HK1122797B - Derivatives of pyrido[2,3-d]pyrimidine, the preparation thereof, and the therapeutic application of the same - Google Patents

Description

Pyrido [2,3-d ] pyrimidine derivatives, their preparation, their use in therapy

The present invention relates to pyrido [2,3-d ] pyrimidine derivatives, their preparation and their use in therapy.

Compounds derived from pyrido [2,3-d ] pyrimidines are described in patent applications WO 01/55147 and WO 03/000011 and in patents EP-B-790997 and US 5733913. These compounds have potential use in the treatment of cell proliferative disorders.

Thus, according to a first aspect, an object of the present invention is a compound corresponding to formula (I):

in the formula:

-R₁is selected from (C)₁-C₆) Alkyl, (C)₁-C₆) Alkyl radical- (C)₃-C₇) Cycloalkyl radical, CH₂COR₃Phenyl, or substituted by hydroxy and/or halogen and/or (C)₁-C₆) Alkyl-substituted phenyl;

-R₃represents a hydroxyl group, (C)₁-C₄) Alkoxy, amino, (C)₁-C₄) Alkylamino radical, di (C)₁-C₄) An alkylamino group;

-Ar₁represents a radical selected from:

wherein X represents O or S, Y represents CH₂Or NH, and R₂Selected from H, (C)₁-C₆) Alkyl or (CH)₂)_nNR₄R₅And R'₂Is (CH)₂)_nNR₄R₅；

-R₄And R₅Each independently of the others represents a radical selected from H, (C)₁-C₄) Alkyl, (C)₁-C₆) Alkyl radical- (C)₃-C₇) Cycloalkyl group, (C)₃-C₇) Cycloalkyl, C (═ NH) NH₂、SO₂(C₁-C₆) Substituent of alkyl, R₅Can also represent CO- (C)₁-C₄) Alkyl, CO- (C)₃-C₇) Cycloalkyl, CO-aryl, SO₂-an aryl, tert-butoxycarbonyl or benzyloxycarbonyl group;

-or R₄And R₅Together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl radical, said radical being unsubstituted or substituted by (C)₁-C₆) Alkyl, (C)₁-C₄) alkyl-OH, COO (C)₁-C₆) Alkyl groups are substituted one or more times;

-Ar₂represents an unsubstituted phenyl group or is selected from halogen atoms, (C)₁-C₄) Alkyl, trifluoromethyl or (C)₁-C₄) The same or different substituents of the alkoxy group are substituted for 1 to 5 times;

n represents 1, 2 or 3.

According to a preferred embodiment, the compounds of the formula (I) have a substituent Ar₁It represents a radical selected from:

in the formula R₂Is CH₃Or (CH)₂)_nNR₄R₅And R'₂Is CH₂NR₄R₅In the formula, R₄And R₅Independently selected from H and (C)₁-C₆) Alkyl, Y represents CH₂Or NH.

The products of the invention advantageously have a substituent Ar₂It represents the following group:

in the formula R₆、R₇Each independently selected from H, CH₃、OCH₃、F、Cl、Br。R₆And R₇Advantageously in 2 and 6 bits.

The products of the invention advantageously have a substituent Ar₂Selected from the group consisting of phenyl, 2-methoxyphenyl, 2, 6-dichlorophenyl, 3, 5-dimethoxyphenyl, 3, 4-dimethoxyphenyl, 2, 6-dibromophenyl, 2-bromo-6-chlorophenyl, 2, 4-dichlorophenyl, 3, 5-dichlorophenyl, 2, 6-dimethylphenyl and 2, 6-difluorophenyl.

According to a preferred embodiment, the compounds of the formula (I) have a substituent Ar₁It represents a radical selected from:

more particularly preferred compounds of the invention are:

(N- [2- (2, 1, 3-benzothiadiazol-5-ylamino) -6- (2, 6-dichlorophenyl) pyrido [2,3-d ] pyrimidin-7-yl ] -N' - (1, 1-dimethylethyl) -urea).

The present invention is directed to the following example compounds.

The compounds of the invention may be (i) in achiral, or racemic, or stereoisomerically-enriched, or enantiomerically-enriched form; (ii) optionally salifying, (iii) optionally hydrating or solvating.

The compounds of formula (I) may contain one or more asymmetric carbon atoms. They may thus exist in enantiomeric or diastereomeric forms. These enantiomers, diastereomers and mixtures thereof, including racemic mixtures, are part of the present invention.

The compounds of formula (I) may exist in the form of a base or an addition salt with an acid. When the compounds of formula (I) contain free acid functions (e.g. carboxylic acid, sulphonic acid, phosphoric acid), these acid functions may be basified with a base to form an addition salt. Such addition salts are part of the present invention.

Advantageously, the addition salts of these acids or bases are prepared using pharmaceutically acceptable acids or bases, respectively, but useful salts of other acids or bases, for example, the salts of acids or bases used in the purification or isolation of the compounds of formula (I), are also part of the invention.

The compounds of formula (I) can also exist in the form of hydrates or solvates, i.e. associated with or bound to one or more water molecules or solvents. Such hydrates or solvates are also part of the present invention.

Within the scope of the invention, it should be understood that:

-a halogen atom: fluorine, chlorine, bromine or iodine;

-an alkyl group: a straight or branched chain saturated aliphatic group. Examples thereof include the following groups: methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, 1-methylethyl group, 1-methylpropyl group, 2-methylpropyl group, 1-dimethylethyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1-dimethylpropyl group, 1, 2-dimethylpropyl group, 2-dimethylpropyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1-dimethylbutyl group, 1, 2-dimethylbutyl group, 1, 3-dimethylbutyl group, 2-dimethylbutyl group, 2, 3-dimethylbutyl group, 3-dimethylbutyl group, 1, 2-trimethylpropyl group, 1-dimethylpropyl group, 1, 2-dimethylpropyl group, 1, 2, 2-trimethylpropyl, 1-ethyl, 1-methylpropyl, 1-ethyl, 2-methylpropyl, 1-ethylbutyl, 2-ethylbutyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-dimethylpentyl, 1, 2-dimethylpentyl, 1, 3-dimethylpentyl, 1, 4-dimethylpentyl, 2, 2-dimethylpentyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 3-dimethylpentyl, 3, 4-dimethylpentyl, 4-dimethylpentyl, 1, 2-trimethylbutyl, 1, 3-trimethylbutyl, 1-ethylbutyl, 2-methylpropyl, 1-ethylbutyl, 2-dimethylpropyl, 1-ethylbutyl, 1, 2, 2-trimethylbutyl, 1, 2, 3-trimethylbutyl, 1, 3, 3-trimethylbutyl, 2, 2, 3-trimethylbutyl, 2,3, 3-trimethylbutyl, 1, 2, 2-tetramethylpropyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 1-ethyl, 1-methylbutyl, 1-ethyl, 2-methylbutyl, 1-ethyl, 3-methylbutyl, 2-ethyl, 1-methylbutyl, 2-ethyl, 2-methylbutyl, 2-ethyl, 3-methylbutyl, 1-propylbutyl, 1- (1-methylethyl) butyl, 1- (1-methylethyl), 2-methylpropyl.

