FR2766819A1 - NOVEL SULFONAMIDE DERIVATIVES OF SUBSTITUTED ANILINES USEFUL AS MEDICAMENTS - Google Patents

Abstract

The invention concerns a novel class of inhibitors of protein prenylation, in particular inhibitors of PFTase and GGTase, corresponding to the formula (I). The invention also concerns the method for preparing said compounds and pharmaceutical compositions containing them and their use as medicines, in particular for treating or preventing cancers, restenosis and atherosclerosis.

Description

 The present invention relates to novel sulfonamides derived from substituted anilines, to a process for their manufacture, to pharmaceutical compositions containing them and to their use as medicaments.

Ras oncogenes are the most common oncogenes found in human tumors and are thought to play an important role in the proliferation of these tumors. In particular, mutated Ras oncogenes have been shown to be present in 50% of colon tumors and in more than 90% of pancreatic cancers (Barbacid, M. Ann Rev Biochem 1987, 56: 779-827; Bos, JL Cancer, Res 1989 49: 46824689). The transformed Ras proteins that are products of these oncogenes are therefore involved in the proliferation and differentiation processes of cancer cells. Consequently, blocking the function of the Ras proteins must result in the inhibition of the growth of tumor cells that depend on the activation of Ras or that express mutated Ras proteins (Perrin, D., Halazy, S. and Hill, BTJ Enzyme
Inhi. 1996; 11: 77-95. Levy, R. Press Med. 1995; 24: 725-729. Sebolt-Leopold, J., S.

Emerging Drugs 1996; 1: 219-239. Hamilton, AD and Sebti, SM Drug News
Perspect. 1995; 8: 138-145; Der, CJ; Cox, AD, Sebti, SM and Hamilton, AD

Anti-Cancer Drugs 1996; 7: 165-172 and Halazy, S. et al. Drugs of the Future, in press).

 Ras proteins, to be active, must be associated with the cell membrane. This process, which depends on post-transcriptional modifications of the Ras gene product, notably involves the addition of a farnesyl group to a cysteine residue of the C-terminal tetrapeptide of the Ras protein.

 The farnesylation of Ras proteins in which farnesylpyrophosphate acts as a co-substrate, is catalyzed by the Protein-Farnesyl-Transferase enzyme (PFTase). Inhibition of PFTase and thus farnesylation of the Ras protein makes it possible to control the proliferation of Ras-mutated cancer cells. This has been demonstrated using PFTase inhibitors such as BZA-SB (James, GL, Goldstein, JL, Brown, MS et al., Science 1993, 260 [5116]: 1937-1942) or the L derivative. -731.734 (Kohl, NE

Mosser, S.D., DeSolms, S.J. et al Science 1993; 260 [5116]: 1934-1937) at the level of cell proliferation but also, more recently, at the level of grafted tumors in mice (Kohl, NE, Wilson, FR and Mosser, SD et al., Proc Natl Acad. Sci.

USA 1994; 91: 9141-9145. Kohl, N.E .; Omer, C.A., Conner, M.W. et al. Nature Med.

1995; 1: 792-797). The farnesylation of proteins catalyzed by the enzyme PFTase is not limited to Ras proteins and plays an important role in the function of other proteins, also involved in cell proliferation, such as for example the Rho B protein or protein tyrosine phosphatase PTPcaax (CA Cates and
Coll., Cancer. Lett. 1997 ; 110: 49-55). Consequently, the PFTase inhibitors find their utility as anti-cancer agents, capable of controlling cell proliferation in tumors in which the farnesylation of proteins plays a determining role.

 Moreover, it has also been demonstrated that the inhibition of geranylgeranylation of certain Ras proteins which is catalyzed by the enzyme geranylgeranyltransferase I could also result in the control of the function of the Ras proteins and, consequently, in the control of their influence on differentiation and cell proliferation (Lerner, EC, Hamilton, AD and Sebti, SM Anti-Cancer Drug Design 1997, 12: 229-238, Lerner, EC, Qian, Y., Hamilton, AD and Sebti, SMJ Biol. Chem., 1995 270: 26770-26773, Yokoyama, K., Zimmerman, K., Scholten, J. and Gelb, MHJ.

Biol. Chem. 1997, 272: 3944-3952, Osman, H., Mazet, J.L. Maume, G. and Maume, B.F. Biophys. Res. Common. 1997, 231: 789-792, Zhang, F.L., Kirschmeier, P.

Carr, D. et al. J. Biol. Chem. 1997, 272-10232-10239). Accordingly, compounds capable of inhibiting geranylgeranyltransferase are also used to control cell proliferation and hence as anticancer agents.

 The control of prenylation (farnesylation and / or geranylgeranylation) of Ras proteins by inhibitors of PFTase or GGTase I is also useful in the treatment of viral infections such as hepatitis delta infections (JC Otto et al. PJ Casey, J. Biol Chem 1996, 271: 4569-4572). On the other hand, the role played by Ras in the process of smooth muscle cell proliferation following vascular injury (Indolfi et al., Nature Med., 1995; 1 (6): 541545) suggests that prenylation inhibitors Ras are potentially useful for the treatment or prevention of atherosclerosis and restenosis.

 The subject of the present invention is a new class of protein prenylation inhibitors, and more particularly inhibitors of PFTase and GGTase, which are distinguished from all the derivatives closest to the prior art by their different chemical structure. whose originality is essentially due to the presence of a suitably substituted sulphonamide function which, unexpectedly, confers on these molecules remarkable biological properties, such as, for example, the potential to inhibit the prenylation of proteins, such as Ras proteins, at the enzymatic level but also at the cellular level.

 The present invention relates to sulfonamides derived from substituted anilines which unambiguously distinguish prenylation inhibitors of the proteins of the prior art by their original chemical structure and by their biological profile.

 The prior state of the art in this field is illustrated in particular by: the FTI-276, FTI-277 derivatives described as PFTase inhibitors (J. Biol Chem.

 1995; 270: 26802-26806); . derivatives GGTI-286, GGTI-287 described as inhibitors of GGTase (J. Biol.

