OA16416A - Pyrazole derivatives, their preparation and their application in therapy. - Google Patents

Abstract

The invention relates to pyrazole derivatives of general formula (I) in which X represents chlorine or fluorine. Method of preparation and application in therapy.

Description

The present invention relates to pyrazole derivatives, to their preparation and to their therapeutic application.

[0002] More particularly, and according to a first aspect, the invention relates to novel specific substituted pyrazoles exhibiting anti-cancer activity, via the modulation of the activity of proteins, in particular kinases.

[0003] Protein kinases are a family of enzymes which catalyze the phosphorylation of hydroxyl groups of specific protein residues such as tyrosine, serine or threonine residues. Such phosphorylations can greatly modify protein function; thus, protein kinases play an important role in the regulation of a wide variety of cellular processes, including but not limited to metabolism, cell proliferation, cell differentiation, cell migration or cell survival. Among the different cellular functions in which the activity of a protein kinase is involved, certain processes represent attractive targets for treating cancerous diseases as well as other diseases.

[0004] Thus, one of the objects of the present invention is to provide compositions having anti-cancer activity, by acting in particular against kinases. Among the kinases for which modulation of the activity is desired, mention may be made of KDR, Tie2, VEGFR-1 (FLT1), VEGFR-3 (Flt4> PDGFR, FGFR. KDR and / or Tie2 kinases are preferred.

[0005] According to the patent application published under WO08065282, compounds corresponding to the following general formula (I) are known: Zi

Formula (I) in which:

) A and Ar are independently selected from the group consisting of: aryl, heteroaryl, substituted aryl, substituted heteroaryl;

2) L is selected from the group consisting of; NH-CO-NH and O-CO-NH;

3) R 1 is selected from the group consisting of: H, R _e , COR ₆ , SO ₂ R ₆ , wherein R _e is selected from H, OR ₇₁ NR ₈ Ro, alkyl, cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, where R? is selected from H, phenyl, alkyl, and wherein Ra and R _e are independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R _e and R _B are linked together to form a 5 to Θ membered saturated ring containing 0 to 3 heteroatoms selected from O, S and N;

4) X is selected from the group consisting of: O and NH;

5) R ₃ is selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl;

6) R4a is selected from the group consisting of: H and (C1-C4) alkyl;

7) R4b is selected from the group consisting of: H and (C1-C4) alkyl;

Θ) R _e is selected from the group consisting of: H, halogen, R _10l CN, 0 (Rw)> OC (O) (R _ro ). OC (0) N (Rio) (Rii), OS (O ₂ ) (Ri ₀ ), N (R _w ) (Rii). N = C (Rto) (Rn), NiRwWOXRn), N (R ₁₂ ) C (0) N (Rio) (Rh), N (Ri ₂ ) C (S) N (R _w ) (R “).

N (Riq) S (02) (Rii). C (0) (Rw). C (O) O (Ri ₀ ), C (O) N (Ri ₀ ) (Rn), C (= N (Rii)) (Rio),

C (= N (ORii)) (Rio). S (Rio). S (O) (R ₁₀ ), S (O ₂ ) (R _W ), S (O ₂ ) O (R _W ), S (O ₂ ) N (Ri ₀ ) (Rh); wherein each Rw, Rn, Ru is independently selected from the group consisting of H, alkyl, alkylene, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, substituted alkyl, substituted alkylene, substituted alkynyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted heterocyclyl, Λ] [0006] In this patent preferably X is O, R3 is methyl, R4a and R4b are H; L is NHCONH; A is phenyl; Ar is phenyl; but in this application no example describes the substitution of Ar and its effect on the pharmacokinetics.

The present invention relates to two compounds included in the previous application and corresponding to formula (I)

(!) in which :

X represents Cl or F [0008] The compounds of formula (I) can exist in the form of bases or of addition salts with acids. Such addition salts form part of the invention.

[0009] The compounds in their two tautomeric forms Indicated below belong to the invention:

These salts can be prepared with pharmaceutically acceptable acids, but salts of other acids useful, for example, for the purification or isolation of compounds of formula (I) also form part of the invention. Among the salts which can be used, mention may in particular be made of the hydrochloride.

The compounds of formula (I) can also exist in the form of hydrates or of solvates, namely in the form of associations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.

Among the compounds of formula (I) which are subjects of the invention, mention may in particular be made of the following compounds:

- 4 ’{3- [3- (2-chloro-4-trlfluoromethyl-phenyl) -ureido] -5-fluoro-benzylamino} -1Hpyrazole-3-carboxamlde and its hydrochloride

- 4- {3- [3- (2-fluoro-4-trifluoromethyl-phenyl) -ureido] -5-fluorO'benzylamino} -1H ”pyrazote-3-carboxamlde and its hydrochloride [0013] According to the invention, the compounds of general formula (I) can be prepared according to the following process.

In the diagrams which follow the starting compounds and the reagents, when their method of preparation is not described, are commercially available or described in the literature, or else can be prepared according to methods which are described therein or which are known to those skilled in the art.

[0014] The invention, according to another of its aspects, also relates to the compounds of formulas x

CHO and

In which X represents F or Cl.

These compounds are useful as intermediates in the synthesis of compounds of formula (I).

[0015] The following examples describe the preparation of the compounds according to the invention. These examples are not limiting and only illustrate the present invention.

Method of synthesis of the examples

Swithtie d * I »party * amlnoovratol *

SvntMit 1> Mrtlt <HÎrvl-urH

+ η WCÀ / Mptojrtx DTWFfMslHjCNITA

Exemplel

A-tS-IS - ^ - chloro ^ -trlfluoromethyl-phenylj-ureldol-Sfluoro-benzylamino} * 1H-pyrazole-3-carboxamide hydrochloride ci

A suspension of 1.64 g (3.48 mmol) of 4- {3 '[3- (2-chloro-4-trifluoramethylphenyl) -uréldo] -5-fluoro-benzylamlno} -1 H-pyrazole-3-carboxamlde in 50 ml of ethanol is stirred at room temperature under an argon atmosphere. Then 35 mL (35 mmol) of a solution of hydrochloric acid in dlethyl ether (1 N) are added dropwise. The reaction medium becomes a clear solution. After 10 hours of stirring at room temperature, the solvents are evaporated off in a rotary evaporator under reduced pressure. The residue obtained is stirred in 50 mL of dlethyl ether for 30 minutes.

After filtration and drying in an oven 1.8 g of 4- {3- [3- (2-chloro4'trifluoromêthyl-phenyl) 'Uréldo] -5'fluoro-benzylamlno} ~ 1H-pyrazole-3-carboxamide hydrochloride are obtained in the form of pale yellow crystals.

