WO2001009112A1

WO2001009112A1 - Novel 8-carbonyl chroman derivatives, preparation and therapeutic use thereof

Info

Publication number: WO2001009112A1
Application number: PCT/FR2000/002189
Authority: WO
Inventors: Bernard Baudoin; Patrick Jimonet; Abdelazize Laoui
Original assignee: Aventis Pharma S.A.
Priority date: 1999-07-30
Filing date: 2000-07-28
Publication date: 2001-02-08
Also published as: FR2796948A1; AU6846600A

Abstract

The invention concerns novel 8-carbonyl chroman which inhibit farnesyl transferase. The invention also concerns their preparation and their therapeutic use.

Description

NEW 8-CARBONYL CHROMANES DERIVATIVES. THEIR PREPARATION AND THEIR USE IN THERAPEUTICS

The present invention relates to new 8-carbonylchroman derivatives of general formula (I)

their preparation, the pharmaceutical compositions containing them and their use for the preparation of medicaments.

The farnesyl transferase protein is an enzyme which catalyzes the transfer of the farnesyl group of farnesyl pyrophosphate (FPP) to the terminal cysteine residue of the tetrapeptide CAAX sequence of a certain number of proteins and in particular of the protein p21Ras, expression of the oncogene. ras. The ras oncogene (H-, N- or K-ras) is known to play a key role in cell signaling pathways and cell division processes. The mutation of the ras oncogene or its overexpression is often associated with human cancers: the mutated p21Ras protein is found in many human cancers and in particular in more than 50% of colon cancers and 90% of pancreatic cancers (Kohi et al ., Science, 260, 1834-1837, 1993).

The inhibition of farnesyl transferase and therefore of farnesylation of the p21Ras protein blocks the ability of the mutated p21Ras protein to induce cell proliferation and to transform normal cells into cancer cells. On the other hand, it has been shown that farnesyl transferase inhibitors are also active on tumor cell lines not expressing mutated or overexpressed ras, but having the mutation of an oncogene or the overexpression of an oncoprotein, the signaling pathway uses farnesylation of a protein, such as a normal p21Ras protein (Nagasu et al., Cancer Research 55, 5310-5314, 1995; Sepp-Lorenzino et al., Cancer Research 55, 5302-5309, 1995 ), or as rhoB (Wei et al, Molecular and Cellular Biology, 19, 1831-1840, 1999).

Farnesyl transferase inhibitors can therefore be inhibitors of cell proliferation and therefore anti-tumor and anti-leukemic agents. 1,5-disubstituted tetrahydronaphthyl derivatives were described in application WO 96/22278 as having an in vitro enzyme activity inhibiting farnesyl transferase at concentrations greater than 1 OnM, as are derivatives of 1,2,3, 4-tetrahydroisoquinolines, described in application WO 96/24612. Other farnesyl transferase inhibitors having an isoquinoline structure have also been described in application EP 0618221. These previous applications therefore presented a hydrocarbon or nitrogen distributor; by distributor is meant the condensed system onto which the functional chains are grafted. It has now been found, and this is what is the subject of the present invention, that the compounds of general formula (I), having as a distributor a heterocyclic oxygenated system (chroman nucleus), distinct from that of the compounds of l he prior art cited above, manifest their inhibitory activity both at the enzymatic level and at the cellular level, and this at quite significant concentrations.

Due to this activity, the compounds of general formula (I) are therefore remarkable anti-tumor and anti-leukemic agents.

Nothing in the prior art suggested bringing about such a modification in the chemical structure and did not allow predicting the advantageous anticancer properties manifested by the present compounds. Furthermore, according to the invention, the new products of general formula (I), farnesyl transferase inhibitors, can be competitive with respect to a Farnesyl Transferase substrate, such as those described by ADCox and CJDer, Biochimica and Biophysica acta, 1333 (1997), f 51-f 71 and in particular the protein p21Ras, such as H-Ras, Ki-Ras, N-Ras, Rho ...; this peculiarity allowing them to act specifically at the level of the substrate.

The present invention relates to new derivatives of general formula (I)

in racemic form, or their stereoisomers as well as in the form of salts.

In the general formula (I):

Rg represents a radical -Riι- (CO) _m -Ri ₂ , for which: Rii represents an alkylene, alkenylene radical; R ₂ represents a hydroxy, alkoxy or amino radical; m is preferably 0 or 1, R9 is He by a single bond at position 4 of the phenyl group to which it is attached; R ₂ represents a hydrogen atom or an alkyl or alkylcarbonyl radical;

R ₃ represents a hydrogen atom or a halogen atom

R ₄ represents a radical Ri,

/ ³

- CH Ri ₄

R ₅ represents a radical -C (O) -Ris

R _ό represents a hydrogen atom

R, R ₈ independently represent a hydrogen atom Ri ₃ , Rit identical or different independently represent a hydrogen atom, or an aryl radical. Preferably, said aryl radical represents naphthyl radicals, such as 2-naphthyl, or phenyl; it may optionally be substituted by one or more atoms or radicals chosen from halogen atoms, alkyl, alkoxy, polyfluoroalkoxy, or aralkoxy radicals, it being understood that Ri ₃ and RU do not each simultaneously represent a hydrogen atom,

Ri ₅ represents a radical chosen from amino, hydroxy and alkoxy radicals in racemic form or their stereoisomers as well as their salts.

In the above and the following:

- The radicals and alkyl portions contain 1 to 10 carbon atoms in a straight or branched chain, and include in particular the radicals and methyl, ethyl, propyl, butyl, pentyl, hexyl portions as well as their iso, dry and tert isomers;

the alkylene radicals and portions define the divalent hydrocarbon radicals, the free valencies of which are carried by the same carbon atom or two different carbon atoms of the alkylene portion, in straight or branched chain, containing from 1 to 10 carbon atoms, and include in particular the methylene, ethylene, propylene, butylene, pentylene, hexylene radicals, as well as their iso, dry and tert isomers;

- the alkenylene radicals define the divalent hydrocarbon radicals having at least one unsaturated double bond, whose free valences are carried by the same carbon atom or two different carbon atoms of the alkenylene portion, in straight or branched chain, containing from 1 to 10 carbon atoms, and include in particular the ethenylene, propenylene, butenylene, pentenylene, hexenylene radicals, as well as their iso, dry and tert isomers;

- the term halogen defines fluorine, chlorine, bromine and iodine atoms; preferably fluorine, chlorine or bromine; - The term cycloalkyle defines a 3 to 6-membered saturated hydrocarbon cyclic radical; it preferably represents the cyclohexyl radical;

- The term aryl of aryl or aralkyl radicals defines a 6 to 10-membered monocarbon or bicyclic aromatic hydrocarbon system, unless otherwise mentioned; aryl preferably represents phenyl, naphthyl; aralkyl preferably represents benzyl;

- the term heteroaryl defines a mono or bicyclic aromatic system, of 5 to 10 links containing from 1 to 4 heteroatoms, chosen from nitrogen, oxygen and sulfur, and preferably represents the thienyl, pyrrolyl, imidazolyl, pyrazolyl radicals , triazolyl, oxazolyle, oxadiazolyle, thiadiazolyle, isothiazolyle, isothiazolyle, pyridazinyle, pyrimidinyle, pyrazinyle, furanyl, thiazolyle, isoxazolyle, tétrazolyle, pyridyle as well as the radicals resulting from the fusion of these cyles above mentioned;

- the term BOC defines the tert.butoxycarbonyl radical,

- the term Ph defines the phenyl radical, - the term Hal defines a halogen atom such as fluorine, chlorine, bromine, iodine.

The products of general formula (I) have at least one asymmetric carbon: this asymmetric carbon can have the configurations (R) or (S); in particular, the products of general formula (I) can have 2 asymmetric carbons, and can therefore be in the form of 4 stereoisomers: 2 diastereoisomers and 2 enantiomers, the enantiomers possibly being in the form of a racemic mixture.

In particular, in the general formula (I), C ^* advantageously has the configuration (S). All the stereoisomeric forms of the compounds of general formula (I) also form part of the invention. Among these stereoisomeric forms according to the invention, the compounds of general formula (I) having a positive rotary power are preferred.

In what precedes and what follows, the expression "stereoisomer", defines the pure form of said stereoisomer or possibly the mixture of stereoisomers "enriched", that is to say containing predominantly said stereoisomer or said form.

Among the products of general formula (I), those for which:

R ₉ represents a radical -Riι- (CO) _m -Ri ₂ , for which: Rii represents an alkylene, alkenylene radical; R ₂ represents an alkoxy, amino radical; m is equal to 0 or 1 from the radicals R ₂ , it is preferred to choose a hydrogen atom; preferably, R represents a hydrogen atom;

preferably> can represent a radical:

-CH (phenyl) with the phenyl nucleus possibly being substituted, preferably in position 3 and / or 4, by one or more substituents chosen independently from halogen atoms, alkoxy or polyfluoroalkoxy radicals; and / or preferably, R ₅ represents a radical -C (O) -Ri ₅ for which Ri ₅ represents an amino radical; and / or preferably, Rβ represents a hydrogen atom; and / or preferably, R and R ₈ each represent a hydrogen atom; in racemic form or their stereoisomers as well as their salts.

By way of illustration and without limitation of the claimed compounds, mention may be made of any compound of general formula (I), selected individually from: 8N- [1 - (S) -carbamoyl-2- (4-chloroρhenyl) -ethyl] -4- {1 - [4- (2- methoxycarbonylvinyl) phenyl] methyl- 1 H-imidazol-5-ylmethylamino} -chroman -8- carboxamide

8N- [1 - (S) -carbamoyl-2- (4-chlorophenyl) -ethyl] -4- {1 - [4- (2- methoxycarbonylethyl) phenyl] methyl- 1 H-imidazol-5-ylmethylamino} -chroman -8- carboxamide

8N- [1 - (S) -carbamoyl-2- (4-chloroρhenyl) -ethyl] -4- {1 - (4- (2- carbamoylethyl) phenyl] methyl- 1 H-imidazol-5-ylmethylamino} -chroman -8- carboxamide 8N- [1 - (S) -carbamoyl-2- (4-chlorophenyl) -ethyl] -4- {1 - (4- (2- carbamoylvinyl) phenyl] methyl- 1 H-imidazol-5- ylmethylamino} -chroman-8- carboxamide

8N- [1 (S) -carbamoyl-2- (4-chloro-phenyl) ethyl] -4- {1 - (4- (3-hydroxypropyl) benzyl] - 1 H- imidazol-5-ylmethylamino} -chroman- 8-carboxamide or their stereoisomers, or in racemic form as well as their salts.

