FR2796946A1 - NOVEL 8-CARBONYL CHROMAN DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE - Google Patents

Abstract

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

Description

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leur préparation, les compositions pharmaceutiques qui les contiennent et leur utilisation pour la préparation de médicaments. NEW 8-CARBONYL CHROMANES DERIVATIVES, THEIR PREPARATION
AND THEIR USE IN THERAPEUTICS
The present invention relates to novel 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 that catalyzes the transfer of the farnesyl group of farnesyl pyrophosphate (FPP) to the cysteine end residue of the tetrapeptide CAAX sequence of a number of proteins and in particular of the p21 Ras protein, expression of the oncogene ras.

The oncogene ras (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 (Kohl et al. Science, 260, 1834-1837, 1993).

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Inhibition of farnesyl transferase and therefore farnesylation of the p21 Ras protein blocks the ability of the mutated p21 Ras protein to induce cell proliferation and 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 that do not express mutated or overexpressed mutations, but that exhibit the mutation of an oncogene or overexpression of an oncoprotein whose The signaling pathway uses famesylation 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 such as rhoB (Wei et al., Molecular and Cellular Biology, 19, 1831-1840, 1999).

Inhibitors of famesyl transferase can therefore be inhibitors of cell proliferation and therefore anti-tumor and anti-leukemic agents.

1,5-disubstituted tetrahydronaphthyl derivatives have been described in application WO 96/22278 as having in vitro farnesyl transferase inhibitory enzyme activity at concentrations greater than 10 nM, as well as 1,2,3,4 derivatives. tetrahydroisoquinolines, described in WO 96/24612.

Other farnesyl transferase inhibitors having an isoquinoline structure have also been described in application EP 0618221. These prior applications therefore had a hydrocarbon or nitrogen distribution; Dispatcher is understood as the condensed system on which the functional chains are grafted.

It has now been found, and this is the subject of the present invention, that the compounds of general formula (I) having, as a tundish, an oxygenated heterocyclic system (chroma nucleus), distinct from that of the compounds of the present invention. previously cited prior art, show their inhibitory activity both enzymatically and at the cellular level, and this at concentrations quite significant.

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

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 Nothing in the prior art suggested such a modification in the chemical structure and did not predict the advantageous anti-cancer properties exhibited by the present compounds.

In addition, according to the invention, the novel products of general formula (I), famesyl transferase inhibitors, may be competitive with a farnesyl transferase substrate, such as those described by ADCox and CJ. Der, Biochimica and Biophysica acta, 1333 (1997), 51-f 71 and in particular the p2lRas protein, such as H-Ras, Ki-Ras, N-Ras, the Rho ... protein; this feature allows them to act specifically at the substrate.

On the other hand, the compounds according to the present invention have remarkable pharmacological qualities, both in terms of activity and bioavailability.

In particular, and this is part of the present invention, the presence of the substituent CONHMe on the chain at position 8 of the chromane ring makes the compounds particularly bioavailable orally.

Because of this property, the compounds are therefore suitable for oral administration.

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

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sous forme racémique, ou de leurs stéréoisomères ainsi que sous forme de sels.

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

In the general formula (I): R 9 represents an atom or radical selected from halogen atoms and / or alkyl, cycloalkyl, alkoxy, cyano, nitro, polyfluoroalkyl radicals, such as trifluoroalkyl, such as trifluoromethyl, polyfluoroalkoxy, such as trifluoroalkoxy, or difluoroalkoxy such as trifluoromethoxy or difluoromethoxy, polyfluoroalkylthio, such as trifluoroalkylthio, such as trifluoromethylthio, aralkyl, aryloxy, aryl, or heteroaryl, optionally substituted with one or more atoms or radicals selected from halogen atoms or alkoxy, alkyl radicals; ; a radical -Ri1-CO-R12, for which R1 represents an alkylene or alkylene radical; R12 represents a hydroxy, alkoxy, amino radical; preferably, R9 is attached to the 4-position of the phenyl group to which it is attached.

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R2 represents a hydrogen atom, an alkyl, alkylcarbonyl radical;
R3 represents a hydrogen atom or a halogen atom;
R4 represents a radical - (CH2) -Ri4 and
R14 represents an aryl radical, optionally substituted by one or more atoms or radicals chosen from halogen atoms, alkyl, hydroxy, nitro, amino, alkoxy, polyfluoroalkoxy, aralkoxy, aminosulfonyl, -Z-OR, -Z-CO radicals; -OR, -Z-CO-
NRR ', for which, by aryl, phenyl is preferred,
R, R 'independently represent a hydrogen atom or an alkyl radical,
Z represents an alkylene radical;
R7, Rg independently represent a hydrogen atom or an alkyl radical; in racemic form or their stereoisomers as well as their salts.

In the foregoing and the following: the radicals and alkyl portions contain 1 to 10 carbon atoms in straight or branched chain, and include in particular the radicals and portions methyl, ethyl, propyl, butyl, pentyl, hexyl and their isomers; iso, sec., tert; the radicals and alkylene portions define the divalent hydrocarbon radicals, the free valences of which are borne by the same carbon atom or two carbon atoms different from the alkylene portion, in a straight or branched chain, containing from 1 to 10 carbon atoms, and include especially the methylene, ethylene, propylene, butylene, pentylene, hexylene radicals, as well as their isomers iso, sec, tert; the alkenylene radicals define the divalent hydrocarbon radicals having at least one double bond, the free valencies of which are borne by the same carbon atom or two carbon atoms different from the alkylene moiety, in a straight or branched chain, containing from 1 to 10 carbon atoms, and include, in particular,

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 ethenylene, propenylene, butenylene, pentenylene and hexenylene radicals, as well as their isomers, iso, sec, tert; the term halogen defines the fluorine, chlorine, bromine and iodine atoms; preferentially fluorine, chlorine or bromine; the term cycloalkyl defines a saturated hydrocarbon cyclic radical of 3 to 6 members; it preferably represents the cyclohexyl radical; the aryl term of the aryl or aralkyl radicals defines a 6- to 10-membered mono or bicyclic hydrocarbon aromatic system, unless otherwise specified: aryl preferably represents the phenyl or naphthyl radicals; aralkyl is preferably benzyl; the term heteroaryl defines a 5- to 10-membered mono or bicyclic aromatic system containing from 1 to 4 heteroatoms, chosen from nitrogen, oxygen and sulfur, and preferably represents the thienyl, pyrrolyl, imidazolyl and pyrazolyl radicals; triazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, furanyl, thiazolyl, isoxazolyl, tetrazolyl, pyridyl and the radicals resulting from the fusion of these above-mentioned rings with the phenyl group; the term BOC defines the tert.butoxycarbonyl radical; the term Ph defines the phenyl radical; the Hal term defines a halogen atom such as Fluorine, Chlorine, Bromine or Iodine.

The products of general formula (I) have at least one asymmetric carbon: this asymmetric carbon may have the configurations (R) or (S); in particular, the products of general formula (I) may have 2 asymmetric carbons, and may therefore be in the form of 4 stereoisomers: 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 stereoisomeric forms of the compounds of general formula (I) are also part of the invention.

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Among these stereoisomeric forms according to the invention, the compounds of general formula (I) having a positive rotatory power are preferred.

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

 Among the products of general formula (I), those for which R 9 represents an atom or radical chosen from halogen atoms, such as chlorine or bromine and / or alkyl radicals, such as methyl or polyfluoroalkoxy, such as trifluoromethoxy, polyfluoroalkyl such as trifluoromethyl, polyfluoroalkylthio such as trifluoromethylthio; preferably methyl; aryl, such as phenyl, optionally substituted with one or more halogen atoms; heteroaryl, such as pyridyl, thiazolyl, thienyl, isoxazolyl; preferably pyridyl, thiazolyl; a radical -Ri1-CO-Ri2, for which: Ri1 represents an alkylene radical, preferably ethylene, alkylene, preferably vinyl; R12 represents a hydroxy, alkoxy, amino radical; preferably, R9 is attached to the 4-position of the phenyl group to which it is attached.

R2 represents a hydrogen atom; R3 represents a hydrogen atom; R4 represents a radical - (CH2) -R14 Ri4 represents an aryl radical, such as phenyl, optionally substituted by one or more atoms or radicals chosen from halogen atoms, such as chlorine, or radicals;

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 alkoxy, polyfluoroalkoxy such as trifluoromethoxy, aralkoxy such as benzyloxy; preferably a halogen atom; R7, R8 represent a hydrogen atom; in racemic form or their stereoisomers as well as their salts.

8N-[ 1 (S)-méthylcarbamoyl-2-(4-chlorophényl)éthyl]-4-[ 1-(4-méthylbenzyl)-1 H- imidazol-5-ylméthylamino]-chroman-8-carboxamide 8N-[ 1 (S)-méthylcarbamoyl-2-(4-chlorophényl)éthyl]-4-[ 1-(4-phénylbenzyl)-1Himidazol-5-ylméthylamino]-chroman-8-carboxamide 8N-[ 1 (S)-méthylcarbamoyl-2-(4-chlorophényl)éthyl]-4-[ 1-(4-chlorobenzyl)-1H- imidazol-5-ylméthylamino]-chroman-8-carboxamide 8N-[ 1 (S)-méthylcarbamoyl-2-(4-chlorophényl)éthyl]-4-[ 1-(4-bromobenzyl)-1H- imidazol-5-ylméthylamino]-chroman-8-carboxamide

8N-[ 1 (S)-méthylcarbamoyl-2-(4-chlorophényl)éthylJ-4- { 1-[4-(3-pyridyl)benzylJ-1 Himidazol-5-ylméthylamino} -chroman-8-carboxamide 8N-[ 1 (S)-méthylcarbamoyl-2-( 4-chlorophényl)éthyl]-4- { 1-[4-(4fluorophényl)benzyl]-1 H-imidazol-5-ylméthylamino } -chroman-8-carboxamide 8N-[ 1 (S)-méthylcarbamoyl-2-(4-chlorophényl)éthyl]-4- {1-[4-(2-

carbamoyléthyl)benzyl]-1 IH-imidazol-5-ylméthylaminol -chroman-8-carboxamide 8N-[ 1 (S)-méthylcarbamoyl-2-(4-chlorophényl)éthyl]-4- {1-[4-(1,3-thiazol-5-

yl)benzyl]- H-imidazol-5-ylméthylamino} -chroman-8-carboxamide 8N-[ (S)-méthylcarbamoyl-2-(4-chlorophényl)éthyl]-4- { 1-[4-(2carbamoylvinyl)benzyl]- H - imidazol- 5- ylméthylamino -chroman-8-carboxamide ou leurs stéréoisomères, ou sous forme racémique ainsi que leurs sels. By way of nonlimiting illustration of the claimed compounds, mention may be made especially of any compound of general formula (I), selected individually from:

8N- [1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-methylbenzyl) -1H-imidazol-5-ylmethylamino] -chroman-8-carboxamide 8N- [1] (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-phenylbenzyl) -1H-imidazol-5-ylmethylamino] -chroman-8-carboxamide 8N- [1 (S) -methylcarbamoyl-2 (4-Chlorophenyl) ethyl] -4- [1- (4-chlorobenzyl) -1H-imidazol-5-ylmethylamino] -chroman-8-carboxamide 8N- [1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ) ethyl] -4- [1- (4-bromobenzyl) -1H-imidazol-5-ylmethylamino] -chroman-8-carboxamide

8 N- [1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4- {1- [4- (3-pyridyl) benzyl] -1-heidazol-5-ylmethylamino} -chroman-8-carboxamide 8N- [ 1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4- {1- [4- (4-fluorophenyl) benzyl] -1H-imidazol-5-ylmethylamino} -chroman-8-carboxamide 8N- [1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4- {1- [4- (2-

carbamoylethyl) benzyl] -1H-imidazol-5-ylmethylaminolchroman-8-carboxamide 8N- [1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4- {1- [4- (1, 3-thiazol-5-

Yl) benzyl] -H-imidazol-5-ylmethylamino} -chroman-8-carboxamide 8N - [(S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4- {1- [4- (2-carbamoylvinyl) benzyl} 1H-imidazol-5-ylmethylaminochroman-8-carboxamide or their stereoisomers, or in racemic form, and their salts.

The present invention also relates to the preparation of new products of general formula (I). Various operating protocols as well as reaction intermediates that can be used to prepare the compounds of formula

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 General (I) are proposed. Of course, are included in the present invention the analogous methods in order to lead to these same compounds: it is within the abilities of those skilled in the art to apply or adapt these methods to implement the invention using of his general knowledge.

dans laquelle R3, R4, R7, Rg sont tels que définis en formule générale (I) et G1 représente un atome d'hydrogène, sous forme de mélange de diastéréoisomères et/ou d'énantiomères, ou bien sous forme de diastéréoisomère ou d'énantiomère pur, par action d'un réactif de formule générale

pour lequel R9 est défini comme précédemment. According to the present invention, the products of general formula (I) in which R 2, R 3, R 4, R 7, R 8, R 9 are as defined in general formula (I), can be obtained from the product of general formula (IIa)

in which R 3, R 4, R 7, R 8 are as defined in general formula (I) and G 1 represents a hydrogen atom, in the form of a mixture of diastereoisomers and / or enantiomers, or in the form of a diastereoisomer or a pure enantiomer, by action of a reagent of general formula

for which R9 is defined as before.

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 molecular sieve 3, then by action of a compound

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 reducing agent, such as sodium cyanoborohydride (NaBH3CN) or sodium triacetoxyborohydride (NaBH (OCOCH3) 3) or the BH3 pyridine complex, by operating in an organic solvent such as ethanol, at a temperature preferably between 0.degree. C and the reflux temperature of the solvent.