-a cycloalkyl group: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.1] heptyl, cyclooctyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, adamantyl.

A compound of formula (I) is prepared by reacting a compound of formula (II):

in the formula R₁And Ar₂Is as defined in (I) with formula Ar'₁NH₂(III) amine reaction, wherein Ar 'is'₁Represents Ar as defined under (I)₁Or Ar₁A precursor of (a); if necessary, the radical Ar 'of the compound is thus obtained'₁Conversion to the group Ar₁。

According to the invention, the compounds of formula (I) can be prepared by a process which is characterized in that the following compounds are reacted:

(i) a compound of the formula:

in the formula R₁₀Is a leaving group, for example: (a) halogen, in particular Cl or Br, or (b) alkyl-s (o) m-, wherein m is 0, 1, or 2; r₁₁Is NHC (O) -NH-R₁(ii) a And

(ii) ar 'of formula'₁NH₂(III) amine, formula Ar'₁Represents Ar as defined under (I)₁Or Ar₁A precursor of (a); the radical Ar 'of the compound thus obtained is, if necessary'₁Conversion to the group Ar₁。

When R is₁₀Is halogen or alkyl-s (o) m-, wherein m ═ 2, the reaction is carried out in a solvent, preferably in the following polar solvents, at a temperature ranging from room temperature to the reflux temperature of the solvent:

(i) for example tetrahydrofuran, dimethyl sulfoxide or ethanol, optionally in the presence of trace amounts of an acid (e.g. hydrochloric acid); or

(ii) In dimethyl sulfoxide, in the presence of a strong base such as tBuOK.

When R is₁₀Is alkyl-S (O) m-, wherein m-0 or 1, preferably at a temperature close to 200 ℃, in the absence of catalyst with molten Ar'₁NH₂(III) carrying out the reaction.

Ar 'radical of Compound (III), if necessary'₁The amine functions present in (a) have been previously salified or protected.

The compound of formula (II) was prepared in the manner described in european patent 790997 and us patent 5733913, as described in scheme 1 below:

scheme 1

mCPBA: meta-chloroperbenzoic acid.

Formula Ar 'is already known'₁NH₂(III) amine, or, by known methods, using the corresponding nitro derivative Ar'₁NO₂(IV) the amine of formula (III) is prepared by reduction using hydrogen in either (i) an acidic medium in the presence of a metal such as iron or zinc powder, or (ii) a catalyst such as Pd/C. Ar' represents Ar or a precursor of Ar.

The compounds of the formula (IV) are known or can be prepared by known methods.

To obtain the compound of the invention in racemic form; optically pure isomers can then be prepared by resolution methods known to those skilled in the art, for example by crystallization from salts with chiral agents. Optically pure compounds of the invention may also be prepared by asymmetric or stereotactic synthesis using chromatographic techniques employing a chiral phase. In addition, the products of the invention can be prepared by forming diastereomers, separating them, and then decomposing the pharmacologically useful diastereomer into its enantiomerically pure active product. Enzymatic techniques may also be employed. Known assisted separation techniques may be employed. They include the techniques discussed in the following references: enantiomers, Racemates and resolution (Enantiomers, Racemates, and solutions), John Wiley and Sons, New York (1981).

The compounds of the invention may also be prepared in stereoisomerically enriched form by preparing synthetic intermediates. Thus, the resolution of the enantiomers of the amine or nitro precursor (IV) of formula (III) can be achieved by the above-described method.

The following examples describe the preparation of certain intermediates and compounds of the invention. These examples are not limiting and are intended to be illustrative of the invention.

The following abbreviations are used in these examples:

boc: tert-butoxycarbonyl group

BOP: benzotriazol-1-yloxytris (dimethylamino) hexafluorophosphate。

THF: tetrahydrofuran (THF)

TA: at room temperature

TFA: trifluoroacetic acid

DCM: methylene dichloride

DMSO, DMSO: dimethyl sulfoxide

DMF: dimethyl formamide

MeOH: methanol

DCCI: dicyclohexylcarbodiimide

DIPEA: diisopropylethylamine

KHSO₄/K₂SO₄：5％KHSO₄/K₂SO₄Solutions of

In DMSO-d, unless otherwise indicated₆Proton Nuclear Magnetic Resonance (NMR) spectra were recorded at 200MHz or 250 MHz. DMSO-d₆The signal was at 2.5ppm and used as reference. The following abbreviations are used in the explanation of the spectra: s: singlet, d: doublet, t: triplet, m: unresolved peak, mt: multiplet, se: broadened singlet, dd: split doublet, qd: quartet, qt: quintuple peak.

F: the melting temperature (degrees Celsius) was determined with a temperature gradient of 1 ℃ per minute using a Buchi B545 apparatus.

MH +: and (4) mass spectrometry. The compounds were analyzed by HPLC-UV-MS (liquid chromatography-UV detection-mass spectrometry) in combination. The apparatus sold using Agilent was chromatographed by HP1100 equipped with an Agilent diode strip detector and an MSD Quad quadrupole mass spectrometer.

The analysis conditions were as follows:

column: symmetry C18 (50X 2.1 mm; 3.5 μm)

Eluent A: h₂O+0.005％TFA，pH 3.15

Eluent B: CH (CH)₃CN+0.005％TFA

Gradient:

time (min)% B

0 0

10 90

15 90

16 0

20 0

Column temperature: 30 deg.C

Flow rate: 0.4mL/min

Detecting: λ 210nm

tr: retention temperature

v: volume.

Preparation of the compound of formula (II).

Preparation 1

N- (t-butyl) -N' - [6- (2, 6-dichlorophenyl) -2- (methylsulfonyl) pyrido [2,3-d ] pyrimidin-7-yl ] urea.

1.14-amino-2- (methylthio) pyrimidine-5-carboxylic acid ethyl ester.

To a suspension of 50.7g of ethyl 4-chloro-2- (methylthio) pyrimidine-5-carboxylate in 400mL of EtOH, while maintaining the temperature at about 20 deg.C, 140mL of 20% NH was added over 20 minutes₄And (4) OH solution. After stirring at room temperature for 20 hours, the reaction medium is concentrated to near dryness in vacuo, then the residue is dissolved in 350mL of water, stirred for 20 minutes, filtered, washed with 3X 60mL of water and then washed at P₂O₅Vacuum drying is carried out in the presence. White solid was obtained, F-134-.