The present invention also relates to the preparation of the new products of general formula (I). Various operating protocols as well as reaction intermediates capable of being used to prepare the compounds of general formula (I) are proposed. Of course, analogous methods are included in the present invention in order to lead to these same compounds: it is within the reach of the skilled person to apply or adapt these methods to implement the invention using of his general knowledge.

According to the present invention, the products of general formula (I) in which R ₂ , R ₃ , R _Λ , R ₅ , Ré, R ₇ , R ₈ , 9 are as defined in general formula (I), can be obtained from the product of general formula (Ha)

in which R ₃ , i, R ₅ , Rό, R, R are as defined in general formula (I) and Gi represents a hydrogen atom or a group protecting the amino function or a group protecting the amino function under form of mixture of isomeric diastereomers and / or enantiomers, or else in the form of pure isomeric diastereomer or enantiomer by the action of a reagent of general formula

for which R9 is defined as in general formula (I).

The reaction of the product of general formula (III) with the product of general formula (IIa) is carried out under reducing amination conditions: in particular, by operating in an organic solvent such as acetonitrile or methanol, in the presence of acid such as acetic acid, on a 3 A molecular sieve, then by the action of a reducing compound, such as sodium cyanoborohydride (NaBH CN) or sodium triacetoxy borohydride (NaBH (OCOCH ₃ ) ₃ ) or BH ₃ pyridine complex, operating in an organic solvent such as ethanol, at a temperature preferably between 0 ° C. and the reflux temperature of the solvent.

The products of general formula (III) in which Rii and Ri ₂ are defined as in general formula (I) can be obtained commercially or by functionalization of commercially available carboxaldehydes according to the methods described by Larock, Comprehensive Organic Transformations, VCH, New York, 1989, or according to the procedures described in the examples, or according to the methods described by J. Jeong Lee J. Heterocyclic. Chem, (1998), 35, 81-89, by S. Sebti J. Med. Chem, (1996), 39, 219, by G. Bold, J. Med. Chem, (1998), 41, 3387-3401.

In particular, the products of general formula (III) in which Rii represents an alkenylene radical and Ri ₂ is defined as in general formula (I) can be obtained from the compounds of general formula (Illa):

in which Hal represents a halogen atom such as bromine, by the action of a reagent of general formula (IIIb)

HRi, -CORi ₂ (Illb) in which Rii represents an alkenylene radical and Ri ₂ are defined as in general formula (I) by Heck reaction. In particular, this reaction can be carried out in the presence of a base, such as an amine, such as triethyl amine, of palladium (such as palladium acetate), of tri-o-tolylphosphine, in an organic solvent such as dimethylformamide, optionally by heating at reflux of the solvent.

When Rii represents an alkylene radical, the compounds of general formula (III) can be obtained from compounds of general formula (III) for which Rii represents an alkenylene radical by reduction, in the presence of reducing agents such as sodium borohydride optionally in the presence of nickel chloride, optionally hexahydrate; then optionally followed in the case where the aldehyde has been reduced to alcohol, by an oxidation reaction of the alcohol intermediate formed into the desired aldehyde, by reaction in the presence of one or more known oxidizing agents per se, such as manganese oxide, chromium trioxide, Swern's reagent, potassium permanganate, etc.

Optionally, when Ri ₂ represents an amino radical, the compounds of general formula (III) can be obtained from compounds of general formula (III) in which Ri ₂ represents an alkoxy radical, by reaction of ammonia in an alcohol such than methanol.

The compounds of general formula (IIIa) can be obtained from the compounds of general formula (IIIc):

_H t ^π -0 by action of a beαzylic halide of formula (Illd):

wherein Hal represents a halogen atom such as bromine, in an organic solvent, such as acetonitrile, in the presence of an inorganic base, such as potassium carbonate.

And optionally, in the case where: a) R ₅ represents a radical -CORi ₅ , where Ri ₅ represents an amino radical, the products of general formula (I) can be obtained from the products of general formula (I) for which Ri ₅ represents an alkoxy radical by the action of ammonia in an organic solvent such as toluene or methanol; b) Ris represents a hydroxy radical, the products of general formula (I) can be obtained by saponification of the compounds of formula (I) for which R ₅ —CORJ ₅ and Ris represents an alkoxy radical. c) R ₂ represents an alkylcarbonyl radical, the products of general formula (I) in which R, R ", R ₅ , D, R7, R", R9 are as defined in general formula (I) can be obtained from corresponding compounds of general formula (I) in which R ₂ represents a hydrogen atom, by action of the corresponding acid of formula R ₂ OH, in which R ₂ represents an alkylcarbonyl radical, or of an activated form of this acid such as an acyl halide, or anhydride of this acid, optionally in the presence of an organic base, such as a triethylamine, or an inorganic base such as potassium carbonate, in an organic solvent such as dichloromethane. d) R represents an alkyl radical, the products of general formula (I) in which R9, R ₃ , R ", R5, D, R7, R ₈ are as defined in general formula (I) can be obtained from corresponding compounds of general formula (I) in which R ₂ represents a hydrogen atom, by the action of the corresponding aldehyde, generally operating by reductive amination under the conditions as described above.

The products of general formula (I) obtained at the end of the process according to the invention can have different stereoisomeric, enantiomeric and / or diastereoisomeric forms, which can be separated by conventional separation methods, such as chromatography or crystallization. For diastereoisomers, use will preferably be made of high performance liquid chromatography on a silica column: normal phase, reverse phase C _{] 8} or chiral phase, and for enantiomers chromatography on a chiral column, such as that of the Pirkle type (Pirkle and coll., Asymétrie Synthesis, vol. 1, Académie Press (1983)), or by synthesis from chiral precursors. It is the same for the products of formula (Ha), in which R ₃ , Ri, R ₅ , R _δ , R ₇ , R ₈ are as defined in general formula (I) and Gι represents a hydrogen atom. , the subsequent synthesis steps can then be carried out from the isomers (enantiomers, diastereoisomers) separated and purified. Also forming part of the present invention are the compounds of general formula (Ha) in which R ₃ , RA, R5, D, R7, Rs are as defined in general formula (I) and Gi represents a hydrogen atom or a group protector of amino function.

The products of general formula (IIa) in which R ₃ , R ", R ₅ , Rβ, R, R ₈ are defined as above, and Gi represents a hydrogen atom can be obtained from compounds of general formula (Ilb )

in which R, R *, R ₅ , R, R7, Rs are defined as above, and Gi represents a protecting group for an amino function chosen from the benzyloxycarbonyl, tert.butoxycarbonyl or vinyloxycarbonyl radicals, by application or adaptation of the methods of conventional deprotection described by TWGreene, Protective groups in organic chemistry, Wiley-interscience (1991), and more particularly by hydrogenolysis in the presence of a catalyst such as palladium on carbon, when Gi represents a benzyloxycarbonyl radical, or by hydrolysis in an acid medium when Gi represents a tert.butoxycarbonyl, vinyloxycarbonyl or benzyloxycarbonyl radical; preferably according to the invention, G represents a tert.butoxycarbonyl radical (BOC) which can be deprotected in particular by operating in an organic solvent such as a halogenated aliphatic hydrocarbon such as dichloromethane, in the presence of trifluoroacetic acid (TFA) or also in the presence of hydrochloric acid, operating in an alcohol, such as methanol or ethanol, or an ether, such as diethyl or dϋsopropyl ether, at a temperature preferably close to 20 ° C. This reaction can optionally be followed by a step of separation of the isomers, diastereoismers and / or enantiomers, according to the methods described above.

The products of general formula (Ilb) in which R, i, R ₅ , Rβ, R, R ₈ are defined as above, and Gi represents a protective group defined as above can be obtained from compounds of general formula (IV )

in which R ₃ , R ₇ , R ₈ and Gi are defined as above, by the action of a compound of general formula (V) corresponding

in which R4, R5, Rό are as defined in general formula (I), operating according to the amidation methods. In particular, this reaction can advantageously be carried out by operating in an organic solvent such as a halogenated aliphatic hydrocarbon such as dichloromethane in the presence of a condensing agent such as 1-ethyl-3- [3- (dimethylamino) hydrochloride. propyl] carbodiimide, 1,1-dicyclohexylcarbodiimide or benzotriazol-1-oxy tris (dimethylamino) phosphonium hexafluorophosphate, optionally in the presence of an activating agent such as hydroxybenzotriazole, at a temperature preferably between 0 ° C. and the reflux temperature of the solvent.

The compound of general formula (V) can be obtained commercially or according to the methods described in the examples, for example using the procedures described by S. Sagan Bioorg. Med. Chem. Lerters (1996), 4, 2167-2178, by W. Oppolzer

Helv.Chim.Acta, (1994), 77, 2366-2380 or according to the methods described by Larock, Comprehensive Organic Transformations, VCH, New York, 1989 for the preparation of functionalized amines.

Preferably, when R ₅ represents a radical -C (O) -Ri ₅ for which Ri ₅ is as defined in the general formula (I), it is preferable to use an amino acid (or a derivative of this amino acid) of series natural, it being understood that the configuration of the amino acid can be modified during the amidation reaction and that several stereoisomers can then be obtained at the end of this reaction.