The product of general formula (Ii) can be obtained commercially or by functionalization of carboxaldehydes commercially available 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. Bott, J. Med. Chem, (1998), 41, 3387-3401.

dans laquelle Hal représente un atome d'halogène tel que le brome, par action d'un réactif de formule générale (HTb) : HRi1-CORi2, dans laquelle Ri1 représente un radical alkénylène et Ri2 est défini comme en formule générale (I) par réaction de Heck. Notamment, cette réaction peut être effectuée en présence d'une base, telle qu'une amine, comme la triéthyle amine, de palladium (tel que l'acétate de palladium), de tri-o-tolylphosphine, dans un solvant organique tel que le diméthylformamide, éventuellement en chauffant au reflux du solvant. In particular, the products of general formula (III) in which R 9 represents a radical -Ri 1 -CO-R 12, in which R 1 represents an alkenylene radical and R 12 is defined as in general formula (I) can be obtained from the compounds of general formula (IIIa):

in which Hal represents a halogen atom such as bromine, by action of a reagent of general formula (HTb): HRi1-CORi2, in which Ri1 represents an alkenylene radical and R12 is 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, palladium (such as palladium acetate), tri-o-tolylphosphine, in an organic solvent such as dimethylformamide, optionally by heating at the reflux of the solvent.

When R 1 represents an alkylene radical, the compounds of general formula (III) can be obtained from compounds of general formula (III) for which R 1 represents an alkylene radical by reduction, in the presence of reducing agents such as

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 that the sodium borohydride optionally in the presence of nickel chloride optionally hexahydrate ,; and optionally followed in the case where the aldehyde has been reduced to alcohol, by an oxidation reaction of the alcohol intermediate formed to the desired aldehyde, by reaction in the presence of one or more oxidizing agents, known per se, such as manganese oxide, chromium trioxide, Swern reagent, potassium permanganate, etc.

Optionally, when R12 represents an amino radical, the compounds of general formula (III) can be obtained from compounds of general formula (III) in which R12 represents an alkoxy radical, by reaction of ammonia in an alcohol such as methanol.

par action d'un halogénure benzylique de formule (IIId) :

dans laquelle Hal représente un atome d'halogène tel que le brome, dans un solvant organique, tel que l'acétonitrile, en présence d'une base minérale, telle que le carbonate de potassium. The compounds of general formula (IIIa) can be obtained from compounds of general formula (IIIc):

by action of a benzyl halide of formula (IIId):

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

And possibly, in cases where: a) R2 represents an alkylcarbonyl radical, the products of general formula (I) in which R3, R4, R7, R8, R9 are as defined in general formula (I) can be obtained from corresponding compounds of general formula (I) in which R2 represents a hydrogen atom, by the action of the corresponding acid of formula

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R 2 OH, wherein R 2 represents an alkylcarbonyl radical, or an activated form of this acid such as an acyl halide, or the anhydride thereof, optionally in the presence of an organic base, such as triethylamine, or a mineral base such as potassium carbonate, in an organic solvent such as dichloromethane. b) R2 represents an alkyl radical, the products of general formula (I) in which
R9, R3, R4, R7, R8 are as defined in general formula (I) can be obtained from the corresponding compounds of general formula (I) in which R2 represents a hydrogen atom, by 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 may have different stereoisomeric, enantiomeric and / or diastereoisomeric forms, which can be separated by conventional separation methods, such as chromatography or crystallization. For the diastereoisomers, use will preferably be made of high performance liquid chromatography on a silica column: normal phase, reverse phase C18 or chiral phase, and for the enantiomers, chiral column chromatography, such as that of the Pirkle type (Pirkle et al. Asymmetric Synthesis, Vol.1, Academic Press (1983)), or by synthesis from chiral precursors.

It is the same for the products of formula (IIa), in which R3, R4, R7, R8 are as defined in general formula (I) and G1 represents a hydrogen atom, the subsequent stages of synthesis being then made from the isomers (enantiomers, diastereoisomers) separated and purified.

The compounds of general formula (IIa) in which R3, R4, R7, R8 are as defined in general formula (I) and G1 represents a hydrogen atom or a group protecting the amino function are also part of the present invention. .

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dans laquelle R3, R4, R7, R8 sont définis comme précédemment et G1 représente un groupe protecteur d'une fonction amino choisi parmi les radicaux benzyloxycarbonyle, tert. butoxycarbonyle ou vinyloxycarbonyle, par application ou adaptation des méthodes de déprotection classiques décrites par T.W.Greene, Protective groups in organic chemistry, Wiley-interscience (1991), et plus particulièrement par hydrogènolyse en présence d'un catalyseur tel que le palladium sur charbon, lorsque G1 représente un radical benzyloxycarbonyle, ou par hydrolyse en milieu acide lorsque G1 représente un radical tert.butoxycarbonyle, vinyloxycarbonyle ou benzyloxycarbonyle ; préférentiellement selon l'invention, G1 représente un radical tert.butoxycarbonyle (BOC) qui pourra être déprotégé notamment en opérant dans un solvant organique tel qu'un hydrocarbure aliphatique halogéné tel que le dichlorométhane, en présence d'acide trifluoroacétique (TFA) ou encore en présence d'acide chlorhydrique, en opérant dans un alcool, tel que méthanol ou éthanol, ou un éther, tel que l'éther de diéthyle ou de diisopropyle, à une température de préférence voisine de 20 C. Cette réaction peut éventuellement être suivie d'une étape de séparation des isomères, diastéréoisomères et/ou énantiomères, suivant les méthodes décrites ci-dessus. The products of general formula ([la) in which R3, R4, R7, Rg are defined as above, and G1 represents a hydrogen atom can be obtained from compounds of general formula (IIb)

wherein R3, R4, R7, R8 are defined as above and G1 represents a protecting group of an amino function selected from benzyloxycarbonyl radicals, tert. butoxycarbonyl or vinyloxycarbonyl, by application or adaptation of conventional deprotection methods 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 G1 represents a benzyloxycarbonyl radical, or by hydrolysis in acidic medium when G1 represents a tert.butoxycarbonyl, vinyloxycarbonyl or benzyloxycarbonyl radical; preferentially according to the invention, G1 represents a tert.butoxycarbonyl radical (BOC) which may 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 in the presence of hydrochloric acid, by operating in an alcohol, such as methanol or ethanol, or an ether, such as diethyl or diisopropyl ether, at a temperature preferably in the region of 20 C. This reaction can optionally be followed a separation step of the isomers, diastereoisomers and / or enantiomers, according to the methods described above.

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dans laquelle R3, R7, R8 et G1 sont définis comme précédemment, par action d'un composé de formule générale (V) correspondant

dans laquelle R4 est défini comme précédemment, en opérant selon les méthodes d'amidification. Notamment, cette réaction peut être effectuée avantageusement en opérant dans un solvant organique tel qu'un hydrocarbure aliphatique halogéné tel que le dichlorométhane en présence d'un agent de condensation tel que le chlorhydrate de 1 -éthyl-3-[3-(diméthylamino)propyl]carbodiimide, le 1,1 -dicyclohexylcarbodiimide ou l'hexafluorophosphate de benzotriazol-1-oxy-tris(diméthylamino)phosphonium, éventuellement en présence d'un agent d'activation tel que l'hydroxybenzotriazole, à une température de préférence comprise entre 0 C et la température de reflux du solvant. The products of general formula (IIb) in which R3, R4, R7, R8 are defined as above and G1 represents a protective group defined as above can be obtained from compounds of general formula (IV)

in which R3, R7, R8 and G1 are defined as above, by the action of a corresponding compound of general formula (V)

wherein R4 is defined as above, operating according to amidation methods. In particular, this reaction can be carried out advantageously 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 hexafluorophosphate benzotriazol-1-oxy-tris (dimethylamino) phosphonium, 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 by using the procedures described by S. Sagan Bioorg. Med. Chem. Letters (1996), 4, 2167-2178, by W.Oppolzer Helv. Chim.Acta, (1994), 77, 236-2380 or according to the methods described by Larock, Comprehensive Organic Transformations, VCH, New York, 1989 for the preparation of functionalized amines.

In particular, it is preferred to use an amino acid (or a derivative of this amino acid) of natural series, it being understood that the configuration of the amino acid may be modified

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 during the amidification reaction and that several stereoisomers can then be obtained at the end of this reaction.

dans laquelle R4 est tel que défini en formule générale (I) et Alk représente un radical alkyle, dans les mêmes conditions que celles utilisées pour l'amidification précédente, puis soit suivie de l'action de la méthylamine, dans un solvant organique tel qu'un alcool, le méthanol de préférence, éventuellement en présence de quantités catalytiques de cyanure de sodium, à une température de préférence comprise entre 0 C et la température de reflux du solvant, en opérant éventuellement en autoclave, ou soit suivie, après hydrolyse du radical -COOAlk en radical carboxy, de l'action de la méthylamine, dans les conditions de couplage décrites ci-avant. Optionally, the products of general formula (IIb) can also be obtained from compounds of general formula (IV) by the action of a compound of general formula (VI)

in which R 4 is as defined in general formula (I) and Alk represents an alkyl radical, under the same conditions as those used for the preceding amidification, and then is followed by the action of methylamine, 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 followed, after hydrolysis of the radical -COOAlk carboxy radical, the action of methylamine, under the coupling conditions described above.

dans laquelle R3, R7, R8 et G1 sont définis comme précédemment, par action d'une base telle qu'un sel de métal alcalin, comme un alkyllithien, éventuellement en présence de diamine complexante telle que la N, N,N',N'tétraméthyléthylènediamine, en opérant notamment dans un solvant organique tel The compounds of general formula (IV) in which G is defined as above can in particular be obtained from the compounds of general formula (VII):

in which R3, R7, R8 and G1 are defined as above, by the action of a base such as an alkali metal salt, such as an alkyl lithium, optionally in the presence of a complexing diamine such as N, N, N ', N tetramethylethylenediamine, in particular by operating in an organic solvent such as

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 an ether such as diethyl ether, at a temperature preferably between -78 ° C. and room temperature, followed by carboxylation carried out for example by means of carbon dioxide, for example in the form of dry ice or CO2 gas.

dans laquelle R3, R7, R8 sont définis comme précédemment, par action d'un sel d'ammoniac tel que l'acétate d'ammonium, en présence de cyanoborohydrure de sodium, en opérant notamment dans un solvant organique, tel qu'un alcool, comme le méthanol, à des températures de préférence comprises entre 0 C et la température d'ébullition du solvant, suivie de la protection du groupe amino par application ou adaptation des méthodes de protection classiques décrites par T. W.Greene, Protective groups in organic chemistry, Wiley-interscience (1991), et plus particulièrement par réaction avec le chloroformiate ou l'anhydride de terbutoxycarbonyle, en présence d'une base par exemple telle que la triéthylamine ou l'hydrogénocarbonate de sodium dans un solvant organique tel qu'un alcool, comme l'éthanol, à une température de préférence comprise entre 0 C et la température d'ébullition du solvant. The compounds of general formula (VII) in which R3, R7, R8 and G are defined as above can be obtained from compounds of general formula (VIII):

in which R3, R7, R8 are defined as above, by the action of an ammonia salt such as ammonium acetate, in the presence of sodium cyanoborohydride, in particular by operating 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 the 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 (VIII) are commercially available or can be obtained by application or adaptation of the methods described by I. M. LOCKHART, The chemistry of heterocyclic compounds, chromenes, chromanones and chromones, 5, 207-428, 1977.

In addition, according to another embodiment of the invention, the novel products of general formula (I), in which R2, R3, R4, R7, R8 and R9 are defined.

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dans laquelle R2, R3, R7, R8, R9 sont définis comme précédemment, par action d'un composé de formule générale (V)

dans laquelle R4 est tel que défini précédemment, en opérant selon les méthodes d'amidification. Notamment, cette réaction peut être effectuée en opérant selon les conditions d'amidification correspondantes décrites plus haut, et en tenant compte des mêmes considérations stéréochimiques. as above, can be obtained from the product of general formula (IX)

in which R2, R3, R7, R8, R9 are defined as above, by the action of a compound of general formula (V)

in which R4 is as defined above, by operating according to the amidation methods. In particular, this reaction can be carried out by operating according to the corresponding amidification conditions described above, and taking into account the same stereochemical considerations.

Also included in the present invention are the compounds of general formula (IX) wherein R9, R2, R3, R7, R8 are defined as in general formula (I).

Generally, the acids of general formula (IX) in which R 9, R 2, R 3, R 7, R 8 are defined as above can be obtained from the corresponding esters of general formula (X):

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dans laquelle R9, R2, R3, R7, Rg sont définis comme précédemment et Alk représente un radical alkyle, le méthyle de préférence, par application ou adaptation des méthodes de saponification connues, décrites notamment par J. March, Advanced Organic Chemistry, Wiley-Interscience (1992) ; avantageusement, la saponification de l'ester de formule générale (X) peut être effectuée dans un solvant organique tel qu'un alcool comme le méthanol ou l'éthanol, éventuellement aqueux, au moyen d'une base minérale telle que la soude ou la potasse ou le carbonate de sodium.

in which R 9, R 2, R 3, R 7 and R 8 are defined as above and Alk represents an alkyl radical, preferably methyl, 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 (X) can be carried out in an organic solvent such as an alcohol such as methanol or ethanol, optionally aqueous, by means of a mineral base such as sodium hydroxide or sodium hydroxide; potash or sodium carbonate.

dans laquelle R2, R3, R7, R8 et Alk sont définis comme précédemment, par action d'un réactif de formule générale Generally, the compounds of general formula (X) in which R 9, R 2, R 3, R 7, R 8 are defined as above can be obtained from compounds of general formula (XI):

in which R2, R3, R7, R8 and Alk are defined as above, by the action of a reagent of general formula

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pour lequel R9 est défini comme précédemment.

for which R9 is defined as before.

