48.14; H, 3.86; N, 10.21.

(131) Found: C, 47.97; H, 3.83; N, 10.27.

Example 13

2-(4-Butylpiperazin-1-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one Hydrochloride

(132) (Compound 13)

(133) Yield: 67%

(134) mp: 239-241 C. (EtOH/H.sub.2O)

(135) MS (m/z): 416 (M.sup.+)

(136) .sup.1H NMR (DMSO-d.sub.6): 10.06 (1H, broad n, NH), 8.85 and 8.76 (two 1H, two s, 2CH), 3.90 (4H, broad s, N(CH.sub.2).sub.2), 2.51 (4H, broad s, N(CH.sub.2).sub.2), 2.32 (2H, t, CH.sub.2), 1.46 and 1.33 (4H, 2 m, 2CH.sub.2), 0.91 (3H, t, CH.sub.3) ppm

(137) Anal. for C.sub.17H.sub.19F.sub.3N.sub.4O.sub.3SHCl:

(138) Calc.: C, 45.09; H, 4.45; N, 12.37.

(139) Found: C, 45.16; H, 4.54; N, 12.30.

Example 14

In Vitro Inhibitory Activity of the Compounds of the Invention Against Mycobacteria

(140) Activity against M. tuberculosis strains H37Rv and NBT1 was determined by the resazurin reduction assay (MIC.sub.99). The method is described in detail in: J. C. Palomino, A. Martin, M. Camacho, H. Guerra, J. Swings, F. Portaels, Antimicrob. Agents Chemother., 2002, 46, 2720-2722. The results are presented in Table 1.

(141) TABLE-US-00001 TABLE 1 H37Rv NTB1 Compound Units MIC.sub.99 MIC.sub.99 1 g/mL 0.001 NA 2 g/mL 0.0002 >10 3 g/mL 0.0002 >10 4 g/mL 0.0002 >10 5 g/mL 0.0003 13.8 6 g/mL 0.001 50.5 7 g/mL 0.0008 27.1 PBTZ169 g/mL 0.0003 >100 NAnot available H37RvBTZ-susceptible wild type strain NTB1BTZ-resistant mutant of H37Rv

(142) It can clearly be derived from Table 1 above that the compounds of the present invention are more effective against the BTZ-resistant mutant NBT1 than the prior art compound PBTZ169, and are equally effective against H37Rv.