Derivatives of m-Guaiacol, Their Preparation and Their Uses

Abstract

The invention concerns derivatives of m-guaiacol, their preparation and their uses as biocides, in particular as antibacterials or disinfectants.

Claims

1. A method for biocidal treatment of a substrate comprising a step of contacting said substrate with a compound of following formula (I): ##STR00049## wherein: V represents: a group —OR, wherein R is a linear or branched alkyl in C.sub.1 to C.sub.4, optionally substituted by at least one halogen, R being in particular a methyl or a perhalogenoalkyl in C.sub.1 to C.sub.4; or I; W, X, Y and Z are each independently chosen from H, the halogens and the linear or branched alkyls in C.sub.1 to C.sub.4, optionally substituted by at least one halogen, W, X, Y and Z being in particular each independently H, a methyl, F, Cl, Br, I or a perhalogenoalkyl in C.sub.1 to C.sub.4; at least one of W, X, Y and Z representing a halogen, the following compound being excluded: ##STR00050## as well as its pharmaceutically acceptable salts.

2. The method according to claim 1, wherein V represents I, and in particular: W and/or Y represent H; and/or X and/or Z represent a halogen, in particular F.

3. The method according to claim 1 of a compound of following formula (Ia): ##STR00051## wherein: R is a linear or branched alkyl in C.sub.1 to C.sub.4, optionally substituted by at least one halogen, R being in particular a methyl or a perhalogenoalkyl in C.sub.1 to C.sub.4; W, X, Y and Z are each independently chosen from H, the halogens and the linear or branched alkyls in C.sub.1 to C.sub.4, optionally substituted by at least one halogen, W, X, Y and Z being in particular each independently H, a methyl, F, Cl, Br, I or a perhalogenoalkyl in C.sub.1 to C.sub.4; at least one of W, X, Y and Z representing a halogen, the following compound being excluded: ##STR00052##

4. The method according to claim 1, wherein: two at least of W, X, Y and Z representing a halogen, in particular two at least of X, Y and Z representing a halogen; X is chosen from the halogens, and at least one of Y and of Z is chosen from the halogens; X and Z are each independently chosen from the halogens, Y representing in particular H or a halogen; or X and Y are each independently chosen from the halogens Z representing in particular H or a halogen; X, Y and Z are each independently chosen from the halogens.

5. The method according to claim 1, wherein W is chosen from H and the linear or branched alkyls in C.sub.1 to C.sub.4, optionally substituted by at least one halogen, R being in particular H, a methyl or a perhalogenoalkyl in C.sub.1 to C.sub.4.

6. The method according to claim 1, wherein: W represents H; and X, Y and Z are each independently chosen from the halogens; where X and Z represent Br and Cl, X representing Br and Z representing Cl, or X representing Cl and Z representing Br, Y representing in particular H; or X and Y represents a halogen, Z representing in particular H; provided that: if Z represents F, then at least one of X and of Y is chosen from F, Br and I; and Y is chosen from Cl, Br and I.

7. The method according to claim 1, wherein said compound is chosen from the group formed by compounds of following structure: ##STR00053## ##STR00054## ##STR00055##

8. The method according to claim 1 wherein the biocidal treatment is an antibacterial treatment.

9. The method according to claim 1 wherein the biocidal treatment is a disinfection of the substrate, said substrate being a fluid or a surface.

10. A method of antimicrobial treatment of a human or an animal comprising topical administration to the human or animal in need thereof of an effective amount of a compound of formula (I) or (Ia) such as defined in claim 1.

11. A compound of following formula (II): ##STR00056## wherein: V represents: a group —OR wherein R is a linear or branched alkyl in C.sub.1 to C.sub.4, optionally substituted by at least one halogen, R being in particular a methyl or a perhalogenoalkyl in C.sub.1 to C.sub.4; or I; W, X, Y and Z are each independently chosen from H, the halogens and the linear or branched alkyls in C.sub.1 to C.sub.4, optionally substituted by at least one halogen, W, X, Y and Z being in particular each independently H, a methyl, F, Cl, Br, I or a perhalogenoalkyl in C.sub.1 to C.sub.4; provided that at least two of W, X, Y and Z represent a halogen; as well as its pharmaceutically acceptable salts; said compound not being one of the following formulae: ##STR00057##

12. The compound according to claim 11, of following formula (IIa): ##STR00058## wherein: R is a linear or branched alkyl in C.sub.1 to C.sub.4, optionally substituted by at least one halogen, R being in particular a methyl or a perhalogenoalkyl in C.sub.1 to C.sub.4; W, X, Y and Z are each independently chosen from H, the halogens and the linear or branched alkyls in C.sub.1 to C.sub.4, optionally substituted by at least one halogen, W, X, Y and Z being in particular each independently H, a methyl, F, Cl, Br, I or a perhalogenoalkyl in C.sub.1 to C.sub.4; provided that: X, Y and Z are each independently chosen from the halogens; or at least one of W and of Y, in particular W, does not represent H; said compound not being one of the following formulae: ##STR00059##

13. A pharmaceutical composition comprising as active substance, a compound of formula (II) or (IIa) such as defined in claim 11, and a pharmaceutically acceptable excipient.

