NOVEL PHENOL DERIVATIVES AND PHARMACEUTICAL OR COSMETIC USE THEREOF

Abstract

The present invention relates to novel compounds of general formula:

##STR00001##

and to the cosmetic or pharmaceutical use thereof.

Claims

1. A compound of formula (I): ##STR00007## in which: R.sub.1 represents a C.sub.2-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.1-6 alkyloxy, S(O).sub.mC.sub.1-6 alkyl, C.sub.1-6 fluoroalkyl, C.sub.1-6 fluoroalkyloxy, (CH.sub.2).sub.nC.sub.3-9 cycloalkyl, (CH.sub.2).sub.nC.sub.3-9 cycloalkyl, C.sub.2-6 -.sub.6 alkyl-OH, (CH.sub.2).sub.nC.sub.1-6 alkyloxy, (CH.sub.2).sub.nC.sub.1-6 fluoroalkyl, (CH.sub.2).sub.pOC.sub.1-6 fluoroalkyl, COR.sub.a, CN, NO.sub.2 or NR.sub.8R.sub.9 group, a halogen or a phenyl or heteroaryl group comprising either a) from 1 to 4 nitrogen atoms or b) an oxygen or sulphur atom and 1 or 2 nitrogen atom(s); [[these]] wherein the phenyl and heteroaryl groups can optionally be substituted with one to three identical or different R.sub.b groups, R.sub.2 and R.sub.3 are identical or different and represent a hydrogen atom or a C.sub.1-9 alkyl, C.sub.3-9 cycloalkyl, C.sub.1-6 fluoroalkyl, (CH.sub.2).sub.rC.sub.3-9 cycloalkyl, C.sub.2-6 alkyl-OH, (CH.sub.2).sub.rC.sub.1-6 alkyloxy, (CH.sub.2).sub.rC.sub.3-7 cycloalkyl, (CH.sub.2).sub.rC.sub.1-6 fluoroalkyl, or (CH.sub.2).sub.qOC.sub.1-6 fluoroalkyl group, optionally, the R.sub.2 and R.sub.3 groups can form, with the carbon atom which bears them, a C.sub.3-9 cycloalkyl group or a heterocycle, R.sub.4, R.sub.5, R.sub.6, R.sub.7 are identical or different and represent either a hydrogen atom or a C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.1-6 alkyloxy, S(O).sub.sC.sub.1-6 alkyl, C.sub.1-6 fluoroalkyl, C.sub.1-6 fluoroalkyloxy, (CH.sub.2).sub.tC.sub.3-9 cycloalkyl, (CH.sub.2).sub.tC.sub.3-9 cycloalkyl, C.sub.1-6 alkyl-OH, (CH.sub.2).sub.tC.sub.1-6 alkyloxy, (CH.sub.2).sub.tC.sub.1-6 fluoroalkyl, (CH.sub.2)OC.sub.1-6 fluoroalkyl, COR.sub.d, CN or NR.sub.8R.sub.9group, or a halogen or a phenyl or heteroaryl group comprising either a) from 1 to 4 nitrogen atoms or b) an oxygen or sulphur atom and 1 or 2 nitrogen atom(s); these phenyl and heteroaryl groups can optionally be substituted with one to three identical or different R.sub.c groups, X represents CH or N; Y represents either a nitrogen atom, or a carbon atom substituted with a C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.1-6 alkyloxy, S(O).sub.vC.sub.1-6 alkyl, C.sub.1-6 fluoroalkyl, C.sub.1-6 fluoroalkyloxy, (CH.sub.2).sub.lC.sub.3-9 cycloalkyl, (CH.sub.2).sub.lC.sub.3-9 cycloalkyl, C.sub.1-6 alkyl-OH, (CH.sub.2).sub.lC.sub.1-6 alkyloxy, (CH.sub.2).sub.lC.sub.1-6 fluoroalkyl, (CH.sub.2).sub.wOC.sub.1-6 fluoroalkyl, COR.sub.e, CN, NR.sub.10R.sub.11 or NO.sub.2 group, a hydrogen atom or a halogen or a phenyl or heteroaryl group comprising either a) from 1 to 4 nitrogen atoms or b) an oxygen or sulphur atom and 1 or 2 nitrogen atom(s); these phenyl and heteroaryl groups can optionally be substituted with one to three identical or different R.sub.b groups, R.sub.a, R.sub.d and R.sub.e are identical or different and represent a C.sub.1-6 alkyl, C.sub.1-6 alkyloxy or NR.sub.12R.sub.13 group; R.sub.b and R.sub.c are identical or different and represent a halogen, or a C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.1-6 alkyloxy, S(O).sub.jC.sub.1-6 alkyl, C.sub.1-6 fluoroalkyl, C.sub.1-6 fluoroalkyloxy, (CH.sub.2).sub.iC.sub.3-7 cycloalkyl, OH, (CH.sub.2).sub.iC.sub.3-7 cycloalkyl, C.sub.1-6 alkyl-OH, (CH.sub.2).sub.iC.sub.1-6 alkyloxy, (CH.sub.2).sub.iC.sub.1-6 fluoroalkyl, (CH.sub.2).sub.zOC.sub.1-6 fluoroalkyl, COR.sub.a, CN or NR.sub.14R.sub.15 group; R.sub.8 and R.sub.8, are identical or different and represent a C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, (CH.sub.2).sub.fC.sub.3-7 cycloalkyl or (CH.sub.2).sub.fC.sub.1-6fluoroalkyl group; R.sub.9, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14and R.sub.15are identical or different and represent a hydrogen atom or a C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, (CH.sub.2).sub.gC.sub.3-7 cycloalkyl or (CH.sub.2).sub.gC.sub.1-6 fluoroalkyl group; optionally, the R.sub.8 and R.sub.9 groups can form, with the nitrogen atom which bears them, a heterocycle; optionally, the R.sub.8, and R.sub.9, groups can form, with the nitrogen atom which bears them, a heterocycle; optionally, the R.sub.10 and R.sub.11 groups can form, with the nitrogen atom which bears them, a heterocycle; optionally, the R.sub.12 and R.sub.13 groups can form, with the nitrogen atom which bears them, a heterocycle; optionally, the R.sub.14 and R.sub.15 groups can form, with the nitrogen atom which bears them, a heterocycle; f, g, i, l, n, r and t are different or identical and are equal to 1, 2 or 3; j, m, s and v are different or identical and are equal to 0, 1 or 2; p, q, u, w and z are different or identical and are equal to 2, 3 or 4; and also a pharmaceutically acceptable salt, solvate, hydrate conformer or rotamer thereof.