Optionally, when R ₅ represents the radical -CORis for which Ri ₅ represents an amino radical, as defined in the general formula (I), the products of general formula (Ilb) can also be obtained from the compounds of general formula (IV ) by the action of a compound of general formula (V)

in which R4 and R * are as defined in general formula (I) and R ₅ represents the radical -CORis for which Ri ₅ represents an alkoxy radical, under the same conditions as those used for the preceding amidation, then is followed by the action of ammonia, in an organic solvent such as an alcohol, preferably methanol, optionally in the presence of catalytic amounts of sodium cyanide, at a temperature preferably between 0 ° C. and the reflux temperature of the solvent, optionally operating in an autoclave, or is followed, after hydrolysis of the radical -COR15 in carboxy radical, the action of ammonia, under the coupling conditions described above.

The compounds of general formula (IV) in which R, R ₇ , R and Gi are defined as above can in particular be obtained from the compounds of general formula (VI):

in which R ₃ , R ₇ , Rs and Gi are defined as above, by the action of a base such as an alkali metal salt, such as an alkyllithian, optionally in the presence of complexing diamine such as N, N, N ' , N'- tetramethylethylenediarnine, operating in particular in an organic solvent such as an ether such as diethyl ether, at a temperature preferably between

-78 ° C and room temperature, followed by a carboxylation carried out for example by means of carbon dioxide, for example in the form of dry ice or CO ₂ gas.

The compounds of general formula (VI) in which R, R, R ₈ and Gι are defined as above can be obtained from compounds of general formula (VII):

in which R ₃ , R ₇ , R ₈ are defined as above by the action of an ammonia salt such as ammonium acetate, in the presence of sodium cyanoborohydride, operating in particular in an organic solvent, such as an alcohol, such as methanol, at temperatures preferably between 0 ° C. and the boiling point of the solvent, followed by protection of the amino group by application or adaptation of the conventional protection methods described by TWGreene, Protective groups in organic chemistry, Wiley-interscience (1991), and more particularly by reaction with chloroformate or terbutoxycarbonyl anhydride, in the presence of a base for example such as triethylamine or sodium hydrogencarbonate in an organic solvent such as an alcohol, such as ethanol, at a temperature preferably between 0 ° C. and the boiling point of the solvent.

The products of general formula (VII) are commercial or can be obtained by application or adaptation of the methods described by I.M. Lockart, The chemistry of heterocyclic compounds, chromenes, chromanones and chromones, 5, 207-428, 1977.

In addition, according to another embodiment according to the invention, the new products of general formula (I), in which R9, R ₂ , R ₃ , R4, R ₅ , Rβ, R, R ₈ are defined as previously, can be obtained from the product of general formula (VIII)

in which R ₉ , R ₂ , R ₃ , R, R ₈ are defined as above, by the action of a compound of general formula (V)

in which R, R ₅ , R _ό are as defined above, operating according to the amidation methods. In particular, this reaction can be carried out by operating under the corresponding amidation conditions described above, and taking into account the same stereochemical considerations.

Also forming part of the present invention, the compounds of general formula (VIII) in which R ₉ , R ₂ , R ₃ , R7, R ₈ are defined as in general formula (I). Generally, the acids of general formula (VIII) in which Rg, R ₂ , R ₃ , R ₇ , Rg, are defined as above can be obtained from the corresponding esters of general formula (IX):

in which R9, R ₂ , R, R7, Rs are defined as above and R represents an alkyl radical, methyl preferably, by application or adaptation of the known saponification methods, described in particular by J. March, Advanced Organic Chemistry, Wiley -interscience (1992); advantageously, the saponification of the ester of general formula (IX) can be carried out in an organic solvent such as an alcohol such as methanol or ethanol, optionally aqueous, by means of an inorganic base such as sodium hydroxide or potash or sodium carbonate.

Generally, the compounds of general formula (IX) in which R, R ₉ , R ₂ , R ₃ , R ₇ , Rs are defined as above can be obtained from compounds of general formula (X):

in which R, R ₃ , R, R ₈ are defined as above, by the action of a reagent of general formula

for which R9 is defined as in general formula (I)

This reaction by means of the compounds of general formula (III) can be carried out under the same conditions of corresponding reductive amination, relating to the compounds of general formulas (III), and described above for the preparation of the compounds of general formula (I) .

Generally, the esters of general formula (X) can be obtained from the corresponding acids of general formula (IV):

in which R, R, R ₈ are defined as above and Gι represents a protective group defined as above, by esterification of the carboxylic acid and deprotection of the amino group; the esterification can be carried out according to any known esterification method, chosen in particular from those described by J. March, Advanced Organic Chemistry, Wiley-interscience (1992); deprotection of the amino group can be carried out by application or adaptation of the conventional deprotection methods described by TWGreene, Protective groups in organic chemistry, Wiley-interscience (1991), and more particularly by hydrolysis in an acid medium when Gi represents a tert-butoxycarbonyl radical; advantageously according to the invention, these reactions can be carried out simultaneously, operating in acidic medium, preferably in the presence of hydrochloric acid, using as alcohol the alcohol of general formula R-OH in which R is defined as above, and at a temperature preferably between 20 ° C. and the reflux of the solvent.

The compounds of general formula (IV) can be prepared as described above.

Generally, the new products of general formula (I) in which R ₉ , R ₂ , R ₃ , R4, Rs, Rό, R7, Rs are defined as above can be obtained after a subsequent deprotection reaction, preferably at the end of process.

The reaction mixtures obtained by the various processes described above are treated according to conventional physical (evaporation, extraction, distillation, chromatography, crystallization, for example) or chemical (formation of salts, for example) methods.

The compounds of formula (I) can optionally be converted into addition salts with a mineral or organic acid by the action of such an acid within an organic solvent such as an alcohol, a ketone, an ether or a solvent chlorine. These salts are also part of the invention; in particular, the products of general formula (I) can be in the form of ditrifluoroacetate, or oxalate.

The present invention also relates to any pharmaceutical composition containing at least one product of general formula (I) in combination with one or more diluents or pharmaceutically acceptable adjuvants whether they are inert or biologically active. The new products of general formula (I) can be in the form of salts, non-toxic and pharmaceutically acceptable. As examples of pharmaceutically acceptable salts, there may be mentioned the addition salts with mineral or organic acids such as acetate, propionate, succinate, benzoate, fumarate, maleate, methanesulfonate, isethionate, theophyllinacetate, salicylate, methylene-bis-b-oxynaphtoate , hydrochloride, sulfate, nitrate and phosphate.

The present invention relates to the use of the compounds of general formula (I) for the preparation of pharmaceutical compositions useful for the treatment and / or the prevention of pathological conditions linked to cell signaling pathways, associated with farnesyl transferase, or to their consequences or symptoms. The present invention also relates to the use of the compounds of general formula (I) according to the invention for the preparation of pharmaceutical compositions useful for inhibiting farnesyl transferase, and more particularly for inhibiting the farnesylation of Ras proteins produced by ras oncogenes. In particular, the present invention relates to the use of the compounds of general formula (I) according to the invention for the preparation of pharmaceutical compositions useful for the treatment of diseases linked to cell proliferation by inhibition of farnesyl transferase and in particular for the treatment diseases linked to cell proliferation, overexpressing any of the H-Ras, N-Ras or K-Ras oncoproteins, or having a mutation in any of the corresponding ras oncogenes.

The invention relates in particular to the use of the compounds of general formula (I) according to the invention for the preparation of pharmaceutical compositions useful for the treatment of diseases linked to cellular, malignant or benign proliferation, cells of various tissues and / or organs, including muscle, bone or connective tissue, skin, brain, lungs, sex organs, lymphatic or renal systems, mammary or blood cells, liver, digestive system, colon, pancreas and the thyroid or adrenal glands, and including the following pathologies: psoriasis, restenosis, solid tumors, Kaposi's sarcoma, carcinomas, cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms tumor, Hodgkin's disease, melanomas, teratocarcinomas, gliomas, multiple myelomas, chronic lymphocytic leukemias, acute or chronic granulocytic lymphomas, and s cancers such as pancreatic, colon, lung, ovarian, breast, brain, prostate, liver, stomach, bladder or testicular cancers. The invention relates very particularly to the use of the compounds of general formula (I) according to the invention, for the preparation of pharmaceutical compositions useful for the treatment of cancers such as pancreatic, colon, lung, ovarian, breast, brain, prostate, liver, stomach, bladder or testicular cancers.

Said treatment can be carried out in particular by inhibiting tumor growth, in particular by inhibiting farnesyl transferase, or else by inhibiting the growth of tumors expressing the activated ras oncogene.

Another object of the present invention is any combination of a product of general formula (I) with one or more compatible and pharmacologically active compounds and / or radiotherapy treatment; said compounds preferably being active ingredients known for their activity inhibiting cell proliferation and particularly for their activity in the treatment of cancer; they may preferably be antiproliferative compounds which act at any of the stages of the signaling pathway of the ras oncogene such as a protein tyrosine kinase inhibitor, or another farnesyl transferase inhibitor, or an HMG-Co-reductase inhibitor , or a gene therapy treatment resulting for example from the administration of a tumor suppressor gene, or the cytotoxic compounds usually used in the treatment of cancer.

