EP0705261A1

EP0705261A1 - Antiproliferative naphthyridines

Info

Publication number: EP0705261A1
Application number: EP94920507A
Authority: EP
Inventors: Nicole Bru-Magniez; Michèle Launay; Jean-Marie Teulon
Original assignee: UPSA SAS
Current assignee: UPSA SAS
Priority date: 1993-06-25
Filing date: 1994-06-24
Publication date: 1996-04-10
Also published as: US5364860A; FI954982A; HUT74162A; NZ268383A; MD457G2; SK155395A3; FI954982A0; FR2706898B1; AU7127594A; CA2161436A1; CN1125444A; EE9400439A; CZ337295A3; FR2706898A1; JPH08511793A; MD457F1; HU9503776D0

Abstract

Dérivatives of formula (I), acid addition salts thereof, and therapeutical uses thereof, in particular as antiproliferative drugs for efficiently treating diseases such as cancer, psoriasis and atherosclerosis, as well as restenosis phenomena or any other condition caused by cell proliferation.

Description

ANTIPROLIFERATIVE NAPHTHYRIDINES

New naphthvridine derivatives. their methods of preparation, pharmaceutical compositions containing them, useful in particular as antiproliferative drugs

The present invention relates, as new products, to the naphthvridine derivatives of general formula (I) below and their addition salts, in particular the pharmaceutically acceptable addition salts.

The compounds of the invention which have antiproliferative properties can be used in the treatment of cancer, psoriasis, atherosclerosis, restenosis phenomena or any other pathology due to cell proliferation in mammals and in particular in mammals. 'man.

The present invention also relates to the process for the preparation of said products and their applications in therapy.

These naphthyridine derivatives are characterized in that they correspond to the general formula (I):

Formula (I) in which:

X represents:

- the hydrogen atom

- a halogen atom

Y represents: - the oxygen atom

- the sulfur atom

- an NH group

R and Ri represent not simultaneously - a hydrogen atom - a CN radical

- a group COOR ', R' being a hydrogen atom or a lower alkyl radical of 1 to 6 carbon atoms

- a CONH2 group

- a CONH (CH ₂ ) n group

in which n is an integer from 0 to 5 and R "represents the hydrogen atom, a halogen atom or a lower alkyl radical of 1 to 6 carbon atoms - an NO2 radical

- a pyridine ring unsubstituted or substituted by a halogen atom

- a thiazole ring unsubstituted or substituted by a lower alkyl radical of 1 to 6 carbon atoms

where R and R-i together form 2-indolinone

R2 represents:

- a lower alkyl radical of 1 to 6 carbon atoms

- a lower cycloalkyl radical of 3 to 7 carbon atoms

- a group in which m is an integer from 0 to 5 and Z * ι and Z ₂ independently represent

- the hydrogen atom - a lower alkyl radical of 1 to 6 carbon atoms

- a halogen atom

- a trifluoromethyl radical

- an OH radical

- an O-lower alkyl radical of 1 to 6 carbon atoms - an S-lower alkyl radical of 1 to 6 carbon atoms

- a radical N0 ₂

- an NH ₂ radical

- a CN radical In the description and the claims, the term lower alkyl means a hydrocarbon chain having from 1 to 6 carbon atoms, linear or branched. A lower alkyl radical is for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl radical.

The term “C ₃ -C ₇ cycloalkyl radical” is understood to mean a saturated cyclic hydrocarbon radical, it is preferably a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl radical.

Halogen means a chlorine, bromine, iodine or fluorine atom. In the description, the following abbreviations have been used:

Phe: phenyl i-Pr: isopropyl (1-methyl I ethyl) Bn: benzyl Py: pyridyl Thz: thiazole

Advantageously, in the context of the present invention, a compound of formula (I) will be used in which at least one of the following conditions is achieved:

- X represents the hydrogen atom - x represents the chlorine atom

- Y represents the oxygen atom

- R represents a pyridine

- R represents a chloropyridine

- R-i represents the CN radical - R represents the 3,5-dichlorophenyl group

- R ₂ represents the 4-methoxyphenyl group

- R2 represents the 3-chlorophenyl group

The particularly preferred compounds of the invention are those which are chosen from the products of formula:

35

According to the invention, the compounds of formula (I) can be synthesized as follows:

The reaction of a 2-chloro nicotinic acid of formula (II) or one of its esters

Formula (II)

in which X is defined as above, on an amine of formula (III)

NH ₂ -R ₂ Formula (III) in which R ₂ is defined as above, by heating without solvent or in a solvent such as toluene or xylene or an alcohol, for example, will lead to 2-amino nicotinic acids of formula (IV) or one of their esters

Formula (IV)

in which, X and R ₂ are defined as above, according to a method known in the literature: US pat. 3,415,834; C. Hoffmann, A. Faure, Bull. Soc. Chim. France 1966, 2316.

By reduction using a conventional reducing agent such as for example, double aluminum and lithium hydride in an organic solvent such as for example tetrahydro furan or ethyl ether of an acid of formula (IV ) or one of its esters, for example methyl or ethyl, the alcohols of formula (V) will be obtained:

Formula (V)

in which X and R ₂ are defined as above.

In the case where R ₂ carries a substantial substitution with certain reducing agents, such as for example nitro or cyano, the reduction of the ester will be chosen by a reducing agent respecting this substitution, for example lithium borohydride prepared "in situ" from potassium borohydride and lithium chloride in tetrahydrofuran or sodium borohydride in dioxane. Oxidation using a mild oxidant such as for example MnC> 2, in an organic solvent such as dichloromethane or chloroform, toluene or xylene, at a temperature between 20 and 80 ° C. alcohol of formula (V), will lead to nicotinic aldehydes of formula (VI)

Formula (VI)

in which X and R ₂ are defined as above.

Reaction of aldehydes of formula (VI) with an alkyl dialkoxypropionate of formula (VII)

OR "'R" OOC-CH ₂ - CH' ^v OR '"

Formula (VII)

in which, R'Υ represents a lower alkyl radical of 1 to 6 carbon atoms, optimally the methyl radical or also with a dialkoxy propionitrile of formula (VII ")

GOLD'"

NC-CH ₂ CH '

^N OR '"

Formula (VIP)

in which, R ′ "has the same meaning as in formula (VII) in tetrahydrofuran in the presence of a sodium or potassium alcoholate will make it possible to obtain the derivatives of formula (VIII):

'"

Formula (VIII)

in which, X, R ₂ and R '"are defined as above, Y' represents an oxygen atom in the case where the reaction was carried out with the compound of formula (VII) or an NH group in the case where the reaction was carried out with the compound of formula (VII ').