Chem. 1995; 270: 26770-26773); Patent application WO 96/30015 which describes peptidomimetic derivatives of the type
aminoalkylbenzamide or aminobenzamide as inhibitors of PFTase; . the patent application WO 96/34851 which describes derivatives of benzene, pyridine,
naphthalene or benzophenone as inhibitors of squalene synthase and PFTase,. the patent application WO 97/17070 which describes benzamides as inhibitors of
isoprenyl protein and protein farnesyl transferase.

dans laquelle
X représente (CH2)n, CO, (CH2)nCO, CO(CH2)n, où n représente un nombre entier compris entre 1 et 5,
R1 représente un reste choisi parmi

dans lesquels, Z représente CH ou N;
Y représente O, S ou NRs;
R6 représente un hydrogène, R'6 ou S02R'6;
R7, R8 et R'8, identiques ou différents, représentent un hydrogène, un reste alkyle linéaire ou ramifié comprenant de 1 à 6 atomes de carbone, un reste phényle, thiényle, benzyle ou phénéthyle dans lesquels le noyau aromatique peut éventuellement être substitué par un reste alkyle linéaire ou ramifié comprenant de 1 à 6 atomes de carbone ou encore par Cl,
Br, F, CF3, OCH3, CN, NO2; R'6 représente un reste alkyle linéaire ou ramifié comprenant de 1 à 6 atomes de carbone, un reste phényle, thiényle, benzyle ou phénéthyle dans lesquels le noyau aromatique peut éventuellement être substitué par un reste alkyle linéaire ou ramifié comprenant de 1 à 6 atomes de carbone ou encore par Cl, Br, F, CF3, OCH3, CN, NO2;
R2 représente un reste alkyle linéaire ou ramifié, saturé ou insaturé, comprenant de 1 à 20 atomes de carbone, un reste aryle, alkylaryle, hétéroaryle ou alkylhétéroaryle, pouvant être diversement substitués par un ou plusieurs résidus choisis parmi R9, OH, OR9, SH,
SR9, NHR9Rlo, COR9, CONR9Rlo, COOR9, NHCOR9, CF3, NO2, CN, Cl, F, Br, OCF3 dans lesquels R9 et Rlo, identiques ou différents, représentent un reste alkyle comprenant de 1 à 5 atomes de carbone en chaîne droite ou ramifiée, un reste aryle ou hétéroaryle;
R3, pouvant être en l'une ou l'autre des positions libres du cycle aromatique auquel il est attaché, représente H, Cl, CF3, Br, I, F, SiMe ou un reste aryle ou hétéroaryle;
R4 représente CH2CH2SCH3, CH2CH2S(O)CH3, CH2CH2SO2CH3, (CH2)mNHCOCH3,
CH20H, CH2CH2OH, CH2CH(CH3)2, (CH2),CONH2, (CH2)mCONHCH3 (CH2)mCONMe2, CH2CH2CH2CH3, CH20CH3, CH2CH20CH3, CH2CH=CH2, CH2SH,
CH2SCH3, CH2SCH2C6H5, CH2CH2SC6H5, CH2CH2S(2-thiényl) et m représente un nombre entier compris entre 1 et 4; R5 représente un hydrogène ou une chaîne alkyle linéaire ou ramifiée comprenant de 1 à 6 atomes de carbone ou un benzyle; leurs sels, hydrates et solvates physiologiquement acceptables pour l'usage thérapeutique; dans les définitions qui précèdent, aryle représente un phényle, naphtyle, tétrahydronaphtyle, indanyle, et hétéroaryle représente un reste choisi parmi un furane, pyrrole, thiophène, thiazole, isothiazole, oxadiazole, imidazole, oxazole, isoxazole, pyridine, pyrimidine, quinazoline, quinoline, quinoxaline, tétrahydroquinoline, benzofurane, benzothiophène, indole, indoline, benzothiazole, benzopyranne, benzoxazole, benzoisoxazole, benzimidazole, chromane.The present invention relates to compounds of general formula (I)

in which
X represents (CH2) n, CO, (CH2) nCO, CO (CH2) n, where n represents an integer between 1 and 5,
R1 represents a residue selected from

wherein, Z is CH or N;
Y represents O, S or NRs;
R6 is hydrogen, R'6 or SO2R'6;
R7, R8 and R'8, which may be identical or different, represent a hydrogen, a linear or branched alkyl radical comprising from 1 to 6 carbon atoms, a phenyl, thienyl, benzyl or phenethyl radical in which the aromatic nucleus may optionally be substituted by a linear or branched alkyl residue comprising from 1 to 6 carbon atoms or else by Cl,
Br, F, CF3, OCH3, CN, NO2; R'6 represents a linear or branched alkyl radical containing from 1 to 6 carbon atoms, a phenyl, thienyl, benzyl or phenethyl radical in which the aromatic nucleus may optionally be substituted by a linear or branched alkyl radical containing from 1 to 6 atoms carbon, or Cl, Br, F, CF3, OCH3, CN, NO2;
R2 represents a linear or branched, saturated or unsaturated alkyl residue comprising from 1 to 20 carbon atoms, an aryl, alkylaryl, heteroaryl or alkylheteroaryl residue, which may be variously substituted by one or more residues chosen from R9, OH, OR9, SH; ,
SR9, NHR9R1lo, COR9, CONR9R1lo, COOR9, NHCOR9, CF3, NO2, CN, Cl, F, Br, OCF3 in which R9 and Rlo, which may be identical or different, represent a straight chain alkyl radical of 1 to 5 carbon atoms or branched, an aryl or heteroaryl residue;
R3, which may be at any of the free positions of the aromatic ring to which it is attached, represents H, Cl, CF3, Br, I, F, SiMe or an aryl or heteroaryl residue;
R4 is CH2CH2SCH3, CH2CH2S (O) CH3, CH2CH2SO2CH3, (CH2) mNHCOCH3,
CH20H, CH2CH2OH, CH2CH (CH3) 2, (CH2), CONH2, (CH2) mCONHCH3 (CH2) mCONMe2, CH2CH2CH2CH3, CH2OCH3, CH2CH2OCH3, CH2CH = CH2, CH2SH,
CH2SCH3, CH2SCH2C6H5, CH2CH2SC6H5, CH2CH2S (2-thienyl) and m represents an integer from 1 to 4; R5 represents a hydrogen or a linear or branched alkyl chain comprising from 1 to 6 carbon atoms or a benzyl; their physiologically acceptable salts, hydrates and solvates for therapeutic use; in the foregoing definitions, aryl represents phenyl, naphthyl, tetrahydronaphthyl, indanyl, and heteroaryl represents a radical selected from furan, pyrrole, thiophene, thiazole, isothiazole, oxadiazole, imidazole, oxazole, isoxazole, pyridine, pyrimidine, quinazoline, quinoline. , quinoxaline, tetrahydroquinoline, benzofuran, benzothiophene, indole, indoline, benzothiazole, benzopyran, benzoxazole, benzoisoxazole, benzimidazole, chroman.