In particular, the other treatments and / or therapeutic products which can be used in combination with the products of general formula (I) can be chosen from antineoplastic drugs, monoclonal antibodies, immunological therapies or radiotherapy or modifiers of biological responses. Response modifiers include, but are not limited to, lymphokines and cytokines such as interleukins, interferons (α, β or δ) and TNF. Other chemotherapeutic agents useful in the treatment of disorders due to abnormal cell spreading include, but are not limited to, alkylating agents such as nitrogen mustards such as mecMoretamine, cyclophosphamide, melphalan and chlorambucil, alkyl sulfonates such as busulfan, nitrosoureas such as carmustine, lomustine, semustine and streptozocin, triazenes such as dacarbazine, antimetabolites such as folic acid analogs such as methotrexate, pyrimidine analogs like fluorouracil and cytarabine, purine analogs like mercaptopurine and thioguanine, natural products like vinca alkaloids like vinblastine, vincristine and Vendesin, taxoid derivatives, topoisomerase inhibitors such as camptothecin derivatives, epipodophyllotoxins such as etoposide and teniposide, antibiotics such as dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin , enzymes such as L-asparaginase, various agents such as platinum coordination complexes such as cisplatin, substituted ureas such as hydroxyurea, methylhydrazine derivatives such as procarbazine, adrenocotic suppressants such as mitotane and aminoglutethymide, hormones and antagonists like adrenocorticosteroids like prednisone , progestins like hydroxyprogesterone caproate, methoxyprogesterone acetate and megestrol acetate, estrogens like diethylstilbestrol and ethynylestradiol, antioestrogens like tamoxifen, androgens like testosterone propionate and fluoxymesterone.

The products according to the invention can be used to prevent or delay the onset or recurrence of pathological conditions or to treat these pathological conditions.

The products according to the invention can be administered by oral, parenteral route, such as intravenous or intraperitoneal or rectal.

The compositions for oral administration include tablets, pills, powders or granules. In these compositions, the active product according to the invention is mixed with one or more inert diluents such as sucrose, lactose or starch. These compositions can include substances other than diluents, for example a lubricant such as magnesium stearate.

As liquid compositions for oral administration can be used pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs containing inert diluents such as water or paraffin oil. These compositions may also include substances other than diluents, for example wetting, sweetening or flavoring products. The compositions according to the invention for parenteral administration can be sterile aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil or injectable organic esters, for example ethyl oleate, can be used. These compositions can also contain adjuvants, in particular wetting agents, emulsifiers and dispersants. Sterilization can be done in several ways, for example using a bacteriological filter, by incorporating steriizing agents into the composition or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium. The compositions for rectal administration are suppositories which may contain, in addition to the active product, excipients such as cocoa butter.

The doses used to implement the methods according to the invention are those which allow a prophylactic treatment or a maximum therapeutic response. The doses vary depending on the form of administration, the particular product selected and the specific characteristics of the subject to be treated. In general, the doses are those which are therapeutically effective for the treatment of disorders due to abnormal cell proliferation, and in particular cytostatic treatment. The products according to the invention can be administered as often and as long as necessary to obtain the desired therapeutic effect. Generally, the doses are, in humans, between 0.1 and 10,000 mg / kg per day, preferably between 100 and 2,000 mg / kg per day. It is understood that, in order to choose the most appropriate dosage, the route of administration, the patient's weight, his general state of health, his age and all the factors which may influence the effectiveness of treatment must be taken into account. . In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated. Example 6 illustrates compositions according to the invention.

The following examples are presented by way of non-limiting illustration of the present invention.

Advantageously in the examples below, C * has the configuration (S); in this case, the other asymmetric carbon possibly present in the molecule can have a configuration (R) or (S): the corresponding compounds are diateroisomers, which will be noted for convenience diastereoisomers A and B.

The corresponding enantiomers, that is to say those for which C * has the configuration (R) can of course also be obtained, in particular by using the appropriate reagent of configuration (R).

Example 1

Preparation of the diastereoisomer A of 8N-fl- (S) -carbamoyl-2- (4-chlorophenylV ethyll-4-π-f4- (2-methoxycarbonylvinvπphenylmethyll-1H-imidazol-5- vImethvIaminol-chroman-8-carboxamide

262 g (3.4 moles) of ammonium acetate are added to 550 ml of a methanolic solution of 4-chromanone (50 g, 0.337 moles) at a temperature in the region of 20 ° C. The reaction mixture is stirred for 2 hours at the same temperature and then treated by progressive addition of sodium cyanoborohydride (15.1 g, 0.24 mole). The reaction is continued for 15 hours at 20 ° C., then the reaction mixture concentrated to dryness under reduced pressure (20 mmHg, 2.6 kPa) at 50 ° C. The crude product is taken up in 1 l of distilled water brought to pH = 10 by addition of ION sodium hydroxide and the organic phase extracted with 3 times 300 ml of dichloromethane, then washed with distilled water, dried over magnesium sulphate and concentrated dry under reduced pressure at 50 ° C. The crude product (46 g) is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (95/5 by volume). 25.3 g (50.4%) of 4-amino-chroman are thus obtained in the form of a brown oil.

To 25 g (0.17 mole) of 4-amino-chroman dissolved in 450 ml of ethanol, 35.3 g (0.42 mole) of sodium hydrogen carbonate are added, then 41.5 g (0.19 mole) of di- tert-butyl dicarbonate. The reaction medium is stirred for 15 hours at a temperature in the region of 20 ° C., then added to 1.5 l of a mixture of distilled water and ice. The precipitate formed is filtered, then washed with water and dried under reduced pressure at 60 ° C. 40.3 g (95.3%) of 4-tert-butoxycarbonylamino-chroman are obtained in the form of a beige powder, melting at 113 ° -14 ° C.

A solution of 12.45 g (0.05 mole) of 4-tert-butoxycarbonylamino-chroman and 10.45 g (0.09 mole) of N, N'-tetramethyl-ethylenediamine in 250 ml of anhydrous diethyl ether cooled to -63 ° C is treated dropwise with 85 ml of a 1.3 M solution in sec-butyl-hthium cyclohexane (0.11 mole). The reaction is continued for 1 hour at the same temperature, then to the orange-brown suspension are added a few sticks of dry ice (previously washed in diethyl ether and wiped). The suspension, which quickly became beige, is brought to a temperature in the region of 20 ° C., then the reaction mixture is acidified (pH = 1) using 4N hydrochloric acid. The precipitate obtained is filtered, washed with water and then dried under reduced pressure at 50 ° C. 7.8 g (53.2%) of 4-tert-butoxy-carbonylamino-chroman-8-carboxylic acid are obtained in the form of a beige powder melting at 185-187 ° C. To a solution of 5.87 g (0.020 mole) of 4-tert-butoxycarbonylamino-chroman-8-carboxylic acid, 5.5 g (0.022 mole) of hydrochloride of the methyl ester of (S) -4-chlorophenylalanine , 2.97 g (0.022 mole) of 1-hydroxy-benzotriazole and 4.55 g (0.045 mole) of triethylamine in 200 ml of dichloromethane, 4.22 g (0.022 mole) of hydrochloride of l- (3- dimethylaminopropyl) -3- ethylcarbodiimide at a temperature in the region of 20 ° C. The reaction is continued for 15 hours at the same temperature. The reaction medium is then washed with 2 times 40 ml of distilled water, then 40 ml of a saturated aqueous solution of sodium hydrogencarbonate and finally 50 ml of a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the organic solution is filtered and then concentrated to dryness under reduced pressure.

Obtained after chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (99/1 by volume), 8.35 g (87.6%) of 8N- [1 (S) - methoxycarbonyl-2- (4-chlorophenyl) -ethyl] -4-tert-butoxycarbonylamino-chroman-8-carboxamide in the form of a pale yellow lacquer.

Mass spectrum: IE, m / z = 488 (M ⁺ ), m / z = 415 (MC ₄ H ₉ O) ⁺ , m / z = 372 (m / z = 415- CHON) ⁺ -, m / z = 292 (MC, ₀ H9O ₂ C1) ⁺ , m / z = 276 (MC, oH, ιO ₂ NCl) ⁺ base peak, m / z = 236 (m / z = 292-C ₄ H ₈ ) ⁺ - , m / z = 220 (m / z = 276-C ₄ H ₈ ) ⁺ , m / z = 175 (mz = 220-CO ₂ H) ⁺ , m / z = 148 (m / z = 175-CO + H) ⁺ -, mz = 57 (C ₄ H ₉ ⁺ )

8 g (0.016 mole) of 8N- [l (S) -methoxycarbonyl-2- (4-chlorophenyl) -ethyl] -4-tert-butoxycarbonylarnino-chroman-8-carboxamide in solution in 30 ml of 6N ammoniacal methanol are heated in an autoclave at 50 ° C for 48 hours. After cooling to a temperature in the region of 20 ° C., the reaction medium is concentrated to dryness under reduced pressure and the residue purified by flash chromatography on a silica column using a mixture of dichloromethane and methanol (98/2 by volume) as eluent. 6.8 g (90%) of 8N- [l (S) -carbamoyl-2- (4-chlorophenyl) -ethyl] -4-tert-butoxycarbonylarnmo-chroman-8-carboxamide are thus obtained in the form of a white fondant powder. at 187-190 ° C.