The dialkyl acetal derivatives of formula (VIII) will be hydrolyzed for example by the action of hydrochloric acid in a solvent such as tetrahydrofuran to give the aldehydes of formula (IX)

Formula (IX) in which, X, R ₂ and Y 'are defined as above.

The action of aldehydes of formula (IX) on an activated methylene of formula (X)

R-CH ₂ -Rι Formula (X)

in which, R and Rj have the same definition as in formula (I) according to the conventional Knoevenagel reaction methods, for example by heating in an alcohol such as methanol or ethanol in the presence of piperidine or of a sodium or potassium alcoholate or sodium or potassium carbonate will lead to the compounds of formula (XI)

Formula (XI) in which, X, R, Ri, Y 'and R ₂ are defined as above.

These derivatives of formula (XI) are derivatives of formula (I) and the derivatives of formula (XI) in which Y 'represents the oxygen atom may, by treatment with P Sιo in xylene at reflux, lead to the derivatives of formula (I) where Y represents the sulfur atom. The derivatives of formula (I) where R ₂ has a nitro function can be reduced to derivatives where R2 has an amino function.

In certain cases, the reaction of the aldehyde of formula (IX) with the nitrile of formula (X) instead of leading directly to the ethylenic compounds of formula (XI) will lead to the hydroxylated compounds of formula (XII)

Formula (XII)

in which, X, R, R * ι, Y 'and R ₂ are defined as above. In this case, the derivatives of formula (XII) will be dehydrated into compounds of formula (XI) by methods known to those skilled in the art, for example by the action of anhydride and trifluoroacetic acid or else of paratoluene sulfonic acid in a solvent such as dichloromethane or chloroform or also toluene or xylene at a temperature between 20 and 130 "C.

The compounds of formula (I) as defined above as well as their addition salts, in particular the pharmaceutically acceptable addition salts, are endowed very good antiproliferative activity.

These properties justify their application in therapy and the invention also relates, as medicaments, to the products as defined by formula (I) above, as well as their addition salts, in particular the salts of pharmaceutically acceptable addition.

Addition salts of certain compounds of formula (I) can be obtained by reaction of these compounds with a mineral or organic acid according to a method known per se. Among the acids which can be used for this purpose are hydrochloric, hydrobromic, sulfuric, phosphoric, 4-toluene sulfonic, methane sulfonic, cyclohexyl sulfamic, oxalic, succinic, formic, fumaric, maleic, citric, aspartic, cinnamic, lactic, glutamic acids. , N-acetylaspartic, N-acetylglutamic, ascorbic, malic, benzoic, nicotinic and acetic.

Thus, the invention also covers a pharmaceutical composition, characterized in that it comprises a pharmaceutically effective amount of at least one compound of formula (I) as defined above or one of its pharmaceutically acceptable addition salts, optionally incorporated in a pharmaceutically acceptable excipient, vehicle or support.

These compositions can be administered by the oral, rectal, parenteral, transdermal or ocular route. These compositions can be solid or liquid and can be presented in the pharmaceutical forms commonly used in human medicine such as, for example, simple or coated tablets, capsules, granules, suppositories, injections, transdermal systems and eye drops. They are prepared according to the usual methods. The active principle, consisting of a pharmaceutically effective amount of at least one compound of formula (I) defined as above or one of its pharmaceutically acceptable addition salts, can be incorporated therein into excipients usually used in these pharmaceutical compositions , such as talc, gum arabic, lactose, starch, magnesium stearate, polyvidone, cellulose derivatives, cocoa butter, semi-synthetic glycerides, aqueous or non-aqueous vehicles, bodies animal or vegetable fats, glycols, various wetting agents, dispersants or emulsifiers, silicone gels, certain polymers or copolymers, preservatives, flavors and colors.

The invention also covers an antiproliferative pharmaceutical composition making it possible in particular to favorably treat any pathology due to cell proliferation characterized in that it comprises a pharmaceutically effective amount at least one compound of the above formula (I) or one of its pharmaceutically acceptable addition salts, optionally incorporated in a pharmaceutically acceptable excipient, vehicle or support.

The invention also covers a process for the preparation of a pharmaceutical composition, characterized in that a pharmaceutically effective amount of at least one compound of formula (I) as defined above, or one of its salts, is incorporated. pharmaceutically acceptable addition to a pharmaceutically acceptable excipient, vehicle or carrier. According to one embodiment, a pharmaceutical composition with antiproliferative activity is prepared which makes it possible in particular to favorably treat cancer, psoriasis, atherosclerosis, restenosis phenomena or any other pathology due to cell proliferation.

According to an alternative embodiment, a composition is prepared formulated in the form of capsules or tablets dosed from 1 mg to 1000 mg or in the form of injectable preparations dosed from 0.1 mg to 500 mg. One can also use formulations in the form of suppositories, ointments, creams, gels, aerosol preparations or eye drops.

The invention also covers a method for the therapeutic treatment of mammals, characterized in that a therapeutically effective amount of at least one compound of formula (I) as defined above, or one of its salts, is administered to this mammal. pharmaceutically acceptable addition. According to an alternative embodiment of this treatment method, the compound of formula (I), either alone or in combination with a pharmaceutically acceptable excipient, is formulated in capsules or tablets dosed from 1 mg to 1000 mg for administration by orally, or in the form of injectable preparations dosed from 0.1 to 500 mg or also in the form of suppositories, ointments, creams, gels, aerosol preparations or eye drops.

In human and animal therapy, the compounds of formula (I) and their salts can be administered alone or in combination with a physiologically acceptable excipient in any form, in particular orally in the form of capsules or tablets or parenterally in the form of injectable solution. Other forms of administration such as suppositories, ointments, creams, gels, aerosol preparations or eye drops can be considered.

As will be clear from the pharmacology tests given at the end of the description, the compounds according to the invention can be administered in human therapy in the abovementioned indications orally in the form of tablets or capsules dosed from 1 mg to 1000 mg or parenterally in the form of injections dosed from 0.1 mg to 500 mg in one or more daily doses for an adult of average weight 60 to 70 kg.

In animal therapy, the daily dose that can be used is between 0.1 and 100 mg per kg.

Other characteristics and advantages of the invention will be better understood on reading which will follow from some examples which are in no way limitative, but given by way of illustration.