2.-9. (canceled)

Description

EXAMPLE 1

2-[(6-Methoxypyridin-2-ylamino)methyl]phenol

[0097] Synthesis According to Scheme 1, Method 1a

[0098] 512 mg (2.41 mmol, 1.5 eq) of sodium triacetoxyborohydride are added to a solution of 200 mg (1.61 mmol, 1 eq) of 6-methoxypyridin-2-ylamine (starting material 1) and 236 mg (2.41 mmol, 1 eq) of 2-hydroxybenzaldehyde (starting material 2) in 20 ml of tetrahydrofuran. The solution is stirred at room temperature for 48 h. It is evaporated and the residue is taken up in 100 ml of dichloromethane and then extracted with a saturated aqueous solution of ammonium chloride. The aqueous phase is extracted twice with dichloromethane. The organic phases are combined and dried over sodium sulphate. The residue is chromatographed on silica gel (5/95 ethyl acetate/heptane). 2-[(6-methoxypyridin-2-ylamino)methyl]phenol is obtained in the form of a white solid. Melting point=103 C.

[0099] .sup.1H NMR (CDCl.sub.3): 3.94 (s, 3H); 4.52 (d, 2H, J=3.08 Hz); 4.95 (s, 1H), 6.03 (dd, 2H, J=6.2 Hz, J=1.64 Hz); 6.85 (t, 1H, J=6.28 Hz, J=7.4 Hz); 6.95 (d, 1H, J=9.04 Hz); 7.15-7.23 (m, 2H); 7.36 (t, 1H, J=7.92 Hz, J=7.96 Hz); 10.21 (s, 1H)

Preparation of the 6-aminopyridine-2-carbonitrile Intermediate

[0100] 340 mg (2.89 mmol, 1 eq) of zinc cyanide are added to 500 mg (2.89 mmol, 1 eq) of 6-bromopyridin-2-ylamine in 10 ml of dimethylformamide in a microwave tube. 170 mg (0.147 mmol, 0.05 eq) of tetrakis(triphenylphosphine)palladium are added. The medium is heated at 170 C. for 1 hour 30 minutes in a microwave oven. 50 ml of ethyl acetate are added to the medium, which is filtered over celite. The filtrate is washed with water and extracted with ethyl acetate. The organic phases are combined and dried over sodium sulphate. The residue is triturated in heptane. 6-Aminopyridine-2-carbonitrile is obtained in the form of an orange solid.