Mass spectrum: IE, m / z = 473 (M ⁺ ), m / z = 429 (M-CH ₂ ON) ⁺ , m / z = 292 (M- C ₉ H ₈ ONCl) ⁺ , m / z = 276 (MC ₉ H ₁₀ ON ₂ C1) ⁺ base peak, m / z = 236 (m / z = 292-C ₄ H ₈ ) ⁺ , m / z = 220 (m / z = 276-C ₄ H ₈ ) ⁺ , m / z = 175 (m / z = 220-CO ₂ H) ⁺ , m / z = 148 (m / z = 175-CO + H) ⁺ , m / z = 57 (C ₄ H ₉ ⁺ )

A suspension of 6.4 g (0.0135 mol) of 8N- [1- (S) -carbamoyl-2- (4-chlorophenyl) - ethyl] -4-tert-butoxycarbonylamino-chroman-8-carboxamide IN of hydrogen chloride in diethyl ether (300 ml) is stirred for 48 hours at a temperature in the region of 20 ° C. To this suspension are then added 20 ml of methanol and the ethereal phase discarded. The methanolic residue is taken up in a mixture of IN aqueous sodium hydroxide (150 ml), distilled water (250 ml) and dichloromethane (200 ml), then the organic phase decanted, washed with water, dried over magnesium sulphate , filtered and concentrated to dryness under reduced pressure at 50 ° C. 5.2 g of crude product are thus obtained, purified by flash chromatography on a silica column using a mixture of dichloromethane and methanol (90/10 by volume) as eluent to yield 2.9 g (58%) of the 8N- [1 (S) -carbamoyl-2- (4-corophenyl) -ethyl] -4-amino-chroman-8-carboxarnide diastereoisomer A Pale yellow meringue with the following characteristics:

Η NMR spectrum (400 MHz, (CD ₃ ) ₂ SO d6, δ in ppm): 1.80 (mt: 1H); from 1.95 to 2.15 (mt: 3H); 2.99 (dd, J = 14 and 8 Hz: 1H); 3.11 (dd, J = 14 and 5 Hz: 1H); 3.93 (t, J = 5 Hz: 1H); from 4.20 to 4.40 (mt: 2H); 4.68 (mt: 1H); 6.94 (t, J = 8 Hz: 1H); 7.16 (br s: 1H); 7.27 (d, J = 8.5 Hz: 2H); 7.37 (d, J = 8.5 Hz: 2H); 7.53 (dd, J = 8 and 1.5 Hz: 1H); 7.56 (broad s: 1H); 7.66 (dd, J = 8 and 1.5 Hz: 1H); 8.30 (d, J = 8 Hz: 1H). Rotatory power: α _D ²⁰ = + 7.7 ± 0.5 (CH ₃ OH, c = 0.5)

To a solution of 10 g (0.104 mole) of 1H-imidazol-4-yl-carboxaldehyde and of 28.6 g (0.1 14 mole) of 4-bromobenzyl bromide in 600 cm 3 of acetonitrile, 28 is added, 75 g of potassium carbonate. The reaction mixture is stirred for 2 hours at reflux of acetonitrile, filtered, then concentrated under reduced pressure. The residue is taken up in 400 cm3 of ethyl acetate, washed twice with 100 cm3 of water, then 100 cm3 of saturated aqueous sodium chloride solution. The solution is dried over magnesium sulfate, filtered, concentrated under reduced pressure. The residue is purified by high performance liquid chromatography (Si 60 phase), eluting with dichloromethane containing 1.5% methanol. 10.35 g (37%) of 1- (4-bromophenyl) methyl-1H-imidazol-5-yl-carboxaldehyde are obtained in the form of a yellow sodium hydroxide melting at 68 ° C., the characteristics of which are as follows: Mass spectrum : IE, mz = 264 M ⁺

To a solution of 2g (0.0075 mole) del- (4-bromophenyl) methyl-1H-imidazol-5-yl-carboxaldehyde, 1.27 cm3 of triethylamine (0.009 mole), 0.02g (0.084mmole) paUadium acetate, 0.1 g of tri-o-tolyl phosphine (0.33 mmol) in 25 cm3 of N, N-dimethylformamide, 0.78 g (0.009 mole) of methyl acrylate is added. After heating at reflux for 12 hours, the reaction mixture is cooled, then concentrated to dryness under reduced pressure at 50 ° C. The residue is dissolved in 50 cm3 of ethyl acetate and washed with three times 20 cm3 of water, then 15 cm3 of a saturated aqueous solution of sodium chloride. The solution is dried over magnesium sulfate, filtered, concentrated under reduced pressure. The residue is purified by high performance liquid chromatography (Si 60 phase), eluting with dichloromethane containing an increasing mixture of 0 to 1% methanol. 0.55 g (27%>) of 1- [4- (2-methoxycarbonylvinyl) phenyl] methyl-1H-imidazol-5-yl-carboxaldehyde is obtained in the form of a yellow solid, the characteristics of which are as follows:

Η NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ in ppm): 3.74 (s: 3H); 5.57 (s: 2H); 6.64 (d, J = 16.5 Hz: 1H); 7.23 (d, J = 8 Hz: 2H); 7.65 (d, J = 16.5 Hz: 1H); 7.71 (d, J = 8 Hz: 2H); 7.98 (s: 1H); 8.31 (s: 1H); 9.73 (s: 1H).

After stirring for 4 hours at a temperature in the region of 20 ° C of a mixture consisting of 0.15 g (0.4 mmol) of 8N- [l (S) -carbamoyl-2- (4-chlorophenyl) -ethyl] -4- amino-chroman-8-carboxamide, 0.13 g (0.44 mmol) del- [4- (2-methoxycarbonylvinyl) phenyl] methyl-1H-imidazol-5-yl-carboxaldehyde and 0.2 ml of acetic acid in 30 ml methanol in the presence of 4A molecular sieve, 0.04 g (0.6 mmol) of sodium cyanoborohydride is added and stirring is continued overnight. The reaction medium is filtered through celite and the filtrate concentrated to dryness under reduced pressure. The residue is taken up in 100 ml of dichloromethane. The organic phase is washed with 20 ml of a saturated solution of sodium hydrogencarbonate, then with 2 times 20 ml of distilled water, then with 20 ml of a saturated solution of sodium chloride, and finally dried over magnesium sulfate , filtered and concentrated to dryness. After purification by high performance liquid chromatography (Si 60 phase), eluting with dichloromethane. 0.12 g (48%) of the 8N- [1- (S) -carbamoyl-2- (4-chlorophenyl) -ethyl] -4- {1- [4- (2-methoxycarbonyl-) diastereomer is obtained. vinyl) phenyl] methyl- 1 H-imidazol-5-ylmethylamino} -chroman-8-carboxamide in the form of a white meringue the characteristics of which are the following: Rotatory power: α _D ²⁰ = + 3.6 ± 0.5 (CH ₃ OH, c = 0.5) N NMR spectrum (400 MHz, (CD ₃ ) ₂ SO d6, δ in ppm): from 1.85 to 2.00 (mt: 2H); from 2.20 to 2.35 (mf spread: 1H); 2.98 (dd, J = 14 and 8 Hz: 1 H); 3.11 (dd, J = 14 and 5 Hz: 1 H); 3.58 (broad d, J = 14 Hz: 1 H); from 3.65 to 3.75 (mt: 2H); 3.74 (s: 3H); from 4.20 to 4.40 (mt: 2H); 4.68 (mt: 1H); 5.36 (br s: 2H); 6.63 (d, J = 16 Hz: 1 H) 6.85 (t, J = 7.5 Hz: 1 H); 6.90 (broad s: 1H); 7.10 (d, J = 8 Hz: 2H); 7.16 (s large 1H); 7.22 (dd, J = 7.5 and 1.5 Hz: 1 H); 7.27 (d, J = 8 Hz: 2H); 7.34 (d, J = 8 Hz 2H); 7.56 (broad s: 1 H); from 7.60 to 7.70 (mt: 4H); 7.76 (broad s: 1 H); 8.27 (d, J = 8 Hz: 1 H).

Example 2

Preparation of the diastereoisomer A of 8N- [l- (S) -carbamoyl-2- (4-chlorophenyl) - ethyll-4- {l- [4- (2-methoxycarbonylethyl) phenvUmethyl-1H-imidazol-5-ylmethylaminol-chroman -8-carboxamide

To a solution of 0.81 g (2.9 mmol) of 1- [4- (2-methoxycarbonyl-vinyl) phenyl] methyl-1 H -imidazol-5-yl-carboxaldehyde prepared in Example 1 and of 0.20 g ( 0.82 mmol) of nickel chloride hexahydrate in 120 cm3 of ethanol 0.57 g (15 mmol) of sodium borohydride is added under an argon atmosphere. After two hours of stirring at room temperature, the reaction medium is filtered through celite and concentrated to dryness under reduced pressure. The residue is purified by high performance liquid chromatography (Si 60 phase), eluting with dichloromethane containing an increasing mixture of 0 to 10% methanol. 0.3 g (38%) of 1- [4- (2-methoxycarbonylethyl) phenyl] methyl-1H-imidazol-5-yl-methanol is obtained in the form of a colorless oil, the characteristics of which are the following:

Η NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ in ppm): 2.62 (t, J = 7.5 Hz: 2H); 2.83 (t, J = 7.5 Hz: 2H); 3.58 (s: 3H); 4.32 (d, J = 5.5 Hz: 2H); 5.10 (t, J = 5.5 Hz: 1 H); 5.19 (s: 2H); 6.82 (br s: 1H); 7.09 (d, J = 8 Hz: 2H); 7.21 (d, J = 8 Hz: 2H); 7.66 (broad s: 1 H).

A solution of 0.3 g (1.09 mmol) of 1- [4- (2-methoxycarbonylethyl) phenyl] methyl-1H-imidazol-5-yl-methanol and 0.31 g (3.55 mmol) of oxide manganese activated is heated 12 hours at reflux. After cooling and filtration through celite, the reaction mixture is concentrated under reduced pressure. 0.14 g (46%) of 1- [4- (2-methoxycarbonylethyl) phenyl] methyl-1 H-imidazol-5-yl-carboxaldehyde is obtained in the form of a yellow oil, the characteristics of which are as follows: Η NMR (400 MHz, (CD ₃ ) ₂ SO d6, δ in ppm): 2.61 (mt: 2H); 2.83 (mt: 2H); 3.58 (s: 3H); 5.49 (s: 2H); 7.13 (d, J = 8 Hz: 2H); 7.20 (d, J = 8 Hz: 2H); 7.93 (s: 1H); 8.24 (s: 1H); 9.72 (s: 1H).