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

dans laquelle R3, R7, R8 sont définis comme précédemment et G1 représente un groupe protecteur défini comme plus haut, par estérification de l'acide carboxylique et déprotection du groupement amino ; peut être effectuée selon toute méthode d'estérification connue, choisie notamment parmi celles décrites par J. March, Advanced Organic Chemistry, Wiley-Interscience (1992) ; la déprotection du groupe amino peut être effectuée par application ou adaptation des méthodes de déprotection classiques décrites par T. W.Greene, Protective groups in organic chemistry, Wiley-interscience (1991), et plus particulièrement par hydrolyse en milieu acide lorsque G1 représente un radical tert.butoxycarbonyle ; avantageusement selon l'invention, ces réactions peuvent être effectuées simultanément, en opérant en milieu acide, de préférence en présence d'acide chlorhydrique, en utilisant comme solvant l'alcool de formule générale R-OH dans Generally, the esters of general formula (XI) can be obtained from the corresponding acids of general formula (IV):

wherein R3, R7, R8 are defined as above and G1 represents a protecting group defined as above, by esterification of the carboxylic acid and deprotection of the amino group; 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); the 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 G1 represents a tert.butoxycarbonyl radical; ; advantageously according to the invention, these reactions can be carried out simultaneously, by operating in acid medium, preferably in the presence of hydrochloric acid, using as solvent the alcohol of general formula R-OH in

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 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, new products of general formula (I) in which R2, R3, R4,
R7, R8, R9 are defined as above can be obtained after a subsequent deprotection reaction, preferably at the end of the process.

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

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

The subject of the present invention is also any pharmaceutical composition containing at least one product of general formula in association with one or more pharmaceutically acceptable diluents or adjuvants that 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, mention may be made of addition salts with inorganic or organic acids such as acetate, propionate, succinate, benzoate, fumarate, maleate, methanesulfonate, isethionate, theophyllinacetate, salicylate, methylenebisboxynaphthoate, 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

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 prevention of pathological conditions related to cellular signaling pathways, associated with farnesyl transferase, or 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 related to cell proliferation by inhibition of farnesyl transferase and in particular for the treatment cell proliferative diseases, overexpressing any of the oncoproteins
H-Ras, N-Ras or K-Ras, or having a mutation of 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 related to cellular, malignant or benign proliferations, cells of various tissues and / or or organs, including muscle, bone or connective tissues, skin, brain, lungs, sexual organs, lymphatic or renal systems, mammary or blood cells, liver, digestive tract, colon, pancreas and thyroid or adrenal glands, including the following conditions: psoriasis, restenosis, solid tumors, Kaposi's sarcoma, carcinomas, cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms' tumor, Hodgkin's disease, melanoma, teratocarcinoma, glioma, multiple myeloma, chronic lymphocytic leukemia, acute or chronic granulocytic lymphoma, and cancers such as pancreatic, colon, lung, ovarian, breast, brain, prostate, liver, stomach, bladder or testicular cancers.

The invention particularly 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 cancers such as pancreatic, colon,

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 lung, ovary, breast, brain, prostate, liver, stomach, bladder or testes.

 The said treatment may be carried out in particular by inhibition of tumor growth, in particular by inhibition of farnesyl transferase, or by inhibition of the growth of tumors expressing the activated ras oncogene.

 Another subject 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 a radiotherapy treatment; compounds being preferably active ingredients known for their inhibitory activity of cell proliferation and particularly for their activity in the treatment of cancer; they may preferentially be antiproliferative compounds acting at any stage of the ras oncogene signaling pathway 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 that can be used in combination with the products of general formula (I) can be chosen from antineoplastic drugs, monoclonal antibodies, immunological therapies or radiotherapies or modifiers of biological responses. The modifiers of the responses include, but are not limited to, lymphokines and cytokines such as interleukins, interferons (?, Ss or 8) and TNF. Other chemotherapeutic agents useful in treating disorders due to abnormal proliferation of cells include, but are not limited to, alkylating agents such as nitrogen mustards such as mechloretamine, cyclophosphamide, melphalan and chlorambucil, alkyl sulfonates such as busulfan, nitrosoureas such as carmustine, lomustine, semustine and streptozocine, triazenes such as dacarbazine, antimetabolites such as folic acid analogues such as methotrexate, pyrimidine analogues

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 such as fluorouracil and cytarabine, purine analogues such as mercaptopurine and thioguanine, natural products such as vinca alkaloids such as vinblastine, vincristine and vendesine, taxoid derivatives, topoisomerase inhibitors such as derivatives camptothecin, 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 coordination of platinum such as cisplatin, substituted ureas such as hydroxyurea, methylhydrazine derivatives such as procarbazine, adrenocorticoid suppressors such as mitotane and aminoglutethymide, hormones and antagonists such as adrenocorticosteroids such as prednisone, progestins such as hydroxyprogesterone caproate, methoxypr ogesterone and megestrol acetate, estrogens such as diethylstilbestrol and ethynylestradiol, antiestrogens such as tamoxifen, androgens such as testosterone propionate and fluoxymesterone.

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

The products according to the invention can be administered orally, parenterally, such as intravenous, or intraperitoneal or rectal, preferably orally.

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 may comprise substances other than diluents, for example a lubricant such as magnesium stearate.

As liquid compositions for oral administration may be used pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs containing inert diluents such as water or paraffin oil.

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These compositions may also comprise substances other than diluents, for example wetting, sweetening or flavoring products.

The compositions according to the invention for parenteral administration may be sterile aqueous or nonaqueous solutions, suspensions or emulsions.
As a solvent or vehicle, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil or injectable organic esters, for example ethyl oleate, may be used. These compositions may also contain adjuvants, in particular wetting agents, emulsifiers and dispersants. The sterilization can be done in several ways, for example using a bacteriological filter, by incorporating sterilizing agents into the composition or by heating. They can also be prepared as 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 of therapeutic response. The doses vary according to the form of administration, the particular product selected and the specific characteristics of the subject to be treated. In general, the doses are those that are therapeutically effective for the treatment of disorders due to abnormal cell proliferation, including cytostatic treatment. The products according to the invention can be administered as often and as long as necessary to achieve the desired therapeutic effect.

Generally, the doses are, in humans, between 0.1 and 10000 mg / kg per day, preferably between 100 and 2000 mg / kg per day. It is understood that, in selecting the most appropriate dosage, the route of administration, the patient's weight, general health, age, and all factors that may affect the efficacy of the treatment should be taken into account. .

In general, the doctor will determine the appropriate dosage depending on age, weight and all other factors specific to the subject to be treated.

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Example 1 illustrates compositions according to the invention.

The following examples are presented by way of illustration and not limitation of the present invention.

Advantageously in the examples below, C * has the cofiguration (S); in this case, the other asymmetric carbon possibly present in the molecule may have a configuration (R) or (S): the corresponding compounds are diatereoisomers, 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).

Préparation du diastéréoisomére A de 8N-il(S)-méthylcarbamoyl-2-(4chIorophénvI)éthvll-rM4-méthvlbenzvIMH-imidazoI-5-YlméthvIaminol- chroman-8-carboxamide
262 g (3,4 moles) d'acétate d'ammonium sont ajoutés à 550 ml d'une solution méthanolique de 4-chromanone (50 g, 0,337 mole) à une température voisine de 20 C. Le mélange réactionnel est agité pendant 2 heures à la même température puis traité par addition progressive de cyanoborohydrure de sodium (15,1 g, 0,24 mole). La réaction est poursuivie 15 heures à 20 C, puis le milieu réactionnel concentré à sec sous pression réduite (20 mmHg, 2,6 kPa) à 50 C. Le produit brut est repris dans 11 d'eau distillée amenée à pH =10 par addition de soude ION et la phase organique extraite par 3 fois 300 ml de dichlorométhane, puis lavée à l'eau distillée, séchée sur sulfate de magnésium et concentrée à sec sous pression réduite à 50 C. Le produit brut (46 g) est purifié par chromatographie sur colonne de silice en éluant avec un mélange de dichlorométhane et de méthanol (95/5 en volumes). On obtient ainsi 25,3 g (50,4%) de 4-aminochromane sous forme d'huile brune. Example 1

Preparation of 8N-il (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl-rM4-methylbenzyl-imidazol-5-ylmethylaminomethyl-8-carboxamide diastereoisomer A
262 g (3.4 mol) of ammonium acetate are added to 550 ml of a methanolic solution of 4-chromanone (50 g, 0.337 mol) 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 the gradual addition of sodium cyanoborohydride (15.1 g, 0.24 mol). The reaction is continued for 15 hours at 20 ° C., and then the reaction medium is concentrated to dryness under reduced pressure (20 mmHg, 2.6 kPa) at 50 ° C. The crude product is taken up in 11 ml of distilled water brought to pH = 10 by addition of ION sodium hydroxide and the extracted organic phase with 3 times 300 ml of dichloromethane, then washed with distilled water, dried over magnesium sulphate and concentrated to dryness 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-aminochroman in the form of a brown oil are thus obtained.

 To 25 g (0.17 mol) of 4-aminochroman in solution in 450 ml of ethanol, 35.3 g (0.42 mol) of sodium hydrogen carbonate and then 41.5 g (0.19 mol) are added. di-tert-butyldicarbonate. The reaction medium is stirred for 15 hours at a

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temperature close to 20 C, then added to 1.5 liters of a mixture of distilled water and ice. The precipitate formed is filtered, then washed with water and dried under reduced pressure at
C. 40.3 g (95.3%) of 4-tert-butoxycarbonylamino-chroman is obtained in the form of a beige powder melting at 113 ° -114 ° 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-butyllithium cyclohexane (0.11 mol). The reaction is continued for 1 hour at the same temperature, then to the brown-orange suspension are added a few sticks of dry ice (previously washed in diethyl ether and wiped). The suspension quickly become beige is brought to a temperature of 20 C and the reaction medium is acidified (pH = 1) with 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-tertbutoxycarbonylamino-chroman-8-carboxylic acid are obtained in the form of a beige powder. at
185-187 C.

 To a solution of 5.87 g (0.020 mol) of 4-tert-butoxycarbonylaminochroman-8-carboxylic acid, 5.5 g (0.022 mol) of (S) -4-chlorophenylalanine methyl ester hydrochloride, 2 97 g (0.022 mol) of 1-hydroxy-benzotriazole and 4.55 g (0.045 mol) of triethylamine in 200 ml of dichloromethane are added 4.22 g (0.022 mol) of 1- (3-dimethylaminopropyl) hydrochloride. -3-ethylcarbodiimide at a temperature of 20 C. The reaction is continued for 15 hours at the same temperature. The reaction medium is then washed with twice 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 sulphate, the organic solution is filtered and then concentrated to dryness under reduced pressure.

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) -

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méthoxycarbonyl-2-(4-chlorophényl)-éthyl]-4-tert-butoxycarbonylamino-chroman-8- carboxamide sous forme de laque jaune pâle.

methoxycarbonyl-2- (4-chlorophenyl) ethyl] -4-tert-butoxycarbonylamino-chroman-8-carboxamide as a pale yellow lacquer.

CHON)+ , m/z=292 (M-C,oH902C1)+, m/z=276 (M-ClOH1102NClt pic de base, m/z=236 (m/z=292-C4H8)+, m/z=220 (m/z=276-CaHa)+, m/z=175 (m/z=220-CO2H)+, m/z=148 (m/z=175-CO+H)+., m/z=57 (C4H9+)
8 g (0,016 mole) de 8N-[I(S)-méthoxycarbonyl-2-(4-chlorophényl)-éthyl]-4- tert-butoxycarbonylamino-chroman-8-carboxamide en solution dans 25 ml de méthylamine sont chauffés en autoclave à 60 C pendant 48 heures. Après refroidissement à une température voisine de 20 C, le milieu réactionnel est concentré à sec sous pression réduite. On obtient ainsi 7,2 g (100 %) de 8N-[I(S)- méthylcarbamoyl-2-(4-chlorophényl)-éthyl]-4-tert-butoxycarbonylamino-chroman-8carboxamide sous forme de poudre beige. Mass spectrum: EI, m / z = 488 (M +), m / z = 415 (M-C4H9O) +, m / z = 372 (m / z = 415)

CHON) +, m / z = 292 (MC, oH902Cl) +, m / z = 276 (M-ClOH11O2NClt peak base, m / z = 236 (m / z = 292-C4H8) +, m / z = 220 (m / z = 276-CaHa) +, m / z = 175 (m / z = 220-CO2H) +, m / z = 148 (m / z = 175-CO + H) +., m / z = 57 (C4H9 +)
8 g (0.016 mol) of 8 N- [I (S) -methoxycarbonyl-2- (4-chlorophenyl) ethyl] -4-tert-butoxycarbonylamino-chroman-8-carboxamide dissolved in 25 ml of methylamine are heated in an autoclave. at 60 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. 7.2 g (100%) of 8N- [I (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4-tert-butoxycarbonylamino-chroman-8carboxamide are thus obtained in the form of a beige powder.

 A suspension of 7.1 g (0.0145 mol) of 8N- [I (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4-tert-butoxycarbonylamino-chroman-8-carboxamide in an IN solution of hydrogen chloride in diethyl ether (250 ml) is stirred for 48 hours at a temperature in the region of 20 ° C. This suspension is then poured into a mixture of 4N aqueous sodium hydroxide (80 ml) and distilled water (350 ml). ml) and dichloromethane (500 ml), then the organic phase decanted, washed with water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure at 50 C. This gives 5.1 g of crude product. purified by flash column chromatography on silica using a mixture of dichloromethane and methanol (96/4 by volume) as eluent to yield 1.5 g (17%) of the 8N- [1 (S) diastereoisomeric A - methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4-amino-chroman-8-carboxamide in the form of beige meringue, the characteristics of which are as follows: Spec from R.M.N. H (300 MHz, (CD3) 2SO d6, 8 ppm): from 1.75 to 1.90 (mt: 1H); from 1.95 to 2.25 (mt: 3H); 2.62 (d, J = 4.5 Hz: 3H); 2.98 (dd, J = 14 and 8 Hz: 1H); 3.08 (dd, J = 14 and 5 Hz: 1H); 3.95 (t, J = 5 Hz: 1H): from 4.25 to 4.40 (mt: 2H); 4.68 (mt: 1H); 6.95 (t, J = 7.5 Hz: 1H); 7.25 (d, J = 8 Hz: 2H); 7.37 (d, J =

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 8 Hz: 7.54 (dd, J = 7.5 and 1.5 Hz: 1H); 7.67 (dd, J = 7.5 and 1.5 Hz: 1H); 8.00 (q, J = 4.5 Hz: 1H); 8.33 (d, J = 7.5 Hz: 1H).