MS: Retention time Tr (min) = 1.01; [M + HJ + m / z = 471; [M-H] - m / z = 469

1H NMR (400 MHz, DMSO-d) δ ppm 4.32 (s, 2 H) 6.89 (d wide, J = 9.6 Hz, 1 H) 7.16 (s wide, 1 H) 7.18 - 7.61 (m, 4 H) 7.68 (d wide, J = 8.9 Hz, 1H) 7.86 (wide s, 1H) 8.44 (d, J = 8.9 Hz, 1H) 8.81 (m wide, 1H) 10.17 (m wide, 1H)

Melting point (Kofler) = 177 ° C

4- {3- [3- (2-Chloro-4-trifluoromethyl-phônyl) -uréldo] -5-fluoro-benzylamlno} 1H-pyrazole-3-carboxamlde

F

A solution of 5.9 g (9.5 mmol) of 4- {3- [3- (2-chloro-4-trlfluoromethyl · phenyl) -uréldo] -5-fluoro-benzylamino} -1H-pyrazole-3- (2,4-dlmethoxy-benzylamlde) and 4.5 g (24 mmol) of paratoluene sulfonlque acid in 400 mL of toluene is heated at reflux for 2 hours. After decantation, the toluene solution is separated from a yellow gum. The gum is diluted in 150 mL of methanol and 500 mL of ethyl acetate. Then 500 ml of water are added. The solution is then cooled and then alkalized with 100 mL of an aqueous solution of potassium hydroxide (10 N). After decantation, the aqueous phase is extracted with a solution of 400 mL of ethyl acetate and 100 mL of methanol. The organic phases are combined and washed with 100 mL of saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure to give a pale yellow solid which is purified on 200 g of silica, eluted with a solution of dlchloromethane. methanol / acetonltrlle 80/10/10 (by volume): 1.77 g of 4- {3- [3- (2chloro-4-trifiuoromethyl-phenyl) -ureldol'5'fluoro-benzylamino} '1H-pyrazole-3carboxamlde are obtained in the form of a white solid,

MS: Retention time Tr (min) = 4.29 [M + HJ + m / z = 471; [M-H] m / z = 469

1H NMR (400 MHz, DMSO-d) δ ppm 4.19 (d, 7 = 6.7 Hz, 2 H) 5.74 (m wide, 1 H) 6.80 (d wide, 7 = 9.6Hz, 1 H) 6.95 - 7.11 (m , 3H) 7.24 (broad m, 1H) 7.42 (dt, 7 = 11.3, 2.3 Hz. 1H) 7.67 (broad d, 7 = 8.9 Hz. 1H) 7.86 (broad s, 1H) 8.44 (d, 7 = 8.9 Hz, 1H) 8.70 (wide s 1H) 9.92 (wide s, 1H) 12.57 (wide s, 1H)

Melting point (Kofler): 220 ^a C

4- {3- [3- (2-Chloro-4-trifluoromethyl-phenyl) -uréldo] -5-fliioro "benzylamjno} -

H-pyrazole-3- (2,4-dimethoxy-benzylamlde)

A solution of 10 g (32 mmol) of 4-amlno-1H-pyrazole-3 (2,4-dimethoxy-benzylamlde) hydrochloride and 5.9 mL (35.2 mmol) of dlisopropylethylamlne in 300 mL of tetrahydrofuran is stirred at room temperature under an argon atmosphere. 3.85 g (35 mmol) of magnesium sulfate and 12.70 g (35.2 mmol) of 1- (2-chloro-4-trlfluoromethyl-phenyl) -3- (3-fluoro-5-formyl-phenyl) ) -urea are added. The reaction mixture is then heated at reflux for 14 hours. The mixture is then cooled to 25 ^e C and 10.08 g (160 mmol) of sodium cyanoborohydride are added slowly. After 12 hours of stirring at room temperature, the mixture is concentrated to dryness on a rotary evaporator. The gum obtained is stirred with 300 mL of water and 500 mL of aqueous sodium hydroxide solution (1N). This suspension is stirred for 30 minutes with 1 L of dichloromethane. After filtration on sintered glass No. 3, the solid obtained is rinsed with 2 fols 500 mL of water and then dried in an oven under vacuum at 40 ° C. The solid is then recrlstalllsé in 800 mL of methanol, hot, to give 8.3 g of 4- {3- (3- (2-chloro-4-trifluoromethyl-phenyl) uréldo] -5-fluoro-benzylamino} - 1H-pyrazole-3- (2,4-dimethoxy-benzylamlde) as a white powder.

MS: Retention time Tr (min) = 4.97; [M + H] + m / z = 621; [M-H] m / z = 619

1H NMR (400 MHz, DMSO-d) S ppm 3.73 (s, 3 H) 3.81 (s, 3 H) 4.19 (d, J = 6.7 Hz, 2 H) 4.33 (d, J = 6.7Hz, 2 H) 5.71 (t wide, J = 6.7 Hz, 1 H) 6.46 (dd, J = 8.3, 2.3 Hz, 1 H) 6.55 (d, J = 2.3 Hz, 1 H) 6.80 (d wide, J = 9.6 Hz , 1H) 7.04 (s wide, 1H) 7.08 (s, 1H) 7.10 (d, J = 8.9 Hz. 1 H) 7.43 (dt, J = 11.4, 2.3 Hz, 1 H) 7.67 (d wide, J = 8.9 Hz, 1H) 7.86 (s wide, 1H) 7.94 (t wide, J = 6.7 Hz, 1H) 8.45 (d, J = 8.9 Hz, 1H) 8.62 (m spread, 1H) 9.79 (m spread, 1H) 12.60 (m spread, 1H)

Melting point (Kofler): 168 ° C l - ^ - Chloro-A-trlfluoromethyl-phenyO-S-fS-fluoro-S-formyl-phenylJ-urea ci

CHO

A solution of 33.15 g (92.68 mmol) of 1- (2-chloro-4-trifluoromethylphenyl) -3- (3-cyanO'5-fluorO'phenyl) -urea in 600 mL of tetrahydrofuran is stirred at - 10 ° C in an argon atmosphere. Then 230 ml of a 20% solution of dIsobutyl aluminum hydride in toluene are added with a regular dropwise drop. The reaction mixture is stirred at room temperature for 12 hours. Then an additional 80 mL of dilsobutylalumlum hydride is added at -10 ° C. After 14 hours of stirring at room temperature, the reaction medium is concentrated to dryness on a rotary evaporator to give a thick oil which is added slowly, with stirring, with 500 g of ice and 100 mL of 100% acetic acid. The suspension obtained is filtered. The solid is then diluted in 2 fols 800 mL of ethyl acetate and the organic solution is washed with 600 mL of saturated sodium chloride solution, dried over magnesium sulfate, filtered, concentrated to dryness in a rotary evaporator and dried in a vacuum oven at 40 ° C to give 29.57 g of 1- (2-chloro-4-trlfluoromethyl-phenyl) -3- (3-fluoro-5-formyl-phenyl) -urea as d 'a pale yellow powder,