The procedure is as in Example 1 for the preparation of 8N- [1- (S) -carbamoyl-2- (4-chlorophenyl) -ethyl] -4- {1 - [4- (2-methoxycarbonylvinyl) phenyl] methyl - 1 H-imidazol-5-ylmethylamino} -chroman-8-carboxamide, but from 0.15 g (0.4 mmol) of 8N- [l (S) -carbamoyl-2- (4-fluorophenyl) ethyl ] -4-anύno-chroman-8-carboxamide, 0.13 g (0.44 mmol) of 1- [4- (2-methoxycarbonylethyl) phenyl] methyl-1H-imidazol-5-yl-carboxaldehyde, 0, 04 g (0.6 mmol) of sodium cyanoborohydride and 0.2 ml of acetic acid in 30 ml methanol in the presence of 4A molecular sieve. Obtained after purification by flash chromatography on a silica column, eluting with dichloromethane containing an increasing mixture of 0 to 10% of methanol 2.9 g (58%) of diastereoisomer A of 8N- [l- (S) -carbamoyl- 2- (4-chlorophenyl) -ethyl] -4- {l- [4- (2-methoxycarbonylethyl) phenyl] methyl-1H-imidazol-5-ylmethylamino} - chroman-8-carboxamide in the form of a white meringue, with the following characteristics:

Rotatory power: α _D ²⁰ = + 17.1 ± 0.7 (CH ₃ OH, c = 0.5)

Η NMR spectrum (400 MHz, (CD ₃ ) ₂ SO d6, δ in ppm): from 1.80 to 2.00 (mt: 2H); 2.25 (mf: 1H); 2.61 (t, J = 8 Hz: 2H); 2.82 (t, J = 8 Hz: 2H); 2.98 (dd, J = 14 and 8 Hz: 1 H); 3.11 (dd, J = 14 and 5 Hz: 1 H); 3.55 to 3.65 (mt: 1H); 3.58 (s: 3H); from 3.60 to 3.75 (mt: 2H); from 4.20 to 4.40 (mt: 2H); 4.68 (mt: 1H); 5.27 (s: 2H); 6.87 (s: 1H); 6.89 (t, J = 8 Hz: 1 H); 7.00 (d, J = 8 Hz: 2H); from 7.10 to 7.20 (mt: 2H); 7.16 (br s: 1H); from 7.20 to 7.30 (mt: 1H); 7.27 (d, J = 8.5 Hz: 2H); 7.34 (d, J = 8.5 Hz: 2H); 7.56 (br s: 1H); 7.68 (dd, J = 8 and 1.5 Hz: 1 H); 7.72 (s: 1H); 8.27 (d, J = 7.5 Hz: 1 H). Example 3

Preparation of the diastereoisomer A of 8N- [l- (S) -carbamoyI-2- (4-chlorophenvπ- ethyll-4-π- (4-f2-carbamoylethyl) phenyllmethyl-1H-imidazol-5-ylmethylamino} - chroman-8 carboxamide

The procedure is as in Example 1 for the preparation of 1 - (4-bromophenyl) methyl-1H-imidazol-5-yl-carboxaldehyde, but from 1.48 g (0.0154 mole) of 1H-imidazol- 4-yl-carboxaldehyde and 3.5 g (0.0154 mole) of 4- (2-methoxycarbonylethyl) benzyl chloride prepared according to the method described by F. Yukitoshi et al. (WO 9747581) in 120 cm3 of acetonitrile and 4.26 g of potassium carbonate. After purification by high performance liquid chromatography (Si 60 phase), eluting with dichloromethane containing 1% methanol, lg (45%) of 1 - [4- (2-methoxycarbonylethyl) phenyl] methyl- 1 H-imidazol- are obtained. 5-yl-carboxaldehyde in the form of a colorless oil, the characteristics of which are as follows: NMR spectrum Η (300 MHz, (CD ₃ ) ₂ SO d6, δ in ppm): 1.15 (t, J = 7, 5 Hz: 3H); 2.59 (t, J = 7.5 Hz: 2H); 2.82 (t, J = 7.5 Hz: 2H); 4.04 (q, J = 7.5 Hz: 2H); 5.50 (s: 2H); 7.13 (d, J = 8 Hz: 2H); 7.20 (d, J = 8 Hz: 2H); 7.94 (d, J = 1 Hz: 1 H); 8.26 (s: 1H); 9.73 (d, J = 1 Hz: 1 H).

0.25 g (0.87 mmol) of 1- [4- (2-methoxycarbonylethyl) phenyl] methyl-1H-imidazol-5-yl-carboxaldehyde in solution in 30 ml of 6N ammoniacal methanol are autoclaved at 50 ° C for 48 hours. After cooling to a temperature in the region of 20 ° C., the reaction medium is concentrated to dryness under reduced pressure and the residue is purified by high performance liquid chromatography (Si 60 phase), eluting with dichloromethane containing an increasing mixture of 0 to 10% methanol. 0.03 g (14%) of 1- [4- (2-carbamoylethyl) phenyl] methyl-1H-imidazol-5-yl-carboxaldehyde is obtained in the form of a colorless oil, the characteristics of which are as follows: operates as in Example 1 for the preparation of the diastereoisomer A of 8N- [1 - (S) -carbamoyl-2- (4-chlorophenyl) -ethyl] -4- {1 - [4- (2-methoxycarbonylvinyl) phenyl ] methyl-1H-imidazol-5-ylmethylamino} -chroman-8-carboxamide, but from 0.15 g (0.4 mmol) of 8N- [l (S) -carbamoyl-2- (4-cMorophenyl) -ethyl] -4-amino-chroman-8-carboxamide, 0.12 g (0, 47 mmol) of 1- [4- (2-carbamoylethyl) phenyl] methyl-1H-imidazol-5-yl-carboxaldehyde, 0.04 g (0.6 mmol) of sodium cyanoborohydride and 0.2 ml of acetic acid in 30 ml methanol in the presence of 4A molecular sieve.

After purification by high performance liquid chromatography (Si 60 phase), eluting with dichloromethane containing an increasing mixture of 0 to 20% of methanol, 0.09 g (36%) of diastereoisomer A of 8N- [l- (S ) -carbamoyl-2- (4-chlorophenyl) -ethyl] -4- {1 - [4- (2-carbamoylethyl) phenyl] methyl- 1 H-imidazol-5-ylmethylamino} -chroman-8-carboxamide in d form '' a sohde cream, the characteristics of which are as follows: Rotatory power: α _D ²⁰ = + 14.6 ± 0.6 (CH ₃ OH, c = 0.5)

Η NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ in ppm): from 1.85 to 2.00 (mt: 2H); 2.32 (wide t, J = 8 Hz: 2H); 2.78 (broad t, J = 8 Hz: 2H); 2.99 (dd, J = 14 and 8 Hz: 1 H); 3.12 (dd, J = 14 and 5 Hz: 1 H); 3.61 (d, J = 14 Hz: 1 H); from 3.65 to 3.75 (mt: 2H); from 4.20 to 4.40 (mt: 2H); 4.69 (mt: 1H); 5.27 (br s: 2H); 6.75 (mf: 1H); 6.88 (s: 1H); 6.90 (t, J = 7.5 Hz: 1 H); 7.01 (d, J = 8 Hz: 2H); from 7.10 to 7.20 (mt: 3H); from 7.25 to 7.30 (mt: 4H); 7.35 (d, J = 8 Hz: 2H); 7.57 (mf: 1H); 7.69 (dd, J = 7.5 and 1.5 Hz: 1 H); 7.72 (d, J = 1 Hz: 1 H); 8.29 (d, J = 7.5 Hz: 1 H).

Example 4

Preparation of the diastereoisomer A of 8N-ll- (S) -carbamoyl-2- (4-chlorophénvπ- éthyll-4- {l- (4- (2-carbamoylvinyl) phenyllmethyl-1H-imidazol-5-ylmethylamino} - chroman- 8-carboxamide

At 50g (0.267 mole) of 4-bromobenzyl alcohol, 0.6g (0.0027 mole) of palladium acetate, 3.25g of tri-o-tolyl phosphine (0.0107 mole) in 159 cm3 of tributylamine ( 0.669 mol) in an autoclave, 22.5 cm ³ (0.331 mol) of acrylic acid are added and the reaction mixture is brought to 100 ° C. for 12 hours. The mixture is then cooled, then treated with an aqueous solution of sodium carbonate and filtered on celite. The filtrate is acidified and the precipitate obtained filtered, washed with water and then dried to yield 42.15 g (89%) of 4-hydroxymethyl-cinnamic acid in the form of a cream solid.

To a suspension of 5.7 g (0.032 mole) of 4-hydroxymethyl-cinnamic acid in 30 ml of dichloromethane, 4.9 ml (0.067 mole) of thionyl chloride are added and the mixture is stirred at room temperature for 3 hours. After dilution with an additional 400 ml of dichloromethane, ammonia is dissolved in the reaction medium (15 min) and the reaction continued overnight at room temperature. The reaction mixture is washed with water (3 x 300 ml), then with 0.1N hydrochloric acid (2 x 100 ml), dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. 4.95 g (79%) of [4- (2-carbamoylvinyl) phenyl] methane chloride are thus obtained in the form of a cream solid.