[0101] Melting point=92 C.

Preparation of the 6-ethoxypyridin-2-ylamine Intermediate

[0102] Introduced into a microwave tube are 500 mg (2.89 mmol) of 2-amino-6-bromopyridine, to which 2 ml of ethanol and 231 mg (5.78 mmol, 2 eq) of sodium hydroxide are added. The mixture is heated for 10 hours in a microwave oven at 170 C. The reaction medium is diluted with 50 ml of dichloromethane and then washed twice with 50 ml of water. The organic phase is concentrated to dryness and the residue is purified by chromatography over silica with, as eluent, heptane/ethyl acetate (1/1). The expected product is obtained in the form of a colourless oil.

Preparation of the 6-isopropoxypyridin-2-ylamine Intermediate

[0103] This intermediate is prepared according to the procedure described for 6-ethoxypyridin-2-ylamine, replacing the ethanol with isopropanol. The expected product is obtained in the form of a colourless oil.

EXAMPLES 2 to 12

[0104] Examples 2 and 12 are described in Table 1 below. The compounds are synthesized according to the procedure described above, replacing the starting materials 1 and 2 mentioned in Example 1 with the products mentioned in Table 1.

TABLE-US-00001 TABLE 1 .sup.1H NMR - 400 MHz (s = singlet, d = doublet, t = Melting triplet, m = multiplet, q = Example IUPAC Starting Starting point quartet, J = coupling # name material 1 material 2 ( C.) constant in Hz) 2 2-[(6- 2-bromo- 2-hydroxy- 127 (CDCl.sub.3) 4.48 (d, 2H, J = 4.28 bromo- pyridin-6- benz- Hz); 5.17 (s, 1H); 6.35 (d, 1H, pyridin-2- ylamine aldehyde J = 8.7 Hz); 6.77 (d, 1H, J = ylamino)- 7.3 Hz); 6.87 (t, 1H, J = 7.4 methyl]- Hz); 7.0 (d, 1H, J = 9.1 Hz); phenol 7.16-7.27 (m, 3H); 9.84 (s, 1H) 3 2-(6- 6-bromo- 5-fluoro- 143 (DMSO) 4.32 (d, 2H, J = 6 bromo- pyridin-2- 2-hydroxy- Hz); 6.5 (d, 1H, J = 8.2 Hz); pyridin-2-yl- ylamine benz- 6.65 (d, 1H, J = 7.4 Hz); amino)- aldehyde 6.77-6.81 (m, 1H); 6.85-6.95 methyl]-4- (m, 2H); 7.3 (t, 1H, J = 8.2 fluoro- Hz); 7.32-7.35 (m, 1H); 9.59 phenol (s, 1H) 4 6-(2- 6-amino- 2-hydroxy- 153 (DMSO) 4.36 (d, 2H, J = 4.8 hydroxy- pyridine-2- benz- Hz); 6.73 (t, 1H, J = 7.4 Hz); benzyl- carbonitrile aldehyde 6.81-6.84 (m, 2H); 7.04-7.08 amino)- (m, 2H); 7.14 (d, 1H, J = 7.4 pyridine-2- Hz); 7.46-7.54 (m, 2H); 9.60 carbonitrile (s, 1H) 5 2-[1-(6- 6-methoxy- 1-(2- 109 (DMSO) 1.35 (d, 3H, J = 6.8 methoxy- pyridin-2- hydroxy- Hz); 3.66 (s, 3H); 5.13-5.16 pyridin-2-yl- ylamine phenyl)- (m, 1H); 5.79 (d, 1H, J = 7.7 amino)- ethanone Hz); 5.94 (d, 1H, J = 7.8 Hz); ethyl]- 6.7 (t, 1H, J = 7.3 Hz); 6.77 (t, phenol 2H, J = 8.2 Hz); 6.97 (t, 1H, J = 7.6 Hz); 7.20-7.24 (m, 2H); 9.42 (s, 1H) 6 2-[(6- 2-amino-6- 2-hydroxy- 125 (DMSO) 4.38 (d, 2H, J = trifluoro- (trifluoro- benz- 5.4 Hz); 6.71-6.82 (m, 3H); methyl- methyl)- aldehyde 6.88 (d, 1H, J = 7.2 Hz); 7.06 pyridin-2-yl- pyridine (t, 1H, J = 7.6 Hz); 7.19 (d, amino)- 1H, J = 7.4 Hz); 7.37-7.40 (m, methyl]- 1H); 7.56 (t, 1H, J = 7.8 Hz); phenol 9.56 (s, 1H) 7 2-[(6- 2-amino-6- 2-hydroxy- not (DMSO) 4.34 (d, 1H, J = chloro- chloro- benz- determined 5.8 Hz); 6.45-6.50 (m, 2H); pyridin-2-yl- pyridine aldehyde 6.72-6.76 (m, 2H) 6.81 (d, amino)- 1H, J = 8 Hz); 7.06 (t, 1H, J = methyl]- 7.6 Hz); 7.15 (d, 1H, J = phenol 7.4 Hz); 7.26-7.29 (m, 1H); 7.38 (t, 1H, J = 7.5 Hz); 9.57 (s, 1H) 8 2-[(6-ethyl- 6-ethyl- 2-hydroxy- not (DMSO) 1.2 (t, 3H, J = pyridin-2-yl- pyridin-2- benz- determined 7.6 Hz); 2.54-2.60 (q, 2H, J = amino)- ylamine aldehyde 7.5 Hz); 4.31 (d, 2H, J = methyl]- 6.12 Hz); 6.33-6.38 (m, 2H); phenol 6.72-6.78 (m, 2H); 7.06-7.12 (m, 2H); 7.18 (d, 1H, J = 7.4 Hz); 7.3 (t, 1H, J = 7.5 Hz); 10.88 (s, 1H) 9 2-[(6- 2-amino-6- 2-hydroxy- 87 (CD.sub.3OD) 1.35 (t, 3H, J = ethoxy- ethoxy- benz- 7.0 Hz); 3.31-3.33 (q, 2H, J = pyridin-2-yl- pyridine aldehyde 7.0 Hz); 4.42 (s, 2H); 5.91- amino)- 5.93 (m, 1H); 6.05 (d, 1H, J = methyl]- 7.8 Hz); 6.75-6.80 (m, 2H); phenol 7.05-7.10 (m, 1H); 7.19-7.22 (m, 1H); 7.29-7.33 (m, 1H) 10 2-[(6- 2-amino-6- 2- not (CD.sub.3OD) 1.26 (t, 6H, J = isopropoxy- isopropoxy- hydroxy- determined 6.1 Hz); 4.43 (s, 2H); 5.03- pyridin-2-yl- pyridine benz- 5.09 (m, 1H); 5.88-5.90 (m, amino)- aldehyde 1H); 6.02-6.04 (m, 1H); 6.74- methyl]- 6.79 (m, 2H); 7.04-7.08 (m, phenol 1H); 7.19-7.21 (m, 1H); 7.3 (t, 1H, J = 7.9 Hz) 11 5-chloro-2- 6-methoxy- 4-chloro- not (DMSO) 3.72 (s, 3H); 4.39 (d, [(6- pyridin-2- 2- determined 2H, J = 5.9 Hz); 5.86 (d, 1H, methoxy- ylamine hydroxy- J = 7.8 Hz); 6.03 (d, 1H, J = pyridin-2-yl- benz- 7.9 Hz); 6.7 (m, 1H); 6.8 (s, amino)- aldehyde 1H); 6.93 (m, 1H); 7.21 d, methyl]- 1H, J = 8.4 Hz); 7.28 (t, 1H, phenol J = 7.8 Hz); 9.73 (s, 1H) 12 2-[(2- 2-trifluoro- 2- 201 (DMSO) 4.34-4.47 (m, 2H); trifluoro- methyl- hydroxy- 6.55-6.85 (m, 3H); 7.1 (t, 1H, methyl- pyrimidin- benz- J = 7.4 Hz); 7.19 (d, 1H, J = pyrimidin-4- 4-ylamine aldehyde 7.3 Hz); 8.15 (d, 1H, J = ylamino)- 5.9 Hz); 8.39-8.47 (m, 1H); methyl]- 9.63 (s, 1H) phenol