 All stereoisomers including all optical isomers of the compounds of general formula (I) are also part of the present invention as well as their mixture in racemic form.

 In particular, the present invention comprises the derivatives of general formula (I) in which the asymmetric carbon atom carrying the substituent R4 is of (R) configuration.

 The present invention also includes the compounds of general formula (I) wherein the asymmetric carbon atom bearing the substituent R4 is of (S) configuration.

The present invention also includes racemic mixtures of compounds of general formula (I) wherein the carbon atom bearing the substituent
R4 is asymmetric.

 The terms (S) and (R) used herein are defined by IUPAC (Pure and Applied Chemistry, 45, 13-30, 1976).

 Among the derivatives of general formula (I) forming part of the present invention, a particularly preferred class of compounds corresponds to the compounds of general formula (I), in which R 3 represents a phenyl residue.

 Another class of compounds that are part of the present invention, which is also particularly preferred, corresponds to the compounds of general formula (I), in which R 1 represents a pyridyl or imidazolyl residue.

 A third class of compounds forming part of the present invention and more particularly preferred is compounds of general formula (I), wherein R4 is CH2CH2CH3, CH2CH2SCH3, CH2CH2SO2CH3, CH2CH2CONH2 or CH2CH2CON (CH3) 2.

A fourth class of compounds forming part of the present invention and more particularly preferred corresponds to the compounds of general formula (I), in which R 4 represents CH 2 CH (CH 3) 2 or (CH 2) 3 CH 3
A fifth class of compounds forming part of the present invention and more particularly preferred is compounds of general formula (I), wherein R5 is methyl or isopropyl.

 A sixth class of compounds forming part of the present invention and more particularly preferred corresponds to the compounds of general formula (I), in which R1 represents CH (NE6) CH2SH.

 Finally, a seventh class of compounds forming part of the present invention and more particularly preferred corresponds to the compounds of general formula (I), in which R 5 is a hydrogen.

dans laquelle R1, R2, X et R3 sont définis comme précédemment et L représente OH, Cl, imidazole, ou encore, le groupe C(=O)L représente la forme activée d'un acide carboxylique, qui est propice à la formation d'une amide après réaction avec une amine,
avec une amine ou le dérivé chlorhydraté d'une amine de formule générale (III)

dans laquelle R5 représente un reste alkyle ou benzyle et R4 est défini comme dans la formule générale (I).The present invention also relates to the process for the preparation of the derivatives of general formula (I) in which R1, R2, X, R3 and R4 are defined as above and R5 represents an alkyl or benzyl residue. This process is characterized in that an intermediate of general formula (II) is condensed

wherein R1, R2, X and R3 are defined as above and L represents OH, Cl, imidazole, or alternatively the group C (= O) L represents the activated form of a carboxylic acid, which is conducive to the formation of an amide after reaction with an amine,
with an amine or the hydrochloride derivative of an amine of the general formula (III)

in which R5 represents an alkyl or benzyl residue and R4 is defined as in the general formula (I).

 The condensation of the intermediate of general formula (II) with the amide of general formula (III) can be carried out by methods and techniques well known to those skilled in the art for preparing an amide from an amine and a carboxylic acid or a derivative of this carboxylic acid.

 Thus, a particularly preferred method for the preparation of compounds of general formula (I) in which R 1, R 2, X, R 3 and R 4 are defined as above and R 5 represents an alkyl or benzoyl radical, consists in condensing a carboxylic acid. of general formula (II) with an amine of general formula (III) using 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide (EDC) and 3-hydroxy-1,2,3-benzotriazin-4 (3H ) -one, in the presence of a tertiary amine such as diisopropylethylamine, in a polar aprotic anhydrous solvent such as dichloromethane, at a temperature of between -15 ° C. and 400 ° C., or, for example, using the benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate in the presence of a tertiary amine (N-methyl morpholine) in a polar solvent (DMF or DMSO) at a temperature between -10 and 350C. It is understood that the condensation of the intermediates (II) and (III) to prepare the compounds of general formula (I) will be under the appropriate conditions which, among other things, can implement the use of adequate protective groups at the functional groups of intermediates (II) or (III). When it is desired to prepare a compound of general formula (I) in which the asymmetric carbon substituted with R4 is of (R) configuration, the condensation of a carboxylic acid of general formula (II) will be carried out, according to the methods and techniques described above, with an asymmetric amine of general formula (III) configuration (R). It is understood that, in the same way, a compound of general formula (I) in which this same asymmetric carbon is of configuration (S) will be prepared by the same methods from an amino acid derivative of formula general (III) in which the asymmetric carbon is of (S) configuration.

dans laquelle R3 et R5 sont définis comme précédemment selon la méthode décrite dans le schéma suivant

The aromatic carboxylic acids of general formula (II) in which L represents OH and R1, R2, X and R3 are defined as in general formula (I) are prepared in 3 steps from the aniline derivatives of general formula (IV )

in which R3 and R5 are defined as above according to the method described in the following diagram