The procedure is as in Example 1 for the preparation of 1 - (4-bromophenyl) methyl-1H-imidazol-5-yl-carboxaldehyde, but from 3.7 g (0.0383 mole) of 1H-imidazol- 4-yl-carboxaldehyde and 7.5 g (0.0383 mole) of [4- (2-carbamoylvinyl) phenyl] methane chloride in 250 cm3 of acetonitrile and 10.6 g (0.0767 mole) of carbonate potassium. After purification by high performance liquid chromatography (Si 60 phase), 1.4 g (29%) of 1- [4- (2-carbamoylvinyl) phenyl] methyl-1H-imidazol-5-yl-carboxaldehyde are obtained. pale yellow solid. The procedure is as in Example 1 for the preparation of the diastereoisomer A of 8N- [1 - (S) -carbamoyl-2- (4-chlorophenyl) -ethyl] -4- {1 - [4- (2-methoxycarbonylvinyl) phenyl] methyl-1H-imidazol-5-ylmethylarnmo} -chroman-8-carboxamide, but from 0.2 g (0.53 mmol) of 8N- [l (S) -carbamoyl-2- (4-cUorophenyl ) ethyl] -4-amino-chroman-8-carboxamide, 0.15 g (0.59 mmol) of 1- [4- (2-carbamoylvinyl) phenyl] methyl-1H- imidazol-5-yl-carboxaldehyde, 0.05 g (0.8 mmol) of sodium cyanoborohydride and 0.25 ml of acetic acid in 30 ml methanol in the presence of 4A molecular sieve. After purification by high performance liquid chromatography (Si 60 phase), eluting with dichloromethane containing an increasing mixture of 0 to 10% methanol, 0.1 g (30%) of diastereoisomer A of 8N- [l- (S ) -carbamoyl-2- (4- chlorophenyl) -ethyl] -4- {1 - [4- (2-carbamoylvinyl) phenyl] methyl- 1 H-imidazol-5-ylmethylamino} -chroman-8-carboxamide in the form of a cream sohde, the characteristics of which are the following: Rotatory power: α _D ²⁰ = +16.1 ± 0.7 (CH ₃ OH, c = 0.5) NMR spectrum Η (300 MHz, (CD ₃ ) ₂ SO d6, δ in ppm): from 1.85 to 2.05 (mt: 2H); from 2.20 to 2.35 (mt: 1H); 2.97 (dd, J = 14 and 8 Hz: 1 H); 3.11 (dd, J = 14 and 5 Hz: 1 H); 3.58 (broad d, J = 14 Hz: 1 H); from 3.60 to 3.75 (mt: 2H); from 4.20 to 4.40 (mt: 2H); 4.67 (mt: 1H); 5.34 (br s: 2H); 6.58 (d, J = 16 Hz: 1 H); 6.85 (t, J = 7.5 Hz: 1 H); 6.89 (s: 1H); from 7.05 to 7.40 (mt: 9H); 7.39 (d, J = 16 Hz: 1 H); from 7.45 to 7.60 (mt: 4H); 7.67 (dd, J = 7.5 and 1.5 Hz: 1 H); 7.75 (s: 1H); 8.27 (d, J = 7.5 Hz: 1 H).

Example 5

Preparation of the diastereoisomer A of 8N- [l (S) -carbamoyl-2- (4-chlorophenyl) ethyI] -4- {l- (4- (3-hydroxypropyI) benzyl] -lH-imidazol-5-ylmethylamino } - chroman-8-carboxamide

To a solution cooled to -20 ° C in THF of 0.27 g of 8N- [1- (S) -carboxamido-2- (4-chloro-phenyl) ethyl] -4- {1 - [4- ( 2-methoxycarbonylethyl) benzyl] - 1 H-imidazol-5-ylmethylarnino} -chroman-8-carboxamide, 0.02 g of lithium aluminum hydride is added and stirring is continued at the same temperature for 2 hours. The reaction mixture is warmed to room temperature, treated with sodium sulphate hydrate and then the crude product purified on a silica column to yield 0.1 g of diastereoisomer A of 8N- [l (S) -carbamoyl-2 - (4-chloro-phenyl) ethyl] -4- {l- (4- (3- hydroxypropyl) benzyl] -lH-imidazol-5-ylmethylanj no} -chroman-8-carboxamide in the form of a cream meringue. : a _D ²⁰ = + 20.9 ± 0.7 (CH ₃ OH, c = 0.5)

Η NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ in ppm): 1.68 (mt: 2H); 1.90 (mt: 2H); 2.20 (mf: 1H); 2.57 (mt: 2H); 2.97 (dd, J = 13.5 and 8 Hz: 1 H); 3.10 (dd, J = 13.5 and 5 Hz: 1 H); 3.38 (mt: 2H): from 3.55 to 3.80 (mt: 3H); from 4.20 to 4.40 (mt: 2H); 4.43 (t, J = 5 Hz: 1 H); 4.68 (mt: 1H); 5.26 (br s: 2H); from 6.80 to 6.95 (mt: 2H); 6.99 (d, J = 8 Hz: 2H); from 7.05 to 7.30 (mt: 6H); 7.33 (d, J = 8 Hz: 2H); 7.54 (broad s: 1 H); from 7.65 to 7.80 (mt: 2H); 8.26 (d, J = 7.5 Hz: 1 H).

EXAMPLE 6A

Evaluation of the farnesyl transferase activity of compounds according to the invention The farnesyl transferase activity is measured by the farnesylated amount of K-ras substrate or of substrate derived from the peptide corresponding to its C-terminal part, the faresyl group being provided by the farnesyl pyrophosphate (FPP).

Specifically, the biotinylated substrate used, representative of K-ras: BIOT- (βA) ₃ -SKD- G- (K) _Ô -SKTKCVIM, is [^ H] farnesyl on its cysteine C, by farnesyl transferase in the presence of [ -1 H] FPP. It is then brought into contact with PVT * - streptavidin (AMERSHAM) ® beads, and is quantified by proximity scintillation (SPA assay) between the tritium and the PVT beads, thanks to the streptavidin / biotin interaction.

Experimentally, the faraesyl transferase purified according to the attached protocol, is diluted for this assay to a concentration such that a consumption of substrates is less than 30%. The final molar concentrations of each substrate are adjusted to their respective Km: 50 nM for the biotinylated peptide K ras and 120 nM for the FPP, brought under 20 μl in a final volume of 100 μl of the reaction mixture based on HEPES buffer 50 mM pH 7.5, 5 mM MgCl ₂ , 40 mM KC1, 5 mM dithiothreitol, Triton XI 00 0.01%. The inhibitors to be tested, initially dissolved at 1 mM in a suitable solvent (DMF or DMSO) are diluted in the assay buffer and are added in the form of 10 μl, in triplicate, to the reaction mixture at a concentration 10 times greater than their final concentration.

The reaction, carried out in OPTIPLATES 96® microtiter plates, is initiated by the enzyme and lasts sixty minutes at 37 ° C. EUe is stopped by adding 150 μl of mixture of a stop buffer at pH 4 consisting of H ₃ PO 0.2 M, MgCl ₂ 1.5 mM, BSA 0.5% (w / v), sodium azide 0.05 % (w / v) containing 200 μg of PVT-streptavidin biUes. After slow stirring for 30 minutes (to remove chemUuminescence), the plates are read in H] CPM in a TOP COUNT® microplate scintiUation counter (PACKARD) where they are transformed into [ ³ H] DPM from a range of colored agent reducing scintillation ("quenching"). The inhibition percentages are calculated relative to a control without inhibitor after subtracting all the ceUe values from a blank containing only the substrates and the buffer.

The IC50s are calculated or measured from the inhibitions obtained at nine different concentrations with the Enzfitter® or Grafit® software. The products according to the invention have IC 50 values of between 0.1 nM and 100 μM.

EXAMPLE 6B

The activity of the compounds according to the invention can also be evaluated by the capacity of said compounds to inhibit the agar growth of clones derived from human tumor lines. For example, cells of the human cohc carcinoma line HCT116, supplied by the ATCC, are grown in a monolayer in a culture medium, Dubelcco modified Eagle, containing 2 mM of L-glutamine, 200 U / ml of penicillin, 200 μg / l of streptomycin supplemented by 10% by volume of heat-inactivated fetal calf serum. The cells in exponent growth are trypsinized, washed with PBS and diluted to a final concentration of 5000 cells / ml in complete culture medium. The inhibitors to be tested, or the control solvent are then added, in a volume of 50 μl, to 2.5 ml of suspension of ceUules, prepared previously, then 0.4 ml of an agar solution, Noble Difco, maintained at 45 ° C and then mixed. The medium thus obtained is immediately thrown into Petri dishes, kept for five minutes at 4 ° C and then incubated at 37 ° C under an atmosphere of 5% CO ₂ . The number of cell clones (> 50 cells) is counted after twelve days of incubation at 37 ° C. under an atmosphere of 5% CO ₂ . Each inhibitor is tested in duphcate at final agar concentrations of 10, 1, 0.1 0.01 and 0.001 μg / ml. The results are expressed as a percentage of clonogenicity inhibition compared to untreated controls. The IC5 ₀ inhibitory doses are determined graphically from the semi-logarithmic means of the values obtained for each concentration.

The products according to the invention inhibit the formation of clones by 50% at concentrations of between 0.1 nM and 100 μM.

EXAMPLE 7

EXAMPLE 7A

Using the usual technique, capsules containing 50 mg of active product having the following composition are prepared: - Active product. 50 mg

- Cellulose 18 mg

- Lactose 55 mg

- Colloidal silica 1 mg

- Carboxymethyl starch sodium 10 mg - Talc 10 mg

- Magnesium stearate 1 mg

EXAMPLE 7B Tablets containing 50 mg of active product having the following composition are prepared according to the usual technique: - Active product 50 mg

- Lactose 104 mg

- Cellulose 40 mg

- Polyvidone 10 mg

- Carboxymethyl starch sodium 22 mg - Talc 10 mg

- Magnesium stearate 2 mg

- Colloidal silica 2 mg

- Mixture of hydroxymethylcellulose, glycerin, titanium oxide (72-3,5-24,5) qs 1 film-coated tablet finished at 245 mg EXAMPLE 7C

A solution for injection containing 50 mg of active product having the following composition is prepared:

- Active product. 50 mg - Benzoic acid 80 mg

- Benzyl alcohol 0.06 ml

- Sodium benzoate 80 mg

- 95% ethanol 0.4 ml

- Sodium hydroxide 24 mg - Propylene glycol 1.6 ml

- Water q.s.p. 4 ml

Claims

1 - Compounds of general formula (I)

in which: R9 represents a radical -Riι- (CO) _m -Ri ₂ , for which:

Rii represents an alkylene, alkenylene radical;

R ₂ represents a hydroxy, alkoxy or amino radical; m is equal to 0 or 1 R ₂ represents a hydrogen atom or an alkyl or alkylcarbonyl radical; R ₃ represents a hydrogen atom or a halogen atom

Rt represents a radical

Ri,

/ ³

- CH Ri ₄

R ₅ represents a radical -C (O) -Ri ₅ ,

R _Ô represents a hydrogen atom;

R ₇ , R ₈ independently represent a hydrogen atom

Ri ₃ , Rit, identical or different, independently represent a hydrogen atom, or an aryl radical, optionally being substituted by one or more atoms or radicals chosen from halogen atoms, alkyl, alkoxy, polyfluoroaUcoxy, or aralkoxy, it being understood that Ri ₃ and Ri _t do not simultaneously represent a hydrogen atom.