Description

EXAMPLES

Example 1: Synthesis of Compounds of the Invention

Synthesis of the Compound SR 7580:

[0125] This compound was obtained by following the operating method such as illustrated in the scheme below:

##STR00029##

[0126] NMR .sup.1H (δ PPM) CDCl.sub.3: 7.10 (d, J=9.8, 1H), 6.60 (d, J=7.8, 1H), 5.52 (s, 1H), 3.82 (s, 3H).

Synthesis of the Compound SR 7581:

[0127] This compound was obtained by following the operating method such as illustrated in the scheme below:

##STR00030##

[0128] NMR .sup.1H (δ PPM) CDCl.sub.3: 7.06 (d, J=10.5 1H), 6.65 (d, J=7.8, 1H), 5.32 (s, 1H), 3.84 (s, 3H).

Synthesis of the Compound SR 7582:

[0129] This compound was obtained by following the operating method such as illustrated in the scheme below:

##STR00031##

[0130] NMR .sup.1H (δ PPM) CDCl.sub.3: 7.50 (s, 1H), 6.54 (s, 1H), 5.44 (s, 1H), 3.78 (s, 3H).

Synthesis of the Compound SR 7583:

[0131] This compound was obtained by following the operating method such as illustrated in the scheme below:

##STR00032##

Synthesis of the Compound SR 7584:

[0132] This compound was obtained by following the operating method such as illustrated in the scheme below:

##STR00033##

[0133] NMR .sup.1H (δ PPM) CDCl.sub.3: 7.90 (s, 1H), 6.53 (s, 1H), 5.27 (s, 1H), 3.83 (s, 3H).

Synthesis of the Compound SR 7585:

[0134] This compound was obtained by following the operating method such as illustrated in the scheme below:

##STR00034##

[0135] NMR .sup.1H (δ PPM) CDCl.sub.3: 6.59 (s, 1H), 5.65 (s, 1H), 3.86 (s, 3H).

Synthesis of the Compound SR 7586:

[0136] This compound was obtained by following the operating method such as illustrated in the scheme below:

##STR00035##

[0137] NMR .sup.1H (δ PPM) CDCl.sub.3: 7.32 (s, 1H), 5.85 (s, 1H), 3.83 (s, 3H).

Synthesis of the Compound SR 7587:

[0138] This compound was obtained by following the operating method such as illustrated in the scheme below:

##STR00036##

[0139] To a solution of 0.5 g of 3-fluoro-5-methoxyphenol in 10 ml of TFA, 1.46 g of NCS (3.1 eq.) is added. The reaction mixture is stirred for 48 hours at 25° C. Then, water and ice are added. A precipitation is formed, and it is filtered on a frit and then rinsed with water. We extract using AcOEt. Silica gel is purified by chromatography on a column (eluant: CH.sub.2Cl.sub.2). 0.52 g is obtained, yield=60%. FP=104° C. (white solid).

[0140] NMR .sup.13C (δ ppm) CDCl.sub.3: 155.0 and 152.5 (C—F), 152.5 (d, C—O), 147.9 (d, C—O), 111.95 (d, C—Cl), 109.6 (d, C—Cl), 106.1 (d, C—Cl).

Synthesis of the Compound SR 7607:

[0141] This compound was obtained by following the operating method such as illustrated in the scheme below:

##STR00037##

[0142] To a solution of 5.2 g of 2-methyl-3-methoxyphenol in 20 ml of TFA, 11.6 g of NCS (2.2 eq.) are added. The reaction mixture is stirred for 16 hours at A.T. 1N NaOH is added, washed by CH.sub.2Cl.sub.2. The aqueous phase is acidified by 3N HCl and extracted using CH.sub.2Cl.sub.2. 5.5 g of product is obtained. Yield=71%. FP=55° C. (white solid).

[0143] NMR .sup.1H (δ ppm) CDCl.sub.3: 7.19 (s, 1H, H.sub.3), 5.54 (s, 1H, OH), 3.77 (s, 3H, OCH.sub.3), 2.15 (s, 3H, CH.sub.3).