MS: Retention time Tr (min) = 4.86; [M + HJ + m / z = 361; [M-H] m / z = 359

1H NMR (400 MHz, DMSO-d) δ ppm 7.35 (ddd, J = 8.4, 2.3, 1.8 Hz, 1 H) 7.67 7.75 (m, 2 H) 7.78 (t, J = 1.8 Hz , 1H) 7.88 (d, J = 1.8 Hz, 1H) 8.45 (d. J = 8.8 Hz, 1H) 8.72 (broad s, 1H) 9.98 (d, J = 1.8 Hz, 1H) 10.07 ( s wide, 1H)

1- (2-Chloro-4-trlfluoromethyl-phenyl) -3- (3-cyano-5-fluoro-phenyl) -ureaY

Cl

A solution of 15 g (110.2 mmol) of 5-fluoro-3-cyanoanillne in 150 mL of tetrahydrofuran is stirred at room temperature under an argon atmosphere, then 17.5 mL (121.22 mmol) of 2-chloro -4-trifluoromethylphenylisocyanate are added. The reaction medium is heated under reflux for 3 hours and then concentrated to dryness on a rotary evaporator. The solid residue obtained is recreated hot in 60 mL of ethyl acetate to give 33.25 g of 1- (2-chloro-4-trlfluoromethyl-phenyl) -3 (3-cyano-5-fluoro-phenyl) -urea as a white solid.

MS: retention time Tr (min) = 4.97; [M + H] *: m / z 356

Melting point (Kofler): 286 ° C

5-fluoro-3-cyanoanlline is commercial.

4-Amlno-1H-pyraïole-3- (2,4-dlmethoxy-benzylamlde) hydrochloride, HCl

A suspension of 6.12 g (20 mmol) of 4-nitro-1H-pyrazole-3- (2,4dlmethoxybenzylamlde) in 340 mL of ethanol is stirred at room temperature. Then 15.8 g (70 mmol) of tin chloride dl-hydrate are added over 5 minutes. The reaction mixture is stirred for 14 hours at room temperature and then concentrated to dryness on a rotary evaporator. The residue obtained is stirred with 330 ml of saturated aqueous sodium hydrogencarbonate solution and 300 ml of dlchloromethane. After decantation, the organic phase is extracted with 2 fols 150 mL of dlchloromethane. The organic phases are combined, washed with 150 ml of saturated sodium chloride solution, dried over magnesium sulfate. After concentration on a rotary evaporator, 4.57 g of 4-amlno-1 H-pyrazole hydrochloride16416

3- (2,4-dlmethoxy-benzylamlde) are obtained in the form of a purplish solid.

SM: IE: [M] +. m / z = 276; base peak m / z = 151

1H NMR (400 MHz, DMSO-d) δ ppm 3.73 (s, 3H) 3.81 (s, 3H) 4.31 (d,> 6.2

Hz, 2H) 4.56 (m spread, 2H) 6.46 (dd,> 8.3, 2.9 Hz, 1 H) 6.55 (d,> 2.9 Hz, 1 H) 7.06 - 7.13 (m, 2 H) 7.84 (t, > 6.2 Hz, 1 H) 12.50 (m spread, 1 H)

Melting point (Buchl): 186 ° C

4-Nitro-1H-pyrazole-3- (2,4-dlmethoxybenzylamlde)

A solution of 14.65 g (76.4 mmol) of 1- (3-dimethylaminopropyl) -3ethylcarbodllmide dlhydrate, 10.32 g (76.4 mmol) of 1-hydroxybenzotrlazole in 50 mL of dimethylformamlde is stirred at room temperature. . 11.7 g (70.03 mmol) of 2,4-dlmethoxybenzylamlne are added then 10.2 g of 4-nltro-3pyrazole carboxylic acid in small portions. After 16 hours of stirring at room temperature, the reaction medium is poured into 500 mL of water. The suspension is filtered and then washed with 2 fols 250 mL of water. The solid obtained is dried in an oven under vacuum at 40 ° C. to give 18.58 g of 4-nitro-1 H-pyrazole-3- (2,4dlmethoxybenzylamlde) in the form of a white solid.

1H NMR (400 MHz, DMSO-φ δ ppm 3.75 (s, 3H) 3.80 (s. 3H) 4.35 (d,> 5.9 Hz, 2H) 6.50 (dd,> 8.3, 2.4 Hz, 1 H) 6.56 (d,> 2.4 Hz, 1 H) 7.21 (d,> 8.3 Hz, 1 H) 8.71 (s broad, 1 H) 8.88 (t broad,> 5.9 Hz, 1 H) 14.13 (m spread, 1 H)

MS (ES +/-) Retention time Tr (min) = 3.23; [M + H] + m / z = 307; [M-H] -m / z = 305

Melting point (Kofler): 192 “C

4-nltro-3-pyrazole carboxylic acid is commercial.

Example 2

4- {3- [3- (2-fluoro-4-trlf1uoromethyl-phenyl) -ureido] -5fluoro-benzylamlno} -1H-pyrazole-3-carboxamide hydrochloride

A suspension of 1.85 g (0.40 mmol) of 4- {3- [3- (2-fluoro-4-trifluoromethylphenyl) -ureido] -5-fluoro-benzylamino} -1H-pyrazole-3-carboxamide in 40 mL of ethanol is stirred at room temperature under an argon atmosphere. 20 mL (40 mmol) of a solution of hydrochloric acid in dlethyl ether (1 N) are added dropwise. The reaction medium becomes a clear solution. After 12 hours of stirring at room temperature, the solvents are evaporated on a rotary evaporator under reduced pressure. The residue obtained is stirred in 200 mL of dlethyl ether for 30 minutes.

After filtration and drying in an oven 1.75 g of 4- (3- (3- (2fluoro-4-trifluoromethyl-phenyl) -urêldo] -5-fluoro-benzylamlno} -1 H-pyrazole-3carboxamide hydrochloride are obtained as pale yellow crystals.

iH NMR (400 MHz. DMSO-de) 6 ppm 4.24 (s, 2H) 6.83 (d, J = 9.0 Hz, 1H) 7.08 (s 1H) 7.18 (br. s., 1H) 7.23 (s, 1 H) 7.35 (br. S., 2 H) 7.42 (dt. J = 11.3, 2.0 Hz. 1 H) 7.54 (d.7 = 8.8 Hz, 1 H) 7.69 (dd. J = 11.2, 1.5 Hz, 1 H) 8.41 (t, J = 8.2 Hz, 1H) 8.99 (s, 1H) 9.54 (s, 1H)

MS: Retention time Tr (min) = 0.97; [M + H] + m / z = 455

Melting point (Kof1er): 184 ° C (with decomposition)

4- {3- [3- (2-Fluoro-4-trlfluoromethyl-phenyl) -uréldo] -5-fluoro-benzylamlno} -

H-pyrazole-3-carboxamide

F

A solution of 22.3 g (36.89 mmol) of 4- {3- [3- (2-fluoro-4-trifluoromethylphenyl) -ureido] -5-fluoro-benzylamino} '1 H-pyrazole-3- ( 2,4-dimethoxy-benzylamide) and 17.54 g (92.22 mmol) of paratoluene sulfonic acid in 600 mL of toluene is heated at reflux for 14 hours. After decantation, the toluene solution is separated from a yellow gum. The gum is stirred for 2 hours in 280 mL of water and 100 mL of sodium hydroxide (10 N). The suspension is filtered. The solid obtained is rinsed with 3 fols 350 mL of water and then dried to give a cream solid which is purified on 350 g of silica, eluted with a solution of dichloromethane / methanol / acetonitrile 95 / 2.5 / 2.5 (in volume): 3.85 g of 4- {3- [3- (2-fluoro-4-trlfluoromethyl-phenyl) -uréldo] -5 ~ fluoro-benzylamino} -1 H-pyrazole-3-carboxamlde are obtained in the form a white solid.