 To a solution of 2 g (0.021 mol) of 1 H-imidazol-4-yl-carboxaldehyde and 4.24 g (0.023 mol) of 4-methylbenzyl bromide in 100 cm3 of acetonitrile, add 5.75 g (0.042 moles) potassium carbonate. The reaction mixture is stirred for 4 hours under reflux of acetonitrile, filtered and the filtrate concentrated under reduced pressure. The residue (5.15 g) is purified by flash column chromatography on silica eluting with dichloromethane containing 2% methanol. 1.6 g (38%) of 1- (4-methylbenzyl) -1H-imidazol-5-ylcarboxaldehyde are obtained in the form of a beige solid melting at 91-93 C.

diastéréoisomére A de 8N-[ 1 (S)-méthylcarbamoyl-2-(4-chloro-phényi)éthyl]-4-[ 1-(4méthylbenzyl)-1H-imidazol-5-ylméthylamino]-chroman-8-carboxamide sous forme d'une meringue blanche dont les caractéristiques sont les suivantes : Pouvoir rotatoire : [alpha]D20 = + 33,8 1,0 (CH30H, c = 0,5) Spectre de masse : IE , m/z=571 M+ Spectre de R.M.N. 1H (400 MHz, (CD3)2SO d6, d en ppm) : de 1,85 à 2,00 (mt : 2H); 2,27 (s : 3H) ; (d, J = 5 Hz : 2,97 (dd, J = 14 et 8 Hz : 1H) ; 3,06 (dd, J = 14 et 5 Hz : IH) ; 3,59 (d, J = 14 Hz : 1H) ; de 3,65 à 3,75 (mt : IH) ; 3,70 (d, J = 14 Hz : 1H) ; de 4,25 à 4,40 (mt : 2H) ; 4,67 (mt : IH) ; 5,26 (AB limite : 2H) ; 6,87 (s : 1H) ; 6,89 (t, J = 8 Hz : IH) ; 6,98 (d, J = 8 Hz : 7,12 (d, J = 8 Hz : 2H) ; de After stirring for 3 hours at a temperature in the region of 20 ° C. of a mixture consisting of 0.349 g (0.9 mmol) of 8N- [I (S) -methylcarbamoyl-2- (4-chlorophenyl) -ethyl] -4- amino-chroman-8-carboxamide, 0.20 g (1 mmol) del- (4-methylbenzyl) -1H-imidazol-5-yl-carboxaldehyde and 0.4 ml of acetic acid in 15 ml of acetonitrile in the presence of molecular sieve 4A, 0.113 g (1.8 mmol) of sodium cyanoborohydride are 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 purified by flash column chromatography on silica eluting with dichloromethane containing 2% methanol. 0.26 g (51%) of the

8N- [1 (S) -methylcarbamoyl-2- (4-chloro-phenyl) ethyl] -4- [1- (4-methylbenzyl) -1H-imidazol-5-ylmethylamino] -chroman-8-carboxamide diastereoisomer A in the form of of a white meringue whose characteristics are as follows: Rotatory power: [alpha] D20 = + 33.8 1.0 (CH30H, c = 0.5) Mass spectrum: IE, m / z = 571 M + Spectrum of 1H NMR (400MHz, (CD3) 2SO d6, d in ppm): 1.85 to 2.00 (mt: 2H); 2.27 (s: 3H); (d, J = 5 Hz: 2.97 (dd, J = 14 and 8 Hz: 1H), 3.06 (dd, J = 14 and 5 Hz: 1H), 3.59 (d, J = 14 Hz) 1H), 3.65 to 3.75 (mt: 1H), 3.70 (d, J = 14 Hz: 1H), 4.25 to 4.40 (mt: 2H), mt: 1H), 5.26 (AB limit: 2H), 6.87 (s: 1H), 6.89 (t, J = 8 Hz: 1H), 6.98 (d, J = 8 Hz: 7). , 12 (d, J = 8 Hz: 2H);

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 7.20 to 7.30 (mt: 3H); 7.34 (d, J = 8 Hz: 2H); 7.68 (dd, J = 8 and 2 Hz: 1H); 7.72 (s: 1H); 8.02 (q, J = 5 Hz: 1H), 8.31 (d, J = 7.5 Hz: 1H).

Préparation du diastéréoisomére A de 8N-fl(S)-méthvlcarbamoyl-2-(4chlorophénvl)éthvll-4- U -( 4-phénvlbenzvl)-1 H -imidazol-S-vlméthvlamino ]- chroman-8-carboxamide
A une solution de 4 g (0,041 mole) de IH-imidazol-4-yl-carboxaldéhyde et de 9,3 g (0,046 mole) de chlorure de 4-phénylbenzyle dans 500 cm3 d'acétonitrile, on ajoute 11,5 g de carbonate de potassium. Le mélange réactionnel est agité pendant 2 heures au reflux de l'acétonitrile, filtré, puis concentré sous pression réduite. Le résidu est repris par 400 cm3 d'acétate d'éthyle, lavé deux fois par 100 cm3 d'eau, puis 100 cm3 de solution aqueuse saturée en chlorure de sodium. La solution est séchée sur du sulfate de magnésium, filtrée, puis concentrée sous pression réduite. Le résidu est purifié par chromatographie liquide à haute performance (phase Si 60) en éluant au dichlorométhane contenant 1,5 % de méthanol . On obtient 2,9 g (26 %) de

1-(4-phénylbenzyl)-1H-imidazol-5-yl-carboxaldéhyde sous forme de solide jaune fondant à 68 C. Example 2

Preparation of 8N-fl (S) -methylcarbamoyl-2- (4chlorophenyl) ethyl-4- (4-phenylbenzyl) -1H-imidazol-5-ylmethylamino] chroman-8-carboxamide diastereoisomer A
To a solution of 4 g (0.041 mol) of 1H-imidazol-4-yl-carboxaldehyde and 9.3 g (0.046 mol) of 4-phenylbenzyl chloride in 500 cm3 of acetonitrile, 11.5 g of potassium carbonate. The reaction mixture is stirred for 2 hours under reflux of acetonitrile, filtered and then concentrated under reduced pressure. The residue is taken up in 400 cm3 of ethyl acetate, washed twice with 100 cm3 of water and then 100 cm3 of saturated aqueous sodium chloride solution. The solution is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by high performance liquid chromatography (Si 60 phase) eluting with dichloromethane containing 1.5% methanol. 2.9 g (26%) of

1- (4-phenylbenzyl) -1H-imidazol-5-ylcarboxaldehyde as a yellow solid melting at 68 ° C.

[ 1 (S)-méthylcarbamoyl-2-(4-chloro-phényl)éthyl]-4-[ 1-(4-phénylbenzyl)-1 H- imidazol-5-ylméthylamino]-chroman-8-carboxamide sous forme d'une meringue blanche dont les caractéristiques sont les suivantes : Pouvoir rotatoire : [alpha]D20 = + 36,6 1,0 (CH30H, c = 0,5) Spectre de masse : DCI , m/z=634 MH+ Spectre de R.M.N.1H (400 MHz, CDC13, d en ppm) : 1,84 (mt : 1H) ; 2,02 (mt : IH); 2,76 (d, J = 5 Hz : 3H) ; 3,11(dd, J = 14 et 8 Hz : 1H) ; 3,25 (dd, J = 14 et 6 Hz : 1H) ; de 3,70 à 3,80 (mt : 1 H) ; 3,74 (d, J = 14 Hz : 1 H) ; 3,80 (d, J = 14 Hz : 1 H) ; The procedure is as in Example 1, but starting from 0.349 g (0.9 mmol) of 8N- [1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4-amino-chroman-8- carboxamide, 0.262 g (1 mmol) of 1- (4-phenylbenzyl) -1H-imidazol-5-ylcarboxaldehyde, 0.4 ml of acetic acid and 0.085 g (1.35 mmol) of sodium cyanoborohydride. 0.13 g (23%) of the 8N-diastereoisomeric A is obtained.

[1 (S) -methylcarbamoyl-2- (4-chloro-phenyl) ethyl] -4- [1- (4-phenylbenzyl) -1H-imidazol-5-ylmethylamino] -chroman-8-carboxamide in the form of a white meringue whose characteristics are as follows: Rotatory power: [alpha] D20 = + 36.6 1.0 (CH30H, c = 0.5) Mass spectrum: DCI, m / z = 634 MH + 1H NMR spectrum ( 400 MHz, CDCl3, d in ppm): 1.84 (mt: 1H); 2.02 (mt: 1H); 2.76 (d, J = 5 Hz: 3H); 3.11 (dd, J = 14 and 8 Hz: 1H); 3.25 (dd, J = 14 and 6 Hz: 1H); from 3.70 to 3.80 (mt: 1H); 3.74 (d, J = 14 Hz: 1H); 3.80 (d, J = 14 Hz: 1H);

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 4.25 (mt: 1H); 4.34 (mt: 1H); 4.84 (mt: 1H); 5.31 (AB limit: 2H); 6.08 (mt: 1H); 6.90 (t, J = 8 Hz: 1H); from 7.05 to 7.30 (mt: 8H); 7.38 (t, J = 8 Hz: 1H); 7.45 (t, J = 8 Hz: 2H); 7.55 (mt: 4H); 7.60 (s: 1H); 8.05 (dd, J = 8 and 2 Hz: 1H); 8.31 (d, J = 7 Hz: 1H).

Préparation du diastéréoisomére A de SN-rl(S)-méth.11..i!!.bamovl-2-(4chIorophénvI)éthvIl-4-fl-(4-chIorobenzYl)-lH-imidazol-5-vlméthylamino]- chroman-8-carboxamide
A une solution fortement agitée et refroidie à 10 C de 200 g de
4-chlorobenzylamine dans 1 litre d'éthanol, on coule goutte à goutte 140 cm3d'acide acétique, laisse revenir le mélange à 20 C puis ajoute en 5 minutes 108 g de dihydroxyacétone et 181 g de thiocyanate de potassium. Après 48 heures d'agitation à
20 C, la suspension noire obtenue est filtrée, le solide est lavé avec de l'éthanol jusqu'à obtention d'un filtrat incolore, puis rincé avec de l'oxyde de diisopropyle, essoré et séché à l'air sur claie. On obtient 75,6 g de 1-(4-chlorobenzyl)-5hydroxyméthyl-2-mercapto-imidazole, sous la forme de cristaux beiges fondant à 242 C. Example 3

Preparation of the diastereoisomere A of SN-R1 (S) -methyl-1-bamovl-2- (4-chlorophenyl) ethyl-4-fl- (4-chlorobenzyl) -1H-imidazol-5-ylmethylamino] chroman -8-carboxamide
To a strongly stirred solution and cooled to 10 ° C. with 200 g of
4-chlorobenzylamine in 1 liter of ethanol is poured dropwise 140 cm3 of acetic acid, the mixture is allowed to return to 20 C and then added in 5 minutes 108 g of dihydroxyacetone and 181 g of potassium thiocyanate. After 48 hours of agitation at
C., the black suspension obtained is filtered, the solid is washed with ethanol until a colorless filtrate is obtained, then rinsed with diisopropyl ether, drained and air dried on a rack. 75.6 g of 1- (4-chlorobenzyl) -5-hydroxymethyl-2-mercapto-imidazole are obtained in the form of beige crystals melting at 242 ° C.

 To 1.5 liters of 30% nitric acid cooled to 8 ° C., 82 g of 1- (4-chlorobenzyl) -5-hydroxymethyl-2-mercaptoimidazole are added in small portions over 45 minutes.

After 30 minutes under cold conditions, the mixture, supplemented with 100 cm3 of 30% nitric acid, is brought to 40 ° C. and then allowed to return to ambient temperature. After stirring for 20 hours at 20 ° C., the reaction mixture is filtered and the filtrate cooled to 0 ° C. is basified slowly while maintaining the temperature at 20 ° C. with 1 liter of 30% sodium hydroxide. The suspension obtained is filtered, the solid is washed with water and then dried in air on a rack. 28.2 g of 1- (4-chlorobenzyl) -5-hydroxymethylimidazole are obtained in the form of a cream solid, melting at 139 ° C.

 To a solution of 23.0 g of 1- (4-chlorobenzyl) -5-hydroxymethylimidazole in 200 cm3 of 1,4-dioxane was added 36.0 g of manganese dioxide. After

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 After stirring for 24 hours at reflux temperature, the reaction mixture is cooled to 20 ° C., filtered through celite, and the filtrate concentrated to dryness under reduced pressure (2.7 kPa). The brown paste obtained is taken up by warming with 250 cm3 of diethyloxide, the resulting suspension is filtered on celite, and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). 17.2 g of 1- (4-chlorobenzyl) -1H-imidazol-5-ylcarboxaldehyde are obtained in the form of orange crystals, melting at 85 ° C.