Example 1: 2- (3-trifluoromethylphenyl) amino-3-hydroxy methyl pyridine

Formula (V) X = H; R ₂ = 3-CF ₃ Phenyl

To a suspension of 52 g of double aluminum and lithium hydride in 1000 ml of anhydrous ethyl ether, a solution of 200 g of 2- (3-trifluoromethylphenyl) amino nicotinic acid in 500 ml is added dropwise. anhydrous tetrahydrofuran. After the end of the addition, the reaction mixture is brought to reflux for 3 hours. After cooling, the excess double hydride is destroyed by addition of ethyl acetate, then of a saturated aqueous solution of sodium sulfate. The precipitate formed is drained and washed with ether. The combined filtrates are evaporated in vacuo and 185.2 g of 2- (3-trifluoromethyl phenyl) amino-3-hydroxy methyl pyridine are recovered in the form of crystals with melting point 103-105 ^* C.

According to this method, the following derivatives of formula (V) are prepared:

Example XR ₂ F (° C) Yield (%)

2 H Phenyl Oil 95

3 H 4-F Phe 89-90 88

4 H 3-SCH3 Phe Oil 95

5 H 2.5-F Phe 71 -74 98

6 H 3-OCH3 Phe 94-95 98

7 H 3-CI Phe 1 14-1 15 94

8 H 4-CI Phe 124-126 95

9 H 3.5-CI Phe 149 90

10 a.m. 4-OCH3 Phe 93 86.5

1 1 H 3-CH3 Phe Oil 92

12 H 4-CH3 Phe Oil 98

Example 13: 2- (3-cyanophenyl) amino-3-hydroxymethyl pyridine

Formula (V): X = H; R ₂ = 3-CN Phenyl To a solution of 39.3 g of methyl 2- (3-cyanophenyl) amino nicotinate in 600 ml of tetrahydrofuran containing 10 g of potassium borohydride, 8 g of lithium chloride are added in small quantities, with stirring. After the end of the addition, the mixture is brought to reflux for 4 h and then concentrated under vacuum. After adding water and ice to the residue obtained, extraction is carried out with ether and the ethereal phase is washed with water and then dried over sodium sulfate.

After evaporation of the ether, 31.6 g of 2- (3-cyanophenyl) amino-3-hydroxymethyl pyridine are obtained in the form of crystals with a melting point of 126 ° C.

According to this process, the following derivatives of formula (V) are prepared

Example XR ₂ F (° C) Yield (%)

14 H 3-N0 ₂ Phe 162 84

3 p.m. 3-CN 4-CI Phe 147 90

1 6 H 3-CN 4-F Phe 126 90

5 PM 4-CN Phe 142 94

18 H i-Pr 91 47

19 Cl 3 _. 4-OCH3 Bn 127 78

20 Cl 3,4-CI Phe 166 48

9 PM Cyclohexyl Oil 94

Example 22: 2- (3-trifluoromethylphenyl) amino nicotinaldehyde

Formula (VI): X = H; R ₂ = 3-CF ₃ Phenyl

To a solution of 185 g of 2- (3-trifluoromethylphenyl) amino-3-hydroxymethyl pyridine, prepared in Example 1 in 2300 ml of chloroform, is added in small fractions 690 g of Mnθ2- After the end of the addition , stirred at room temperature for 6 h. The reaction medium is then filtered through celite and the filtrate is evaporated to dryness. The crystals obtained then, 175 g, are recrystallized from heptane. 160 g of 2- (3-trifluoromethyl phenyl) amino nicotinaldehyde are thus recovered in the form of crystals with melting point 80-81 ^* C.

According to this method, the following derivatives of formula (VI) are prepared Example XR ₂ F (° C) Yield (%)

23 H Phényl 77-78 80

24 H 3-CN Phe 153-154 60

25 H 4-F Phe 67-68 71

26 H 3-SCH ₃ Phe 63-64 70

27 H 2.5-F Phe 129-130 76

28 H 3-OCH3 Phe 65-66 75

29 H 3-CI Phe 99-100 78

30 H 3-N0 ₂ Phe 166 76

31 H 3-CH3 Phe 95-97 79

32 H 3-CN 4-CI Phe 203 60

33 H 3-CN 4-F Phe 193 80

34 H 4-CI Phe 101 -102 60

35 H 3,5-CI Phe 159 92

36 H 4-OCH3 Phe 84 54

37 H 2-CI Phe 101 70

38 H 4-CH3 Phe 55-58 72

39 5-CI 3,5-CI Phe 183 81

40 H 4-CN Phe 166 93

41 H i-Pr Oil 84

42 5-CI 3,4-OCH ₃ Bn 1 14 42

43 H Cyclohexyl Oil 73

Example 44: 1- (3,5-dichlorophenyl) -1, 2-dihydro-3-dimethoxymethyl-2-oxo-1, 8-naphthyridine

Formula (VIII): X = H; R '"= CH ₃ ; Y' = O; R ₂ = 3,5-CI Phenyl

A solution of 42.7 g of 2- (3,5-dichlorophenyl) amino nicotinaldehyde prepared in Example 35 in 500 ml of tetrahydrofuran containing 35.6 g of methyl 3,3-dimethopropionate is stirred for 24 h at room temperature. and a solution of sodium methylate prepared from 5.5 g of sodium in 100 ml of methanol. The reaction mixture is then concentrated under vacuum, then added with water and the crystals formed are drained, washed carefully with water and dried. Are thus obtained 44.25 g of 1- (3,5-dichlorophenyl) -1, 2-dihydro-3-dimethoxymethyl-2-oxo-1, 8- naphthyridine in the form of white crystals of melting point 190 ^° C. Yield 75.7%.

According to this method, the following derivatives of formula (VIII) are prepared:

Example XR ₂ R "'Y" F (° C) Yield (%)

45 H 4-OCH ₃ Phe CH ₃ 0 210 58

46 H 3-CI Phe CH ₃ 0 112-118 70

47 H 2-CI Phe CH ₃ 0 125 51

48 H 3-CH3 Phe CH ₃ 0 139 57

49 H 4-CH3 Phe CH ₃ 0 108 1 7

50 H 3-SCH3 Phe CH ₃ 0 155 78

51 H 4-CN Phe CH ₃ 0 152-153 64

52 H Phenyl CH ₃ 0 146 58

53 H 3-CF ₃ Phe CH ₃ 0 143 67

54 H 3-N0 ₂ Phe CH ₃ 0 198 55

55 Cl 3,5-CI Phe CH ₃ 0 194 67

56 H i-Pr CH ₃ 0 Oil -

57 Cl 3,4-OCH ₃ Bn CH ₃ 0 123 49

58 H Cyclohexyl CH ₃ 0 Oil -

Example 59: 1,2-dihydro-3-dimethoxymethyl-2-imino-1 - (4-methoxy phenyl) -1.8-naphthyridine