EXAMPLE 13

2-[(6-Bromopyrazin-2-ylamino)methyl]phenol

[0105] Synthesis According to Scheme 1, Method 1b

[0106] Introduced into a 50 ml round-bottomed flask is 1 g (4.2 mmol) of 2,6-dibromopyrazine (starting material 3), to which 15 ml of dimethyl sulphoxide, 638 mg (4.2 mmol, 1eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1.03 g (8.4 mmol, 2 eq) of 2-hydroxybenzylamine (starting material 4) are added; the mixture is left stirring for 2 h at room temperature. The reaction medium is diluted with 50 ml of ethyl acetate and then the mixture is washed with 50 ml of a saturated solution of ammonium chloride, and then twice with 50 ml of water. The organic phases are dried over magnesium sulphate, filtered and concentrated to dryness. The residue is purified by chromatography over silica with, as eluent, a heptane/ethyl acetate (8/2) mixture. 2-[(6-Bromopyrazin-2-ylamino)methyl]phenol is obtained in the form of a white solid.

[0107] Melting point=168 C.

[0108] .sup.1H NMR (DMSO): 4.36 (d, 1H, J=5.3 Hz); 6.74-6.76 (m, 1H); 6.83 (dd, 1H); 7.07-7.11 (m, 1H); 7.17 (dd, 1H); 7.75 (s, 1H); 7.80-7.83 (m, 1H); 7.96 (s, 1H); 9.61 (s, 1H)

EXAMPLES 14 to 18

[0109] Examples 14 to 18 are described in Table 2 below. The compounds are synthesized according to the procedure described above, replacing the starting materials 3 and 4 mentioned in Example 13 with the products mentioned in Table 2.

TABLE-US-00002 TABLE 2 .sup.1H NMR - 400 MHz (s = singlet, d = doublet, t = Melting triplet, m = multiplet, q = Example IUPAC Starting Starting point quartet, J = coupling # name material 3 material 4 ( C.) constant in Hz) 14 2-[(2- 2,4- 2-hydroxy- not (CD.sub.3OD) 4.53 (m, 2H); 6.45 chloro- dichloro- benzyl- determined (d, 1H, J = 6.0 Hz); 6.78- pyrimidin- pyrimidine amine 6.83 (m, 2H); 7.10-7.14 (m, 4-ylamino)- 1H); 7.22 (d, 1H, J = methyl]- 6.9 Hz); 7.83 (m, 1H) phenol 15 2-[(2- 2,4- 2-hydroxy- not (CD.sub.3OD) 4.42-4.52 (m, 2H) bromo- dibromo- benzyl- determined 6.48 (d, 1H, J = 6.0 Hz); pyrimidin- pyrimidine amine 6.78-6.83 (m, 2H); 7.12 (t, 4-ylamino)- 1H, J = 8.2 Hz); 7.21-7.23 methyl]- (m, 1H); 7.76-7.86 (m, 1H) phenol 16 2-[(2- 2,4- 2-hydroxy- not (DMSO) 2.17 (s, 3H); 4.40 chloro-6- dichloro-6- benzyl- determined (s, 2H); 6.35 (s, 1H); 6.74 (t, methyl- methyl- amine 1H, J = 7.4 Hz); 6.82 (d, 1H, pyrimidin- pyrimidine J = 7.9 Hz); 7.06-7.12 (m, 4-ylamino)- 2H); 8.04 (s, 1H); 9.60 (s, 1H). methyl]- phenol 17 2-[(6- 2,6- 2-hydroxy- not (DMSO) 4.39 (d, 2H, J = chloro-4- dichloro-4- benzyl- determined 5.4 Hz); 6.73-6.84 (m, 4H); trifluoro- trifluoro- amine 7.080 (t, 1H, J = 7.6 Hz); methyl- methyl- 7.17 (d, 1H, J = 7.4 Hz); pyridin-2- pyridine 7.83 (s, 1H); 9.61 (s, 1H) ylamino)- methyl]- phenol 18 2-[(6- 2,6- 2-hydroxy- 138 (DMSO) 2.12 (s, 3H); 4.32 chloro-4- dichloro-4- benzyl- (d, 2H, J = 5.5 Hz); 6.28 (s, methyl- methyl- amine 1H); 6.37 (s, 1H); 6.73 (t, pyridin-2- pyridine 1H, J = 7.4 Hz); 6.8 (d, 1H, J = ylamino)- 8 Hz); 7.04 (t, 1H, 7.7 Hz); methyl]- 7.12-7.17 (m, 2H); 9.58 (s, 1H) phenol