Synthesis of the Compound SR 7608:

[0144] This compound was obtained by following the operating method such as illustrated in the scheme below:

##STR00038##

Synthesis of the Compound SR 7609:

[0145] This compound was obtained by following the operating method such as illustrated in the scheme below:

##STR00039##

[0146] NMR .sup.1H (δ PPM) CDCl.sub.3: 6.79 (d, J=2.8, 1H), 6.56 (d, J=2.8, 1H), 5.63 (s, 1H), 3.77 (s, 3H).

Synthesis of the Compound SR 7610:

[0147] This compound was obtained by following the operating method such as illustrated in the scheme below:

##STR00040##

[0148] To a solution of 3.4 g of 3,4-difluoro-5-methoxyphenol in 20 ml of TFA, 2.98 g of NCS (1.05 eq.) are added in small quantities (the flask is immersed in an ice bath during the addition). It is left to rise to room temperature and the reaction mixture is stirred for 16 hours. Then, water and ice are added. A precipitation is formed, and it is filtered on a frit and then rinsed with water. The residue is returned into CH.sub.2Cl.sub.2 and washed with water. The organic phase is dried on MgSO.sub.4, filtered and evaporated. Purification is carried out by chromatography on a silica gel column, with as eluent: CH.sub.2Cl.sub.2/AcOEt/cyclohexane=3/1/1. 1.7 g of product is obtained.

[0149] Yield=41%. FP=87.6° C. (white solid).

[0150] NMR .sup.1H (δ ppm) CDCl.sub.3 6.48 (dd, 1H), 5.40 (s, 1H, OH), 3.87 (s, 3H).

Synthesis of the Compound SR 7611:

[0151] This compound was obtained by following the operating method such as illustrated in the scheme below:

##STR00041##

[0152] To a solution of 0.23 g of 3,4-difluoro-5-methoxyphenol in 4 ml of TFA, 0.27 g of NBS (1.05 eq.) is added in small quantities (the flask is immersed in an ice bath during the addition). It is left to rise to room temperature and the reaction mixture is stirred for 16 hours. Then, water and ice are added. A precipitation forms itself and it is filtered on a frit then rinsed with water. The residue is taken up in CH.sub.2Cl.sub.2 and washed with water. The organic phase is dried on MgSO.sub.4, filtered and evaporated. Purification is carried out by chromatography on a silica gel column, with, as eluent: CH.sub.2Cl.sub.2. 0.2 g of product is obtained. Yield=58%. FP=67.5° C. (white solid).

[0153] NMR .sup.1H (δ ppm) CDCl.sub.3 6.50 (dd, 1H), 5.48 (s, 1H, OH), 3.87 (s, 3H).

Synthesis of the Compound SR 7612:

[0154] This compound was obtained by following the operating method such as illustrated in the scheme below:

##STR00042##

[0155] To a solution of 0.28 g of 3,4-difluoro-5-methoxyphenol in 5 ml of TFA, 0.41 g of NIS (1.05 eq.) is added in small quantities (the flask is immersed in an ice bath during the addition). It is left to rise to room temperature and the reaction mixture is stirred for 16 hours. Then, water and ice are added. A precipitation forms itself and it is filtered on a frit then rinsed with water. The residue is returned into CH.sub.2Cl.sub.2 and washed with water. The organic phase is dried on MgSO.sub.4, filtered and evaporated. Purification is carried out by chromatography on a silica gel column, with, as eluent: CH.sub.2Cl.sub.2. 0.16 g of product is obtained. Yield=32%. FP=91.1° C. (brown solid).

[0156] NMR .sup.1H (δ ppm) CDCl.sub.3 6.52 (dd, 1H), 5.36 (s, 1H, OH), 3.87 (s, 3H).

Synthesis of the Compound SR 7613:

[0157] This compound was obtained by following the operating method such as illustrated in the scheme below:

##STR00043##

[0158] To a solution of 4.18 g of 4-fluoro-5-methoxyphenol in 100 ml of 1,2-dichloroethane, 4.1 g of NCS (1.05 eq.) is added. The reaction mixture is refluxed for 4, 5 days (progression of the reaction controlled by LCMS). It is extracted using CH.sub.2Cl.sub.2. Purification is carried out by chromatography on a silica gel column (cyclohexane/AcOEt=1/1). Yield=87%.

[0159] NMR .sup.1H (δ ppm) CDCl.sub.3: 7.06 (d, 1H, J=10.5 Hz, H.sub.6), 6.65 (d, 1H, J=7.8 Hz, H.sub.6), 5.32 (s, 1H, OH), 3.84 (s, 3H, OCH.sub.3).