1H NMR (400 MHz, DMSO-cfe) Ô ppm 4.18 (d,> 5.9 Hz, 2 H) 5.68 - 5.77 (m, 1 H) 6.80 (d,> 8.8 Hz, 1H) 7.01 - 7.08 ( br. s., 1H) 7.04 (s, 1H) 7.06 (s, 1H) 7.24 (br. s., 1H) 7.40 (dt,> 11.4, 2.0 Hz, 1H) 7.54 (d,> 8.3 Hz, 1 H) 7.69 (d,> 11.5 Hz, 1 H) 8.41 (t,> 8.4 Hz. 1 H) 8.92 (br. S „1 H) 9.40 (br. S., 1 H) 12.55 (br . s., 1 H)

MS: Retention time Tr (min) = 4.09 [M + H] + m / z = 455; [M-HJ- m / z = 453

Melting point (Kofler): 233 ° C

4- (3- [3- (2-Fluoro-4-trifluoromethyl-phenyl) -uréldo] -5-fluoro-benzylamlno} -

H-pyrazol © -3- (2,4-dlmethoxy-benzylamide) ^

F

A solution of 11.40 g (36.45 mmol) of 4-amino-1Hpyrazole-S- ^ A-dimethoxy-benzylamide hydrochloride) and 6.65 mL (40.09 mmol) of dilsopropylethylamlne in 360 mL of tetrahydrofuran is stirred at room temperature under an argon atmosphere. 4.35 g (36.45 mmol) of magnesium sulfate and 13.80 g (35.2 mmol) of 1- (2-fluoro-4-trlfluoromethyl-phenyl) -3- (3-fluoro-5-formylphenyl ) -urea are added. The reaction mixture is then heated at reflux for 14 hours. The mixture is then cooled to 25 ° C. then 11.46 g (182.25 mmol) of sodium cyanoborohydride are added slowly. After 72 hours of stirring at room temperature, the mixture is concentrated to dryness on a rotary evaporator. The gum obtained is stirred with 400 ml of water and 500 ml of sodium hydroxide solution (1N). This suspension is stirred for 1 hour then filtered through sintered glass N'3, the solid obtained is rinsed with 3 fols 500 mL of water and then dried in an oven under vacuum at 40 ° C to give 22.45 g of 4- {3- [3- (2-Fluoro-4-trifluoromethylphenyl) -ureldo] -5-fluoro-benzylamlno) -1H-pyrazole-3- (2,4-dimethoxy-benzylamlde) as a pinkish solid.

iH NMR (500 MHz, DMSO-cfë) δ ppm 3.73 (s, 3 H) 3.81 (s, 3 H) 4.18 (d, J = 6.3 Hz, 2 H) 4.33 (S, 2 H) -5.70 (t, J = 6.2 Hz, 1 H) 6.47 (d, J = 8.2 Hz, 1 H) 6.55 (s, 1 H) 6.79 (d, J = 9.1 Hz, 1 H) 7.05 (s, 1 H) 7.07 - 7.12 ( m, 2 H) 7.41 (d, J = 11.3 Hz, 1 H) 7.53 (d, J = 8.2 Hz, 1 H) 7.68 (d, J = 11.3 Hz, 1 H) 7.95 (br. s „1 H) -8.40 (t, J = 8.2 Hz, 1H) 9.25 (br. S., 2H) 12.52 (br. S., 1H)

MS: Retention time Tr (min) = 4.79; [M + H] + m / z = 605; [M-HJ- m / z = 603

Melting point (Kofler): 152 ° C

- (2-Fluoro-4-trlfluoromethyl-phenyl) -3- (3-fluoro-5-formyl-phenyl) -urea

F

CHO

A © solution of 11.90 g (34.87 mmol ©) d © 1- (2-fluoro-4-trifluoromethylphenyl) -3- (3-cyano-5-fluoro-phenyl) -urea in 150 mL of © tetrahydrofuran is stirred at -2 ° C under an argon atmosphere. Then 86 ml of a © solution of hydride © d © di-lsobutyl aluminum at 20% in hexane are added with a regular drop by drop. The reaction mixture is stirred at room temperature for 12 hours. Then an additional 60 mL of dllsobutylalumlum hydride is added at -2 ° C. After 3 hours of stirring at room temperature, the reaction medium is concentrated to dryness on a rotary evaporator to give a thick oil which is added slowly with stirring with 500 g of ice © and 300 mL of 100% acetic acid © . The suspension obtained is filtered. The solid obtained is washed with 4 fols 150 mL of water, drained and dried in a vacuum oven at 40 ° C to give 13.95 g of 1- (2-fluoro-4trifluoromethyl'phényiy-S-ÎB -fluoro-S-formyl-phenylJ 'Urea as a pale yellow solid.

1H NMR (400 MHz, DMSO-cfe) δ ppm 7.33 - 7.38 (m, 1 H) 7.57 (d, J = 8.8 Hz, 1 H) 7.69 - 7.75 (m, 2 H) -7.79 (s, 1 H) 8.41 (t,> 8.3 Hz, 1 H) 9.05 (br. S „1 H) 9.65 (s, 1 H) 9.98 (d,> 1.7 Hz, 1 H)

MS: Retention time Tr (min) = 4.62; [M + H] + m / z = 345; [M-H] - m / z = 343

Melting point (Kofler): 247 ° C

1- (2-Fluoro-4-trlfluoromethyl-phenyl) -3- (3-cyano-5-fluoro-phenyl) -urea

F

CN

A solution of 6.15 g (45.18 mmol) of 5-fluoro-3-cyanoaniline in 90 ml of tetrahydrofuran is stirred at room temperature under an argon atmosphere. 4.3 mL (36.14 mmol) of disphosgene are added dropwise then 30 mL (135.54 mmol) of trlethylamine. After 3 hours of refluxing of the reaction mixture, a solution of 7.10 g (39.64 mmol) of 4-amlno-3-fluoro-trlfluoromethylbenzene in 10 ml of tetrahydrofuran is added slowly. Reflux is maintained for 2 more hours. The medium is then stirred in 100 mL of water and then extracted with 100 mL of ethyl acetate. The organic phase is washed with 100 ml of a saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness on a rotary evaporator. The solid residue obtained is recrystallized while hot from 90 mL of acetonitrile to give 10.35 g of 1- (2-fluoro-4-trlfluoromethyl-phenyl) -3- (3-cyano-

5-fluoro-phenyl) -ufée as a cream solid.