<tb><SEP> H <SEP> HI <SEP> 7R3
<tb><SEP> N <SEP> N <SEP> 1) 01S02R2
<tb>(1V><SEP> R1-XL '<SEP> x <SEP> Base <SEP> (Il)
<tb><SEP> or <SEP> or <SEP> 5
<tb><SEP> R1-XL <SEP> ll <SEP> 2) <SEP> LiOH
<tb><SEP> (V) <SEP> o
<Tb>
The intermediates of general formula (V), in which R 1, X, R 3 and R 5 are described as above, are obtained by condensation of a substituted aniline of general formula (IV) with an electrophile R 1 -X L 'in which R 1 and X are defined as before and L 'represents a leaving group such as for example Cl, Br, I,
OSO2CH3, OSO2CF3 or OTosyl. This reaction will be carried out in the presence of an organic or inorganic base such as for example NaH, tBuOK, Cs2CO3, a tertiary amine, in a polar anhydrous solvent such as THF, DMF, DMSO at a temperature between -20 and When X is CO or (CH 2) nCO, the synthesis of the intermediates of the general formula (V) by condensation of the aniline derivatives of the formula (IV) with R 1 -LH represents the formation of an amide by condensation of an amine with a carboxylic acid derivative, L being defined as above, the methods and techniques employed being similar to those previously described for this type of transformation.

 In the particular case of the intermediates of formula (II) in which X represents (CH 2) n a method for preparing intermediates of general formula (V) consists in carrying out a reductive amination with the aid of an aldehyde of formula R 1 (CH 2 n-CHO, wherein R1 is defieni as previously, an amine of general formula (IV) and a reducing agent such as NaBH4, NaBH3CN, NaBH (OAc) 3 in a polar anhydrous solvent such as THF, DMF, MeOH, at a given pH which can be controlled by the addition of an acid, such as acetic acid, at a temperature between -200 and 800C.

 Transformation of the intermediates of general formula (V) into sulfonamides of general formula (II) is carried out by methods and techniques well known to those skilled in the art for preparing a sulfonamide from an amine, such as, for example condensation of an amine with a sulfonyl chloride carried out in the presence of an organic or inorganic base, such as for example NaH, tBuOK, Cs2CO3, a tertiary amine, in a polar anhydrous solvent such as THF, DMF, DMSO, CH2Cl2 at a temperature between -20 and 800C.

The intermediates of general formula (II) may also be prepared from the aniline derivatives of general formula (IV) by an alternative method first implementing the sulfonylation of the amine according to the following scheme

<tb><SEP> H <SEP> R3
<tb><SEP> 1) <SEP> CISO2R2 <SEP> R2N <SEP> N
<tb><SEP> s
<tb> Base <SEP> Base <SEP> N1 <SEP> OR5 <SEP> 1) <SEP> X <SEP> R <SEP> (II)
<tb> o <SEP> O <SEP> o <SEP> 11 <SEP> 2) <SEP> LiOH
<tb><SEP> 1) <SEP> o
<Tb>
The intermediate sulphonamides of general formula (VI) are prepared by reaction of an aniline of general formula (IV) with a sulphonyl chloride of formula
R2SO2Cl wherein R2 is defined as above in the presence of a base such as a tertiary amine. The condensation of the intermediate sulphonamides (VI) thus formed with an electrophile of formula L'-X-R1 in which L 'represents a leaving group and X is defined as above allows the preparation of the intermediates of general formula (II), in the presence of an organic or inorganic base such as for example NaH, tBuOK, Cs2CO3.

It is understood that the two methods for preparing the carboxylic acids of general formula (II), whether via anilines (V) or sulfonamides (VI) will implement, as an ultimate step, the hydrolysis of the ester function of the derivatives thus formed, hydrolysis which will be carried out in an acid medium or in a basic medium, a particularly preferred method using the use of
LiOH in a polar anhydrous solvent such as THF, MeOH at a temperature between 0 C and 800C.

dans laquelle R3, Rq et R5 sont définis comme précédemment, avec successivement deux électrophiles qui sont L'-X-Rl, et ClSO2R2 dans lesquels X, R2 et R1 sont définis comme précédemment, et L' représente un groupe partant, comme Br,
Cl, I, OMes, OTos, OTf ou un précurseur d'un groupe partant nécessitant une activation lors de la condensation, par les méthodes et techniques décrites ci-dessus pour la préparation de l'intermédiaire (II) à partir de l'aniline de formule (IV). The compounds of general formula (I) may also be prepared by condensation of an intermediate of general formula (VII)

in which R3, Rq and R5 are defined as above, with successively two electrophiles which are L'-X-R1, and ClSO2R2 in which X, R2 and R1 are defined as above, and L 'represents a leaving group, such as Br,
Cl, I, OMes, OTos, OTf or a precursor of a leaving group requiring activation during condensation, by the methods and techniques described above for the preparation of the intermediate (II) from aniline of formula (IV).

The order of introduction of the electrophiles, the experimental conditions, the choice of the nature of the bases used and the nature of L 'will depend on the chemical structure of the intermediate (VII) but especially of the nature of X and will be determined Consequently. Thus, when X represents CH 2, a particularly preferred method consists first of all in condensing the aniline of general formula (VII) with an aldehyde of formula RICHE in which R 1 is defined as above, in the presence of an agent reducing agent, by techniques well known to those skilled in the art, under the name of reductive amination, and which implement a reducing agent such as
NaBH4, NaBH3CN or NaBH (OAc) 3 in a polar anhydrous solvent such as
THF, MeOH, EtOH at a temperature between -20 and 800C.

 This condensation will be followed by a sulphonylation using the reaction of the intermediate thus formed with a sulphonyl chloride of formula ClSO 2 R 2 in which R 2 is defined as above, in the presence of an organic or inorganic base such as for example NaH, tBuOK, Cs2CO3, a tertiary amine, in a polar anhydrous solvent such as THF, DMF, DMSO, CH2Cl2 at a temperature between -20 and 80 ° C.

dans laquelle R3 est défini comme précédemment.The intermediates of general formula (VII) are obtained in two stages from a derivative of general formula (VIII)

wherein R3 is defined as above.