1.2[ 4-amino-2- (methylthio) pyrimidin-5-yl ] methanol.

To 39.68g of the ester obtained in the preceding step dissolved in 1 l of THF are added 210mL of 1M LiAlH over 45 minutes₄Solution in THF while maintaining the temperature below 30 ℃. Stirring was continued for an additional 1 hour, then the temperature was lowered to 5 ℃ and 9mL of water, 6.5mL of 5N sodium hydroxide, and an additional 32mL of water were added dropwise. After stirring for 10 minutes, the solid was filtered and rinsed with THF. The filtrate was concentrated to dryness in vacuo and the residue was redissolved in 600mL of boiling toluene, filtered quickly hot to remove a little insoluble material and the filtrate was allowed to cool overnight. The resulting white crystals were filtered, washed with a small amount of toluene, then with ether and dried, F ═ 124-.

1.34-amino-2- (methylthio) pyrimidine-5-carbaldehyde.

Over 2 minutes, 79.5g of active MnO were added to a suspension of 23.8g of the alcohol obtained in the previous step in 1600mL of chloroform₂Then stirred overnight at room temperature; the solid was filtered and washed with 3X 75mL of CHCl₃Washing, and vacuum concentrating the filtrate to dryness; the white solid residue was dissolved in ether, filtered and dried, F184-.

1.46- (2, 6-dichlorophenyl) -2- (methylthio) pyrido [2,3-d ] pyrimidin-7-amine.

After a solution of 21g of the aldehyde obtained in the preceding step in 240mL of DMF had been cooled to 5 ℃ over 5 minutes, 5.47g of 60% NaH was added, followed by addition in small portions over 20 minutes29.05g of 2, 6-dichlorophenylacetonitrile were added. Stirred at 5 ℃ for 30 minutes and then at room temperature overnight. The reaction medium was cooled to 5 ℃ and 65mL of NH were added₄A saturated solution of Cl, then 500mL of water/ice mixture; filtering the generated red precipitate, washing with water for 2 times, fully dehydrating, washing with diethyl ether and 100mL of chloroform, and washing with diethyl ether; after drying, a light brown solid was obtained, F ═ 250-.

The washed ether and chloroform phases are concentrated to dryness and then dissolved in a small amount of chloroform, to which solution ether: a second 3.15g portion was obtained, with a total of 33.07 g.

1.5N- (t-butyl) -N' - [6- (2, 6-dichlorophenyl) -2- (methylthio) pyrido [2,3-d ] pyrimidin-7-yl ] urea.

To a solution of 29.9g of the previously obtained amine in 300mL of DMF, 4.6g of 60% NaH was added over 10 minutes, maintaining the temperature below 25 ℃; stirring was continued for another 20 minutes, then 12.2mL of t-butyl isocyanate was added over 20 minutes, followed by stirring overnight. The reaction medium is slowly poured into 800mL of a water/ice mixture +100mL of 6N HCl; the precipitate formed is filtered, washed with water, dehydrated and then stirred in 300mL of diethyl ether for 1 hour, filtered again, washed with diethyl ether and dried. A light brown solid was obtained, F195 ═ 196 ℃ (decomposed), m 26.5 g.

6N- (t-butyl) -N' - [6- (2, 6-dichlorophenyl) -2- (methylsulfonyl) pyrido [2,3-d ] pyrimidin-7-yl ] urea.

To a solution of 21.95g of the previously obtained urea in 300mL of chloroform was added 27g of m-chloroperbenzoic acid (77%) over 25 minutes while maintaining the temperature below 25 ℃. A precipitate formed. After 2 hours, the reaction medium is diluted with 1 l of dichloromethane and Na is then added₂SO₄Further, 14g of Ca (OH) was added₂. After stirring for 30 minutes, the solid was filtered, washed with dichloromethane, and the filtrate was concentrated to dryness. The residue is triturated hot in 80mL of diethyl ether; it was allowed to cool and the white solid was then filtered, washed with ether and dried, F ═ 138-.

The following compounds of the general formula (II) can be prepared in the same manner as described for the preparation of 1:

TABLE 1

Preparation of	Ar2	R1	NMR
				1	2, 6-dichlorophenyl	Tert-butyl radical	1.40：s：9H；3.50：s：3H；7.50-7.70：m：3H；8.55：s：1H；9.10：s：1H；9.60：s：1H；9.95：s：1H。
2	2, 6-dichlorophenyl	Phenyl radical	3.50ppm：s：3H；7.10ppm：t：1H；7.40ppm：t：2H；7.55-7.75ppm：m：5H；8.60ppm：s：1H；9.60ppm：s：1H；9.80ppm：s：1H；11.90ppm：s：1H。
				3	3, 5-Dimethoxyphenyl	Tert-butyl radical	1.40ppm：s：9H；3.50ppm：s：3H；3 80ppm：s：6H；6.65-6.80ppm：mt：3H；7.75ppm：s：1H；8.45ppm：s：1H；9.60ppm：s：1H；9.80ppm：s：1H。
4	2, 6-dichlorophenyl	Ethyl radical	1.20ppm：t：3H；3.40ppm：qd：2H；3.50ppm：s：3H；7.50ppm-7.75ppm：m：3H；8.55ppm：s：1H；9.40ppm：s：1H；9.60ppm：s：1H；9.70ppm：s：1H。

5	3, 4-Dimethoxyphenyl	Tert-butyl radical	1.40ppm：s：9H；3.45ppm：s：3H；3.80ppm：s：3H；3.90ppm：s：3H；7.10-7.20ppm：m：3H；7.75ppm：s：1H；8.45ppm：s：1H；9.55ppm：s：1H；9.80ppm：s：1H。
				6	Phenyl radical	Tert-butyl radical	1.40ppm：s：9H；3.50ppm：s：3H；7.60ppm：se：6H；8.45ppm：s：1H；9.40ppm：s：1H；9.80ppm：s：1H。
7	2-methoxyphenyl radical	Tert-butyl radical	1.40ppm：s：9H；3.50ppm：s：3H；3.80ppm：s：3H；7.10-7.40ppm：mt：4H；7.60ppm：t：1H；8.40ppm：s：1H；9.60ppm：s：1H；9.80ppm：s：1H。
				8	2, 6-dibromophenyl	Tert-butyl radical	1.40ppm：s：9H；3.50ppm：s：3H；7.40ppm：t：1H；7.85ppm：d：2H；8.50ppm：s：1H；9.00ppm：s：1H；9.60ppm：s：1H；10.00ppm：s：1H。