Ris represents a radical chosen from amino, hydroxy and alkoxy radicals; in racemic form or their stereoisomers as well as their salts.

2 - Compounds according to claim 1 for which R ₉ represents a radical -Ri (CO) _m -Ri ₂ , for which:

Rii represents an alkylene, alkenylene radical;

Ri represents an alkoxy, amino radical; m is 0 or 1; R ₂ represents a hydrogen atom;

R ₃ represents a hydrogen atom;

Ri represents a radical:

-CH ₂ (phenyl) with the phenyl nucleus possibly being substituted, by one or more substituents chosen independently from halogen atoms, alkoxy or polyfiuoroalkoxy radicals;

Rs represents a radical -C (O) -Ri ₅ for which Ri ₅ represents an amino radical;

Rβ represents a hydrogen atom;

R ₇ and R ₈ each represent a hydrogen atom; in racemic form or their stereoisomers as well as their salts.

3 - Compounds according to any one of the preceding claims chosen individually from:

8N- [1 - (S) -carbamoyl-2- (4-chlorophenyl) -ethyl] -4- {1 - [4- (2-methoxycarbonylvinyl) phenyl] methyl-1H-imidazol-5-ylmethylamino} -chroman- 8-carboxamide

8N- [1 - (S) -carbamoyl-2- (4-chlorophenyl) -ethyl] -4- {1 - (4- (2-carbamoylethyl) phenyl] methyl- 1 H-imidazol-5-ylmethylamino} -chroman -8-carboxamide 8N- [1 - (S) -carbamoyl-2- (4-chlorophenyl) -ethyl] -4- {1 - (4- (2-carbamoylvinyl) phenyl] memyl-1H-imidazol-5-ylmethylamino} -chroman- 8-carboxamide

4 - Process for preparing the compounds of general formula (I) according to any one of the preceding claims, for which R ₂ , R ₃ , Rt, Rs, R _é , R ₇ , Rs, R ₉ are as defined in claim 1 characterized in that the product of general formula (Ha) is condensed

in which R ₃ , Rt, R ₅ , Rβ, R7, Rs are as defined in claim 1 and Gi represents a hydrogen atom, with a reagent of general formula

for which R ₉ is defined as in claim 1 by operating under conditions of reductive amination.

5 - Process for the preparation according to claim 4 of the compounds of general formula (I) for which R ₉ , R ₂ , R ₃ , Rt, Rό, R7, Rs are as defined in claim 1 and Rs represents a radical -CORis, where Ri ₅ represents an amino radical, characterized in that one proceeds from the products of general formula (I) for which Ri ₅ represents an alkoxy radical by the action of ammonia.

6 - Process for the preparation according to claim 4 of the compounds of general formula (I) according to any one of claims 1 to 3, for which Rg, R ₂ , R ₃ , R _t , R ₆ , R ₇ ,

R ₈ are as defined in claim 1 and R ₅ represents a radical -CORis, where Ri ₅ represents a hydroxy radical, characterized in that one proceeds by saponification of the compounds of formula (I) for which Rs = -CORis and Ri ₅ represents an alkoxy radical.

7 - Process for the preparation according to claim 4 of the compounds of general formula (I) according to any one of claims 1 to 3 for which Rg, R ₃ , R _t , R ₅ , R _e ,

R ₇ , Rs are as defined in claim 1 and R ₂ represents an alkylcarbonyl radical, characterized in that one proceeds from the compounds of general formula (I) corresponding in laqueUe R ₂ represents a hydrogen atom, by action corresponding acid of formula R ₂ OH, in which R ₂ represents an alkylcarbonyl radical, or of an activated form of this acid.

8 - Process for the preparation according to claim 4 of the compounds of general formula (I) according to any one of claims 1 to 3, for which Rg, R ₃ , R, R ₅ , R _é , R ₇ , Rs are such that defined in claim 1 and R ₂ represents an alkyl radical characterized in that one proceeds from the compounds of general formula (I) corresponding in which R ₂ represents a hydrogen atom, by action of the corresponding aldehyde.

9 - Compounds of general formula (Ha)

wherein R ₃ , Rt, R ₅ , Ré, R ₇ , Rs, are as defined in claim 1 and Gi represents a hydrogen atom or a group protecting the amino function.

10 - Process for preparing the compounds of general formula (Ha) according to claim 9 for which R ₃ , Rt, R ₅ , R _é , R7, Rs are as defined in claim 9 and Gi represents a hydrogen atom characterized in what we deprotect the compounds of general formula (Ilb)

in which R ₃ , Rt, R ₅ , D, R7, Rs are defined as above, and Gi represents a protecting group for an amino function.

11 - Process according to claim 10 characterized in that the compounds of general formula (Ilb) as defined in claim 10 for which R ₃ , Rt, Rs, Rό, R7, Rs, Gi are defined as in claim 10 are obtained at from compounds of general formula (IV)

in which R ₃ , R, R ₈ and Gi are defined as above, by the action of a compound of general formula (V) corresponding

in laqueUe R ", R ₅ , Ré are as defined above, operating according to the amidation methods.

12 - Process according to claim 10 characterized in that the compounds of general formula (Ilb) for which R ₅ represents the radical -CORi ₅ for which Ri ₅ represents an amino radical characterized in that one proceeds from the compounds of general formula (IV)

in which R ₃ , R7, Rs and Gi are defined as above, by the action of a compound of general formula (V)

in which t and D are as defined above and R ₅ represents the radical -CORis for which Ris represents an alkoxy radical, under amidification conditions, then either followed by the action of ammonia, or is followed, after hydrolysis of the -CORis radical into carboxy radical, by the action of ammonia.

13 - Process according to claims 11 or 12 characterized in that the compounds of general formula (IV) are obtained from the compounds of general formula (VI):

in which R ₃ , R ₇ , Rs are defined as above and Gi are defined as in claim 10, by the action of a base, followed by a carboxylation,

the compounds of general formula (VI) being obtained from the compounds of general formula (VII):

in which R, R ₇ , R ₈ are defined as above by the action of an ammonia salt, in the presence of sodium cyanoborohydride, followed by the protection of the amino group.

14 - Process according to claim 13 characterized in that the base is an alkali metal salt.

15 - Process for preparing the compounds of general formula (I) according to any one of claims 1 to 3, for which R9, R ₂ , R ₃ , Rt, Rs, Re, R7, Rs are as defined in claim 1 characterized in that one proceeds from the product of general formula (VIII)

in which R ₂ , R ₃ , R ₇ , R ₈ , Rg are defined as above, by the action of a compound of general formula (V)

in which Rt, R ₅ , Ré are as defined above by operating according to the amidation methods,

the acids of general formula (VIII) in which R, R ₇ , R ₈ , Rg are defined as above, being obtained from the corresponding esters of general formula (IX):

in laqueUe R ₂ , R ₃ , R7, Rs, Rg are defined as above, and R represents an alkyl radical, by saponification.

16 - Compounds of general formula (VIII)

wherein R ₂ , R ₃ , R7, Rs, R are defined as in claim 1.

17 - Process for preparing the compounds of general formula (IX) according to claim 15 in laqueUe R, R ₂ , R ₃ , R ₇ , Rs, R9 are defined as in claim 15 characterized in that one proceeds from the compounds of general formula (X):

in which R, R ₃ , R ₇ , R _8> are defined as in claim 15, by the action of a reagent of general formula

for which Rg is defined as above, operating under amination conditions. 18 - Preparation process according to claim 17, characterized in that the esters of general formula (X) are obtained from the corresponding acids of general formula (IV):

in which Gi is defined as in claim 10 by esterification of the carboxylic acid and deprotection of the amino group.

19 - Process according to claim 10 for laqueUe Gi represents a protective group of an amino function chosen from the benzyloxycarbonyl, tert.butoxycarbonyl or vinyloxycarbonyl radicals

20 - Process according to claims 11, 12, 15 characterized in that the amidation reaction is carried out by operating in the presence of a condensing agent and optionally in the presence of an activating agent.

21 - Process according to claim 20 characterized in that the condensing agent is chosen from l-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride, 1, 1 -dicyclohexylcarbodiimide or benzotriazol hexafluorophosphate -1-oxy tris (dimethylamino) phosphonium,

22 - Process according to claim 20 characterized in that the activating agent is chosen from hydroxybenzotriazole.

23 - Process according to claims 4 and 17 characterized in that the reaction is carried out by operating in an organic solvent in the presence of acid and then by the action of a reducing compound. 24 - Process according to claim 23 characterized in that the reducing compound is sodium cyanoborohydride (NaBH ₃ CN) or sodium triacetoxy-borohydride (NaBH (OCOCH ₃ ) ₃ ) or the BH ₃ .pyridine complex.

25 - Pharmaceutical composition containing at least one compound of claims 1 to 3 in association with one or more pharmaceutically acceptable dUuants or adjuvants whether inert or biologically active.

26 - Use of the compounds of claims 1 to 3 for the preparation of pharmaceutical compositions useful for the treatment and / or prevention of pathological conditions associated with cellular signaling pathways associated with farnesyl transferase, or their consequences or symptoms.

27 - Use of the compounds of claims 1 to 3 for the preparation of pharmaceutical compositions useful for inhibiting farnesyl transferase.

28 - Use of the compounds of claims 1 to 3 for the preparation of pharmaceutical compositions useful for the treatment of diseases caused by cell proliferation.

29 - Use of the compounds of claims 1 to 3 for the preparation of pharmaceutical compositions useful for the treatment of cancers.

30 - Association of a compound of claims 1 to 3 with one or more compatible and pharmacologically active compounds and / or radiotherapy treatment.