Formula (VIII): X = H; R "'= CH ₃ ; Y' = NH; R ₂ = 4-OCH ₃ Phenyl

According to the procedure of Example 44, but starting from 14.6 g of 2- (4-methoxyphenyl amino) nicotinaldehyde and 11.15 g of 3,3-dimethoxypropionitrile (1.5 eq), the following is obtained washing the solid obtained with ether 10.5 g of 1, 2-dihydro-3-dimethoxymethyl-2-imino-1- (4-methoxyphenyl) -1, 8-naphthyridine in the form of an off-white solid of point of fusion 167 "C. Yield 50.6%. Example 60: [1- (3,5-dichlorophenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin 3-yl] carboxaldehyde

Formula (IX): X = H; Y '= O; R ₂ = 3,5-CI Phenyl

A suspension of 44.25 g of 1- (3,5-dichlorophenyl) - 1,2-dihydro-3-dimethoxymethyl-1,8-naphthyridine prepared in Example 44 in 450 ml of tetrahydrofuran is stirred at ambient temperature. 66 ml of 10% aqueous hydrochloric acid (1.5 eq). The solid goes into solution and then a precipitate forms. After 24 h, the reaction mixture is concentrated under vacuum and the residue obtained is taken up in dichloromethane; the organic phase is washed with 10% sodium bicarbonate then with water and dried over magnesium sulfate. After concentration under vacuum, the solid obtained is taken up in ether and drained to give 35.3 g of [1- (3,5-dichlorophenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin- 3-yl] carboxaldehyde with a melting point of 250 "C. Yield 91%.

According to this method, the following derivatives of formula (IX) are prepared:

Example XR ₂ Y 'F (° C) Yield (%)

61 H 4-OCH ₃ Phe 0 245 95

62 H 3-CI Phe 0 223 94

63 H 2-CI Phe 0 238 90

64 H 3-CH3 Phe 0 244 86

65 H 4-CH3 Phe 0 234 60

66 H 3-SCH3 Phe 0 204 74

67 H 4-CN Phe 0> 250 83

68 H Phe 0> 250 90

69 H 3-CF3 Phe 0 220 90

70 H 3-N0 ₂ Phe 0 263 90

71 Cl 3,5-CI Phe 0 240 83

72 H i-Pr 0 88 33

73 Cl 3,4-OCH ₃ Bn 0 191 89

74 H Cyclohexyl 0 192-194 26

Example 75: [1, 2-dihydro-1- (4-hydroxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] carboxaldehyde

Formula (IX): X = H; Y '= O; R ₂ = 4-OH Phenyl

10 g of [1- (4-methoxyphenyl) -1,2-dihydro-2-oxo-1,8,8-naphthyridine-3-yl] carboxaldehyde prepared in Example 61 are dissolved in 300 ml of chloroform stabilized with amylene. The yellow solution is cooled to -30 ° C, then 71 ml of a 1 M solution of BBr3 in dichloromethane are added dropwise with stirring at this temperature. The temperature is then allowed to rise to ambient, and the stirring is continued for 15 hours. The reaction medium is hydrolyzed by adding 100 ml of water, then the precipitate is filtered, washed with water and then with isopropanol and dried. 8.6 g of [1- (4-hydroxyphenyl) -1, 2-dihydro-2-oxo-1, 8-naphthyridin-3-yl] carboxaldehyde are thus obtained in the form of a yellow solid with a melting point> 250 ° C. Yield 90%.

Example 76: [1,2-dihydro-2-imino-1 - (4-methoxyphenyl) -1, 8-naphthyridin-3-yl] carboxaldehyde, hydrochloride Formula (IX): X = H; Y '= NH; R ₂ = 4-OCH ₃ Phenyl

10.9 g of 1,2-dihydro-3-dimethoxymethyl-2-imino-1- (4-methoxyphenyl) -1,8-naphthyridine prepared in Example 59 are suspended in 110 ml of tetrahydrofuran and placed under agitation. After the addition of 18.5 ml of 10% aqueous hydrochloric acid (1.5 eq), the solid goes into solution and then gradually a precipitate is observed. After 8 h, the solid is drained and washed with a little tetrahydrofuran.

7.6 g of [1, 2-dihydro-2-imino-1- (4-methoxyphenyl) -1, 8-naphthyridin-3-yl] carboxaldehyde, hydrochloride are thus obtained in the form of a pale yellow point solid 170 ^* C. 72% yield.

Example 77: 3- [1- (3,5-dichlorophenyl) -1,2-dihydro-2-oxo-1,8,8-naphthyridin-3-yl] -3-hydroxy-2- (3-pyridyl) propionitrile

Formula (XII): X = H; Y '= O; R ₂ = 3,5-CI Phenyl; R = 3-pyridyl;

R _{1 =} CN

5.7 g of [1- (3,5-dichlorophenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] carboxaldehyde prepared in Example 60 are suspended in 60 ml ethanol with 2.33 ml of 3-pyridyl acetonitrile (1, 2 eq) and a few drops of piperidine. The medium is brought to reflux for 4 h and then cooled. The solid formed is drained and washed with ethanol. 7.2 g of 3- [1 - (3,5-dichlorophenyl) -1,2-dihydro-2-oxo-1, 8-naphthyridin-3-yl] -3- hydroxy-2- (3 pyridyl) propionitrile in the form of a melting point of white solid 260 ^° C. Yield 91%.

Example 78: 3- [1 - (3,5-dichlorophenyl) -1, 2-dihydro-2-oxo-1, 8- naphthyridin-3-yl] -2- (3-pyridyl) -2-propene nitrile

Formula (I): X = H; Y = O; R ₂ = 3,5-CI Phenyl; R = 3-pyridyl; R-, = CN

3 g of 3- [1 - (3,5-dichlorophenyl) -1, 2-dihydro-2-oxo-1, 8-naphthyridin-3-yl] -3- hydroxy-2- (3-pyridyl) propionitrile prepared in Example 77 are placed in suspension in 20 ml of dichloromethane. After adding 1.05 ml of trifluoroacetic acid (2 eq), a yellow solution is obtained which becomes bright yellow with temperature rise after addition of 1.44 ml of trifluoroacetic anhydride (1.5 eq). This solution is stirred a hour then added with water; the organic phase is decanted, washed with a 10% sodium bicarbonate solution, then with water and dried over magnesium sulfate. After concentration in vacuo, the solid obtained is washed with ether and dried to give 2.6 g of 3- [1 - (3,5-dichlorophenyl) -1,2-dihydro-2-oxo-1,8 -naphthyridin-3-yl] -2- (3-pyridyl) -2-propene nitrile in the form of a bright yellow solid with melting point 261 ^* C. Yield 91%.