1H NMR (400 MHz, DMSO-cfe) ôppm 7.47 (d, J = 8.3 Hz, 1 H) 7.57 (d, J = 8.6 Hz, 1 H) 7.69 (s, 1 H) 7.70 - 7.75 (m, 2 H) 8.37 (t, J = 8.4 Hz, 1 H) 9.17 (br. S., 1 H) 9.63 (br, s „1 H)

SM: retention time Tr (min) »1.1; [M + Hf: m / z 341.

Melting point (Kofler): 253 ° C

The products of the invention are useful as agents which inhibit one or more reactions catalyzed by a kinase. KDR and / or Tle2 are kinases for which the products of the invention will be particularly useful as inhibitors.

The reasons why these kinases are chosen are given below:

KDR

KDR (Kinase insert Domain Receptor) also called VEGF-R2 (Vascular Endothelial Growth Factor Receptor 2), is mainly expressed in endothelial cells. This receptor binds the pro-anglogenic factor VEGF, and thus mediates a transductal signal via the activation of its intracellular kinase domain. Direct inhibition of the kinase activity of VEGF-R2 makes it possible to reduce the phenomenon of anglogenesis in the presence of exogenous VEGF (Vascular Endothelial Growth Factor) (Strawn et al., Cancer Research, 1996, vol. 56, pp. 3540-3545). This process has been demonstrated in particular using VEGF-R2 mutants (Millauer et al., Cancer Research, 1996, vol. 56, p.16151620). The VEGF-R2 receptor seems to have no other function in the adult than / that linked to the angiogenic activity of VEGF, In addition to this central role in the dynamic angiogenic process, recent results suggest that the expression of VEGF contributes to the survival of tumor cells after chemotherapy and radiotherapy, highlighting the potential synergy of KDR inhibitors with other agents (Lee et al. Cancer Research, 2000, vol. 60, p.5565-5570).

Tie2

Tle-2 (TEK) is a member of a family of tyrosine kinase receptors specific for endothelial cells. Tle2 is the first receptor with tyrosine kinase activity known to have the agonist (angiopoietin 1 or Ang1) which stimulates the autophosphorylation of the receptor and cell signaling [S. Davis et al (1996) Cell 87, 1161-1169] and the antagonist (angiopoietin 2 or Ang2) [P.C. Maisonpierre et al. (1997) Science 277, 55-60). Angiopoietin 1 may have a synergistic effect with VEGF in the late stages of neoangiogenesis [AsaharaT. Wax. Res (1998) 233-240]. The knockout experiments and the transgenic manipulations of the expression of Tie2 or Ang1 lead to animals which present defects in vascularization [DJ. Dumont et al (1994) Genes Dev. 8, 1897-1909 and C. Suri (1996) Cell 87, 1171-1180], Angl's binding to its receptor results in the autophosphorylatlon of the Tle2 kinase domain which is essential for neovascularization as well as for recruitment and the interaction of vessels with pericytes and smooth muscle cells; these phenomena contribute to the maturation and stability of the newly formed vessels [P.C. Maisonpierre et al (1997) Science 277, 55-60]. Lin et al (1997) J. Clin. Invest. 100, 8: 2072-2078 and Lin P. (1998) PNAS 95, 8829-8834, have shown inhibition of tumor growth and vascularization, as well as a decrease in lung metastases, during adenoviral or injections of the extracellular domain of Tie-2 (Tek) in models of breast tumor and melanoma xenografts.

For the reasons that follow, Tle2 inhibitors can be used in situations where neovascularization or angiogenesis occurs inappropriately, i.e. in cancers in general but also in particular cancers such as Kaposi's sarcoma. or childhood hemoangloma, rheumatoid arthritis, osteoarthritis and / or its associated pain, inflammatory bowel diseases such as ulcerative colitis or Crohn's disease, pathologies of the eye such as age-related macular degeneration, diabetic retinopathies, chronic inflammation, psoriasis.

Angiogenesis is a process of generating new capillary vessels from pre-existing vessels. Tumor angiogenesis (formation of

new blood vessels), essential for tumor growth, is also one of the essential factors of metastatic dissemination (Oncogene. 2003 May 19; 22 (20): 3172-9; Nat Med. 1995 Jan; 1 (1): 27-31 .).

This neovascularlsatlon is due to the migration, then to the proliferation and differentiation of endothelial cells under the influence of angiogenic factors secreted by cancer cells and stroma cells (Recent Prog Horm Res. 2000; 55: 15- 35; 35-6).

The angiopoietin 1 / Tle2 receptor system plays a major role in the maturation of vessels by allowing the recruitment of peri-endothelial cells to stabilize the vessel (Cell. 1996 Dec 27; 87 (7): 1161-9, Recent Prog Horm Res, 2004; 59: 51-71). Thus it has been shown that the administration of the soluble recombinant form of the extracellular domain of the Tie-2 receptor (exTek) inhibits tumor angiogenesis in murine tumor models as well as metastatic development (Pengnlan Lin, Jake A. Buxton, Ann Acheson, Czeslaw Radziejewski, Peter C. Malsonplorre, George D, Yancopoulos, Keith M. Channon, Laura P. Haie, Mark W. Dewhlrst, Samuel E. George, and Kevin G. Peters, Proc Natl Acad Sel USA. 1998 Jul 21; 95 (15): 8829-34; Cecllia Melanl, Antonella Stoppacciaro, Chiara Foronl, Federlca Fellcettl, Alessandra Caré and MarloP. Colombo, Cancer Immunol Immunother. 2004 Jul; 53 (7): 600-8). In endothelial cells in culture, stimulation of Tie2 activates the flight of PI3 kinase, p42 / p44 voles involved in cell proliferation and migration; of PAF synthesis (Cell Signal. 2006 Apr 14; ahead of prlnt) vole Involved in pro-inflammatory activity. Stimulation of Tle2 stimulates Akt flight and inhibits apoptosis (Laura M DeBusk, Dennis E Hallahan, Pengnlan Charles Un, Exp Cell Res. 2004 Aug 1; 298 (1): 167-77) a transduction flight known for its importance in cell survival.