[0160] To a solution of 4.7 g of 2-chloro-4-fluoro-5-methoxyphenol in 100 ml of THF at 0° C., 2.1 g of NaH (2 eq.) are added in small quantities. It is left to rise to room temperature and the reaction mixture is stirred for 6 hours. Then, 7.4 ml of ClSiiPr.sub.3 (1.3 eq.) is added at 0° C. After 16 hours of stirring, it is hydrolysed by water. It is extracted thanks to AcOEt and purified by chromatography on a silica gel column (cyclohexane/CH.sub.2Cl.sub.2=1/1). Yield=64%.

[0161] NMR .sup.1H (δ ppm) CDCl.sub.3: 7.09 (d, J=10.8 Hz, 1H, H.sub.6), 6.55 (d, J=8 Hz, 1H, H.sub.3), 3.82 (s, 3H, OCH.sub.3), 1.2 (m, 3H, 3H.sub.iPr), 1.13 (d, 18H, 6CH.sub.3).

[0162] 0.45 g of (2-chloro-4-fluoro-5-methoxyphenoxy)triisopropylsilane and 70 ml of THF are introduced into a three-necked flask under mechanical stirring and under nitrogen atmosphere at −70° C., 1.4 ml of nBuLi (2.5M 2.5 eq.) are added with caution. The solution is left to stir for 1 hour then 0.8 g of C.sub.2Cl.sub.6 (2.5 eq.) is added into the solution in the THF at −70° C.

[0163] After 1 hour of stirring, the reaction mixture is gently raised to room temperature. It is extracted using AcOEt and the residue obtained is purified by chromatography on a silica gel column (cyclohexane then cyclohexane/CH.sub.2Cl.sub.2=1/1). 0.3 g of product is obtained, Yield=60%.

[0164] NMR .sup.1H (δ ppm) CDCl.sub.3: 6.50 (d, J=7.6 Hz, 1H, H.sub.6), 3.83 (s, 3H, OCH.sub.3), 1.30 (m, 3H, 3H.sub.iPr), 1.12 (d, 18H, 6CH.sub.3).

[0165] To a solution of 10 g of 2,3-dichloro-4-fluoro-5-methoxyphenoxy)triisopropylsilane in 100 ml of THF, 35.4 ml of TBAF (1M, 1.3 eq.) are added. The reaction mixture is stirred for 72 hours at room temperature. It is extracted using AcOEt and purified by chromatography on a silica gel column (CH.sub.2Cl.sub.2). 5.2 g of product are obtained, Yield=91%. FP=100.1° C. (beige solid).

[0166] NMR .sup.1H (δ ppm) CDCl.sub.3: 6.61 (d, J=7.2 Hz, 1H, H.sub.6), 5.51 (s, 1H, OH), 3.86 (s, 3H, OCH.sub.3).

Synthesis of the Compound SR 7614:

[0167] This compound was obtained by following the operating method such as illustrated in the scheme below:

##STR00044##

[0168] To a solution of 4.18 g of 4-fluoro-5-methoxyphenol in 100 ml of 1,2-dichloroethane, 4.1 g of NCS (1.05 eq.) are added. The reaction mixture is refluxed for 4.5 days (progression of the reaction controlled by LCMS). It is extracted using CH.sub.2Cl.sub.2. Purification is carried out by chromatography on a silica gel column (cyclohexane/AcOEt=1/1). Yield=87%.

[0169] NMR .sup.1H (δ ppm) CDCl.sub.3: 7.06 (d, 1H, J=10.5 Hz, H.sub.6), 6.65 (d, 1H, J=7.8 Hz, H.sub.6), 5.32 (s, 1H, OH), 3.84 (s, 3H, OCH.sub.3).

[0170] To a solution of 4.7 g of 2-chloro-4-fluoro-5-methoxyphenol in 100 ml of THF at 0° C., 2.1 g of NaH (2 eq.) are added in small quantities. It is left to rise to room temperature and the reaction mixture is stirred for 6 hours. Then, 7.4 ml of ClSiiPr.sub.3 (1.3 eq.) are added at 0° C. After 16 hours of stirring, it is hydrolysed by water. It is extracted using AcOEt and purified by chromatography on a silica column (cyclohexane/CH.sub.2Cl.sub.2=1/1). Yield=64%.

[0171] NMR .sup.1H (δ ppm) CDCl.sub.3: 7.09 (d, J=10.8 Hz, 1H, H.sub.6), 6.55 (d, J=8 Hz, 1H, H.sub.3), 3.82 (s, 3H, OCH.sub.3), 1.2 (m, 3H, 3H.sub.iPr), 1.13 (d, 18H, 6CH.sub.3).