9	2-bromo-6-chlorophenyl	Tert-butyl radical	1.40ppm：s：9H；3.45ppm：s：3H；7.50ppm：t：1H；7.65ppm：d：1H；7.80ppm：d：1H；8.50ppm：s：1H；9.00ppm：s：1H；9.50ppm：s：1H；9.90ppm：s：1H。
				10	2, 6-dibromophenyl	Ethyl radical	1.15 ppm: t: 3H; 3.30 ppm: qd: 2H (masked with DOH); 3.50 ppm: s: 3H; 7.40 ppm: t: 1H; 7.85 ppm: d: 2H; 8.50 ppm: s: 1H; 9.25 ppm: s: 1H; 9.60 ppm: s: 1H; 9.70 ppm: s: 1H.
11	2-bromo-6-chlorophenyl	Phenyl radical	(DMSO+TFA)3.55ppm：s：3H；7.10ppm：t：1H；7.30-7.90ppm：m：7H；8.60ppm：s：1H；9.65ppm：s：1H。
				12	2, 6-dibromophenyl	Phenyl radical	3.55ppm：s：3H；7.10ppm：t：1H；7.35ppm：qd：3H；7.60ppm：d：2H；7.85ppm：d：2H；8.60ppm：s：1H；9.70ppm：s：1H；9.80ppm：s：1H；12.00ppm：s：1H。
13	2, 4-dichlorophenyl	Butyl radical	1.35ppm：s：9H；3.50ppm：s：3H；7.45-7.60ppm：mt：2H；7.80ppm：s：1H；8.40ppm：s：1H；8.80ppm：s：1H；9.55ppm：s：1H；9.80ppm：s：1H。

14	2, 6-dimethylphenyl	Tert-butyl radical	1.40ppm：s：9H；2.00ppm：s：6H；3.50ppm：s：3H；7.10ppm：s：1H；7.25-7.45：m：3H；8.45ppm：s：1H；9.60ppm：s：1H；9.80ppm：s：1H。
				15	2, 6-difluorophenyl	Tert-butyl radical	1.40ppm：s：9H；3.50ppm：s：3H；7.25-7.40：mt：2H；7.55-7.70ppm：mt：1H；8.65ppm：s：1H；9.20ppm：s：1H；9.60ppm：s：1H；9.75ppm：s：1H。
16	2, 6-dichlorophenyl	(iv) isopropyl group	1.20ppm：d：6H；3.50ppm：s：3H；3.85-4.00ppm：mt：1H；7.50-7.70ppm：m：3H；8.50ppm：s：1H；9.25ppm：s：1H；9.65ppm：s：1H；9.75ppm：se：1H。

Preparation of the compound of formula (III).

The preparation numbers used are associated with the compound numbers of table 2 below.

Preparation 17 and 18

A commercial product.

Preparation 19

Prepared according to J.het.chem., 1986, 23, 1645-1649, isolated as the hydrochloride salt.

Preparation 20

Prepared according to l. 1, l. chem.soc. 1928, 121.

Preparation 21

21.1

To 1.12g of 5-nitro-benzo [ b ] in 50mL of THF over 8 hours]2.27g of NaBH was added in small portions to ethyl furan-2-carboxylate₄And then stirred for 40 hours. 5mL of methanol and 5mL of water were added. The reaction medium is extracted with AcOEt, the organic phase is extracted with water and 5% KHSO₄/K₂SO₄The solution was washed with water and then with saturated NaCl solution. After drying and concentration under reduced pressure, 0.74g of the desired product was collected as a solid.

21.2

730mg of the product obtained in step 21.1 are dissolved in 9mL of DCM, the temperature being kept at 5 ℃. 1mL of triethylamine was added at 5 ℃ followed by 536mg of methanesulfonyl chloride over 15 minutes. The temperature is maintained at 5 ℃ for 15 minutes, and the reaction medium is then allowed to warm to room temperature for 55 minutes. The reaction medium is diluted with DCM and water. The organic phase is decanted, washed with water, saturated NaCl solution, dried and evaporated under reduced pressure. 0.98g of an oil containing the mesylate (desired product) and the chloride (benzo [ b ] is obtained]CH at furan 2-position₂OH is covered with CH₂Cl substituted products).

21.3

0.97g of the product from step 21.2 in 10mL of DMF is treated with 1.05g of diethylamine for 18 hours. The reaction medium is extracted with AcOEt, the organic phase is washed with water, saturated NaCl solution, dried and the solvent is evaporated under reduced pressure. 0.93g of an oil is obtained.

21.4

To 1.16g of the product obtained in step 21.3 in 40mL of THF was added over 25 minutes 4.48g of Zn powder at-5 ℃ followed by 5mL of acetic acid. After a reaction time of 1 hour and 15 minutes, the residual solid was removed from the reaction medium by filtration, the solid was washed with a small amount of THF, the organic phases were combined, diluted with AcOEt and water and adjusted to pH 9 with 10N NaOH. After decantation, the organic phase was separated and washed with 15% Na₂CO₃The solution, water, saturated NaCl solution were washed, dried and evaporated. 900mg of oil are obtained.

Preparation 22

22.1

To 1.64g of 2-chloromethyl-5-nitro-benzo in 25mL of DMFTo oxazole (prepared according to Synth. communications, 1989, 19, 2921-2924) was added 1.26g of sodium azide, followed by stirring at room temperature overnight. The reaction medium is poured into 150mL of AcOEt, washed 2 times with ice-water and then with saturated NaCl solution. The organic phase was dried and concentrated under reduced pressure. 1.42g of a black oil are obtained.

22.2

To 1.40g in 30mL of AcOEt over 10 minutes2.84g of triphenylphosphine were added to the product obtained in step 22.1, and after 10 minutes, 1.16mL of water were added again within 2 minutes. After 24 hours stirring was carried out at 60 ℃ and then cooling. The reaction medium is diluted with AcOEt and the organic phase is washed with water, saturated NaCl solution. The organic phase was dried and concentrated under reduced pressure. The residue was dissolved in Et₂O, then extracted 2 times with 1N HCl. The acidic phases were combined, contacted with AcOEt and then adjusted to pH 10 with 10N NaOH. After decantation, the organic phase is washed with water, saturated NaCl solution. The organic phase was dried and concentrated under reduced pressure. 468mg of the expected product are obtained in the form of an oil.

22.3

The product from step 22.2 was dissolved in 10mL DCM, 0.4 equivalent triethylamine was added, followed by 1.1 equivalent BOC₂And O. After 5 hours, the reaction medium is freed from CH₂Cl₂Diluting with 5% KHSO₄/K₂SO₄The solution, water, saturated NaCl solution wash. The crude product was dried and evaporated under reduced pressure to yield 388mg of the desired product.