The preparation of the intermediates of formula (VII) starting from the precursors of formula (VIII) implements in a first stage the condensation of this precursor with an amine of formula (III), according to the methods and techniques well known to man of the art for preparing an amide by condensation of a carboxylic acid with an amine and more particularly those which have been described previously for the preparation of the compounds of formula (I) from amines (III) and derivatives of formula (II) . This condensation will be followed by the reduction of the nitro function to amine which will be carried out using catalytic hydrogenation according to the methods and techniques well known to those skilled in the art to reduce an aromatic nitro to aniline. Another method which will preferably be used is reduction with tin salts, such as SnCl 2-2H 2 O, and ferric salts, such as Sel 3, in a solvent of the type
EtOH or AcOEt at a temperature between OOC and 800C.

 The derivatives of general formula (I) in which R5 = H are prepared by hydrolysis in a basic or acidic medium, according to the methods and techniques well known to those skilled in the art for hydrolyzing an ester to a carboxylic acid, of a derivative of general formula (I) in which Rs represents an alkyl or benzyl radical, in particular using a lithium, potassium or sodium hydroxide.

Also to be considered as part of the present invention are all the methods for preparing a compound of general formula (I) from another derivative of general formula (I) in which at least one of substituents R 1, R 2, X
R3, R4 or R5 is different. Thus, by way of example, a compound of general formula (I) in which R 3 represents Br may be converted into a compound of general formula (I) in which R 3 represents an aryl or heteroaryl residue as defined above by reaction with a corresponding boronic acid, such as aryl
B (OH) 2 or heteroaryl-B (OH) 2, in the presence of palladium, according to a method well known to those skilled in the art under the name of "Suzuki coupling". Similarly, the derivatives of general formula ( I) in which R2 represents a bromine-substituted aryl or heteroaryl residue may be converted, according to the same method, into derivatives of the general formula (I) in which R2 represents an aryl or heteroaryl radical substituted with an aryl or heteroaryl radical. By way of a complementary example, the derivatives of formula (I), in which R 6 represents a hydrogen, can be converted into derivatives of general formula (I) in which R 6 represents SO 2 R 6 after reaction with a sulphonyl chloride of formula ClSO 2 R ' 6 in the presence of an organic or inorganic base such as for example NaH, tBuOK, Cs2CO3.

It will be understood that, in certain reactions or sequences of chemical reactions which lead to the preparation of compounds of general formula (I), it is necessary or desirable to protect possible sensitive groups in synthetic intermediates in order to avoid undesirable side reactions . This can be achieved by the use (introduction and deprotection) of conventional protecting groups such as those described in "Protective Groups in Organic Synthesis", TW Greene, John
Wiley & Sons, 1981 and "Protecting Groups", PJ Kocienski, Thieme Verlag, 1994. The appropriate protective groups will therefore be introduced and removed at the most appropriate stage to do this and using the methods and techniques described in the references. previously mentioned.

 When it is desired to isolate a compound in the salt state of general formula (I) in which R5 represents a hydrogen, this can be achieved by treating the free acid of general formula (I) in which Rs = H by a appropriate base, preferably in equivalent amount.

Such pharmaceutically acceptable salts include cation salts such as lithium, sodium, potassium, calcium, magnesium, aluminum,
Ammonium, quaternary ammoniums and salts formed after reaction of a carboxylic acid of general formula (I) in which R5 = H with a non-toxic organic amine. When it is desired to isolate a compound in the form of salt of general formula (I) containing at least one basic function, this can be achieved by treating the free base of general formula (I) in which there exists at least one basic function with a suitable acid, preferably in equivalent amount.

 Among the physiologically acceptable salts of the compounds of general formula (I) are salts obtained by addition of organic or inorganic acids such as hydrochlorides, hydrobromides, sulphates, phosphates, benzoates, acetates, naphthoates, ptoluenesulphonates, methanesulphonates, sulphamates, ascorbates. , tartrates, citrates, oxalates, maleates, salicylates, fumarates, succinates, lactates, glutarates, glutaconates.

 When the methods described above for preparing the compounds of the invention give mixtures of diastereoisomers, these isomers can be separated by conventional methods such as preparative chromatography.

 When the new compounds of general formula (I) have one or more asymmetric centers, they can be prepared in the form of a racemic mixture or in the form of enantiomers, whether by enanheselective synthesis or by resolution.

 The present invention relates to the use of the compounds described above as therapeutically active substances.

The compounds of the present invention are potent inhibitors of protein prenylation, more particularly farnesylation or geranylgeranylation of oncoproteins by their ability to inhibit Farnesyl Protein.
Transferase and / or geranylgeranyl transferase.

 The compounds of the present invention are useful, alone or in combination with other products, for the treatment of cancers in general and more particularly of cancers such as, for example, colorectal, pulmonary or pancreatic carcinomas or else myeloid leukemias.

The compounds of the present invention, because of their ability to inhibit prenylation of proteins and more particularly the PFTase and / or GGTase enzymes, are also useful for the prevention of cancers (see GJ Kelloff et al., Cancer
Epidemiol. Biomarkers & Prev. 1997 ; 6: 267-282).

Another aspect of
as an active ingredient, a compound of general formula (I) optionally combined with one or more therapeutic agents, such as, for example, anti-cancer agents such as, for example, cytotoxic anticancer agents such as navelbine, vinflunine, taxol, taxotere 5-fluorouracil, methotrexate, doxorabicin, camptothecin, etoposide, cis-platinum or BCNU, and
a pharmaceutically acceptable excipient.

 These compositions may, for example, be in the form of solid, liquid compositions, emulsions, lotions or creams.

 As solid compositions for oral administration may be used tablets, pills, powders (gelatin capsules, cachets) or granules.

In these compositions, the active ingredient according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under an argon stream. These compositions may also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.

 As liquid compositions for oral administration, it is possible to use pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil. of paraffin. These compositions may comprise substances other than diluents, for example wetting agents, sweeteners, thickeners, flavoring agents or stabilizers.