[0172] 0.59 g of (2-chloro-4-fluoro-5-methoxyphenoxy)triisopropylsilane and 70 ml of THF are introduced in a three-necked flask under mechanical stirring and nitrogen atmosphere at −70° C., 1.8 ml of nBuLi (2.5M 2.5 eq.) are added with caution. The solution is left under stirring for 1 hour then 1.5 g of CBr.sub.4 (2.5 eq.) are added into solution in the THF at −78° C. After 30 minutes of stirring, the reaction mixture is gently raised to room temperature. It is extracted using AcOEt and purified by chromatography on a silica gel column (cyclohexane then cyclohexane/CH.sub.2Cl.sub.2=1/1). Yield=55%.

[0173] NMR .sup.1H (δ ppm) CDCl.sub.3: 6.56 (d, J=8 Hz, 1H, H.sub.6), 3.83 (s, 3H, OCH.sub.3), 1.28 (m, 3H, 3H.sub.iPr), 1.13 (d, 18H, 6CH.sub.3).

[0174] To a solution of 0.4 g of 3-bromo-2-chloro-4-fluoro-5-methoxyphenoxy)triisopropylsilane in 50 ml of THF, 1.3 ml of TBAF (1M, 1.3 eq.) are added. The reaction mixture is stirred for 16 hours at room temperature. It is extracted using AcOEt and purified by chromatography on a silica gel column (CH.sub.2Cl.sub.2). Yield=81%. FP=110° C. (beige solid).

[0175] NMR .sup.1H (δ ppm) CDCl.sub.3: 6.68 (dd, J=7.6 Hz, J=1.2 Hz, H.sub.6), 5.47 (s, 1H, OH), 3.87 (s, 3H, OCH.sub.3).

Synthesis of the Compound SR 7615:

[0176] This compound was obtained by following the operating method such as illustrated in the scheme below:

##STR00045##

[0177] To a solution of 9.14 g of 4-fluoro-5-methoxyphenol in 150 ml of CH.sub.3CN, 12.02 g of NBS (1.05 eq.) are added. The reaction mixture is refluxed for 16 hours. It is extracted using AcOEt and the obtained residue is purified by chromatography on a silica gel column in (CH.sub.2Cl.sub.2). Yield=90%.

[0178] NMR .sup.1H (δ ppm) CDCl.sub.3: 7.19 (d, J=10 Hz, 1H, H.sub.3), 6.68 (d, J=7.6 Hz, 1H, H.sub.6), 5.31 (s, 1H, OH), 3.85 (s, 3H, OCH.sub.3).

[0179] To a solution of 3.07 g of 2-bromo-4-fluoro-5-methoxyphenol in 100 ml of THF at 0° C., 1.1 g of NaH (2 eq.) are added in small quantities. It is left to rise to room temperature and the reaction mixture is stirred for 3 hours. Then, 3.6 ml of ClSiiPr.sub.3 (1.2 eq.) are added at 0° C. After 24 hours of stirring, it is hydrolysed by water. It is extracted with AcOEt and purified by chromatography on a silica column (cyclohexane/CH.sub.2Cl.sub.2=1/1). Yield=67%.

[0180] NMR .sup.1H (δ ppm) CDCl.sub.3: 7.23 (d, J=10.4 Hz, 1H, H.sub.3), 6.55 (d, J=8 Hz, 1H, H.sub.6), 3.82 (s, 1H, OCH.sub.3), 1.31 (m, 3H, 3H.sub.iPr), 1.14 (d, 18H, 6CH.sub.3).

[0181] 4.1 ml of HNiPr.sub.2 (2.5 eq.) and 180 ml of THF are introduced in a three-necked flask under mechanical stirring and under nitrogen atmosphere, between −10° C. to 0° C., 11.7 ml of nBuLi (2.5M 2.5 eq.) are added with caution. The solution is left under stirring for 30 minutes, then 4.4 g of (2-bromo-4-fluoro-5-methoxy-phenoxy)-triisopropylsilane in solution in the THF are added at −70° C. After 1 hours of stirring, 6.9 g of C.sub.2Cl.sub.6 (2.5 eq.) are added in solution in the THF. The reaction mixture is stirred for 1 hour, then gently raised to room temperature and left under stirring for 1 hour. It is extracted using AcOEt and purified by chromatography on a silica column (cyclohexane/CH.sub.2Cl.sub.2=1/1). Yield=94%.

[0182] NMR .sup.1H (δ ppm) CDCl.sub.3: 6.51 (d, J=7.4 Hz, H.sub.6), 3.83 (s, 3H, OCH.sub.3), 1.31 (m, 3H, 3H.sub.iPr), 1.14 (d, 18H, 6CH.sub.3).