The addition of Extek (soluble Tle2 receptor) Inhibits the formation of endothelial cell pseudo tubules on Matrigel (Cecllia Melanl, Antonella Stoppacciaro, Chiara Foronl, Federlca Fellcettl, Alessandra Caré and MarloP. Colombo, Cancer immunol Immunother. 2004 Jul; 53 (7): 600-8. These studies indicate that the Tie2 / Anglopoletin system is necessary during the early stages of vascular bud formation in adult tissues and that a function of the Tle-2 receptor is to increase the survival of endothelial cells during the formation of blood vessels. In addition, angiopoletlne-l stimulates the proliferation of lymphatic endothelial cells as well as lymphangiogenesis (development of lymphatic new vessels) preferred pathway for metastatic development (Tohru „„ Morlsada , Yulchl Olke, Yoshihlro Yamada, Takashi Urano, Masakl Akao, Yoshlaki Kubota, Hlromitsu Maekawa, Yoshishlge Kimura, Masako Ohmura, Takeshl

Mlyamoto, Shiro Nozawa, Gou Young Koh, Kari Alltalo, and Toshio Suda, Blood. 2005 Jun 15; 105 (12): 4649-56).

Among the enzypes having a role in anglogenesis we can also cite PDGFRp (Guzman and Laurence H. Hurley, Univ of Arizona Molecular Clonlng of the Human PDGFR-beta Promoter and Targeting the G-Quadruplex-Formlng Region to Control gene Expression; Blomedlcal Drug Discovery, Genomics / Gentlcs, Therapeutic), FGFR1 (Somala Elbauomy Elsheikh, Andrew R Green, ¹ Maryou BK Lambros, Nicholas C Turner, Matthew J Grainge, ³ Des Powe, ¹ lan O Ellls, and Jorge S Rels-Fllho, FGFR1 amplification in breast carcinomas: a chromogenlc in situ hybridization analysis; FLT1 (Shlbuya M (2007). Vascular endothelial growth factor receptor-1 (VEGFR-1 / FIM): a dual regulator for anglogenesls .. Angioganesis 9 (4): 225- 30; discussion 231 and VEGFR3 (Tamela, T. et al. Blocking VEGFR-3 suppresses anglogenlc sprouting and vascular network formation, Nature 454, 656660 (20058).

Angiogenesis processes therefore play a major role in the progression of many solid tumors. In addition, it has been shown that the probability of the appearance of metastases increases very strongly with the increase in the vascularization of the primary tumor (Br J Cancer. 2002 May 20; 86 (10): 1566-77, The potential role of pro-anglogenic agents in leukemia and lymphoma has also been and more recently documented. In general, it has been reported that cell clones in these pathologies can either be destroyed naturally by the immune system or switch to an angiogenic phenotype. which promotes their survival and then their proliferation.This change in phenotype is induced by overexpression of angiogenic factors, in particular by macrophages and / or mobilization of these factors from the extracellular matrix (Thomas DA, Glles FJ, Cortès J, Albltar M, Kantarjian HM., Acta Haematol, ¢ 2001), vol 207, ρρ106Ί90.

There is a correlation between the process of angiogenesis of the bone marrow and the extramedullar disease in CML (chronic myelomonocytic leukemia), Different studies show that the inhibition of angiogenesis could represent a therapeutic choice in this pathology (Leuk Res. 2006 Jan; 30 (1): 54-9; Hlstol Histopathol. 2004 Oct; 19 (4): 1245-60. In addition, it is strongly suggested that activation of the Tle2 / angiopoletin system is involved in the development of bone marrow angiogenesis in patients with multiple myeloma (Blood. 2003 Jul 15; 102 (2): 638-45

Determination of the activity of compounds - Experimental protocols

1. KDR

The inhibitory effect of the compounds is determined in an In vitro substrate phosphorylation test by a scintillation technique (96-well plate of the basic Flash Plate type).

The cytoplasmic domain (residues 790-1356) of the human KDR enzyme was cloned as a GST fusion into the baculovirus expression vector pFastBac. The protein was expressed in SF21 cells, purified and activated by autophosphorylation. The substrate is composed of residues 658-850 of PLCγ expressed and purified as a GST fusion protein.

The kinase activity of KDR is measured in 20 mM MOPS buffer, 10 mM MgCl2, 10 mM MnCl2, 1 mM DTT, pH = 7.4, The compounds are initially diluted in 100% DMSO and then prepared in 10X solution in DMSO 30 % - 70% buffer. 10 μΙ of 10X solution are deposited then 70 μΙ of buffer containing 150 ng (1.6 pmole) of KDR enzyme at 4 ° C. The reaction is started by adding 20 μΙ of solution containing 2 μg (41 pmole) of PLC substrate% 0.5 pCI of y ^ PfATP] and 2 μM of cold ATP. The plate is agitated. After 30 minutes of incubation at 37 ° C, the incubation buffer is removed and the wells are washed three times with 300 µl of PBS. The radioactivity is measured in each well using a Trilux-pWallac radioactivity counter.

The background noise is determined by measuring the radioactivity in four different wells containing ΓΑΤΡ (radiolabeled and cold) and the substrate, in the absence of enzyme and compound. The control activity is measured in four different wells containing all the reagents but in the absence of compound.

Inhibition of KDR activity with the compound of the invention is expressed as a percentage inhibition of the control activity determined in the absence of compound.

2.

Tle2

The inhibitory effect of the compounds is determined in an In vitro substrate phosphorylation test by a scintillation technique (96-well plate of the basic Flash Plate type).

The coding sequence of human Tle2 corresponding to the amino acids of the intracellular domain 774-1124 was introduced into a baculovirus expression vector pFastBacGT in the form of a GST fusion protein. GST-Tie2 was purified and activated by autophosphorylation. The substrate is composed of residues 658 to

850 of PLCy expressed and purified as a GST fusion protein.

The kinase activity of Tle2 is measured in a 20 mM MOPS buffer, pH 7.4, containing 10 mM MgCh, 10 mM MnCl ₂ , 1 mM DTT. The compounds are initially diluted in 100% DMSO and then prepared in 10X solution in 30% DMSO, 70% buffer. 10 μl of 10X solution are deposited then 70 μl of buffer containing 100 ng (1.5 pmol) of Tle2 enzyme at 4 ^q C. The reaction is started by adding 20 μl of solution containing 2 μg (41 pmol) of PLCy substrate , 0.5 yCl of γ ^ ΡΙΑΤΡ] and 2 yM of cold ATP. The plate is agitated. After 30 minutes of incubation at 37 C ^q, the incubation buffer is removed and the wells are washed three fools with 300 yl of PBS. The radioactivity is measured in each well using a TrIlux-pWallac radioactivity counter.

The background noise is determined by measuring the radioactivity in four different wells containing ΓΑΤΡ (radiolabeled and cold) and the substrate, in the absence of enzyme and compound. The control activity is measured in four different wells containing all the reagents but in the absence of compound.

The inhibition of Tie2 activity is calculated and expressed as a percentage of inhibition relative to the control activity determined in the absence of compound.