 The sterile compositions for parenteral administration may preferably be aqueous or nonaqueous solutions, suspensions or emulsions.

As the solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents may be used. These compositions may also contain adjuvants, in particular wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers. Sterilization can be carried out in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation 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 or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

 The compositions for topical administration may be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.

 The doses depend on the effect sought, the duration of treatment and the route of administration used; they are generally between 0.001 g and 1 g, preferably between 0.005 g and 0.25 g per day, preferably orally for an adult with unit doses ranging from 0.1 mg to 500 mg of active substance, preferably from 1 mg to 50 mg.

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

The examples which follow illustrate the invention without, however, limiting its scope.

EXAMPLE 1
N- [3-phenyl-4 - [(L-methionine) carbonyl] phenyl] -NH-imidazol-5-ylmethyll
benzenesulfonamide
EXAMPLE 1A
Methyl 2-phenyl-4-nitrobenzoate
A solution of methyl 2-chloro-4-nitrobenzoate (50 g, 0.23 mol), phenylboronic acid (31.1 g, 0.26 mmol), sodium carbonate (2.0 M aqueous, 140 mL) ) and dichlorobis (triphenylphosphine) palladium (3.3 g, 4.6 mol) in dioxane (350 mL) is refluxed for 20 hours. The reaction medium is then diluted with ethyl ether (500 ml) and ethyl acetate (500 ml), washed with water (2 × 200 ml) and saturated sodium chloride (NaCl) solution. . The organic phase is dried over magnesium sulphate (MgSO4), filtered and concentrated in vacuo. The residue is purified by crystallization from hexane / AcOEt (1/1) to give a white solid. H
NMR (400MHz, CDCl3) 8.25 (d, J = 2.3Hz, 1H), 8.24 (dd, J = 11.9, 2.3Hz, 1H), 7.94 (d, J = 11, 9Hz, 1H), 7.48-7.40 (m, 3H), 7.35-7.30 (m, 2H), 3.68 (s, 3H).

EXAMPLE 1B
Methyl 2-phenyl-4-aminobenzoate
A solution of compound 1A (10 g, 38.9 mmol), palladium on carbon (10.4 g) and ammonium formate (12.3 g, 0.19 mol) in methanol (150 mL ) is refluxed for 3 hours. The solvent is then evaporated and the residue is dissolved in a minimum of AcOEt and purified by filtration on silica (200 g; 75/25).
Petroleum ether / AcOEt) to give a white solid (8.7 g, 98%). 1H NMR (400MHz, CD30D) 7.80 (d, J = 12.4Hz, 1H), 7.40-7.25 (m, 5H), 6.65 (dd, J = 12.4, 2, 4Hz, 1H), 6.57 (d, J = 2.4Hz, 1H), 3.60 (s, 3H).

EXAMPLE 1C
Methyl 4- [(1H-triphenylmethylimidazol-4-ylmethyl) amino] -2-phenyl-benzoate
To a solution of compound 1B (3 g, 13.2 mmol) in dichloroethane (66 mL) is added 1H-triphenylmethylimidazol-4-carboxaldehyde (4.4 g, 13.2 mmol) (prepared according to Hunt, JT and J. Med Chem., 1996, 39, 353-358) and acetic acid (4.1 mL, 79.2 mmol). After stirring 15 minutes, NaBH (OAc) 3 (3.1 g, 14.5 mmol) is added portionwise and the resulting medium is stirred for 3 hours at room temperature. At this time, 0.2 eq of aldehyde and 0.2 eq of NaBH (OAc) 3 are added to terminate the reaction. The reaction medium is then diluted in AcOEt and then washed with a saturated solution of NaHCO3. The aqueous phase is extracted twice with AcOEt and the combined organic phases are washed with a saturated solution of
NaCl, dried over MgSO4, filtered and evaporated. The residue is purified by "flash" chromatography on silica to give a white foam whose spectrum
NMR corresponds to the expected structure.

EXAMPLE 1D
N - (1H-triphenylmethylimidazol-4-ylmethyl) -N - [(3-phenyl-4-carboxy) phenyl]
benzenesulfonamide
A solution of compound 1C (2 g, 3.64 mmol) and benzenesulfonyl chloride (835 μM, 4.73 mmol) in pyridine (40 mL) is stirred for 6 hours at room temperature. The pyridine is then co-evaporated with toluene and the residue diluted in dichloromethane. The organic phase is washed with a solution
1N HCl and then a saturated solution of NaCl, dried over MgSO 4, filtered and evaporated. The solid thus obtained is used as it is in the following reaction.

 A solution of compound 1D (2 g) in a mixture of saturated aqueous lithium hydroxide (2.9 mL) and methanol (10 mL) is heated at 60 ° C for 12 hours.

The reaction medium is then acidified to pH approximately equal to 2 with concentrated hydrochloric acid and then extracted with ethyl acetate. The combined organic phases are washed with saturated NaCl solution, dried over MgSO 4, filtered and evaporated. The crude product is sufficiently pure to be used in the next reaction without purification.

EXAMPLE 1E N- (1H-triphenylmethylimidazol-4-ylmethyl)
N- [3-phenyl-4- [(umethionine methyl ester) carbonyl] phenyl]
benzenesulfonamide
A solution of 1D (1g, 1.5 mmol), EDC (284 mg, 1.5 mmol),
HOOBt (241 mg, 1.48 mmol) in dichloromethane (30 mL) is stirred for 1 hour and then a solution of methyl ester of L-methionine hydrochloride (326 mg, 1.6 mmol) in diisopropylamine (290 1.6 mmol) and dichloromethane (20 ml) are added to the reaction medium. The reaction is stirred for 16 hours and then diluted in dichloromethane. The organic phase is washed successively with 1 N HCl, saturated NaHCO 3 solution and saturated NaCl solution and then dried over MgSO 4, filtered and evaporated. The residue is purified by silica column flash chromatography to provide the desired product (800 mg, 66%). 1H NMR (400MHz, CDCl3) δ 7.67 (d, J = 8.6Hz, 1H), 7.58-7.55 (m, 1H), 7.49-7.47 (m, 1H), 7.37-7.12 (m, 18H), 7.05-6.91 (m, 8H), 6.58 (s, 1H), 5.85 (d, J = 7.6 Hz, 1H), 4.76 (AB, 2H), 4.664.62 (m, 1H), 3.64 (s, 3H), 2.11-2.07 (m, 2H), 1.92 (s, 3H), 1 , 92-1.83 (m, 1H), 1.701.61 (m, 1H).