[0183] To a solution of 1 g of 2-bromo-3-chloro-4-fluoro-5-methoxyphenoxy)triisopropylsilane in 100 ml of THF, 3.2 ml of TBAF (1M, 1.3 eq.) are added. The reaction mixture is stirred for 16 hours at room temperature. It is extracted using AcOEt and purified by chromatography on a silica gel column (cyclohexane/CH.sub.2Cl.sub.2=1/1).

[0184] Yield=80%. FP=104° C. (brown solid).

[0185] NMR .sup.1H (δ ppm) CDCl.sub.3: 6.65 (d, J=7.2 Hz, H.sub.6), 5.45 (s, 1H, OH), 3.87 (s, 3H, OCH.sub.3).

Synthesis of the Compound SR 7616:

[0186] This compound was obtained by following the operating method such as illustrated in the scheme below:

##STR00046##

[0187] To a solution of 0.4 g of 3-bromo-5-methoxyphenol in 5 ml of TFA, 0.54 g of NCS (2.05 eq.) is added in small quantities (the flask is immersed in an ice bath during the addition). It is left to rise to room temperature and the reaction mixture is stirred for 16 hours. Then, 50 ml of water and ice are added. A precipitation is formed, and it is filtered on a frit then rinsed with water. The residue is taken-up in CH.sub.2Cl.sub.2 and washed with water. The organic phase is dried on MgSO.sub.4, filtered and evaporated. Purification is carried out by chromatography on a silica gel column with eluant CH.sub.2Cl.sub.2. 0.4 g (Yield=75%) of expected product is obtained.

[0188] FP=136° C. (white solid)

[0189] NMR .sup.1H (δ ppm) CDCl.sub.3: 6.66 (s, 1H, H.sub.6), 5.66 (s, 1H, OH), 3.88 (s, 3H, OCH.sub.3).

Synthesis of the Compound SR 7617:

[0190] This compound was obtained by following the operating method such as illustrated in the scheme below:

##STR00047##

[0191] To a solution of 5.8 g of 4-chloro-3-methoxyphenol in 50 ml of CH.sub.3CN, 7.8 g of NBS (1.2 eq.) are added. The reaction mixture is brought to reflux for 16 hours, 0.8 g of NBS are added, and the mixture is brought to reflux for 4 hours. It is extracted by AcOEt and purified by chromatography on a silica gel column (cyclohexane/AcOEt=2/1). 4 g of 2-bromo-4-chloro-5-methoxyphenol (Yield=46%) and 3.5 g of 2,6-dibromo-4-chloro-5-methoxyphenol (Yield=30%-sr7617) are obtained.

[0192] 2-bromo-4-chloro-5-methoxyphenol: NMR .sup.1H (δ ppm) CDCl.sub.3: 7.43 (s, 1H, H.sub.3), 6.64 (s, 1H, H.sub.6), 5.54 (s, 1H, OH), 3.89 (s, 3H, OCH.sub.3).

[0193] SR 7617: FP=96.6° C. (white solid). NMR .sup.1H (δ ppm) CDCl.sub.3: 7.52 (s, 1H, H.sub.3), 5.89 (s, 1H, OH), 3.89 (s, 3H, OCH.sub.3).

Synthesis of the Compound SR 7618:

[0194] This compound was obtained by following the operating method such as illustrated in the scheme below:

##STR00048##

[0195] NMR .sup.1H (δ PPM) CDCl.sub.3: 7.27 (dd, J=6.1, J=9.3 1H), 6.87 (dd, J=7.1, J=10.2, 1H), 5.12 (s, 1H).

Biological Evaluations

[0196] Each test was controlled with three controls (T): [0197] 1 T culture positive (single strain) [0198] 1 T culture negative (strain in the presence of triclosan) [0199] 1 T DMSO (strain in the presence of DMSO)

[0200] The bacterial growth is evaluated by measuring the optical density (DO) at 600 nm using NanoDrop.

[0201] To compare the effect of the molecule tested with that of triclosan, the following ratio is calculated: [DO(single strain)−DO(strain+triclosan)]/[DO(single strain)−DO(strain+molecule)].

[0202] This ratio permits a classification of the molecules in 4 effect levels: [0203] 0=no effect observed; [0204] 1=effect observed only when the molecule is tested pure; [0205] 2=effect observed at several concentrations, but which gradually decreases the dilutions; [0206] 3=strong effect observed at each concentration of molecule tested.

Example 2: Evaluation of Compounds of the Invention on a Micrococcus luteus Reference Strain

[0207] The molecules are put in a solution in DMSO and diluted in PBS.

[0208] The results are outlined in the table below:

TABLE-US-00001 Tested molecules Effect level sr7583 3 sr7584 2 sr7585 3 sr7607 2 sr7608 2 sr7609 3 sr7610 2 sr7611 2 sr7612 2 sr7614 3 sr7615 3 sr7616 3 sr7618 2

Example 3: Evaluation of Compounds of the Invention on the Wild-Type Phenotype of Reference Strains Gram+ et Gram−

[0209] A screening of molecules of the invention on several wild-type phenotype strains has been carried out.