EXAMPLE 19

2-[(6-Methoxypyrazin-2-ylamino)methyl]phenol

[0110] Synthesis According to Scheme 2, Method 2b

[0111] Introduced into a microwave tube are 363 mg (1.29 mmol) of 2-[(6-bromopyrazin-2-ylamino)methyl]phenol, prepared as described previously in Example 12, to which 3 ml of methanol and 103 mg (2.58 mmol, 2 eq) of sodium hydroxide are added. The reaction mixture is then heated for 30 mins in a microwave oven at 150 C. and is then diluted with 50 ml of ethyl acetate. The mixture is neutralized with an ammonium chloride solution to pH=7, decanted and the organic phase is washed twice with 50 ml of water. The organic phase is dried over magnesium sulphate, filtered, and concentrated to dryness. The residue is purified by chromatography over silica with, as eluent, heptane/ethyl acetate (7/3). 2-[(6-Methoxypyrazin-2-ylamino)methyl]phenol is obtained in the form of a white solid.

[0112] Melting point=158 C.

[0113] .sup.1H NMR (DMSO): 3.78 (s, 1H); 4.40 (d, 2H, J=5.2 Hz); 6.73 (t, 1H, J=7.4 Hz); 6.81 (d, 1H, J=8 Hz); 7.05 (t, 1H, J=7.8 Hz); 7.19 (d, 1H, J=7.4 Hz); 7.26 (s, 1H); 7.31-7.32 (m, 1H); 7.50 (s, 1H); 9.55 (s, 1H).

EXAMPLE 20

2-[(2-Methoxypyrimidin-4-ylamino)methyl]phenol

[0114] This compound is prepared according to the procedure described for Example 19, starting from 2-[(2-chloropyrimidin-4-ylamino)methyl]phenol. 2-[(2-Methoxypyrimidin-4-ylamino)methyl]phenol is obtained in the form of a white solid.

[0115] Melting point=161 C.

[0116] .sup.1H NMR (CD.sub.3OD): 3.90 (s, 3H); 4.53 (s, 3H); 6.15 (d, 2H, J=6.0 Hz); 6.77-6.81 (m, 2H); 7.07-7.12 (m,1H); 7.21 (d, 1H, J=7.4 Hz); 7.78 (s, 1H)

EXAMPLE 21

2-[(2-Methoxy-6-methylpyrimidin-4-ylamino)methyl]phenol

[0117] This compound is prepared according to the procedure described for Example 19 above, starting from 2-[(2-chloro-6-methylpyrimidin-4-ylamino)methyl]phenol.

[0118] .sup.1H NMR (DMSO): 2.12 (s, 3H); 3.74 (s, 3H); 4.38 (m, 2H); 6.04 (s, 1H); 6.73 (t, 1H, J=7.4 Hz); 6.80 (d, 1H, J=8.0 Hz); 7.06 (t, 1H, J=7.7 Hz); 7.11 (d, 1H, J=7.3 Hz); 7.65 (s, 1H); 9.71 (s, 1H).

EXAMPLE 22

2-[(6-Methylsulphanylpyridin-2-ylamino)methyl]phenol

[0119] Synthesis According to Scheme 2, Method 2a

[0120] Introduced into a microwave tube are 300 mg (1.28 mmol) of 2-[(6-chloropyridin-2-ylamino)methyl]phenol, to which 5 ml of dimethyl sulphoxide and 448 mg (6.4 mmol, 5 eq) of sodium methanethiolate are added. The reaction mixture is heated for 16 h at 90 C. The reaction medium is diluted with 50 ml of ethyl acetate and then washed with 50 ml of a saturated ammonium chloride solution then 250 ml of distilled water. The organic phase is dried over magnesium sulphate then filtered and concentrated to dryness. The residue is purified by chromatography over 40 g of silica with, as eluent, heptane/ethyl acetate (7/3). The product obtained is put back into solution in ethyl acetate, heptane is added until the solution becomes cloudy, it is then cooled to 0 C. and filtered. 2-[(6-Methylsulphanylpyridin-2-ylamino)methyl]phenol is obtained in the form of a white solid.