Preparation of N- [3-phenyl-4- [(L = methionine) carbonyl] phenyl] -N- [1H-imidazol-5-
ylmethyl] benzenesulfonamide
To a solution of the compound 1E (0.29 mmol) in THF (2 mL) is added LiOH (1 M in H 2 O, 587 CIL) and the resulting solution is stirred for 3 hours at room temperature. The medium is then diluted in CH 2 Cl 2 and then acidified to pH = 2 with 1N HCl and the aqueous phase is extracted three times with a CH 2 Cl 2 / MeOH (75/25) mixture. The combined organic phases are dried over MgSO 4, filtered and evaporated to yield a white foam (235 mg) sufficiently pure to be used in the next reaction. To a solution of acid in CHOC2 (3 mL) is added dropwise trifluoroacetic acid (1.5 mL) and the medium is stirred for 2 hours at room temperature. Triethylsilane is then added until complete disappearance of the intense yellow coloring. The resulting solution is co-evaporated with toluene and the resulting solid residue is filtered or triturated with Et2O to remove residual triphenylmethane. The product obtained is purified by preparative reverse phase HPLC on a C-18 column under the following conditions: 220 nM, UV detector, flow rate 50 mL / m, gradient of 10% acetonitrile and 90% water (0.1% TFA) 70% acetonitrile (0.1% TFA) (0.1% TFA) in 40 minutes. Fractions> 98% purity are pooled and lyophilized to yield the desired product. aD = -32.4 (c = 0.13, MeOH); 1H NMR (400MHz, CD30D) δ 8.80 (s, 1H), 7.76-7.58 (m, 6H), 7.45; (d, J = 8.2 Hz, 1H), 7.387.25 (m, 6H), 7.14 (dd, J = 8.2, 1.8Hz, 1H), 7.06 (d, J = 1, 8Hz, 1H), 4.99 (AB, 2H), 4.46 (dd, J = 9.6, 4Hz, 1H), 2.20-2.13 (m, 1H), 2.08-1, 97 (s + m, 5H), 1.78-1.75 (m, 1H), MSm / e565 (100, MH +), 239 (11.3), 207 (14.0), 115 (16.8). ).

EXAMPLE 2
N- [3-phenyl-4 - [(L-methionine) carbonyl] phenyl] -NH-imidazol-5-ylmethyl]
methylsnlfonam ide
EXAMPLE 2A 4-nitro-2-phenyltoluene
To a solution of acetone (240 mL) and water (210 mL) was added phenylboronic acid (12.4 g, 0.24 mol), 2-bromo-4-nitrotoluene (21.0 g; 0.24 mol), potassium carbonate (33.6 g, 0.24 mol) and palladium acetate (0.87 g, 3.9 mmol).

The addition of Pd (OAc) 2 is exothermic. The resulting black medium is refluxed for 10 hours and then filtered through Celite. After decantation, the aqueous phase is extracted twice with ether and then dried over MgSO 4, filtered and evaporated to yield a yellowish solid. The latter is washed successively with 50 mL and 20 mL of methanol to provide a beige solid (18.5 g, 89%). 1H NMR (400MHz, CDCl3) δ 8.11-8.09 (m, 2H), 7.48-7.39 (m, 4H), 7.32-7.30 (m, 2H), 2, 36 (s, 3H).

EXAMPLE 2B
4-nitro-2-benzoic acid
Derivative 2A (16 g, 75 mmol) is dissolved in pyridine (83 mL) and water (152 mL). The medium is brought to a temperature of about 100 ° C., then the portion-per-portion addition of KMnO 4 (83.0 g, 0.52 mol) is carried out, the resulting black solution is refluxed for a further 2 hours and then filtered. Hot on Celite The filter cake is washed with hot water (70 ° C). The filtrate is washed with ethyl acetate (250 mL) and then the aqueous phase is diluted in dichloromethane (500 mL) and brought to a pH of about 2 with 6N HCl. The organic phase is dried on
MgSO4, filtered and evaporated to yield the desired acid (15.5 g, 85%). 1H NMR (400MHz, CHCl 3) δ 8.26 (dd, J = 8.4, 2.2Hz, 1H), 8.19 (d, J = 2.2Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.45-7.38 (m, 5H).

EXAMPLE 2C
4-nitro-2-phenylbenzoyl- (L) -methionine methyl ester
This compound is prepared from compound 2B according to the same procedure as in Example 1E. It is purified by washing with a minimum of ethanol to yield a fluffy white solid, the yield is 72%. 1H NMR (400MHz, CHCl 3) δ 8.27-8.22 (m, 2H), 7.80 (d, J = 8.4Hz, 1H), 7.53-7.43 (m, 5H), , 08 (d, J = 7.6 Hz, 1H), 4.67 (dd, J = 9.6, 4.0Hz, 1H), 2.08-1.91 (m, 6H), 1.82- 1.73 (m, 1H).

EXAMPLE 2D
4-amino-2-phenylbenzoyl- (L) -methionine methyl ester
Derivative 2C (16 g, 41.2 mmol) is dissolved in ethyl acetate (500 mL) and SnCl 2. 2H2O (46.5 g, 0.21 mmol) is added in one stroke. The resulting cloudy medium is heated at reflux for 2 hours and then dissolved in crushed ice and brought to a pH of about 8 with saturated NaHCO 3 solution. The aqueous phase is extracted twice with 250 ml of AcOEt then dried over MgSO4, filtered and evaporated to provide a whitish foam. This foam is dissolved in CH 2 Cl 2 and then treated with a solution of HCl in ether. A gel is formed which is filtered under vacuum and then dried at 40 ° C for 12 hours to give a beige solid (15.6 g, 96%) aD = -40.7 (c = 0.58,
MeOH). 1H NMR (400MHz, DMSO-d6) δ 8.68 (d, J = 7.6Hz, 1H), 7.49 (d, J = 8.1Hz, 1H), 7.43-7.14 (m.p. , 6H), 4.39-4.33 (m, 1H), 3.63 (s, 3H), 2.28-2.14 (m, 2H), 1.99 (s, 3H), 1, 88-1.75 (m, 2H).