8N-[ 1 (S)-méthylcarboxamido-2-(4-chloro-phényl)éthyl]-4-[ 1-(4-chlorobenzyl)-1 H- imidazol-5-ylméthylamino]-chroman-8-carboxamide sous forme d'une meringue blanche dont les caractéristiques sont les suivantes : Pouvoir rotatoire : aD20 = + 38,1 0,9 (CH30H, c = 0,5) Spectre de masse : DCI , m/z=592 MH+ Spectre de R.M.N. 1H (400 MHz, (CD3)2S0 d6, d en ppm) : de1,85 à 2,00 (mt : 2H); 2,26 (mt : 1H) ; 2,61 (d, J = 5 Hz : 2,97 (dd, J = 14 et 8 Hz : 1H) ; 3,06 (dd, J = 14 et 5 Hz : 1H) ; 3,56 (dd, J = 14 et 6 Hz : 1H) ; de 3,65 à 3,75 (mt : 2H) ; 4,20 à 4,40 (mt : 2H) ; (mt : 1H) ; 5,31 (AB limite : 2H) ; de 6,80 à 6,95 (mt : 2H) ; 7,08 (d, J = 8 Hz : de 7,15 à 7,30 (mt : 3H) ; 7,34 (d, J = 8 Hz : 7,37 (d, J = 8 Hz : 7,67 (dd, J = 8 et 2 Hz : 1H) ; 7,75 (s : 1H) ; 8,01 (q, J = 5 Hz : 1H) ; 8,30 (d, J = 8 Hz : 1H). The procedure is as in Example 1, but starting from 0.349 g (0.9 mmol) of 8N- [1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4-amino-chroman-8 carboxamide, 0.221 g (1 mmol) of 1- (4-chlorobenzyl) -1H-imidazol-5-ylcarboxaldehyde, 0.4 ml of acetic acid and 0.085 g (1.35 mmol) of cyanoborohydride; sodium. 0.12 g (23%) of the diastereoisomer A of

8N- [1 (S) -methylcarboxamido-2- (4-chloro-phenyl) ethyl] -4- [1- (4-chlorobenzyl) -1H-imidazol-5-ylmethylamino] -chroman-8-carboxamide in form of a white meringue whose characteristics are as follows: Rotatory power: aD20 = + 38.1 0.9 (CH30H, c = 0.5) Mass spectrum: DCI, m / z = 592 MH + 1 H NMR spectrum ( 400 MHz, (CD3) 2SO d6, d in ppm): from 1.85 to 2.00 (mt: 2H); 2.26 (mt: 1H); 2.61 (d, J = 5 Hz: 2.97 (dd, J = 14 and 8 Hz: 1H), 3.06 (dd, J = 14 and 5 Hz: 1H), 3.56 (dd, J); = 14 and 6 Hz: 1H), 3.65 to 3.75 (mt: 2H), 4.20 to 4.40 (mt: 2H), (mt: 1H), 5.31 (AB limit: 2H); from 6.80 to 6.95 (mt: 2H), 7.08 (d, J = 8 Hz: from 7.15 to 7.30 (mt: 3H), 7.34 (d, J = 8); Hz: 7.37 (d, J = 8 Hz: 7.67 (dd, J = 8 and 2 Hz: 1H), 7.75 (s: 1H), 8.01 (q, J = 5 Hz: 1H); 8.30 (d, J = 8 Hz: 1H).

Préparation du diastéréoisomére A de 8N-il(S)-méthylcarbamoyl-2-(4chlorophénrl)éthvll-4-f 1-(4-bromobenzyl)-1H-imidazol-5-ylméthylaminol- chroman-8-carboxamide
A une solution de 10 g (0,104 mole) de 1 H-imidazol-4-yl-carboxaldéhyde et de 28,6 g (0,114 mole) de bromure de 4-bromobenzyle dans 600 cm3 d'acétonitrile, Example 4

Preparation of 8N-il (S) -methylcarbamoyl-2- (4chlorophenyl) ethyl-4-1- (4-bromobenzyl) -1H-imidazol-5-ylmethylaminol-chroman-8-carboxamide diastereoisomer A
To a solution of 10 g (0.104 mol) of 1 H-imidazol-4-yl-carboxaldehyde and 28.6 g (0.114 mol) of 4-bromobenzyl bromide in 600 cm3 of acetonitrile,

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[ 1 (S)-méthylcarbamoyl-2-(4-chloro-phényl)éthylJ-4-[ 1-(4-bromobenzyl)-1 H- imidazol-5-ylméthylamino] -chroman-8-carboxamide sous forme d'une meringue blanche dont les caractéristiques sont les suivantes : Pouvoir rotatoire : [alpha]D20 = + 34,4 0,9 (CH30H, c = 0,5) Spectre de masse : DCI , m/z=636 MH+ Spectre de R.M.N. 1H (400 MHz, (CD3)2SO d6, d en ppm) : de1,85 à 2,00 (mt : 2H); 2,62 (d, J = 5 Hz : 3H) ; 2,98 (dd, J = 14 et 8 Hz : 1H) ; 3,07 (dd, J = 14 et 5 Hz : 1 H) ; 3,56 (d, J = 14 Hz : 1 H) ; 3,67 (mt : 1 H) ; 3,70 (d, J = 14 Hz : 1 H) ; de 4,20 à 4,40 (mt : 2H) ; (mt : 1H) ; 5,29 (AB limite : 2H) ; de 6,85 à 6,95 (mt : 2H) ; 7,02 (d, J = 9 Hz : 7,21 (d large, J = 8 Hz : 1H) ; 7,25 (d, J = 8 Hz : 7,34 (d, J = 8 Hz : 2H) ; 7,50 (d, J = 9 Hz : 7,68 (d large, J = 8 Hz : 1H) ; 7,74 (s : 1H) ; 8,01 (q, J = 5 Hz : 1H) ; 8,30 (d, J = 8 Hz : 1H). 28.75 g of potassium carbonate are added. The reaction mixture is stirred for 2 hours under reflux of acetonitrile, filtered and then concentrated under reduced pressure. The residue is taken up in 400 cm3 of ethyl acetate, washed twice with 100 cm3 of water and then 100 cm3 of saturated aqueous sodium chloride solution. The solution is dried over magnesium sulfate, filtered and 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-bromobenzyl) -1H-imidazol-5-ylcarboxaldehyde are obtained in the form of a yellow solid melting at 68 ° C., the characteristics of which are as follows: Mass spectrum: IE , m / z = 264 M +
The procedure is as in Example 1, but starting from 0.349 g (0.9 mmol) of 8N- [1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4-amino-chroman-8- carboxamide, 0.265 g (1 mmol) of 1- (4-bromobenzyl) -1H-imidazol-5-ylcarboxaldehyde, 0.4 ml of acetic acid and 0.085 g (1.35 mmol) of sodium cyanoborohydride. 0.25 g (44%) of the 8N-diastereoisomeric A is obtained.

[1 (S) -methylcarbamoyl-2- (4-chloro-phenyl) ethyl] -4- [1- (4-bromobenzyl) -1H-imidazol-5-ylmethylamino] -chroman-8-carboxamide as a white meringue with the following characteristics: Rotatory power: [alpha] D20 = + 34.4 0.9 (CH30H, c = 0.5) Mass spectrum: DCI, m / z = 636 MHz + 1H NMR spectrum ( 400 MHz, (CD3) 2SO d6, d in ppm): from 1.85 to 2.00 (mt: 2H); 2.62 (d, J = 5 Hz: 3H); 2.98 (dd, J = 14 and 8 Hz: 1H); 3.07 (dd, J = 14 and 5 Hz: 1H); 3.56 (d, J = 14 Hz: 1H); 3.67 (mt: 1H); 3.70 (d, J = 14 Hz: 1H); from 4.20 to 4.40 (mt: 2H); (mt: 1H); 5.29 (AB limit: 2H); from 6.85 to 6.95 (mt: 2H); 7.02 (d, J = 9 Hz: 7.21 (d wide, J = 8 Hz: 1H), 7.25 (d, J = 8 Hz: 7.34 (d, J = 8 Hz: 2H); 7.50 (d, J = 9 Hz: 7.68 (broad d, J = 8 Hz: 1H), 7.74 (s: 1H), 8.01 (q, J = 5 Hz: 1H); 8.30 (d, J = 8 Hz: 1H).

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Préparation du diastéréoisomére A de 8N-f 1(S)-méthylcarbamoyl-2-(4chlorop hvI1-4-! 1-[ 4-(3- pvrid vl)benzvU:il!:jmidazol-5-vlméthvlamino }- chroman-8-carboxamide
A une solution de 0,8g (0,003 mole) del-(4-bromobenzyl)-IH-imidazol-4-ylcarboxaldéhyde et de 0,44g (0,0036 mole) d'acide 3-pyridyl-boronique (préparé selon le procédé décrit par G M.Ujjainwalla et al. dans le brevet WO 9855479) dans un mélange de 30 cm3 de toluène et de 1 cm3 d'éthanol, on ajoute 0,12 g (0,1 mmole) de tétrakis(triphénylphosphine) palladium puis 2 cm3 de solution aqueuse contenant 0,64 g (0,006 mole) de carbonate de potassium, et enfin 0,44 g (0,003 mole) de iodure de sodium. Le mélange réactionnel est agité pendant 24 heures au reflux du mélange de solvants, filtré, décanté. La phase aqueuse est lavée deux fois par 20 cm3 de dichlorométhane. La solution organique est séchée sur du sulfate de magnésium et concentrée sous pression réduite. Après purification par chromatographie-flash sur colonne de silice en éluant avec un mélange de dichlorométhane et de méthanol (100/0 à 95/5 en volumes), on obtient 0,2 g (25 %) de 1-[4-(3-pyridyl)benzyl]-IHimidazol-5-yl-carboxaldéhyde sous forme d'une huile brune dont les caractéristiques sont les suivantes : Spectre de masse : IE , m/z=263 M+
On opère comme dans l'exemple 1, mais à partir de 0,29 g (0,75 mmole) de 8N-[ 1 (S)-méthylcarbamoyl-2-(4-chlorophényl)-éthyl]-4-amino-chroman-8- carboxamide, de 0,21 g (0,8 mmole) de 1-[4-(3-pyridyl)benzyl]-IH-imidazol-5-ylcarboxaldéhyde, de 0,4 ml d'acide acétique et de 0,069 g (1,1 mmole) de cyanoborohydrure de sodium. On obtient 0,29 g (61 %) du diastéréoisomére A de

8N-[ 1 (S)-méthylcarbamoyl-2-(4-chlorophényl)éthyl]-4- { 1 -[4-(3-pyridyl)benzyl]- H- imidazol-5-ylméthylamino}-chroman-8-carboxamide sous forme d'une meringue blanche dont les caractéristiques sont les suivantes : Pouvoir rotatoire : aD20 = + 39,1 0,9 (CH30H, c = 0,5) Example 5

Preparation of the Diastereoisomeric A of 8N-1 (S) -methylcarbamoyl-2- (4chloropyryl) -1- [4- (3-pyridyl) benzyl] imidazol-5-ylmethylamino} -chroman-8 carboxamide
To a solution of 0.8 g (0.003 moles) del- (4-bromobenzyl) -1H-imidazol-4-ylcarboxaldehyde and 0.44 g (0.0036 moles) of 3-pyridylboronic acid (prepared by the process described by G M.Ujjainwalla et al., in WO 9855479) in a mixture of 30 cm3 of toluene and 1 cm3 of ethanol, 0.12 g (0.1 mmol) of tetrakis (triphenylphosphine) palladium is added and then 2 cm3 of aqueous solution containing 0.64 g (0.006 mol) of potassium carbonate, and finally 0.44 g (0.003 mol) of sodium iodide. The reaction mixture is stirred for 24 hours under reflux of the solvent mixture, filtered, decanted. The aqueous phase is washed twice with 20 cm3 of dichloromethane. The organic solution is dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash column chromatography on silica eluting with a mixture of dichloromethane and methanol (100/0 to 95/5 by volume), 0.2 g (25%) of 1- [4- (3%) are obtained. pyridyl) benzyl] -H-imidazol-5-yl-carboxaldehyde in the form of a brown oil whose characteristics are as follows: Mass spectrum: IE, m / z = 263 M +
The procedure is as in Example 1, but starting from 0.29 g (0.75 mmol) of 8N- [1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4-amino-chroman. Carboxamide, 0.21 g (0.8 mmol) of 1- [4- (3-pyridyl) benzyl] -1H-imidazol-5-ylcarboxaldehyde, 0.4 ml of acetic acid and 0.069 g. g (1.1 mmol) of sodium cyanoborohydride. 0.29 g (61%) of the diastereoisomer A of

8 N- [1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4- {1 - [4- (3-pyridyl) benzyl] -H-imidazol-5-ylmethylamino} -chroman-8-carboxamide in the form of a white meringue whose characteristics are as follows: Rotatory power: aD20 = + 39.1 0.9 (CH30H, c = 0.5)

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Hz : l H) ; 3,60 (d, J = 14 Hz : 1 H) ; 3,70 (mt : I H) ; 3,74 (d, J = 14 Hz : tu) ; de 4,25 à 4,40 (mt : 2H) ; 4,66 (mt : 1H) ; 5,38 (s large : 2H) ; 6,84 (t, J = 7,5 Hz : 1H) ; 6,90 (s large : 1H) ; 7,18 (d, J = 8 Hz : 2H) ; de 7,20 à 7,30 (mt : 3H) ; (d, J = 8 Hz : 2H) ; 7,48 (dd, J = 8 et 5 Hz : 1H) ; de 7,60 à 7,70 (mt : 3H) ; (s large : 1H) ; de 7,95 à 8,10 (mt : 2H) ; 8,31 (d, J = 7,5 Hz : 1H) ; 8,57 (dd, J = 5 et 1,5 Hz : 1H) ; 8,87 (d, J = 1,5 Hz: 1H). 1H NMR Spectrum (300 MHz, (CD3) 2SO d6, 8 ppm): 1.85 to 2.05 (mt: 2H); 2.61 (d, J = 4.5 Hz: 3H); 2.96 (dd, J = 14 and 8 Hz: 1H); 3.06 (dd, J = 14 and 5

Hz: 1H); 3.60 (d, J = 14 Hz: 1H); 3.70 (mt: 1H); 3.74 (d, J = 14 Hz: tu); from 4.25 to 4.40 (mt: 2H); 4.66 (mt: 1H); 5.38 (brs: 2H); 6.84 (t, J = 7.5 Hz: 1H); 6.90 (brs: 1H); 7.18 (d, J = 8 Hz: 2H); from 7.20 to 7.30 (mt: 3H); (d, J = 8 Hz: 2H); 7.48 (dd, J = 8 and 5 Hz: 1H); from 7.60 to 7.70 (mt: 3H); (s wide: 1H); from 7.95 to 8.10 (mt: 2H); 8.31 (d, J = 7.5 Hz: 1H); 8.57 (dd, J = 5 and 1.5 Hz: 1H); 8.87 (d, J = 1.5 Hz: 1H).