22.4

The product obtained in step 19.3 was quantitatively reduced using Zn/AcOH to give an oil according to the method described for preparation 18.4.

Preparation 23

23.1

Prepared according to l.hetro.chem., 1973, 10, 755.

23.2

The product obtained in step 23.1 was reduced with Sn/HBr in water according to chem.abstr., 1950, 4474.

Preparation 24

Prepared according to J.Hetero.chem., 1970, 7, 1019-1027.

Preparation 25

Prepared according to Boll. Sci. Fac. Chim. Ind. Bologna, 1964, p.22, pages 33-37.

Preparation 26

Prepared according to the procedure described in patent application WO 92/05164.

The characteristics of the compounds of formula (III) are listed in table 2 below:

TABLE 2 preparation of the Compounds of formula (III)

Exemplary compound numbers correspond to those listed in table 3 below, which illustrates the chemical structure and physical properties of certain compounds of the invention. When they contain asymmetric carbons, these compounds are obtained in racemic form.

Example 1: (Compound No. 1) N- [2- (2, 1, 3-benzothiadiazol-5-ylamino) -6- (2, 6-dichlorophenyl) pyrido [2,3-d]Pyrimidin-7-yl]-N' - (1, 1-dimethylethyl) -urea.

To 3.32g (20mmol) of the amine of preparation 17 of Table 2 in 45mL of DMSO, 3.21g (28.6mmol) of t-BuOK was added over 15 minutes, followed by 7.71g of (b) (N) (n) over 20 minutes16.5mmol) the urea of preparation 1 of Table 1. After 2 hours 1g t-BuOK was added, followed by 2 hours 1g t-BuOK. After 6 hours of reaction, the reaction medium is diluted with ice-water and extracted with AcOEt. The organic phase was washed 2 times with water, once with saturated NaCl solution, dried and concentrated under reduced pressure. Crude product in Et₂Trituration in a mixture of O/heptane, filtration of the precipitate and purification by chromatography on silica gel eluting with CHCl₃AcOEt 88/12 (v/v). 5g of the expected product are obtained. MH⁺＝539。

Example 2: (Compound No. 2) N- [2- (2, 1, 3-benzothiadiazol-4-ylamino) -6- (2, 6-dichlorophenyl) pyrido [2,3-d]Pyrimidin-7-yl]-N' - (1, 1-dimethylethyl) -urea.

Compound 2 was prepared in the same manner as compound 1 using the amine of preparation 18 of table 2.

Example 3: (Compound No. 3) N- [6- (2, 6-dichlorophenyl) -2- [ (1, 3-dihydro-2, 2-dioxido-2, 1-benzisothiazol-5-yl) amino group]Pyrido [2,3-d]Pyrimidin-7-yl]-N' - (1, 1-dimethylethyl) -urea.

437mg of the mixture of the amine of preparation 19 of Table 2 in the form of the hydrochloride salt and 750mg of the urea of preparation 1 of Table 1 were heated in 15mL of ethanol for 5 hours. The reaction medium was evaporated to dryness and then dissolved in 50mL of CHCl₃And 20mL of saturated NaHCO₃In the solution of (1). The organic phase was decanted and washed with water, saturated NaCl solution. The organic phase was dried and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of AcOEt in 0-20% (v/v) chloroform. 275mg of a yellow solid are obtained. MH⁺：572。

Example 4: (Compound No. 4) N- [6- (2, 6-dichlorophenyl) -2- [ (2-methyl-6-benzo)Azolyl) amino]Pyrido [2,3-d]Pyrimidin-7-yl]-N' - (1, 1-dimethylethyl) -urea.

210mg of the amine of preparation 20 of Table 2And 562mg of the urea of preparation 1 of Table 1 were heated at 45 ℃ for 8 hours in 20mL of ethanol containing 0.02mL of concentrated HCl. After concentration under reduced pressure, the residue was purified by silica gel chromatography eluting with CHCl₃MeOH: 98/2 (v/v). 300mg of product are isolated as a yellow solid. MH⁺：536。

Example 5: (Compound No. 5) N- [6- (2, 6-dichlorophenyl) -2- [ [2- [ (diethylamino) methyl ] methyl group]-5-benzofuranyl]Amino group]Pyrido [2,3-d]Pyrimidin-7-yl]-N' - (1, 1-dimethylethyl) -urea.

Compound 5 was prepared in the same manner as compound 4 using amine 21.4 of preparation 21 in table 2.

Example 6: (Compound No. 6) [ [5- [ [6- (2, 6-dichlorophenyl) -7- [ [ [ (1, 1-dimethylethyl) amino group]Carbonyl radical]Amino group]Pyrido [2,3-d]Pyrimidin-2-yl]Amino group]-2-benzoAzolyl radical]Methyl radical]-1, 1-dimethylethyl carbamate.

Compound 6 was prepared in the same manner as compound 4 using amine 22.4 of preparation 22 of table 2.

Example 7: (Compound No. 7) N- [2- [ [2- (aminomethyl) -5-benzoAzolyl radical]Amino group]-6- (2, 6-dichlorophenyl) pyrido [2,3-d]Pyrimidin-7-yl]-N' - (1, 1-dimethylethyl) -urea.

In 2mL DCM, 190mg Compound 6 was treated with 3mL TFA for 1 h. After concentration under reduced pressure, the residue was dissolved in a mixture of DCM/water and 15% Na was added₂CO₃The solution was adjusted to pH 9. After decantation, the organic phase is washed with water, saturated NaCl solution, dried and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with 0-10% (v/v) methanol in DCM. 100mg of a yellow solid are isolated. MH⁺：551。

Example 8: (Compound No. 8) N- [6- (2, 6-dichlorophenyl) -2- (imidazo [1, 2-a)]Pyridin-6-ylamino) pyrido [2,3-d]Pyrimidin-7-yl]-N' - (1, 1-dimethylethyl) -urea.

Compound 8 was prepared in the same manner as compound 4 using amine 23.2 of preparation 23 of table 2.

Example 9: (Compound No. 9) N- [6- (2, 6-dichlorophenyl) -2- ([1, 2, 4)]Triazolo [1, 5-a]Pyridin-6-ylamino) pyrido [2,3-d]Pyrimidin-7-yl]-N' - (1, 1-dimethylethyl) -urea.

Compound 9 was prepared in the same manner as compound 4 using the amine of preparation 24 of table 2.