3, Screening of molecules by measuring by radioactive labeling the phosphorylation activity of FLTI kinase in the presence of PFCy substat.

The kinase activity of FLT1 is measured in the same way as the Inhlbitlon of Tie2 with a reaction mixture composed of 70 μL of kinase buffer containing 13 nM of FLT1 enzyme per well

The inhlbitlon of FLT1 activity is calculated and expressed as a percentage inhibition relative to the control activity determined in the absence of compound.

The percentage of Inhibltlon corresponding to each concentration of molecules is calculated as follows:

% inhibition = (average of CRMs of treated wells - average of CPMs of control wells) / (CPM of untreated wells - average of CPMs of controls) x 100

4. Screening of molecules measuring by radioactive labeling the phosphorylation activity of PDGFR kinase in the presence of the substrate PLCy

The test is carried out in parallel with that carried out with the enzyme FLT1 using en in place of 13 nM of Flt1; 16 nM of PDGFR enzyme and in the 96-well plates, 16 μl of GST-PDGFR enzyme at 4 mg / ml (for a purity of 80%) are mixed, batch VLT802

5. Screening of molecules measuring by radioactive labeling the phosphorylation activity of FGFR kinase in the presence of the PLCy substrate

The test is carried out in a manner parallel to that carried out with the enzyme FLT1 using instead of 13 nM of Flt1; 27 nM of FGFR enzyme and in the 96-well plates, 18μΙ of GST-FGFR enzyme are mixed at 1.1 mg / ml (for a purity of 100%): (Batch JCE3666)

Results:

The compounds of the examples of the invention have a concentration inhibiting 50% of the activity of the kinase which is generally between 0.1 nM and 2 μΜ on KDR and / or TIE2, preferably between 0.1 nM and 500 nM _t and more preferably between 0.1 nM and 50 nM. The values in Table 1, below, are given by way of illustration.

COMPOUNDS KDR ΠΜ Tie2 nM PDGFRp nM FGFR1 nM FLT1 nM VEGFR3 nM • w 0 Ÿ, F "Z 3 36 11 54 3 3 VV ' Ύ T W Λ 2 39 20 92 1.3

The compounds according to the invention have been the subject of pharmacological tests making it possible to determine their hepatic clearance.

Assessment of Intrinsic Clearance of Compounds Using Human Hepatocytes: Experimental Protocol.

NB: The In vitro test described below on human liver cells is used to predict an important pharmacokinetic parameter: metabollsation by the liver for a given compound when it is administered to humans.

Culture condition:

Incubations of cryopreserved preparations of human hepatocytes (from IVT: IVT-TLN-180608 from In Vitro Technologies, Inc, Baltimore, Maryland, USA and fresh preparations of human hepatocytes (from Biopredlc: HEP200239) were made in plates comprising 48 wells coated with collagen.

Experimental conditions:

The kinetics were started by the addition, in the culture medium, of the compounds at a final concentration of 5μΜ, in the absence or in the presence of Ketoconazole 10μΜ (inhibitor of CYP3A4 The incubation volume is 100 μί, the incubation time: 0 - 24 hours (usual kinetic points: 0-0.5 -1 - 2 - 4 - 6 - 8 - 24 hours).

The kinetics were stopped by the addition of acetonltrile / water, with cortlcosterone, as internal standard. The cells were detached and then lysed. Intracellular and xtracellular media were pooled and frozen (-20 ° C) to be stored until LC-MS / MS analysis.

LC-MS / MS analytical method:

The combined intracellular and extracellular media were thawed, sonicated, vortexed, and centrifuged at 3000g for 20 minutes. The supernatants were injected and analyzed by LC-MS / MS,

Data processing and “grading” • The maximum initial In vitro rate was calculated for specific metabolites of cytochrome P450 and expressed in nmol / hour / million cells.

V = [concentration at T (n) - concentration at T (n-1)] / [T (n) - T (n-1)]

Intrinsic clearance was determined and expressed in mL / hour / mL of cell

Clmt = dose / AUC0-24h

Dose = amount at T (0) (nmoles / milllon of cells)

AUC0-24h: calculated by WlnNonlin, with a non-compartmentalized analysis, modeling an intravenous injection of bolus type

The classification of Intrinsic clearance was defined as follows:

Cli _{n (} <0.040 mL.hr ' ¹ .10'® cell: intrinsic clearance Intermediate

0.040 <Clmi <0.120 mL.hr ' ¹ .10' ^th cell; low intrinsic clearance

Clmi> 0.040 mL.hr ' ¹ .1 θ' ⁶ cells: high intrinsic clearance

Donor demographic information:

Preparations of cryopreserved human hepatocytes:

IVT: IVT, TLN group: Male, Caucasian, 25 years old

Fresh human hepatocyte preparations:

From Blopredlc: HEP200239: Female, Unknown, 58 years old

On this test, the intrinsic clearance value of the compound described in the example is 0.057 ml / hour / mlllon of cell (value classified as Intermediate with low inter-individual variability).

The intrinsic clearance value of the compound described in Example 2 is 0.055 mUhour / mllIIon of cell (value classified as Intermediate with low inter-individual variability).

[0024] Other tests consisting in measuring the in vivo activity of the compounds of the invention on colon tumors were carried out.

[0025] This activity on colon tumors of the compounds of the invention was studied on B16 melanoma. In comparison, the product of example 19 of application WO08065282 was tested.

The efficacy of a product can be determined In vivo by different criteria, it can be determined by the percentage of tumor inhibition% T / C which represents the ratio between the average weight of tumors in the treated group (T) and the average weight tumors in the control group (C) on day 12 or 13 of treatment. We consider an active product when the T / C ratio is less than 42% and a product having a high antitumor activity when the T / C is less than 10%. (Corbett TH et al., Cancer Research, 42, 1707-1715 (1982).

To demonstrate the effectiveness of a compound, we can also determine the Iog10 killed cells which is determined according to the following formula:

log-d q of killed cells »TC (days) /3.32 XT (d in which TC represents the delay in cell growth which is the average time, in days, for tumors in the treated group (T) and tumors in the control group (C) have reached a predetermined value (750 mg for example) and Tj represents the time, in days, necessary for the doubling of the volume of the tumor in the control animals [TH, CORBETT et al., Cancer, 4Q, 2660.2680 (1977); FM, SCHABEL et al., Cancer Drug Development, Part B, Methods In Cancer Research, 17, 3-51, New York, Academie Press Inc. (1979)] A product is considered to be active if log- ιο of killed cells is greater than or equal to 0.7 A product is considered to be very active if the log-jθ of killed cells is greater than 2.8.