Préparation du diastéréoisomére A de 8N-[l(SVméthvIcarbamovl-2-(4chlorouhényl)éthyll-4-{1-(4-(4-fluorophényl)benzyll-1H-imidazol-5- ylméthylaminol-chroman-8-carboxamide
0,25 g (0,94 mmole) de 1-(4-bromobenzyl)-IH-imidazol-5-yl-carboxaldéhyde sont mis à réagir avec 0,155 g (1,10 mmole) d'acide 4-fluorobenzène boronique, 0,20 g (1,88 mmole) de carbonate de sodium, 0,07 g (0,06 mmole) de tétrakis(triphénylphosphine)palladium et 0,140 g (0,94 mmole) de iodure de sodium dans un mélange de 1 ml d'eau, de 1 ml d'éthanol, de 0,5 ml de diméthylformamide et de 10 ml de toluène. Après 12 heures d'agitation à une température voisine du reflux, le mélange réactionnel est refroidi et décanté. La phase organique est lavée à l'eau distillée et avec une solution aqueuse saturée en chlorure de sodium, séchée sur sulfate de magnésium et concentrée à sec sous pression réduite. Le produit brut est purifié par chromatographie liquide à haute performance (phase Si 60) en éluant au dichlorométhane contenant un mélange croissant de 0 à 1 % de méthanol. On obtient

0,21 g (80 %) de 1-[4-(4-fluorophényl)benzyl]-1H-imidazol-5-yI-carboxaldéhyde sous forme d'une meringue crème. Example 6

Preparation of 8N- [1 (S) -methylcarbamoyl-2- (4chlorouhenyl) ethyl-4- {1- (4- (4-fluorophenyl) benzyl] -1H-imidazol-5-ylmethylaminol-chroman-8-carboxamide Diastereoisomeric A
0.25 g (0.94 mmol) of 1- (4-bromobenzyl) -1H-imidazol-5-ylcarboxaldehyde are reacted with 0.155 g (1.10 mmol) of 4-fluorobenzene boronic acid, 20 g (1.88 mmol) of sodium carbonate, 0.07 g (0.06 mmol) of tetrakis (triphenylphosphine) palladium and 0.140 g (0.94 mmol) of sodium iodide in a mixture of 1 ml of water, 1 ml of ethanol, 0.5 ml of dimethylformamide and 10 ml of toluene. After stirring for 12 hours at a temperature close to reflux, the reaction mixture is cooled and decanted. The organic phase is washed with distilled water and with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure. The crude product is purified by high performance liquid chromatography (Si 60 phase) eluting with dichloromethane containing an increasing mixture of 0 to 1% methanol. We obtain

0.21 g (80%) of 1- [4- (4-fluorophenyl) benzyl] -1H-imidazol-5-yl-carboxaldehyde as a cream meringue.

8N-[ 1 (S)-méthylcarbamoyl-2-(4-chlorophényl)-éthyl]-4-amino-chroman-8- carboxamide, de 0,23 g (0,8 mmole) de 1-[4-(4-fluorophényl)benzyl]-IH-imidazol-5yl-carboxaldéhyde, de 0,4 ml d'acide acétique et de 0,069 g (1,1 mmole) de The procedure is as in Example 1, but starting from 0.29 g (0.75 mmol) of

8N- [1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4-amino-chroman-8-carboxamide, 0.23 g (0.8 mmol) of 1- [4- (fluorophenyl) benzyl] -H-imidazol-5-yl-carboxaldehyde, 0.4 ml of acetic acid and 0.069 g (1.1 mmol) of

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[ 1 (S)-méthylcarbamoyl-2-(4-chlorophenyl)ethyl]-4- ( 1-[4-(4-fluorophényl)benzyl]- 1 H-imidazol-5-ylmethylamino}-chroman-8-carboxamide sous forme d'une meringue blanche dont les caractéristiques sont les suivantes : Pouvoir rotatoire : [alpha]D20 = + 38,7 0,8 (CH30H, c = 0,5) Spectre de R.M.N. 1H (300 MHz, (CD3)2SO d6, 8 en ppm) : 1,85 à 2,00 (mt : 2H); de 2,20 à 2,35 (mt : 1H) ; 2,62 (d, J = 4,5 Hz : 3H) ; 2,97 (dd, J = 14 et 8 Hz : 1H) ; 3,07 (dd, J = 14 et 5 Hz : 1H) ; de 3,55 à 3,80 (mt : 3H) ; de 4,20 à 4,40 (mt : 2H) ; 4,67 (mt : 1H) ; 5,36 (s large : 2H) ; 6,85 (t, J = 7,5 Hz : 1 H) ; 6,91 (s : 1H) ; 7,16 (d, J = 7,5 Hz : de 7,20 à 7,40 (mt : 7H) ; 7,59 (d, J = 7,5 Hz : 7,68 (mt : 3H); 7,79 (s : 1H) ; 8,03 (mt : 1H) ; 8,32 (d, J = 7,5 Hz : 1H). sodium cyanoborohydride. 0.22 g (45%) of the 8N-diastereoisomeric A is obtained.

[1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4- (1- [4- (4-fluorophenyl) benzyl] -1H-imidazol-5-ylmethylamino} -chroman-8-carboxamide under white meringue shape with the following characteristics: Rotatory power: [alpha] D20 = + 38.7 0.8 (CH30H, c = 0.5) 1H NMR spectrum (300 MHz, (CD3) 2SO d6 , 8 ppm): 1.85 to 2.00 (mt: 2H), 2.20 to 2.35 (mt: 1H), 2.62 (d, J = 4.5 Hz: 3H); , 97 (dd, J = 14 and 8 Hz: 1H), 3.07 (dd, J = 14 and 5 Hz: 1H), from 3.55 to 3.80 (mt: 3H), from 4.20 to 4.40 (mt: 2H), 4.67 (mt: 1H), 5.36 (s wide: 2H), 6.85 (t, J = 7.5 Hz: 1H), 6.91 (s, 1H), 1H), 7.16 (d, J = 7.5 Hz: 7.20 to 7.40 (mt: 7H), 7.59 (d, J = 7.5 Hz: 7.68 (m.t. 3H), 7.79 (s: 1H), 8.03 (mt: 1H), 8.32 (d, J = 7.5 Hz: 1H).

Préparation du diastéréoisomére A de 8N-[l(S)-méthvlcarbamovl-2-(4chIorophénvl)éthvn-4-(l-[4-(2-carbamovléthvl)benzvn-lH-imidazol-5vlméthylamino)-chroman-8-carboxamide
A une solution de 1,48 g (0,0154 mole) de I H-imidazol-4-yl-carboxaldéhyde et 3,5 g (0,0154 mole) de chlorure de 4- (2-méthoxycarbonyléthyl)benzyle selon le procédé décrit par F. Yukitoshi et al. (brevet WO 9747581) dans 120 cm3 d'acétonitrile, on ajoute 4,26 g de carbonate de potassium. Le mélange réactionnel est agité pendant 2 heures au reflux de l'acétonitrile, filtré, puis concentré sous pression réduite. Le résidu est repris par 100 cm3 d'acétate d'éthyle, lavé deux fois par 30 cm3 d'eau, puis 30 cm3 de solution aqueuse saturée en chlorure de sodium. La solution est séchée sur du sulfate de magnésium, filtrée, concentrée sous pression réduite. Le résidu est purifié par chromatographie liquide à haute performance (phase Si 60) en éluant au dichlorométhane contenant 1 % de méthanol. On obtient 1 g (45 %) de 1-[4-

(2-méthoxycarbonyléthyl)benzyl]-1H-imidazol-5-yl-carboxaldéhyde sous forme d'une huile incolore dont les caractéristiques sont les suivantes : Spectre de R.M.N. 'H (300 MHz, (CD3)2SO d6, 8 en ppm) : 1,15 (t, J = 7,5 Hz : 3H); 2,59 (t, J = 7,5 Hz : 2,82 (t, J = 7,5 Hz : 4,04 (q, J = 7,5 Hz : 2H) ; 5,50 Example 7

Preparation of 8N- [1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl-4- (1- [4- (2-carbamoylethyl) benzyl] -1H-imidazol-5-ylmethylamino) -chroman-8-carboxamide diastereoisomer A
To a solution of 1.48 g (0.0154 mol) of 1 H-imidazol-4-yl-carboxaldehyde and 3.5 g (0.0154 mol) of 4- (2-methoxycarbonylethyl) benzyl chloride according to the process described by F. Yukitoshi et al. (Patent WO 9747581) in 120 cm3 of acetonitrile is added 4.26 g of potassium carbonate. The reaction mixture is stirred for 2 hours under reflux of acetonitrile, filtered and then concentrated under reduced pressure. The residue is taken up in 100 cm3 of ethyl acetate, washed twice with 30 cm3 of water and then 30 cm3 of saturated aqueous sodium chloride solution. The solution is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by high performance liquid chromatography (Si 60 phase) eluting with dichloromethane containing 1% methanol. We obtain 1 g (45%) of 1- [4-

(2-Methoxycarbonylethyl) benzyl] -1H-imidazol-5-ylcarboxaldehyde as a colorless oil having the following characteristics: 1 H NMR Spectrum (300 MHz, (CD3) 2SO d6, 8 ppm) 1.15 (t, J = 7.5 Hz: 3H); 2.59 (t, J = 7.5 Hz: 2.82 (t, J = 7.5 Hz: 4.04 (q, J = 7.5 Hz: 2H);

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0,25g (0,87 mmole) de 1-[4-(2-méthoxycarbonyléthyl)benzyl]-lH-imidazol-5- yl-carboxaldéhyde en solution dans 30 ml de méthanol ammoniacal 6N sont chauffés en autoclave à 50 C pendant 48 heures. Après refroidissement à une température voisine de 20 C, le milieu réactionnel est concentré à sec sous pression réduite et le résidu est purifié par chromatographie liquide à haute performance (phase Si 60) en éluant au dichlorométhane contenant un mélange croissant de 0 à 10% de méthanol. (s: 2H); 7.13 (d, J = 8 Hz: 2H); 7.20 (d, J = 8 Hz: 7.94 (d, J = 1Hz: 1H), 8.26 (s: 1H), 9.73 (d, J = 1Hz: 1H).

0.25 g (0.87 mmol) of 1- [4- (2-methoxycarbonylethyl) benzyl] -1H-imidazol-5-ylcarboxaldehyde dissolved in 30 ml of 6N ammonia methanol are heated in an autoclave at 50 ° C. for 48 hours. 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 a mixture of 0 to 10% methanol.

8N-[ l (S)-méthylcarbamoyl-2-( 4-chlorophényl)-éthyl]-4-amino-chroman-8- carboxamide, de 0,21 g (0,8 mmole) de 1-[4-(2-carbamoyléthyl)benzyl]-IH-imidazol- 5-yl-carboxaldéhyde, de 0,4 ml d'acide acétique et de 0,069 g (1,1 mmole) de cyanoborohydrure de sodium. On obtient 0,25 g (53 %) du diastéréoisomére A de 8N-

[ 1 (S)-méthylcarbamoyl-2-(4-chlorophényl)éthyl]-4- { 1-[4-(2-carbamoyléthyl)benzyl]- lH-imidazol-5-ylméthylamino}-chroman-8-carboxamide sous forme d'une meringue blanche dont les caractéristiques sont les suivantes : Pouvoir rotatoire : [alpha]D20 = + 33,4 0,8 (CH30H, c = 0,5) Spectre de R.M.N. 'H (400 MHz, (CD3)2SO d6, 8 en ppm) : 1,85 à 2,00 (mt : 2H); 2,34 (t, J = 8 Hz : 2,61 (d, J = 4,5 Hz : 2,77 (t, J = 8 Hz : 2H) ; 2,98 (dd, J = 14 et 8 Hz : 1H) ; 3,07 (dd, J = 14 et 5,5 Hz : 1H) ; 3,60 (d, J = 14 Hz : 1H) ; de 3,65 à 3,70 (mt : 1H) ; 3,70 (d, J = 14 Hz : 1H) ; de 4,20 à 4,40 (mt : 2H) ; 4,67 (mt : 1H) ; 5,26 (s large : 2H) ; 6,77 (mf : 1H) ; 6,87 (s : 1H) ; 6,89 (t, J = 8 Hz : 1H) ; 7,00 (d, J = 8 Hz : 7,16 (d, J = 8 Hz : 2H) ; de 7,20 à 7,30 (mt : 4H) ; 7,35 (d, J = 8 Hz : 2H) ; 7,68 (dd, J = 8 et 1,5 Hz : 1H) ; 7,71 (s : 1H) ; 8,02 (q, J = 4,5 Hz :

IH); 8,32 (d, J = 8 Hz: IH). 0.03 g (14%) of 1- [4- (2-carbamoylethyl) benzyl] -1H-imidazol-5-ylcarboxaldehyde are obtained in the form of a colorless oil, the characteristics of which are as follows: Mass spectrum: DCI, m / z = 258 MH +
The procedure is as in Example 1, but starting from 0.29 g (0.75 mmol) of

8N- [1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4-amino-chroman-8-carboxamide, 0.21 g (0.8 mmol) of 1- [4- carbamoylethyl) benzyl] -1H-imidazol-5-ylcarboxaldehyde, 0.4 ml of acetic acid and 0.069 g (1.1 mmol) of sodium cyanoborohydride. 0.25 g (53%) of the 8N-diastereoisomeric A is obtained.