Example 10: (Compound No. 10) N- [2- (2, 1, 3-benzoOxadiazol-5-ylamino) -6- (2, 6-dichlorophenyl) pyrido [2,3-d]Pyrimidin-7-yl]-N' - (1, 1-dimethylethyl) -urea.

To a mixture of 0.468g of preparation 1 and 0.202g of the amine (III) of preparation 25 of Table 2, 0.168g of tBuOK was added in 6mL of DMSO over 25 minutes and then 0.168g over 1 hour. After stirring for 2 hours, the reaction medium is extracted with ethyl acetate and washed successively with water and with a saturated NaCl solution. With Na₂SO₄After drying and evaporation of the ethyl acetate, the crude product is purified by flash chromatography on silica gel, eluting with a gradient of 0-8% (v/v) of ethyl acetate in dichloromethane. A light brown powder was obtained, with m 0.22 g. MH + ═ 523.

Example 11: (Compound No. 11) N- [2- (1, 3-dihydro-2, 2-dioxido-2, 1, 3-benzothiadiazol-5-ylamino) -6- (2, 6-dichlorophenyl) pyrido [2,3-d]Pyrimidin-7-yl]-N' - (1, 1-dimethylethyl) -urea.

Compound 11 was prepared in the same manner as compound 4 using the amine of preparation 26 of table 2.

Examples 12 to 21: (Compound No. 12-21)

Compounds 12-21 were prepared in the same manner as Compound 1 using amine (III) prepared 17 in Table 2 and the appropriate urea selected from the product of formula (II) prepared in Table 1.

Example 12: (Compound No. 12) N- [2- (2, 1, 3-Benzothiadiazol-5-ylamino) -6- (2-bromo-6-chlorophenyl) pyrido [2,3-d]Pyrimidin-7-yl]-N' - (1, 1-dimethylethyl) -urea.

Example 13: (Compound No. 13) N- [2- (2, 1, 3-benzothiadiazol-5-ylamino) -6- (2, 6-dichlorophenyl) pyrido [2,3-d]Pyrimidin-7-yl]-N' -ethyl-urea.

Example 14: (Compound No. 14) N- [2- (2, 1, 3-benzothiadiazol-5-ylamino) -6- (2, 6-dibromophenyl) pyrido [2,3-d]Pyrimidin-7-yl]-N' - (1, 1-dimethylethyl) -urea.

Example 15: (Compound No. 15) N- [2- (2, 1, 3-benzothiadiazol-5-ylamino) -6- (2, 6-dibromophenyl) pyrido [2,3-d]Pyrimidin-7-yl]-N' -ethyl-urea.

Example 16: (Compound No. 16) N- [2- (2, 1, 3-benzothiadiazol-5-ylamino) -6- (2, 6-dichlorophenyl) pyrido [2,3-d]Pyrimidin-7-yl]-N' -phenyl-urea.

Example 17: (Compound No. 17) N- [2- (2, 1, 3-Benzothiadiazol-5-ylamino) -6- (3, 5-dimethoxyphenyl) pyrido [2,3-d]Pyrimidin-7-yl]-N' - (1, 1-dimethylethyl) -urea.

Example 18: (Compound No. 18) N- [2- (2, 1, 3-Benzothiadiazol-5-ylamino) -6-phenylpyrido [2,3-d ]]Pyrimidin-7-yl]-N' - (1, 1-dimethylethyl) -urea.

Example 19: (Compound No. 19) N- [2- (2,1, 3-Benzothiadiazol-5-ylamino) -6- (2, 6-dimethylphenyl) pyrido [2,3-d]Pyrimidin-7-yl]-N' - (1, 1-dimethylethyl) -urea.

Example 20: (Compound No. 20) N- [2- (2, 1, 3-Benzothiadiazol-5-ylamino) -6- (2, 6-difluorophenyl) pyrido [2,3-d]Pyrimidin-7-yl]-N' - (1, 1-dimethylethyl) -urea.

Example 21: (Compound No. 21) N- [2- (2, 1, 3-benzothiadiazol-5-ylamino) -6- (2, 6-dichlorophenyl) pyrido [2,3-d]Pyrimidin-7-yl]-N' - (1-methylethyl) -urea.

Tables 3 and 4 below illustrate the chemical structures and physical properties of certain embodiments of the present invention. In these tables, Me, Et, iPr and tBu represent methyl, ethyl, isopropyl and tert-butyl, respectively, and Boc (or BOC) represents the group tert-butoxycarbonyl.

TABLE 3

TABLE 4

Compound (I)	R1	Ar2	NMR characteristics
				12	Tert-butyl radical	2-bromo-6-chlorophenyl	1.50ppm：s：9H；7.45ppm：t：1H；7.65ppm：d：1H；7.80ppm：d：1H；8.00ppm：dd：2H；8.15ppm：s：1H；8.25ppm：s：1H；9.20ppm：s：1H；9.30ppm：s：1H；10.75ppm：s：1H；10.85ppm：s：1H。
13	Ethyl radical	2, 6-dichlorophenyl	(DMSO + deuterated TFA)1.15 ppm: t: 3H; 3.35 ppm: qd: 2H; 7.50-7.70 ppm: m: 3H; 8.00 ppm: dd: 2H; 8.45 ppm: s: 1H; 9.00 ppm: s: 1H; 9.30 ppm: s: 1H.
				14	Tert-butyl radical	2, 6-dibromophenyl	1.50ppm：s：9H；7.35ppm：t：1H；7.80ppm：d：2H；8.00ppm：dd：2H；8.15ppm：s：2H；9.15ppm：s：1H；9.30ppm：s：1H；10.75ppm：s：1H；10.85ppm：s：1H。