[0121] Melting point=61 C.

[0122] .sup.1H NMR (DMSO): 2.38 (s, 3H); 4.38 (d, 2H, J=5.6 Hz); 6.21 (d, 1H, J=8.2 Hz); 6.34 (d, 1H, J=7.4 Hz); 6.72 (t, 1H, 7.3 Hz); 6.93-6.96 (m, 1H); 7.04 (t, 1H, J=7.7 Hz); 7.15 (d, 1H, J=7.1 Hz); 7.23 (t, 1H, J=7.6 Hz); 9.65 (s, 1H).

EXAMPLE 23

2-[(6-Methanesulphinylpyridin-2-ylamino)methyl]phenol

[0123] 160 mg (0.66 mmol) of 2-[(6-methanesulphanylpyridin-2-ylamino)methyl]phenol and 406 mg (0.66 mmol, 1 eq) of oxone are mixed in 20 ml of dioxane. After stirring for one hour at room temperature, the reaction medium is heated at 90 C. for 4 h. After returning to room temperature, the reaction medium is diluted with 50 ml of ethyl acetate and then washed twice with 50 ml of water. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness. The residue is purified by chromatography over silica, eluting with a heptane/ethyl acetate (1/1) mixture. 2-[(6-Methanesulphinylpyridin-2-ylamino)methyl]phenol is obtained in the form of a white solid.

[0124] Melting point=133 C.

[0125] .sup.1H NMR (CDCl.sub.3): 2.89 (s, 3H); 4.51 (d, 2H, J=6.2 Hz); 5.32-5.33 (m, 1H); 6.5 (dd, 1H); 6.87-6.95 (m, 2H); 7.19-7.28 (m, 2H); 7.30-7.59 (m, 1H); 7.62 (t, 1H, J=7.3 Hz); 9.28 (s, 1H).

EXAMPLE 24

2-[(6-Methanesulphonylpyridin-2-ylamino)methyl]phenol

[0126] 80 mg (0.33 mmol) of 2-[(6-methanesulphanylpyridin-2-ylamino)methyl]phenol and 406 mg (0.66 mmol, 2 eq) of oxone are mixed in 20 ml of dioxane and heated for 16 h at 90 C. The reaction medium is diluted with 50 ml of ethyl acetate and then washed twice with 50 ml of water. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness. The residue is purified by chromatography over silica, eluting with a heptane/AcOEt (1/1) mixture. 2-[(6-Methanesulphonylpyridin-2-ylamino)methyl]phenol is obtained in the form of a slightly green solid.

[0127] .sup.1H NMR (CDCl.sub.3): 3.12 (s, 3H); 5.32-5.33 (m, 1H); 6.58 (d, 1H, J=7.9 Hz); 6.79-6.83 (m, 1H); 6.87 (d, 1H, J=7.4 Hz); 7.3 (d, 1H, J=6.6 Hz); 7.5 (t, 1H, J=7.2 Hz); 8.56 (s, 1H).

EXAMPLE 25

2-[(6-Methoxypyridin-2-ylamino)methyll-6-methyl]phenol

[0128] Synthesis According to Scheme 1, Method 1c

[0129] 80 mg (2.1 mmol, 6 eq) of lithium aluminium hydride are added in small fractions to a mixture of 90 mg (0.35 mmol) of 2-hydroxy-N-(6-methoxypyridin-2-yl)-3-methylbenzamide in 10 ml of dioxane. The reaction medium is heated at 80 C. for 16 h. 80 mg (2.1 mmol, 6 eq) of lithium aluminium hydride are added again and the medium is heated at 80 C. for 4 h. The reaction medium is diluted with 50 ml of ethyl acetate and washed with 50 ml of a saturated solution of ammonium chloride, and then twice with 50 ml of water. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness. The residue is purified by chromatography over silica, eluting with a heptane/ethyl acetate (1/1) mixture. 2-[(6-methoxypyridin-2-ylamino)methyl]-6-methylphenol is obtained in the form of a white solid.