Example 79: 3- [1- (3,5-dichlorophenyl) -1, 2-dlhydro-2-oxo-1, 8- naphthyrldln-3-yl] -2- (2-pyridyl) -2-propene nitrile

Formula (I): X = H; Y = O; R ₂ = 3,5-CI Phenyl; R = 2-pyridyl; Ri = CN

3.2 g of [1- (3,5-dichlorophenyl) -1,2-dihydro-2-oxo-1, 8-naphthyridin-3-yl] carboxaldehyde prepared in Example 60 are brought to reflux in 30 ml ethanol with 1.4 ml of 2-pyridyl acetonitrile (1.2 eq) and a few drops of piperidine. After 3 h of reflux, the reaction mixture is cooled, the bright yellow precipitate formed is drained and washed with ethanol to give 3.77 g of 3- [1- (3,5-dichlorophenyl) -1,2-dihydro - 2-oxo-1,8-naphthyridin-3-yl] -2- (2-pyridyl) -2-propene nitrile in the form of bright yellow crystals after purification by chromatography on a silica column (eluent: dichloromethane). Melting point 319 ^* C. Yield 70%.

Example 80: 3- [1, 2-dihydro-1- (4-methoxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] -2- (4-pyridyl) -2-propene nitrile

Formula (I): X = H; Y = O; R ₂ = 4-OCH ₃ Phenyl; R = 4-pyridyl; R-, = CN

2.8 g of [1,2-dihydro-1- (4-methoxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] carboxaldehyde prepared in Example 61 are added to a suspension of 1.6 g of 4-pyridyl acetonitrile hydrochloride (1 eq) in 80 ml of ethanol containing 0.253 g of sodium (1.1 eq). The reaction mixture is brought to reflux for 3 h then cooled to room temperature. The solid formed is drained, washed with ethanol and with water, then is recrystallized from methoxy ethanol. 1.3 g of 3- [1, 2-dihydro-l- (4-methoxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] -2- (4-pyridyl) -2- are thus obtained. propene nitrile in the form of bright yellow crystals with a melting point of 283 ° C. Yield 34.5%.

Example 81: 3- [1- (3,5-dichlorophenyl) -1, 2-dihydro-2-oxo-1, 8- naphthyrldin-3-yl] -2- (4-pyridyl) -2-propene nitrile

Formula (I): X = H; Y = O; R ₂ = 3,5-CI Phenyl; R = 4-pyridyl; Ri = CN

According to the procedure of Example 80 but starting from 3.2 g of [1- (3,5-dichlorophenyl) -1, 2-dihydro-2-oxo-1, 8-naphthyridin-3-yl] carboxaldehyde , after recrystallization from methoxy ethanol 1.68 g of 3- [1- (3,5-dichlorophenyl) -1,2- dihydro-2-oxo-1, 8-naphthyridin-3-yl] -2- (4-pyridyl) -2-propene nitrile in the form of a bright yellow solid with a melting point 256-257 ° C. Yield 40%.

Example 82: 3- [1, 2-dihydro-1- (4-methoxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] -2- (3-pyridyl) -2-propene nitrile

Formula (I): X = H; Y = O; R ₂ = 4-OCH ₃ Phenyl; R = 3-pyridyl; Ri = CN

According to the procedure of Example 79 but starting from 2.8 g of [1,2-dihydro-1- (4-methoxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] carboxaldehyde and 1, 3 ml of 3-pyridyl acetonitrile (1.2 eq), 2.5 g of yellow solid are obtained which are purified by chromatography on a silica column (eluent dichloromethane - ethyl ether 9/1). 1.5 g of 3- [1, 2-dihydro-1 - (4-methoxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] -2- (3-pyridyl) -2- are thus obtained. propene nitrile as a bright yellow solid with a melting point of 244 ° C. Yield 40%.

Example 83: 3- [1,2-dihydro-1- (4-methoxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] -2- (2-pyridyl) -2-propene nitrile

Formula (I): X = H; Y = O; R ₂ = 4-OCH ₃ Phenyl; R = 2-pyridyl; Ri = CN

2.8 g of [1, 2-dihydro-1- (4-methoxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] carboxaldehyde are suspended in 90 ml of ethanol with 1.2 ml of 2-pyridyl acetonitrile (1, 1 eq). A solution of 0.023 g of sodium in 10 ml of ethanol (0.1 eq) is then added. The pale yellow suspension obtained is stirred for 24 h. Gradually it becomes bright yellow. The precipitate formed is drained, washed with ethanol and then with ether. 3.4 g of 3- [1, 2-dihydro-1- (4-methoxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] -2- (2-pyridyl) -2- are thus obtained. propene nitrile in the form of an orange-yellow solid with a melting point of 251 ° C. Yield 89.5%.

According to this method, the following derivatives of formula (I) are prepared:

Example XR ₂ YR. RF (° C) Yield (%)

84 H 3-CI Phe 0 CN 2-Py 301 51

85 H 3-CI Phe 0 CN 3-Py 256-258 25

86 H 2-CI Phe 0 CN 3-Py 229-231 34

87 H 3-CH ₃ Phe 0 CN 2-Py 284 53

88 H 3-CH3 Phe 0 CN 3-Py 272 55

89 H 4-CH3 Phe 0 CN 3-Py 229-232 25

90 H 3-SCH3 Phe 0 CN 3-Py 242-244 81

91 H 3,5-CI Phe 0 CN CONH2 289 62

92 H 4-CN Phe 0 CN 3-Py 262 38

93 H Phényl 0 CN 3-Py 265 60

94 H 3.5-CI Phe 0 CN 6-CI 3-Py 263.5 44

95 H 3-CF3 Phe 0 CN 3-Py 189 13

96 H 3,5-CI Phe 0 CN 2-Me 4-Thz 312 68

97 H 3-CI Phe 0 CN COOEt 214 88

98 H 2-CI Phe 0 CN COOEt 194 88

99 H 3-CI Phe 0 CN COOH 245 80

100 H i-Pr 0 CN 3-Pyr 137-138 60

101 Cl 3,4-OCH ₃ Bn 0 CN 3-Pyr 208 31

102 H 3,5-CI Phe 0 H N02 269 23

103 H Cyclohexyl 0 CN 3-Pyr 216-218 58

Example 104: [[1, 2-dihydro-1- (3-methylphenyl) -2-oxo-1, 8-naphthyridin-3-yl] -methylene-3-yl] oxindole

Formula (I): X = H; Y = O; R ₂ = 3-CH ₃ Phenyl;

According to the procedure of Example 83, 3 g of [1,2-dihydro-1- (3-methylphenyl) - 2-0x0-1, 8-naphthyridin-3-yl] carboxaldehyde prepared in Example 64 give 2.9 g of [[1,2-dihydro-1- (3-methylphenyl) -2-oxo-1, 8-naphthyridin-3-yl] -methylene-3-yl] oxindole in the form of an orange solid of melting point>310'C. Yield 75%.