15	Ethyl radical	2, 6-dibromophenyl	1.30ppm：t：3H；3.30ppm：qd：2H；7.35ppm：t：1H；7.80ppm：d：2H；8.00ppm：dd：2H；8.15ppm：s：1H；8.50ppm：s：1H；9.15ppm：s：1H：9.20ppm：s：1H；10.20ppm：s：1H；10.70ppm：s：1H。
				16	Phenyl radical	2, 6-dichlorophenyl	7.15ppm：t：1H；7.50-7.70ppm：mt：5H；7.75-8.10ppm：mt：4H；8.30ppm：s：1H；9.25ppm：s：1H；9.35ppm：s：1H；9.50ppm：s：1H；10.85ppm：s：1H；13.30ppm：s：1H。
17	Tert-butyl radical	3, 5-Dimethoxyphenyl	1.50ppm：s：9H；3.70ppm：s：6H；6.65ppm：s：3H；7.30ppm：s：1H；8.00ppm：dd：2H；8.20ppm：s：1H；9.20ppm：s：1H；9.30ppm：s：1H；10.50ppm：s：1H；10.70ppm：s：1H。
				18	Tert-butyl radical	Phenyl radical	1.50ppm：s：9H；7.25ppm：s：1H；7.45-7.65ppm：m：5H；8.00ppm：dd：2H；8.20ppm：s：1H；9.20ppm：s：1H；9.35ppm：s：1H；10.50ppm：s：1H；10.75ppm：s：1H。
19	Tert-butyl radical	2, 6-dimethylphenyl	1.45ppm：s：9H；2.00ppm：s：6H；6.55ppm：s：1H；7.20-7.40：m：3H；7.95ppm：dd：2H；8.10ppm：s：1H；9.15ppm：s：1H；9.30ppm：s：1H；10.45ppm：s：1H；10.65ppm：s：1H。
				20	Tert-butyl radical	2, 6-difluorophenyl	1.45ppm：s：9H；7.15-7.30：mt：2H；7.50-7.70ppm：mt：1H；7.95ppm：dd：2H；8.25ppm：s：1H；8.45ppm：s：1H；9.15ppm：s：1H；9.30ppm：s：1H；10.50ppm：s：1H；10.70ppm：s：1H。

21

(iv) isopropyl group

2, 6-dichlorophenyl

1.35ppm：d：6H；3.80-4.00ppm：mt：1H；7.40-7.55ppm：mt：1H；7.60-7.65ppm：mt：2H；7.95ppm：dd：2H；8.15ppm：s：1H；8.60ppm：s：1H；9.15ppm：s：1H；9.25ppm：s：1H；10.45ppm：d：1H；10.75ppm：s：1H。

The compounds of the invention are the subject of pharmacological tests capable of determining their anticancer activity.

In vitro assays of compounds of formula (I) of the invention were performed on a panel of human tumor lines derived from:

-breast cancer: MDA-MB231 (American type culture Collection, Rockville, Maryland, USA, ATCC-HTB26), MDA-A1 or MDA-ADR (so-called multidrug-resistant cell line MDR, described in "blood cell counter", 12 (1): 15-25, 1991, by E.Collomb et al), and MCF7(ATCC-HTB22),

-prostate cancer: DU145(ATCC-HTB81) and PC3(ATCC-CRL1435),

-colon cancer: HCT116(ATCC-CCL247) and HCT15(ATCC-CCL225),

-lung cancer: h460(Carmichael, Cancer Research 47 (4): 936-942, 1987 and proposed by the national Cancer institute, Frederick Cancer Research and development center, Frederick, Maryland, USA),

-glioblastoma: SF268(Westphal, described in (Biochemical & Biophysical Research Communications)132 (1): 284-289, 1985 and proposed by the American national cancer institute, Frederick cancer Research and development center, Frederick, Maryland, USA),

-leukemia: CMLT1(Kuriyama et al, Blood, 74: 1989, 1381-containing 1387, Soda et al, British Journal of Haematology, 59: 1985, 671-containing 679 and Drexler, leukemia research, Leukemias research, 18: 1994, 919-containing 927, DSMZ company (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH), Mascheroder Weg 1b, 38124 Braunschweig, Germany). K-562(Lozzio et al, in J Natl cancer Inst 50: 535 (1973)), Lozzio et al, in blood, 45: 321(1975), DSMZ n ° ACC 10, KG-1a (Koeffler et al, in blood, 56: 265(1980), in DSMZ n ° ACC 421), and Kasumi-1(Asou et al, in blood, 77: 2031(1991), in DSMZ n ° ACC 220).

According to Fujishita T et al Oncology, 2003, 64(4), 399-(MTS) assays confirm cell proliferation and viability. In this assay, the mitochondrial capacity of viable cells to convert their MTS to a colored compound after 72 hours of culture of a compound of formula (I) of the invention was determined. The compounds of the invention resulted in a 50% decrease in cell proliferation and viability (CI) based on tumor lines and test compounds₅₀) The concentration of (B) is 1nM to 10. mu.M. For example, CI for K-562 cell line Compound No. 1₅₀CI for KG-1a cell line at 40nM₅₀50nM of CI for the Kasumi-1 line₅₀Was 40 nM. Compound No. 5 to CI of K-562 line₅₀CI of Compound number 9 at 5nM₅₀19nM, CI of Compound No. 13₅₀Was 74 nM. CI for Compound No. 7 versus SF268 cell line₅₀Was 43 nM.

Thus, it is apparent that the compounds of formula (I) according to the present invention cause tumor cell proliferation and reduced viability. Thus, it appears that the compounds of the present invention have anti-cancer activity and activity in the treatment of other proliferative diseases, such as for example psoriasis, restenosis, arteriosclerosis, AIDS, as well as therapeutic activity in diseases caused by vascular smooth muscle cell proliferation and in rheumatoid polyarthritis.

Thus, according to a further aspect, the present invention is directed to medicaments containing a compound of formula (I), or an addition salt of the compound with a pharmaceutically acceptable acid, or a hydrate or solvate of the compound of formula (I).

These medicaments have therapeutic applications, in particular in the treatment or prevention of diseases which are caused or exacerbated by the proliferation of cells, in particular tumour cells. The products of the invention can be used for the manufacture of a medicament for use in the treatment of disorders, in particular cancer.

As inhibitors of tumor cell proliferation, these compounds are useful for the prevention or treatment of leukemia, primary and metastatic solid tumors, carcinomas and cancers, in particular: breast cancer; lung cancer; small bowel, colon and rectal cancers; cancers of the respiratory tract, oropharynx, and hypopharynx; esophageal cancer; liver cancer, gastric cancer, bile duct cancer, gallbladder cancer, pancreatic cancer; urethral cancers including kidney, urothelium and bladder; female genital tract cancers, including uterine cancer, cervical cancer, ovarian cancer, choriocarcinoma, and chorioepithelioma; cancer of the male genital tract, including prostate cancer, seminal vesicle cancer, testicular cancer, germ cell tumors; endocrine adenocarcinomas including thyroid, pituitary, and adrenal gland cancers; skin cancer including hemangioma, melanoma, sarcoma including Kaposi's sarcoma; brain tumor, nerve tumor, eye tumor, meninges tumor including astrocytoma, glioma, glioblastoma, eye tumor, neuroma, neuroblastoma, schwannoma, meningioma; tumors caused by hematopoietic malignancies; leukemias (acute lymphocytic leukemia (ALL), Acute Myelocytic Leukemia (AML), Chronic Myelocytic Leukemia (CML), Chronic Lymphocytic Leukemia (CLL)), greenish leukemia, plasmacytoma, T-cell or B-cell leukemia, non-Hodgkins or Hodgkins lymphoma, myelomas, and various hematological malignancies.