[0210] The strains initially selected are: [0211] Gram+: Streptococcus equi subsp zooepidemicus and Staphylococcus aureus [0212] Gram−: Escherichia coli, Klebsiella pneumoniae and Stenotrophomonas maltophila.

[0213] The results are outlined in the table below:

TABLE-US-00002 Molecules S. zooepidemicus S. aureus E. coli K. pneumoniae S. maltophila sr7583 2 2 sr7585 3 3 3 2 2 sr7609 2 2 2 2 sr7614 2 2 3 2 2 sr7615 3 3 3 2 2 sr7616 3 2 3 3 2

Example 4: Evaluation of Compounds of the Invention on Strains Presenting High Levels of Resistance

[0214] Compounds of the invention were tested on 4 strains of E. coli, 3 strains of K. pneumoniae and 4 strains of S. aureus with the resistance profiles below.

TABLE-US-00003 ATB Gram− AMX AMC CEF CEQ COL STP K GM AN TET RA SUL FLU ENO MAR Escherichia Strain 1 R R R R S R R R S R R R R R R coli Strain 2 R R R R S R R R S R R R R R R Strain 3 R R R R S R R R S R R R R R R Strain 4 R R R R S R R R S R R R R R R ATB Gram− AMC CEF CEQ COL STP K GM AN TET SUL FLU ENO MAR Klebsiella Strain 1 S R R S R R R S R R S S S pneumoniae Strain 2 S S S S R S S S R R R R S Strain 3 R R R S R S S S R S S S S ATB Gram+ PEN AMX AMC CEF CEQ STP K GM TET E RA SUL ENO MAR Staphylococcus Strain 1 R R R R R S R R R R S S R R aureus Strain 2 R R R R R S R R R R S S R R Strain 3 R R R R R S R R R S S S R R Strain 4 R R R R R S R R R R S S R R PEN: penicillin; AMX: amoxicillin; AMC: amoxicillin-clavulanic acid; CEF: ceftiofur; CEQ: cefquinome; COL: Colistin, STP: streptomycin; K: kanamycin; GM: gentamycin; AN: Amikacin; TET: tetracycline; E: erythromycin; RA: rifampicin; SUL: sulfamide; ENO: enrofloxacin; MAR: marbofloxacin; FLU: flumequine.

[0215] The molecules were tested at concentrations (mg/ml) of 1; 0.5 and 0.1 compared with the triclosan used at 0.1 mg/ml.

[0216] The results obtained on the strains of E. coli are the following:

TABLE-US-00004 Concentration Effects E. coli Molecules (mg/ml) Δ DO (0 < 1 < 2 < 3) Strain 1 Triclosan 0.1 1.005 3 sr7585 1 0.920 3 0.5 0.746 0.1 0.196 sr7615 1 0.896 2 0.5 0.777 0.1 0.047 sr7616 1 0.857 2 0.5 0.640 0.1 0.089 Strain 2 Triclosan 0.1 1.197 3 sr7585 1 1.097 3 0.5 0.964 0.1 0.313 sr7615 1 1.082 2 0.5 0.886 0.1 0.080 sr7616 1 1.069 3 0.5 0.854 0.1 0.331 Strain 3 Triclosan 0.1 0.948 3 sr7585 1 0.893 3 0.5 0.736 0.1 0.186 sr7615 1 0.882 2 0.5 0.526 0.1 0.029 sr7616 1 0.825 3 0.5 0.679 0.1 0.141 Strain 4 Triclosan 0.1 1.080 3 sr7585 1 0.979 3 0.5 0.848 0.1 0.322 sr7615 1 0.945 3 0.5 0.809 0.1 0.253 sr7616 1 0.853 3 0.5 0.868 0.1 0.308

[0217] The results obtained on the strains of K. pneumoniae are the following:

TABLE-US-00005 Concentration Effects K. pneumoniae Molecules (mg/ml) Δ DO (0 < 1 < 2 < 3) Strain 1 Triclosan 0.1 0.824 3 sr7585 1 0.644 3 0.5 0.595 0.1 0.251 sr7615 1 0.640 2 0.5 0.490 0.1 0.025 sr7616 1 0.646 3 0.5 0.594 0.1 0.236 Strain 2 Triclosan 0.1 0.893 3 sr7585 1 0.701 2 0.5 0.620 0.1 0.035 sr7615 1 0.621 2 0.5 0.518 0.1 −0.021 sr7616 1 0.686 2 0.5 0.641 0.1 0.151 Strain 3 Triclosan 0.1 1.092 3 sr7585 1 0.872 2 0.5 0.683 0.1 0.265 sr7615 1 0.913 2 0.5 0.598 0.1 0.134 sr7616 1 0.847 2 0.5 0.652 0.1 0.213