The efficacy of the compounds on solid tumors can be determined experimentally as follows:

The animals subjected to the experiment, generally C57BL / 6 female mice, are grafted bilaterally by the subcutaneous route with 30 to 60 mg of a fragment of human tumor B 16 (Tumor reference) on day 0. animals bearing the tumors are randomized before being subjected to the various treatments and controls. In the case of treatment of tumors of the present invention, treatment was initiated at an early stage, 3-4 days after implantation. The animals which underwent the treatment with the compounds had a weight of about 20 g. Tumor-bearing animals were also subjected to the same treatments with the excipient alone in order to be able to dissociate the toxic effect of the excipient from the specific effect of chemotherapy on the tumor. The administrations of the compounds were made orally at the doses indicated in the tables and with the excipients indicated in the tables according to a double daily administration. These administrations were carried out for 8 to 11 days depending on the studies, after implantation of the tumor.

Tumors are measured two or three times per week until the tumor reaches about 2 g or Until the animal's death if this occurs before the tumor reaches 2 g. The animals are autopsied during sacrifice.

The antitumor activity is determined according to the various parameters recorded.

By way of examples, the results obtained with the compounds of the invention used at their optimum dose are given in the following tables.

[0027] Thus the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt of the latter with a pharmaceutically acceptable acid.

According to another of its aspects, the invention relates to the compounds corresponding to formula (I) for their application as a medicament in the treatment of cancer. The compounds according to the invention can be used for the preparation of medicaments, in particular of angiogenesis inhibitor medicaments.

These medicaments find their use in therapy, in particular in the treatment of cancerous tumors, in particular of solid tumors.

[0030] According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, of said compound, as well as at least one pharmaceutically acceptable excipient.

The excipients are chosen, depending on the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, Intratracheal, Intranasal, transdermal or rectal administration, the active principle of formula (l) cl Above, or its salt, may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the treatment of the above disorders or diseases.

[0032] Appropriate unit administration forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual and buccal administration forms, transdermal, subcutaneous, intramuscular or intravenous administration.

By way of example, a unit form of administration of a compound according to the invention in tablet form may comprise the following components \

Compound according to the invention Mannltol

Croscaramellose sodium Corn starch

Hydroxypropyl-methylcellulose

Magnesium stearate

50.0 mg

223.75 mg

6.0 mg

15.0 mg

2.25 mg

3.0 mg Orally, the dose of active principle administered per day can reach 1200 mg / kg, in one or more doses.

There may be particular cases where higher or lower dosages are appropriate: such dosages are not outside the scope of the invention. According to usual practice, the dosage appropriate for each patient is determined by the doctor according to the mode of administration, the weight and the response of said patient.

The present invention, according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises the administration, to a patient, of an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt thereof. zf

EVALUATION OF EXAMPLE 1 AGAINST EARLY MURINE MELANOMA B16

Comments H DT active Active Active Inactive β »φ a. 1 a .g -a (0 CO CM CO o> = 5 43 ο φ B o _ | o - CM CM S £ E CO 6.2 CM " T-C JOL 750 CD CD c CO di v T / C < % day CM IO O v m 45 = Φ «© · ÔÔ O Ό CD O) CO 10 c E £ £ O o> „ (0-89) i? o_ K <7 m K M T 3 U> t <0 0) t: b t- CO CM CO <N CM S * w "b CM K (D '' T S E o 0 3 · = »Û. ~ T “ oo CD CO CO "3 O, b Or O 2 ê CO ίΓ o 5 CO m £ .9 (15 % BW of i -2. 1 + o + +11 φ 3 ra b _ S »o -g 5 o 2 LD tn u> 10 o t 3 _ffl Or ^- O o o o o 2 2 tx vs Total dose e mg / kg JB æ AT 3178 <0 CD 0> T- CM CO CM T * T “* 5 vs Φ "c o o CD œ o> CM (D 44 g E O vs é p.o r [ratio * R CM, o o = Q. Ό .E W— .. <M JD M- V container E E Ο Ό Q, E e M Q " U φ X 3 O 3 o x O READ -> LU CL

EVALUATION OF EXAMPLE 2 AGAINST EARLY MURINE MELANOMA B16

Comments Toxic HNTD active Active Active Total cell kill log I ® O <r “ T-C in days 750 mg , Tt O O iri iri ri T / C in% day 11 Mean tumor weight in mg on day 11 (tidy) 0 (0-14) 46 (0-95) 201 (23-822) 736 (222-1328) % BWC (day of nadir) co* T *. v- K “Ϊ́? œ “f 8 ÿ T τV CO e> + Death due to product (day of death) "R FT laughed (û (fl tO r- ο δ δ cî ο V- S δ 0/10 Total dose in mg / kfl θ ο S ® £ S ΙΟ 10 ® J2 CM τ- Dosage in mg / kg / adm 'P CM ΙΟ Ο s S5 5 Compound p.o. (Day administration) Example 2 Day 3-10 (2x / d) Day 3-10 Excipient PO 3-10 (2x / d)

8. E £ σ> g

Q CO

Formulation: Example 2 = 20% labrasol _f 5% solutol, 75% glucose, 5% water. Abbreviations used: BWC = body weight change, HNTD = highest nontoxic dose, HDT = highest dose tested.

Comments HDT active Active Inactive Total cell kill log CM ©. T * T T-C in days 750 mg CM CD, co T / Cen % day 12 © O CD w co m Average tumor weight in mg on day 12 (range) 441 (270-594) 459 (394-949) 849 (576-1093) 1522 (1000-1762) % BWC (day of nadir) +8.3 (14) +10.6 (14)> 0.0 (4) T— CO 00 T- + Death due to product (day of death) O O O 0/10 Total dose in mg / kg AA ~ CO c *> O S s | CM v ^œ Dosage in mg / kg / adm 120.0 74.4 46.1 1 Compound (day of administration) Example 18 of WO08065282 p.o. 3-13 (2x / d) Excipient p.o. 3-13 (2x / d)

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Claims (9)

1. Compound corresponding to formula (I) in which: X represents chlorine or fluorine, in the form of a base or of an addition salt with an acid. 2. Compound of formula (l) according to claim 1, characterized in that X represents chlorine, in the form of a base or of an addition salt with an acid. 3. Process for preparing a compound of formula (I) according to any one of claims 1 to 2, characterized in that the following compound is reacted '' o'V n-n H with the compound 'TÇrY'à. ,, CHO in the presence of dllsoproplyethylamlne in an inert medium, then in a second step, the amine is deprotected with para toluene sulfonic acid. 4. Method according to claim 3, characterized in that the inert medium in an apolar aprotlque medium, preferably tetrahydrofuran. 5, Compound of formula x CHO where X represents chlorine or fluorine. 6. Compound of formula o / o F where X represents chlorine or fluorine. 7. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 2, or an addition salt of this compound with a pharmaceutically acceptable acid. 8. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 2, or a pharmaceutically acceptable salt of this compound, as well as at least one pharmaceutically acceptable excipient. 9. A compound corresponding to formula (I) according to any one of claims 1 to 2 for its application as a medicament in the treatment of cancer.