[1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4- {1- [4- (2-carbamoylethyl) benzyl] -1H-imidazol-5-ylmethylamino} -chroman-8-carboxamide in form of a white meringue whose characteristics are as follows: Rotatory power: [alpha] D20 = + 33.4 0.8 (CH30H, c = 0.5) NMR spectrum H (400 MHz, (CD3) 2SO d6 8 in ppm): 1.85 to 2.00 (mt: 2H); 2.34 (t, J = 8 Hz: 2.61 (d, J = 4.5 Hz: 2.77 (t, J = 8 Hz: 2H), 2.98 (dd, J = 14 and 8 Hz) : 1H), 3.07 (dd, J = 14 and 5.5 Hz: 1H), 3.60 (d, J = 14 Hz: 1H), 3.65 to 3.70 (mt: 1H); 3.70 (d, J = 14 Hz: 1H), 4.20 to 4.40 (mt: 2H), 4.67 (mt: 1H), 5.26 (s wide: 2H); (mf: 1H), 6.87 (s: 1H), 6.89 (t, J = 8 Hz: 1H), 7.00 (d, J = 8 Hz: 7.16 (d, J = 8 Hz) : 2H), 7.20 to 7.30 (mt: 4H), 7.35 (d, J = 8 Hz: 2H), 7.68 (dd, J = 8 and 1.5 Hz: 1H); 7.71 (s: 1H); 8.02 (q, J = 4.5 Hz):

H); 8.32 (d, J = 8 Hz: 1H).

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Préparation du diastéréoisomére A de 8N-[I(S)-méthylcarbamoyl-2-(4chlorophénvnéthvH-4-U-[4-(l,3-thiazol-5-vl)benzvll-lH-imidazol-5ylméthvlamino)-chroman-8-carboxamide 0,150 g (0,57 mmole) de 1-(4-bromo-benzyl)-1H-imidazol-5-yl- carboxaldéhyde, 0,08 g (0,84 mmole) d'acétate de potassium, 0,2 ml (2,83 mmoles) de 1,3-thiazole et 0,03 g (0,028 mmole) de tétrakis(triphénylphosphine) palladium en solution dans le N, N diméthylacétamide sont traités selon le procédé décrit par G. Bold et al., J Med. Chem, (1998), 41, 3387-3401. On obtient après purification par chromatographie-flash sur colonne de silice en éluant avec du dichlorométhane,

0,15 g (100 %) de l-[4-(l,3-thiazol-5-yl)-benzyl]-lH-imidazol-5-yl-carboxaldéhyde sous forme d'une huile jaune. Example 8

Preparation of 8N- [I (S) -methylcarbamoyl-2- (4chlorophenyl) -NH-4-U- [4- (1,3-thiazol-5-yl) benzyl] -1H-imidazol-5-ylmethylamino] -chroman-8 diastereoisomer A -carboxamide 0.150 g (0.57 mmol) of 1- (4-bromo-benzyl) -1H-imidazol-5-ylcarboxaldehyde, 0.08 g (0.84 mmol) of potassium acetate, 0.2 ml (2.83 mmol) of 1,3-thiazole and 0.03 g (0.028 mmol) of tetrakis (triphenylphosphine) palladium dissolved in N, N-dimethylacetamide are treated according to the method described by G. Bold et al., J Med. Chem, (1998), 41, 3387-3401. After purification by flash column chromatography on silica eluting with dichloromethane,

0.15 g (100%) of 1- [4- (1,3-thiazol-5-yl) benzyl] -1H-imidazol-5-ylcarboxaldehyde as a yellow oil.

Spectrum of R.M.N. H (300 MHz, (CD3) 2SO d6, d in ppm): 5.56 (s: 2H); 7.27 (d, J = 8.5 Hz: 7.67 (d, J = 8.5 Hz: 2H), 7.96 (d, J = 1 Hz: 1H), 8.29 (s: 2H) 9.08 (bs: 1H) 9.53 (d, J = 1 Hz: 1H).

carboxamide, de 0,22 g (0,8 mmole) de 1-[4-(1,3-thiazol-5-yl)benzyll-IH-imidazol-5- yl-carboxaldéhyde, de 0,4 ml d'acide acétique et de 0,069 g (1,1 mmole) de cyanoborohydrure de sodium. On obtient 0,21g (44 %) du diastéréoisomére A de 8N-

[ 1 (S)-méthylcarbamoyl-2-(4-chlorophényl)éthyl]-4- {1-[ 4-(1 ,3-thiazol-5-yl)benzyl]- 1H-imidazol-5-ylméthylamino}-chroman-8-carboxamide sous forme d'une meringue blanche dont les caractéristiques sont les suivantes : Pouvoir rotatoire : [alpha]D20 = + 33,5 0,9 (CH30H, c = 0,5) Spectre de R.M.N. 'H (300 MHz, (CD3)2SO d6, # en ppm) : de 1,85 à 2,00 (mt : 2H); 2,61 (d, J = 4,5 Hz : 3H) ; 2,96 (dd, J = 14 et 8 Hz : 1H) ; 3,07 (dd, J = 14 et 5 Hz : 1 H) ; 3,58 (d, J = 14 Hz : 1 H) ; 3,69 (mt : 1H) ; 3,72 (d, J = 14 Hz : 1 H) ; de 4,20 à 4,40 (mt : 2H) ; 4,67 (mt : 1H) ; 5,35(s large : 2H) ; 6,83 (t, J = 7,5 Hz : 1H) ; 6,90 (s large : 1H) ; 7,14 (d, J = 8 Hz : de 7,20 à 7,30 (mt : 3H) ; (d, J = 8 Hz : The procedure is as in Example 1, but starting from 0.29 g (0.75 mmol) of 8N- [1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4-amino-chroman. -8-

carboxamide, 0.22 g (0.8 mmol) of 1- [4- (1,3-thiazol-5-yl) benzyl] -IH-imidazol-5-yl-carboxaldehyde, 0.4 ml of acid acetic acid and 0.069 g (1.1 mmol) of sodium cyanoborohydride. 0.21 g (44%) of the 8N-diastereoisomeric A is obtained.

[1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4- {1- [4- (1,3-thiazol-5-yl) benzyl] -1H-imidazol-5-ylmethylamino} -chroman 8-carboxamide in the form of a white meringue having the following characteristics: Rotatory power: [alpha] D20 = + 33.5 0.9 (CH30H, c = 0.5) 1 H NMR spectrum (300 MHz (CD3) 2SO d6, # in ppm): 1.85 to 2.00 (mt: 2H); 2.61 (d, J = 4.5 Hz: 3H); 2.96 (dd, J = 14 and 8 Hz: 1H); 3.07 (dd, J = 14 and 5 Hz: 1H); 3.58 (d, J = 14 Hz: 1H); 3.69 (mt: 1H); 3.72 (d, J = 14 Hz: 1H); from 4.20 to 4.40 (mt: 2H); 4.67 (mt: 1H); 5.35 (brs: 2H); 6.83 (t, J = 7.5 Hz: 1H); 6.90 (brs: 1H); 7.14 (d, J = 8 Hz: from 7.20 to 7.30 (mt: 3H)) (d, J = 8 Hz:

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 2H); 7.62 (d, J = 8 Hz: 2H); 7.65 (dd, J = 7.5 and 1.5 Hz: 1H); 7.77 (d, J = 1 Hz: 1H); 7.99 (q, J = 4.5 Hz: 1H); 8.28 (s: 1H); 8.30 (d, J = 7.5 Hz: 1H); 9.08 (s: 1H).

Préparation du diastéréoisomére A de 8N-Fl(S)-méthylcarbamoyl-2-(4chloronhényl)éthyll-4-(1-f4-(2-carbamoylvinyl)benzyll-1H-imidazol-5vlméthvIaminol-chroman-8-carboxamide
A 50g (0,267 mole) d'alcool 4-bromobenzylique, 0,6g (0,0027 mole) d'acétate de palladium, 3,25g de tri-o-tolyl phosphine (0,0107 mole) dans 159 cm3 de tributylamine (0,669 mole) dans un autoclave, on ajoute 22,5 cm3(0,331 mole) d'acide acrylique et le mélange réactionnel est porté à 100 C pendant 12 heures. Le mélange est alors refroidi, puis traité avec par une solution aqueuse de carbonate de sodium et filtré sur célite. Le filtrat est acidifié et le précipité obtenu filtré, lavé à l'eau puis séché pour conduire à 42,15 g (89 %) d'acide 4-hydroxyméthyl-cinnamique sous forme d'un solide crème. Example 9

Preparation of 8N-Fl (S) -methylcarbamoyl-2- (4-chloronhenyl) ethyl-4- (1-4- (2-carbamoylvinyl) benzyl] -1H-imidazol-5-ylmethylaminol-chroman-8-carboxamide diastereoisomer A
To 50 g (0.267 moles) of 4-bromobenzyl alcohol, 0.6 g (0.0027 moles) of palladium acetate, 3.25 g of tri-o-tolyl phosphine (0.0107 moles) in 159 cc of tributylamine ( 0.669 moles) in an autoclave was added 22.5 cm3 (0.331 moles) of acrylic acid and the reaction mixture was heated 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 mol) of 4-hydroxymethyl-cinnamic acid in 30 ml of dichloromethane, 4.9 ml (0.067 mol) of thionyl chloride are added and the mixture is stirred at room temperature for 3 hours. hours. After dilution with an additional 400 ml of dichloromethane, ammonia is dissolved in the reaction medium (15 min) and the reaction is continued overnight at room temperature.

The reaction mixture is washed with water (3 × 300 ml) and then with 0.1 N hydrochloric acid (2 × 100 ml), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure. 4.95 g (79%) of 4- (2-carboxamidovinyl) benzyl chloride are thus obtained in the form of a cream solid.

 The procedure is as in Example 4 for the preparation of 1- (4-bromo-benzyl) -1H-imidazol-5-yl-carboxaldehyde, but starting with 3.7 g (0.0383 mol) of imidazol-4 -yl-carboxaldehyde and 7.5 g (0.0383 moles) of 4- (2-carboxamidovinyl) benzyl chloride in 250 cm3 of acetonitrile and 10.6 g (0.0767 moles) of potassium carbonate. After purification by high-performance liquid chromatography

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vinyl)benzyl]-1H-imidazol-5-yl-carboxaldéhyde sous forme de solide jaune pâle. performance (Si phase 60), 1.4 g (29%) of 1- [4- (2-carboxamido)

vinyl) benzyl] -1H-imidazol-5-yl-carboxaldehyde as a pale yellow solid.

[l(S)-méthylcarbamoyl-2-(4-chlorophényl)éthyl]-4-{l-[4-(2-carbamoylvinyl)benzyl]- 1H-imidazol-5-ylméthylamino}-chroman-8-carboxamide sous forme d'une meringue blanche dont les caractéristiques sont les suivantes :
Pouvoir rotatoire : [alpha]D20 = + 32,1 0,9 (CH30H, c = 0,5) Spectre de R.M.N. 'H (300 MHz, (CD3)2SO d6,# en ppm) : 1,85 à 2,00 (mt : 2H);
2,61 (d, J = 4,5 Hz : 3H) ; 2,97 (dd, J = 14 et 8 Hz : 1H) ; 3,07 (dd, J = 14 et 5 Hz :
1H) ; 3,58 (d, J = 14 Hz : 1H) ; de 3,65 à 3,75 (mt : 2H) ; de 4,20 à 4,40 (mt : 2H) ;
4,67 (mt : 1H) ; 5,34 (s large : 2H) ; 6,58 (d, J = 16 Hz : 1H) ; 6,86 (t, J = 7,5 Hz :
1H) ; 6,89 (s large : 1H) ; de 7,05 à 7,15 (mt : 1H) ; 7,10 (d, J = 8 Hz : 2H) ; de 7,20 à
7,25 (mt : 1H) ; 7,24 (d, J = 8 Hz : 2H) ; 7,34 (d, J = 8 Hz : 2H) ; 7,39 (d, J = 16 Hz :
1H) ; de 7,45 à 7,55 (mt : 1H) ; 7,50 (d, J = 8 Hz : 2H) ; 7,67 (dd, J = 7,5 et 1,5 Hz :
1H) ; 7,75 (d, J = 1 Hz : 1H) ; 7,99 (q, J = 4,5 Hz : 1H) ; 8,30 (d, J = 7,5 Hz : 1H). The procedure is as in Example 1, but starting from 0.47 g (1.2 mmol) of 8N- [1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4-amino-chroman. Carboxamide, 0.33 g (1.3 mmol) of 1- [4- (2-carbamoylvinyl) benzyl] -1H-imidazol-5-ylcarboxaldehyde, 0.7 ml of acetic acid and 0.12 g (1.8 mmol) of sodium cyanoborohydride. 0.25 g (31%) of the 8N-diastereoisomeric A is obtained.

[(1S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4- {1- [4- (2-carbamoylvinyl) benzyl] -1H-imidazol-5-ylmethylamino} -chroman-8-carboxamide in form a white meringue whose characteristics are as follows:
Rotation: [alpha] D20 = + 32.1 0.9 (CH30H, c = 0.5) 1H NMR Spectrum (300 MHz, (CD3) 2SO d6, # in ppm): 1.85 to 2, 00 (mt: 2H);
2.61 (d, J = 4.5 Hz: 3H); 2.97 (dd, J = 14 and 8 Hz: 1H); 3.07 (dd, J = 14 and 5 Hz:
1H); 3.58 (d, J = 14 Hz: 1H); from 3.65 to 3.75 (mt: 2H); from 4.20 to 4.40 (mt: 2H);
4.67 (mt: 1H); 5.34 (brs: 2H); 6.58 (d, J = 16Hz: 1H); 6.86 (t, J = 7.5 Hz:
1H); 6.89 (brs: 1H); from 7.05 to 7.15 (mt: 1H); 7.10 (d, J = 8 Hz: 2H); from 7.20 to
7.25 (mt: 1H); 7.24 (d, J = 8 Hz: 2H); 7.34 (d, J = 8 Hz: 2H); 7.39 (d, J = 16 Hz:
1H); from 7.45 to 7.55 (mt: 1H); 7.50 (d, J = 8 Hz: 2H); 7.67 (dd, J = 7.5 and 1.5 Hz:
1H); 7.75 (d, J = 1 Hz: 1H); 7.99 (q, J = 4.5 Hz: 1H); 8.30 (d, J = 7.5 Hz: 1H).

EXAMPLE 10A Evaluation of the famesyl transferase activity of compounds according to the invention
The farnesyl transferase activity is measured by the farnesylated amount of K-ras substrate or substrate derived from the peptide corresponding to its C-terminal portion, the famesyl group being provided by farnesyl pyrophosphate (FPP).