[0218] The results obtained on the strains of S. aureus are the following:

TABLE-US-00006 Concentration Effects S. aureus Molecules (mg/ml) Δ DO (0 < 1 < 2 < 3) Strain 1 Triclosan 0.1 0.441 3 sr7585 1 0.445 3 0.5 0.445 0.1 0.352 sr7615 1 0.428 3 0.5 0.434 0.1 0.250 sr7616 1 0.445 3 0.5 0.443 0.1 0.276 Strain 2 Triclosan 0.1 0.459 3 sr7585 1 0.457 3 0.5 0.458 0.1 0.385 sr7615 1 0.382 3 0.5 0.412 0.1 0.308 sr7616 1 0.459 3 0.5 0.458 0.1 0.303 Strain 3 Triclosan 0.1 0.532 3 sr7585 1 0.530 3 0.5 0.529 0.1 0.459 sr7615 1 0.445 0.5 0.482 3 0.1 0.310 sr7616 1 0.525 3 0.5 0.529 0.1 0.299 Strain 4 Triclosan 0.1 0.490 3 sr7585 1 0.486 3 0.5 0.491 0.1 0.405 sr7615 1 0.418 3 0.5 0.450 0.1 0.351 sr7616 1 0.491 3 0.5 0.491 0.1 0.291

[0219] In conclusion, compounds of the invention have revealed to have MICs (Minimal Inhibitory Concentrations) of the same magnitude as triclosan on multi-resistant strains.

Example 4: In Vitro Cytotoxicity Tests

Cell Culture and Cell Proliferation Tests

[0220] The human cell strain KB (epidermoid carcinoma) was obtained from the NCI (National Cancer Institute) and cultivated in the D-MEM medium added with 10% of foetal bovine serum (Invitrogen) in the presence of penicillin, streptomycin and fungizone in flasks of 75 cm.sup.3 under CO.sub.2 at 5%. The cells were deposited on tissue culture microplates with 96 wells and a density of 650 cells/well in 200 μl of medium and treated 24 hours later with compounds of the invention dissolved in DMSO at concentrations going from 0.5 nM to 10 μM using a Biomek 3000 (Beckman-Coulter) automaton. The controls received the same volume of DMSO (1% of final volume). After 72 hours of exposure, the MTS reagent (Celltiter 96Aqueous One solution, Promega) was added and incubated for 3 hours at 37° C.: the absorbance was measured at 490 nm and the results of inhibition of the cell proliferation were calculated according to the ratio [(1−(OD490treated/OD490control))×100].

Results: Cytotoxicity at 10.sup.−5 and 10.sup.−6M on Triplicate KB Cells, Measured after 72 Hours of Exposure.

[0221] The percentage of inhibition of cell growth with respect to the cells receiving the same quantity of DMSO is outlined in the table below.

TABLE-US-00007 10.sup.−5 M 10.sup.−6 M Triclosan 78 ± 3   5 ± 12 sr7580 16 ± 4  5 ± 8 sr7581 0 ± 6 0 ± 6 sr7582 1 ± 7 0 ± 9 sr7583 0 ± 7 0 ± 8 sr7584 0 ± 6 0 ± 9 sr7585 0 ± 5 0 ± 6 sr7586 0 ± 2 6 ± 8 sr7587 0 ± 4 8 ± 4 sr7607 0 ± 2 0 ± 5 sr7608  7 ± 11  0 ± 14 sr7614 6 ± 4 0 ± 3 sr7615 0 ± 3 0 ± 4 sr7616 0 ± 9 0 ± 8

[0222] This study has made it possible to highlight an absence of marked cytotoxicity of molecules of the invention, in the concentration range corresponding to their use.

Example 5: Affinity Tests for Androgenic Receptors

[0223] The affinity of Triclosan (reference compound) and of the compound sr7615 of the present invention for androgenic receptors was measured by the percentage of inhibition of the bonding of a radioactive marked ligand (testosterone) specific to the androgenic receptors.

Results

[0224] In the context of this example, results showing an inhibition greater than 50% are considered as representing significant effects of a compound.

[0225] The results obtained are presented in the table below.

TABLE-US-00008 Concentration % of inhibition (average of Compound tested the two measurements) Triclosan 10.sup.−5 M 79.8 Sr7615 10.sup.−5 M 3.1

[0226] Also, Triclosan bonds itself significantly to the androgenic receptors (endocrine disruptor), contrary to the compound of the present invention.