Example 105: 3-fl - (3.5-dlchlorophenyl.-1.2-dlhydro-2-thloxo-1.8- naphthyridin-3-yl] -2- (3-pyridyl) -2-propene nitrile

Formula (I): X = H; Y = S; R ₂ = 3,5-CI Phenyl; R = 3-pyridyl; R, = CN

0.9 g of 3- [1- (3,5-dichlorophenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -2- (3- pyridyl) -2-propene nitrile prepared in Example 78 are brought to reflux in 15 ml of xylene with 0.23 g of phosphorus pentasulfide for 8 hours.

The medium is filtered hot and the filtrate brought to room temperature. The precipitate formed is drained, washed with ether.

0.1 g of 3- [1- (3,5-dichlorophenyl) -1, 2-dihydro-2-thioxo-1, 8-naphthyridin-3-yl] -2- (3-pyridyl) is thus obtained. 2-propene nitrile in the form of an orange solid with melting point 260-261 ^* C. Yield 10%.

Exam ^p le 106: 3- [1, 2-dihydro-l- (4-hydroxyphenyl) -2-oxo-1, 8- naphthyridin-3-yl] -3-hydroxy-2- (3-pyridyl) propionitrile

Formula (XII): X = H; Y '= O; R ₂ = 4-OH Phenyl; R = 3-pyridyl; R _{1 =} CN

2.7 g of [1,2-dihydro-l- (4-hydroxyphenyl) -2-0X0-1, 8-naphthyridin-3-yl] carboxaldehyde prepared in Example 75 are placed in suspension in 90 ml of ethanol with 1.4 ml of 3-pyridyl acetonitrile (1, 3 eq). A solution of 0.023 g of sodium in 10 ml of ethanol (0.1 eq) is then added. The yellow suspension obtained is stirred for 24 h. The precipitate formed is drained, washed with ethanol and then with ether. 3.2 g of 3- [1,2-dihydro-1- (4-hydroxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] -3-hydroxy-2- (3-pyridyl are thus obtained ) propionitrile as a melting point of 309 ^* C. yellow solid Yield 87%.

Example 107: 3- [1, 2-dihydro-1 - (3-nitrophenyl) -2-oxo-1, 8-naphthyridin-3-yl] -3-hydroxy-2- (3-pyridyl) -propionitrile Formula (XII): X = H; Y '= O; R ₂ = 3-NO ₂ Phenyl; R = 3-pyridyl; R _{1 =} CN

According to the procedure of Example 83 but starting from 3.0 g of [1- (3-nitrophenyl) -

1, 2-dihydro-2-oxo-1, 8-naphthyridin-3-yl] carboxaldehyde, 2.6 g of 3- [1,2-dihydro-1- (3-nitrophenyl) -2-oxo- are obtained 1, 8-naphthyridin-3-yl] -3-hydroxy-2- (3-pyridyl) -propionitrile as a bright yellow solid with melting point 197 ° C. Yield 63%.

Example 108: 3- [6-chloro-1- (3,5-dichlorophenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -3-hydroxy-2- (3- pyridyl) propionitrile

Formula (XII): X = Cl; Y '= O; R - 3-pyridyl; RT = CN; R ₂ = 3,5-CI Phe

3.8 g of [6-chloro-1 - (3,5-dichlorophenyl) -1, 2-dihydro-2-oxo-1, 8-naphthyridin-3-yl] - carboxaldehyde prepared in Example 71 are placed suspended in 140 ml of methanol with 1.5 ml of 3-pyridyl acetonitrile (1.3 eq). A solution of 0.023 g of sodium in 10 ml of methanol (0.1 eq) is then added. The yellow suspension obtained is stirred for 24 h. The precipitate formed is drained, washed with methanol and then with ether. 4.0 g of 3- [6-chloro-1 - (3,5-dichlorophenyl) -1, 2-dihydro-2-oxo-1, 8-naphthyridin-3-yl] -3- hydroxy- are thus obtained 2- (3-pyridyl) propionitrile in the form of a yellow solid with a melting point of 242 ° C. Yield 84%.

Example 109: 3- [1, 2-dihydro-1- (4-hydroxyphenyl) -2-oxo-1, 8-naphthyridin- 3-yl] -2- (3-pyridyl) -2-propene nitrile

Formula (I): X = H; Y = O; R ₂ = 4-OH Phenyl; R = 3-pyridyl; R- = CN

2.5 g of 3- [1,2-dihydro-1- (4-methoxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] -2- (3-pyridyl) -2-propene nitrile prepared in Example 82 are dissolved in 100 ml of chloroform stabilized with amylene. The yellow solution is cooled to -40 ° C., then 13.2 ml of a 1M solution of BBr3 in dichloromethane (2 eq) are added dropwise, with stirring, at this temperature. The temperature is then allowed to rise to ambient, and the stirring is continued for 15 hours. The reaction medium is hydrolyzed by adding 100 ml of water, then the aqueous phase is separated, extracted several times with dichloromethane. A precipitate appears which is wrung, washed with acetone and dried. 0.21 g of 3- [1, 2-dihydro-1 - (4-hydroxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] -2- (3-pyridyl) -2- is thus obtained. propene nitrile in the form of a yellow solid with a melting point> 317 ° C. Yield 9%.

Example 110: 3- [6-chloro-1- (3,5-dichlorophenyl) -1, 2-dihydro-2-oxo-1, 8-naphthyridin-3-yl] -2- (3-pyridyl) -2 -propene nitrile

Formula (I): X = Cl; Y = O; R ₂ = 3,5-CI Phenyl; R = 3-pyridyl; R-, = CN

According to the procedure of Example 78 but using 2.1 g of 3- [6-chloro-1- (3,5-dichlorophenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin -3-yl] -3-hydroxy-2- (3-pyridyl) propionitrile, prepared in Example 108, 1.9 g of 3- [6-chloro-1 - (3,5-dichlorophenyl) - are obtained 1, 2-dihydro-2-oxo-1, 8-naphthyridin-3-yl] -2- (3-pyridyl) -2-propene nitrile in the form of a bright yellow solid with a melting point 279 ° C. Yield 94%.