According to other aspects, the invention relates to pharmaceutical compositions containing as active ingredient a compound of the invention. These pharmaceutical compositions contain an effective dose of at least one compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate of said compound, and at least one pharmaceutically acceptable excipient. The pharmaceutical composition may also contain other anticancer agents.

The excipients are selected from the usual excipients known to those skilled in the art according to the desired pharmaceutical dosage form and mode of administration.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or a possible salt, solvate or hydrate thereof, is mixed with usual pharmaceutical excipients and administered in unit dosage form to animals or humans for the prophylactic treatment of the above-mentioned disorders or diseases.

Suitable unit dosage forms include oral dosage forms, such as tablets, soft or hard gelatin capsules, powders, granules and oral liquids or suspensions; by sublingual, buccal, intratracheal, intraocular, intranasal administration, inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration; rectal dosage forms and implants. For topical application, the compounds of the present invention may be used in creams, gels, ointments or lotions.

The unit dosage forms for administration of tablets as compounds of the invention may contain the following components:

compound of the invention 50.0mg

Mannitol 223.75mg

6.0mg of croscarmellose sodium

Corn starch 15.0mg

Hydroxypropyl methylcellulose 2.25mg

Magnesium stearate 3.0mg

The above-mentioned compound of formula (I) is administered in a dose of 0.002-2000mg per day, preferably 0.1-300mg/kg per day, per kg body weight of the mammal to be treated. For use in humans, the dose may preferably be 0.02 to 10000mg, more particularly 1 to 3000mg per day, depending on the age of the subject to be treated and the type of treatment (prophylaxis or therapy).

There may be cases where the dosage is either high or low; such dosages are not outside the scope of the present invention. According to the usual practice, the appropriate dosage for each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.

According to another aspect of the invention, the invention also relates to a method of treatment of the above-mentioned diseases, which comprises administering to a patient an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

According to the invention, the compound(s) of formula (I) may be administered together with one (or more) anticancer active ingredients, especially antitumor compounds, such as alkylating agents like alkylsulfonates (busulfan), dacarbazine, procarbazine, mechlorethamine (mechlorethamine, melphalan, fluazinine), cyclophosphamide, ifosfamide; nitrosoureas, such as carmustine, lomustine, streptozotocin; antineoplastic alkaloids, such as vincristine, vinblastine; taxanes, such as paclitaxel or docetaxel; anti-tumor antibiotics, such as actinomycin C; intercalators, anti-tumor metabolism antagonists, folic acid antagonists, methotrexate; a purine synthesis inhibitor; purine analogs, such as mercaptopurine or 6-thioguanine; pyrimidine synthesis inhibitors, aromatase inhibitors, capecitabine, pyrimidine analogs such as fluorouracil, gemcitabine, cytarabine, and cytarabine; brequinar; topoisomerase inhibitors, such as camptothecin or etoposide; anticancer hormone agonists and congeners, such as tamoxifen; kinase inhibition, imatinib; a growth factor inhibitor; anti-inflammatory agents, such as xylan polysulfate, corticosteroids, prednisone, dexamethasone, anti-topoisomerase enzymes, such as etoposide, antracyclines, including doxorubicin, bleomycin, mitomycin and mithramycin; anticancer metal complexes, platinum complexes, cisplatin, carboplatin, oxaliplatin; interferon alpha, triphenylthiotepa, altretamine; an anti-angiogenic agent; salicyline polyamine; an adjuvant for immunotherapy; a vaccine.

According to the invention, the compounds of formula (I) may also be administered together with one or more other active ingredients effective against one of the above-mentioned diseases, such as antiemetics, analgesics, anti-inflammatory agents, anti-cachexia agents.

It is also possible to combine the compounds of the invention with radiotherapy. These treatments may be performed simultaneously, separately or sequentially. The doctor adjusts his therapy according to the patient to be treated.

Claims (14)

1. A compound of the formula:

characterized in that Ar is₂And R₁The method comprises the following steps:

2, 6-dichlorophenyl and tert-butyl;

or 2-bromo-6-chlorophenyl and tert-butyl;

or 2, 6-dichlorophenyl and ethyl;

or 2, 6-dibromophenyl and tert-butyl;

or 2, 6-dibromophenyl and ethyl;

or 2, 6-dichlorophenyl and phenyl;

or 3, 5-dimethoxyphenyl and tert-butyl;

or phenyl and tert-butyl;

or 2, 6-dimethylphenyl and tert-butyl;

or 2, 6-difluorophenyl and tert-butyl;

or 2, 6-dichlorophenyl and isopropyl.

2. A compound of the formula:

3. pharmaceutical composition, characterized in that it comprises a compound according to any one of claims 1 to 2, and at least one pharmaceutically acceptable excipient.

4. Pharmaceutical composition according to claim 3, characterized in that it also contains at least one other active anticancer ingredient.

5. Pharmaceutical, characterized in that it comprises a compound according to any one of claims 1 to 2, or an addition salt of this compound with a pharmaceutically acceptable acid.

6. Use of a compound according to any one of claims 1-2 in the manufacture of an anti-cancer formulation.

7. Use of a compound according to any one of claims 1-2 in the manufacture of a medicament for the treatment or prevention of a disease caused or exacerbated by cell proliferation.

8. The use according to claim 7 for the prevention or treatment of cancer.

9. The use according to claim 7 for the prevention or treatment of cancer.

10. Use according to claim 7 for the prevention or treatment of leukemia.

11. Use according to claim 7, for the prevention or treatment of primary and metastatic solid tumors.

12. Process for the preparation of the compounds according to claim 1, characterized in that a compound of formula:

in the formula R₁And Ar₂Is as defined in claim 1, with an amine of the formula

13. Process for the preparation of the compounds according to claim 1, characterized in that the following compounds are reacted:

(i) a compound of the formula:

in the formula

-Ar₂As defined in claim 1,R₁₀is a leaving group;

-R₁₁is NHC (O) -NH-R₁，R₁Is as defined in claim 1;

(ii) and an amine of the formula:

in the formula:

(a) when R is₁₀Is halogen or alkyl-S (O)_m-wherein m ═ 2, the reaction is carried out in a solvent at a temperature between room temperature and the reflux temperature of the solvent;

(b) when R is₁₀Is alkyl-S (O)_m-, where m is 0 or 1, with the proviso that

Carrying out reaction;

if necessary, of the formula

The amine function of the compounds of (a) has been previously salified or protected.

14. The method of claim 13, wherein R₁₀Is (a) halogen selected from Cl or Br, or (b) alkyl-S (O)_m-, where m ═ 0, 1, or 2.