[0130] .sup.1H NMR (CDCl.sub.3): 2.19 (s, 3H); 3.89 (s, 3H); 4.46 (d, 2H, J=6.7 Hz); 4.75 (s, 1H); 5.93-5.97(m, 2H); 6.68 (t, 1H, J=7.4 Hz); 6.92 (d, 1H, J=7.5 Hz); 7.0 (d, 1H, J=7.4 Hz); 7.27 (t, 1H, J=7.9 Hz), 9.66 (s, 1H).

Preparation of the 2-hydroxy-N-(6-methoxypyridin-2-yl)-3-methylbenzamide Intermediate

[0131] 10 ml of thionyl chloride are added to 1.47 g (16.11 mmol) of 2-hydroxy-3-methylbenzoic acid and the reaction mixture is heated at 90 C. for 2 h. The reaction medium is concentrated to dryness by azeotroping with toluene. The residue is then put into solution in 10 ml of pyridine, to which 600 mg (4.83 mmol, 1 eq) of 2 methoxypyridin-6-amine are added dropwise, and the reaction medium is left stirring at room temperature for 1 h 30 mins. 30 ml of 1 M sodium hydroxide (19.34 mmol, 4 eq) are added and the reaction medium is heated at 60 C. for 16 h. The reaction medium is diluted with 100 ml of ethyl acetate, the aqueous phase is extracted and washed with 50 ml of ethyl acetate. The aqueous phase is then acidified at 0 C. with 37% HCl dropwise to pH=4. The organic phases are extracted twice with 50 ml of ethyl acetate and then they are washed twice with 50 ml of water. The organic phases are concentrated to dryness and the residue is purified by chromatography over silica, eluting with a heptane/ethyl acetate (1/1) mixture. 2-Hydroxy-N-(6-methoxypyridin-2-yl)-3-methylbenzamide is obtained in the form of a white solid.

[0132] .sup.1H NMR (CDCl.sub.3): 2.23 (s, 3H); 3.84 (s, 3H); 6.48 (d, 1H, J=8 Hz); 6.78 (t, 1H, J=7.7 Hz); 7.26 (d, 1H, J=7.3 Hz); 7.38 (d, 1H, J=8 Hz); 7.58 (t, 1H, J=8 Hz); 7.76 (d, 1H, J=7.7 Hz); 8.31 (s, 1H); 12.12 (s, 1H).

[0133] All the NMR (nuclear magnetic resonance) spectra are in agreement with the proposed structures. The chemical shifts are expressed in parts per million. The internal reference is tetramethylsilane. The following abbreviations are used: CDCl.sub.3 =deuterated chloroform, DMSO=deuterated dimethyl sulphoxide, CD.sub.3OD=deuterated methanol.

EXAMPLE 26

Biological Tests

[0134] The compounds according to the invention show inhibitory properties on receptors of AR type. This AR receptor-inhibiting activity is measured in a transactivation test through the KdR (resting), KdA (active) and Kdapp (apparent) dissociation constants according to the method set out in J. Molecular Biology (1965), 12(1), 88-118, Monod J. et al.

[0135] The expression AR-type receptor inhibitor means, according to the invention, any compound which has a Kdapp dissociation constant of less than or equal to 1M, and a KdR/KdA ratio10, in a transactivation test.

[0136] The preferred compounds of the present invention have a dissociation constant of less than or equal to 500 nM and advantageously less than or equal to 100 nM.

[0137] The transactivation test is carried out in the PALM (PC3 Androgen receptor Luciferse MMTV) cell line which is a stable transfectant containing the PMMTV-neo-Luc (reporter gene) and pSG5puro-AR plasmids.

[0138] In this study, the affinity of each product for the 2 receptor states (KdR and KdA) is determined, as is an apparent Kd (KdApp). This constant is a result of the 2 Kd, but also depends on the initial equilibrium of the receptor between the active state and the resting state (L.sub.0) and on its expression level. It is determined by means of the following formula:

1/KdApp=(L0/(1+L0))(1/KdR)+(1/(1+L0))(1/KdA)

[0139] To determine these constants, cross curves of the test product against a reference agonist, methyltrienolone, are produced in 96-well plates. The test product is used at 10 concentrations and the reference agonist at 7 concentrations.

[0140] By way of illustration, a Kdapp of 40 nM is obtained for the compound (1), a Kdapp of 2 nM is obtained for the compound (2), a Kdapp of 8 nM is obtained for the compound (19), a Kdapp of 1000 nM is obtained for the compound (18) and a Kdapp of 200 nM is obtained for the compound (4).