Example 111: 3-ri .2-dihvdro-l - (3-nitrophénγl.-2-oxo-1.B- naphthyridin-3-yl] -2- (3-pyridyl) -2-propene nitrile

F Foorrmmuullee ((II)) :: XX == HH ;; YY == OO ;; RR ₂₂ == 33 - NN00 ₂₂ PPhhéénnyyll ;; RR == 33 - pρyyrriiddyyll ;; RRi, == C <N

According to the procedure of Example 78 but starting from 4.2 g of 3- [1, 2-dihydro-1- (3-nitrophenyl) -2-oxo-1, 8-naphthyridin-3-yl] -3 -hydroxy-2- (3-pyridyl) -propionitrile, prepared in Example 107, after purification on a column of silica (eluent: dichloromethane), 0.7 g of 3- [1, 2-dihydro-1 - ( 3-nitrophenyl) -2-oxo-1, 8-naphthyridin-3-yl] -2- (3-pyridyl) -2-propene nitrile in the form of a bright yellow solid with a melting point of 272-274 ° C. Yield 18%.

Example 112: 3- [1 - (3-aminophenyl) -1, 2-dihydro-2-oxo-1, 8- naphthyridin-3-yl] -2- (3-pyridyl) -2-propene nitrile

Formula (I): X = H; Y = O; R ₂ = 3-NH ₂ Phenyl; R = 3-pyridyl; R _t = CN

0.5g of 3- [1,2-dihydro-1- (3-nitrophenyl) -2-oxo-1,8-naphthyridin-3-yl] -2- (3-pyridyl) - 2-propene nitrile prepared at Example 111 are suspended in 15 ml of methanol and 10ml of water in the presence of 0.5g of iron powder. The suspension is heated to 50 ° C. and 0.5 ml of concentrated hydrochloric acid is added dropwise. The reaction mixture is brought to reflux for 45 minutes then cooled to room temperature. The remaining iron is removed, the filtrate diluted with water, treated with 0.5 g of potassium carbonate and extracted with dichloromethane. The organic phase is decanted, washed with water, dried and concentrated. Obtained after purification on a silica column (eluent: dichloromethane / methanol 98.5 / 1.5) 0.2 g of 3- [1 - (3-aminophenyl) -1, 2-dihydro-2-oxo-1, 8-naphthyridin-3-yl] -2- (3-pyridyl) -2-propene nitrile as a bright yellow solid of melting point 280 ^° C. Yield 40%.

Example 113: N-2- (4-chlorophenyl) ethyl cyanacetamide

Formula (X): R, = CN;

5.6 g of ethyl cyanacetate and 7.8 g of 4-chlorophenethyl amino are brought to reflux for 9 h in 50 ml of ethanol. A solution is obtained which gives, after concentration and cooling, a residue which crystallizes. This is taken up in ether, wrung, washed with ether. 7.8 g of N-2- (4-chlorophenyl) ethyl cyanacetamide are thus obtained in the form of a white solid with a melting point of 122 ° C. Yield 70%.

Example 114: N- (3-methylphenyl) methyl cyanacetamide

Formula (X): R-, = CN;

5.6g of ethyl cyanacetate and 6.06g of 3-methyl benzylamine are brought to reflux

9h in 40ml of ethanol. A solution is obtained which gives, after cooling, a precipitate which is drained, washed with ethanol and ether. 4.8 g of N- (3-methylphenyl) methyl cyanacetamide are thus obtained in the form of a white solid with a melting point of 115 ° C. Yield 51%. Example 115: N- [2- (4-chlorophenyl) ethyl] 2-cyano-3- [1,2-dihydro-1- (4-methoxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] -2- propenamide

Formula (I): X = H; Y = O; R ₂ = 4-OCH ₃ Phenyl; R, =

1.4 g of [1, 2-dihydro-1 - (4-methoxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] carboxaldehyde and 1.1 g of N- [2- (4-chlorophenyl ) ethyl] -cyanacetamide (1eq) prepared in Example 113 are placed in solution in 100ml of tetrahydrofuran. 0.7 g of potassium carbonate (1 eq) are added, and the reaction mixture is stirred at room temperature for 24 hours. The insoluble material is filtered, the filtrate concentrated and the residue taken up hot in isopropanol. After hot filtration, 0.87 g of N- [2- (4-chlorophenyl) ethyl] 2-cyano-3- [1,2-dihydro-1- (4-methoxyphenyl) -2-oxo-1 is obtained. 8-naphthyridin-3-yl] -2-propenamide in the form of a yellow solid with a melting point of 242 ° C. Efficiency 36%

Example 116: N- (3-methylphenyl) methyl 2-cyano-3- [1, 2-dihydro-1- (4-methoxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] -2- propenamide

Formula (I): X = H; Y = O; R ₂ = 4-OCH ₃ Phenyl; R, = CN

According to the procedure of Example 115, 2.8 g of [1, 2-dihydro-l- (4-methoxyphenyl) - 2-oxo-1, 8-naphthyridin-3-yl] carboxaldehyde and 1.9 g of N- (3-methylphenyl) methyl) cyanacetamide (1eq) prepared in Example 114 react to give after purification on a silica column (eluent: cylohexane / ethyl acetate 5/5) and recrystallization from isopropanol 0, 43g of N- (3-methylphenyl) methyl 2-cyano-3- [1, 2-dihydro-1- (4-methoxyphenyl) - 2-oxo-1,8, naphthyridin-3-yl] -2-propenamide form of a yellow solid with a melting point of 188 ° C. 9.5% yield PHARMACOLOGY

Measurement of the inhibition of cell proliferation of fibroblasts balb c 3T3 induced by a growth factor in the smooth muscle cells of rat aortas

i- Principle

The inhibition of cell proliferation induced by a growth factor (example: PDGF) is evaluated by measuring the incorporation of ³ H-thymidine into the fibroblasts balb c 3T3.

II. Procedure

The blab fibroblasts c 3T3 cells are grown at 37 ^° C in 5% C0 ₂ to the sub-confluence and then placed for 24 hours in a quiescent low serum medium. They are then pretreated for one hour with the molecule to be tested and then stimulated for 24 hours by a growth factor (example: PDGF). The incorporation of ³ H-thymidine is carried out during the last 2 hours. All these steps are carried out at 37 "C, in 5% C0 ₂ .

The reaction is terminated by aspiration of the reaction medium, detachment of the cells, then filtration of the lysed cells through glass fiber filters.