 Specifically, the biotinylated substrate used, representative of K-ras: BIOT- (ssA) 3 -SKDG- (K) 6 -SKTKCVIM, is [3H] famesylated on its cysteine C, by farnesyl transferase in the presence of [3H] FPP . It is then brought into contact with PVT * -streptavidin beads (AMERSHAM), and is quantified by proximity scintillation.

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 (SPA assay) between tritium and PVT beads, thanks to the streptavidin / biotin interaction.

 Experimentally, the farnesyl transferase purified according to the protocol attached, is diluted for this assay at a concentration such that a substrate consumption of less than 30% is obtained. The final molar concentrations of each substrate are adjusted to their respective Km: 50 nM for the biotinylated K ras peptide and 120 nM for the FPP, brought to 20 l in a final volume of 100 l of the reaction mixture based on 50 mM HEPES buffer pH 7.5, 5 mM MgCl 2, 40 mM KCl, 5 mM dithiothreitol, Triton XI 00 0.01%.

Inhibitors to be tested, initially dissolved at 1 mM in a suitable solvent (DMF or DMSO), are diluted in the assay buffer and added in the form of
10 l, in triplicate, in 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. It is stopped by adding 150 μl of a mixture of a pH 4 stop buffer consisting of H 3 PO 4. , 2 M, 1.5 mM MgCl 2, 0.5% (w / v) BSA, 0.05% (w / v) sodium azide containing 200 μg PVT-streptavidin beads.

 After stirring slowly for thirty minutes (to remove chemiluminescence), the plates are read in [3H] CPM in a TOP COUNT microplate scintillation counter (PACKARD) where they are transformed into [3H] DPM from a range. of quenching agent.

 The inhibition percentages are calculated relative to a control without inhibitor after subtraction of all the values of that of a blank containing only the substrates and the buffer.

 IC50's are calculated or measured from the inhibitions obtained at nine different concentrations with Enzfitter or Grafit software. The products according to the invention have IC50 values of between 0.1 nM and 100 M.

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EXAMPLE 10B
The activity of the compounds according to the invention can also be evaluated by the ability of said compounds to inhibit agar growth of clones derived from human tumor lines. For example, cells of the human colon carcinoma line HCTI 16, provided by the ATCC, are grown in a monolayer in a culture medium, Dubelcco modified Eagle, containing 2 mM L-glutamine, 200 U / ml penicillin 200 μg / ml of streptomycin supplemented with 10% by volume heat-inactivated fetal calf serum. Exponentially growing cells 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 cell suspension, prepared previously, then 0.4 ml of agar solution, Noble, is added. Difco, kept at 45 C then mixed. The medium thus obtained is immediately discarded in Petri dishes, held 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 duplicate at final agar concentrations of 10.1, 0.1 0.01 and 0.001 μg / ml. The results are expressed as percentage inhibition of clonogenicity compared to untreated controls. The IC50 inhibitory doses are determined graphically from the semi-logarithmic averages of the values obtained for each concentration.

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

EXAMPLE 11
EXAMPLE 11 To the usual procedure, capsules are prepared at 50 mg of active product having the following composition: active ingredient .................... .................................................. 50 mg - Cellulose .............................................. ................................. 18 mg

<Desc / Clms Page number 42>

- Eau..........................................................................q.s.p. 4 ml- Lactose ................................................ .................................. 55 mg - Colloidal Silica ........... .................................................. ......... 1 mg - Sodium carboxymethyl starch .................................... ......... 10 mg - Talc ..................................... .................................................. 10 mg - magnesium stearate ............................................ ............ 1 mg
EXAMPLE 11B 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 - Hydroxymethylcellulose mixture, glycerin, titanium oxide (72-3,5-24,5) qsp1 film-coated tablet completed mg 245
EXAMPLE 11C An injectable solution containing 50 mg of active product having the following composition is prepared: active ingredient ............................. ........................................... 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 ................................................ .......................... qs 4 ml

Claims (25)

1 - Compounds of general formula (I): in which: R 9 represents an atom or radical selected from halogen atoms and / or radicals - alkyl, cycloalkyl, alkoxy, cyano, nitro, polyfluoroalkyl, such as trifluoroalkyl, polyfluoroalkoxy; , such as trifluoroalkoxy, or difluoroalkoxy, polyfluoroalkylthio, such as trifluoroalkylthio, aralkyl, aryloxy, aryl, or heteroaryl, optionally substituted with one or more atoms or radicals selected from halogen atoms or alkoxy, alkyl radicals; a radical -ERi1-CO-R12, for which R1 represents an alkylene or alkylene radical; R12 represents a hydroxy, alkoxy, amino radical; R2 represents a hydrogen atom, an alkyl, alkylcarbonyl radical; R3 represents a hydrogen atom or a halogen atom; R4 represents a radical - (CH2) -Ri4 and R4 represents an aryl radical, optionally substituted by one or more atoms or radicals chosen from halogen atoms, alkyl, hydroxy and nitro radicals, amino, alkoxy, polyfluoroalkoxy, aralkoxy, aminosulfonyl, -Z-OR, -Z-CO-OR, -Z-CONRR ', R, R' independently represent a hydrogen atom or an alkyl radical, Z represents an alkylene radical; R7, R8 independently represent a hydrogen atom or an alkyl radical; in racemic form or their stereoisomers as well as their salts. 2 - Compounds according to claim 1, for which: R 9 represents an atom or radical chosen from halogen atoms and / or alkyl, polyfluoroalkoxy, polyfluoroalkyl or polyfluoroalkylthio radicals; phenyl, optionally substituted with one or more halogen atoms; pyridyl, thiazolyl, thienyl, isoxazolyl,

 - a radical -Ri, -CO-Ri2, for which: Ri1 represents an alkylene radical, alkenylene; R12 represents an alkoxy, amino, hydroxy radical; R2 represents a hydrogen atom; R3 represents a hydrogen atom; R4 represents a radical - (CH2) -R14 Ri4 represents a phenyl radical, optionally substituted by one or more atoms or radicals chosen from halogen atoms, alkoxy, polyfluoroalkoxy and aralkoxy radicals; R7, R8 represent a hydrogen atom; in racemic form or their stereoisomers as well as their salts. <Desc / Clms Page number 45>  3 - Compounds according to any one of the preceding claims selected individually from: 8N- [1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-methylbenzyl) -1H-imidazole -5-ylmethylamino] -chroman-8-carboxamide

 8 N- [1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-phenylbenzyl) -1 Himidazol-5-ylmethylamino] -chroman-8-carboxamide 8N- [1 (S ) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-chlorobenzyl) -1H-imidazol-5-ylmethylamino] -chroman-8-carboxamide 8N- [1 (S) -methylcarbamoyl); 2- (4-Chlorophenyl) ethyl] -4- [1- (4-bromobenzyl) -1H-imidazol-5-ylmethylamino] -chroman-8-carboxamide

 8 N- [1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4- [4- (3-pyridyl) benzyl] H- imidazol-5-ylmethylamino} -chroman-8-carboxamide 8N [1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4- {1- [4- (4-fluorophenyl) benzyl] -H-imidazol-5-ylmethylamino} -chroman-8-carboxamide 8N [1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4- {1- [4- (2-carbamoylethyl) benzyl] -H-imidazol-5-ylmethylamino} -chroman-8-carboxamide 8N [1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4- {1- [4- (1,3-thiazol-5-yl) benzyl] -1H-imidazol-5-ylmethylamino 8N- [1 (S) -methylcarbamoyl-2- (4-chlorophenyl) ethyl] -4- {1- [4- (2- (4-chlorobenzoyl)] -chroman-8-carboxamide

 carbamoylvinyl) benzyl] -1H-imidazol-5-ylmethylamino} -chroman-8-carboxamide or their stereoisomers, or in racemic form, and their salts. 4 - Process for the preparation of the compounds of general formula (I) according to any one of the preceding claims, wherein R2, R3, R4, R7, R8 and R9 are as defined in claim 1, characterized in that: from the product of general formula (IIa) <Desc / Clms Page number 46>

 in which R3, R4, R7, R8 are as defined in claim 1 and G, represents a hydrogen atom, by action of a reagent of general formula

 wherein R9 is defined as in claim 1 operating under reductive amination conditions. 5 - Preparation process according to claim 4 compounds of general formula (I) according to any one of claims 1 to 3 wherein R9, R3, R4, R7, Rg are as defined in claim 1 and R2 represents a radical alkylcarbonyl, characterized in that one proceeds from the corresponding compounds of general formula (I) wherein R2 represents a hydrogen atom, by action of the corresponding acid of formula R20H, wherein R2 represents an alkylcarbonyl radical, or of an activated form of this acid. 6 - Preparation process according to claim 4 compounds of general formula (I) according to any one of claims 1 to 3, wherein R3, R4, R7, R8 are as defined in general formula (I) and R2 represents an alkyl radical characterized <Desc / Clms Page number 47>  in that one proceeds from the corresponding compounds of general formula (I) in which R2 represents a hydrogen atom, by action of the corresponding aldehyde. 7 - Compounds of general formula (IIa)

 wherein R3, R4, R7, R8 are as defined in claim 1 and G1 represents a hydrogen atom, or a protecting group of the amino function. 8 - Process for the preparation of the compounds of general formula (IIa) according to claim 7 wherein R3, R4, R7, Rg are as defined in claim 1 and G1 represents a hydrogen atom characterized in that the compounds of general formula (IIb)

 wherein R3, R4, R7, R8 are as defined in claim 1, G1 represents a protecting group of an amino function. <Desc / Clms Page number 48>  9 - Process according to claim 8 characterized in that the compounds of general formula (IIb) wherein R3, R4, R7, Rg, G, are defined as in claim 8 are obtained from compounds of general formula (IV)

 in which R3, R7, Rs and G, are defined as above, by action of a corresponding compound of general formula (V)

 wherein R4 is defined as above, operating according to amidation methods. 10 - Process according to claim 8 characterized in that the compounds of general formula (IIb) wherein R3, R4, R7, Rg, G, are defined as in claim 8 are obtained from the compounds of general formula (IV)

 in which R3, R7, R8 and G1 are defined as above, by the action of a compound of general formula (VI)

 in which R4 is defined as above, and Alk represents an alkyl radical, <Desc / Clms Page number 49>  under amidification conditions, then followed by the action of methylamine, or is followed, after hydrolysis of the radical -COOAlk carboxy radical, the action of methylamine. 11 - Process according to claims 9 or 10 characterized in that the compounds of general formula (IV) are obtained from the compounds of general formula (VII):

 in which R 3, R 7, R 5 are defined as above, G 1 represents a protecting group of the amino function, as defined by claim 8, by action of a base, followed by carboxylation, the compounds of general formula (VII ) being obtained from the compounds of general formula (VIII):

 wherein R3, R7, R8, 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. 12 - Process according to claim 11characteriser in that the base is an alkali metal salt. 13 - Process for the preparation of the compounds of general formula (I) as defined according to any one of claims 1 to 3 wherein R2, R3, R4, R7, R8, R9 are defined as in claim 1 characterized in that proceeds from the product of general formula (IX) <Desc / Clms Page number 50>

 in which R2, R3, R7, R8, R9 are defined as above, by the action of a compound of general formula (V)

 in which R4 is defined as above, by operating according to the amidation methods, the acids of general formula (IX) in which R2, R3, R7, R8, R9 are defined as previously being obtained from the corresponding esters of general formula (X):

 in which R2, R3, R7, R8, R9 are defined as above and Alk represents an alkyl radical, by saponification. <Desc / Clms Page number 51>  14 - Compounds of general formula (IX):

 wherein R2, R3, R7, R8, R9 are defined as in claim 1. 15 - Process for the preparation of the compounds of general formula (X) according to claim 13 wherein R2, R3, R7, R8, R9, Alk are defined as in claim 13 characterized in that one proceeds from compounds of general formula ( XI):

 in which R2, R3, R7, R8, Alk are defined as in claim 13, by the action of a reagent of general formula

<Desc / Clms Page number 52>  for which R9 is defined as above, operating under amination conditions. 16 - Preparation process according to claim 15, characterized in that the esters of general formula (XI) are obtained from the corresponding acids of general formula (IV):

 wherein R3, R7, R8 are defined as above, G is defined as in claim 8 by esterification of the carboxylic acid and deprotection of the amino group.  17 - Process according to claim 8 wherein G, represents a protective group of an amino function selected from benzyloxycarbonyl radicals, tert. butoxycarbonyl or vinyloxycarbonyl 18 - Process according to claims 9, 10, 13 characterized in that the amidification reaction is carried out in the presence of a condensing agent and optionally in the presence of an activating agent. 19 - Process according to claim 18 characterized in that the condensing agent is chosen from 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride, 1,1-dicyclohexylcarbodiimide or benzotriazol hexafluorophosphate -1-oxy-tris (dimethylamino) phosphonium. 20 - Process according to claim 18, characterized in that the activating agent is chosen from hydroxybenzotriazole. <Desc / Clms Page number 53> 21 - Process according to claims 4 and 15 characterized in that the reductive amination reaction is carried out by operating in an organic solvent in the presence of acid and then by action of a reducing compound.  22. The process as claimed in claim 21, 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. 23 - Pharmaceutical composition containing at least one compound of the claims 1 to 3 in combination with one or more pharmaceutically acceptable diluents or adjuvants whether inert or biologically active. 24 - 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 related to cellular signaling pathways, associated with farnesyl transferase, or their consequences or symptoms. Use of the compounds of claims 1 to 3 for the preparation of pharmaceutical compositions useful for inhibiting farnesyl transferase. 26 - Use of the compounds of claims 1 to 3 for the preparation of pharmaceutical compositions useful for the treatment of diseases related to cell proliferations. 27 - Use of the compounds of claims 1 to 3 for the preparation of pharmaceutical compositions useful for the treatment of cancers. 28 - Association of a compound of claims 1 to 3 with one or more compatible and pharmacologically active compounds and / or radiotherapeutic treatment.