III. Expression of results

The results are expressed as a percentage inhibition of the stimulation of incorporation of ³ H-thymidine due to the action of the growth factor.

The results obtained show that the compounds of formula (I) powerfully inhibit the proliferation of fibroblasts balb c 3T3 stimulated by PDGF. Product% inhibition of the incorporation of 3H-thymidine stimulated by PDGF, for example in fibroblasts balb c 3T3

1 E-6M 1 E-7M CI50

78 95 0.3μM

79 76

80 24

81 64 26 0.2μM

82 55

83 48

85 82 24

86 66

87 63

88 59

89 24

92 29

93 41

94 65

95 38

100 17

103 51

109 18

110 54

111 57 TOXICOLOGY

Preliminary studies have demonstrated the good tolerance of the compounds of formula (I) up to the dose of 300 mg / kg administered intraperitoneally and orally in rats.

Claims

1. Naphthyridine derivatives characterized in that they correspond to the general formula (I)

Formula (I) in which

X represents:

- the hydrogen atom

- a halogen atom

Y represents:

- the oxygen atom

- the sulfur atom

- an NH group

R and R-i do not simultaneously represent:

- a hydrogen atom

- a CN radical

- a CONH _{2 group}

- a CONH (CH ₂ ) n group in which n is an integer from 0 to 5 and R "represents the hydrogen atom, a halogen atom or a lower alkyl radical of 1 to 6 carbon atoms

- a radical N0 ₂

- a pyridine ring unsubstituted or substituted by a halogen atom - a thiazole ring unsubstituted or substituted by a lower alkyl radical of 1 to 6 carbon atoms

where R and Ri together form 2-indolinone

R ₂ represents:

- a lower alkyl radical of 1 to 6 carbon atoms

- a lower cycloalkyl radical of 3 to 7 carbon atoms

- a group in which m is an integer from 0 to 5 and Zj and Z ₂ independently represent:

- the hydrogen atom

- a lower alkyl radical of 1 to 6 carbon atoms - a halogen atom

- a trifluoromethyl radical

- an OH radical

- an O-lower alkyl radical of 1 to 6 carbon atoms

- an S-lower alkyl radical of 1 to 6 carbon atoms - an N0 ₂ radical

- an NH ₂ radical

- A CN radical as well as their addition salts, in particular the pharmaceutically acceptable addition salts.

2. Derivatives according to claim 1 characterized in that X represents the hydrogen atom or the chlorine atom.

3. Derivatives according to any one of claims 1 to 2 characterized in that Y represents the oxygen atom.

4. Derivatives according to any one of claims 1 to 3 characterized in that R represents a pyridine or a chioropyridine.

5. Derivatives according to any one of claims 1 to 4 characterized in that R- represents the radical CN.

6. Derivatives according to any one of claims 1 to 5 characterized in that R ₂ represents the 3,5-dichlorophenyl group or the 4-methoxyphenyl group or the 3-chlorophenyl group.

7. A derivative according to claim 1 characterized in that it is:

3- [1- (3,5-dichlorophenyl) -1, 2-dihydro-2-oxo-1, 8-naphthyridin-3-yl] -2- (3-pyridyl) -2-propene nitrile, of structural formula :

8. Derivatives according to claim 1, characterized in that they are chosen from the following derivatives:

3- [1 - (3,5-dichlorophenyl) -1,2-dihydro-2-oxo-l, 8-naphthyridin-3-yl] -2- (4-pyridyl)) - 2- propene nitrile, of formula developed:

3- [1- (3,5-dichlorophenyl) -1,2-dihydro-2-oxo-1, 8-naphthyridin-3-yl] -2- (6-chloropyridin-3-yl) - 2-propene nitrile , developed formula:

3- [6-chloro-1 - (3,5-dichlorophenyl) -1, 2-dihydro-2-oxo-1, 8-naphthyridin-3-yl] -2- (3-pyridyl) - 2-propene nitrile , developed formula:

3- [1 - (3-chlorophenyl) -1, 2-dihydro-2-oxo-1, 8-naphthyridin-3-yl] -2- (3-pyridyl) -2-propene nitrile, of structural formula:

3- [1,2-dihydro-1- (4-methoxyphenyl) -2-oxo-1, 8-naphthyridin-3-yl] -2- (3-pyridyl) -2-propene nitrile, of structural formula:

9. Processes for preparing the compounds of formula (I) according to any one of claims 1 to 8 characterized in that an aldehyde of formula (IX) is reacted

Formula (IX)

in which X and R ₂ are as defined in formula (I) and Y 'represents the oxygen atom or the NH group, with an activated methylene of formula (X)

R-CH ₂ -R-

Formula (X)

in which R and R-j are as defined in formula (I) according to the conventional Knoevenagel reaction methods, for example by heating in an alcohol such as methanol or ethanol in the presence of piperidine or a sodium alcoholate or potassium or a sodium or potassium carbonate, this reaction being followed when necessary, that is to say when the derivative obtained is an alcohol, of a dehydration reaction by methods known to those skilled in the art. art, for example by the action of anhydride and trifluoroacetic acid or of paratoluene sulfonic acid in a solvent such as dichloromethane or chloroform or also toluene or xylene at a temperature between 20 and 130 ^* VS ; obtaining the compounds of formula (I) in which Y represents the sulfur atom being carried out by treatment with PS * ιo in xylene at reflux of the compounds of formula (I) in which Y represents the oxygen atom. ιo. Pharmaceutical composition, characterized in that it comprises a pharmaceutically effective amount of at least one compound of formula (I) as defined in any one of claims 1 to 8 or one of its pharmaceutically acceptable addition salts, optionally incorporated in a pharmaceutically acceptable excipient, vehicle or support. 11. Pharmaceutical composition with antiproliferative activity, characterized in that it contains a pharmaceutically effective amount of at least one compound of formula (I) as defined in any one of claims 1 to 8, or one of its pharmaceutically acceptable addition salts, optionally incorporated in an excipient, vehicle or carrier pharmaceutically acceptable. 12. Method for preparing a pharmaceutical composition, characterized in that a pharmaceutically effective amount of at least one compound of formula (I) as defined in any one of claims 1 to 8 or one of its incorporates is incorporated. pharmaceutically acceptable addition salts, in a pharmaceutically acceptable excipient, vehicle or carrier. 13. The method of claim 12, characterized in that the pharmaceutical composition is formulated in the form of capsules, tablets dosed from 1 mg to 1000 mg or in the form of injectable preparations dosed from 0.1 to 500 mg.