EXAMPLE 2E 4- [(1H-triphenylmethylimidazol-4-ylmethyl) amino] -2-phenylbenzoyl
(L) -methionine methyl ester
This compound is prepared from compound 2D according to the same procedure as in Example 1C. Purification by "flash" chromatography on silica using CH 2 Cl 2 / acetone in the proportions 80/20 makes it possible to obtain a beige foam (74%). 1H NMR (400MHz, CDCl3)? 7.67 (d, J = 8.6Hz, 1H), 7.42-7.28 (m, 15H), 7.12-7.09 (m, 6H), 6H NMR (CDCl3)? , 73 (s, 1H), 6.62 (dd, J = 8.2, 2.0Hz, 1H), 6.47 (d, J = 2.0Hz, 1H), 5.68 (d, J = 7.6 Hz, 1H), 4.64-4.60 (m, 1H), 4.26 (s, 2H), 3.64 (s, 3H), 2.11-2.07 (m, 2H). 1.92 (s, 3H), 1.92-1.83 (m, 1H), 1.70-1.61 (m, 1H).

EXAMPLE 2F
N-3-phenyl-4 - [(L -methionine methyl ester) carbonyl] phenyl]
N- [11-triphenylmethylimidazol-4-ylmethyl] methylsulfonamide
This compound is synthesized from intermediate 2E according to a procedure analogous to Example 1D except that the benzenesulphonyl chloride is replaced by mesyl chloride. The compound obtained is directly involved in the following reaction after carrying out the usual treatments.

N- [3-phenyl-4 - [(L-methionine) carbonyl] phenyl] -N- [1H-imidazol-5-ylmethyl]
methyl sulfonamide
This compound is obtained from intermediate 2F according to the method used in Example 1.

 NMR (400MHz, CDCl 3) δ 8.81 (s, 1H), 7.56 (d, J = 8.08Hz, 1H), 7.51-7.47 (m, 2H), 7.43-7. , 37 (m, 6H), 5.10 (AB, 2H), 4.49 (dd, J = 9.6, 4.0Hz, 1H), 3.08 (s, 3H), 2.202.13 (m.p. , 1H), 2.08-1.97 (s + m, 5H), 1.78-1.75 (m, 1H); MS m / e 503 (100, MH +), 354 (7.2), 274 (6.9), 206 (6.8).

The following compounds were synthesized either using the reaction sequence described in Example 1 or that described for Example 2.

EXAMPLE 3
N- [3-phenyl-4 - [(b-methionine) carbonyl] phenyl] -N- [1H-imidazol-5-ylmethyl]
benzylsulfonamide aD = -15.9 (c = 0.11, MeOH), lHRMN (400MHz, CD30D) 8.17 (s, 1H), 7.51 (d, J = 8.2Hz, 1H), 7.48 -7.35 (m, 12H), 7.23 (d, J = 1.8 Hz, 1H), 4.97 (AB, 2H), 4.57 (s, 2H), 4.49 (dd, J); = 9.6, 4Hz, 1H), 2.20-2.13 (m, 1H), 2.08-1.97 (s + m, 5H), 1.78-1.75 (m, 1H) , MS m / e 579 (100, Mi +), 288 (14.6), 258 (17.4), 165 (16.8).

EXAMPLE 4
N- [3-phenyl-4 - [(L-methionine) carbonyl) phenyl] -N- [1H-imidazol-5-ylmethyl] - (Z) -
styrene sulfonamide 1H NMR (400MHz, CD30D) δ 8.80 (s, 1H), 7.62 (d, J = 8.2Hz, 1H), 7.51-7.25 (m, 15H), 5.08 (AB, 2H), 4.46 (dd, J = 9.6, 4.0Hz, 1H), 2.20-2.13 (m, 1H), 2.08-1.97 (s + m, 5H), 1.78-1.75 (m, 1H), MS m / e 591 (100, MH +), 442 (23.4), 362 (10.7).

EXAMPLE 5
N- [3-phenyl-4 - [(L-methionine) carbonyl] phenyl] -N- [1H-imidazol-5-ylmethyl] -4-fluorobenzenesulfonamide &alpha; D = -31.6 (c = 0.14, MeOH) 1H NMR (400MHz, CD3OD) δ 8.65 (s, 1H), 7.75-7.71 (m, 2H), 7.46 (d, J = 8.2Hz, 1H), 7.38; -7.30 (m, 9H), 7.16 (dd, J = 8.2, 1.6Hz, 1H), 4.98 (AB, 2H), 4.47 (dd, J = 9.2, 4.0 Hz, 1H), 2.20-2.13 (m, 1H), 2.08-1.97 (s + m, 5H), 1.78-1.75 (m, 1H), MS m 583 (100, MH +), 354 (14.4), 267 (6.1), 207 (10.7), 115 (5.4).

EXAMPLE 6
N- [3-phenyl-4 - [(L-methionine) carbonyl] phenyl-N- [1H-imidazol-5-ylmethyl] -
4-chlorobenzenesulfonamide 1H NMR (400MHz, CD30D) δ 8.57 (s, 1H), 7.65 (A2B2, 4H), 7.46 (d, J = 8.2Hz, 1H), 7.38-7 , 34 (m, 3H), 7.30-7.26 (m, 3H), 7.16 (dd, J = 8.2, 2.0Hz, 1H), 7.08 (d, J = 2, 0Hz, 1H), 4.98 (AB, 2H), 4.46 (dd, J = 9.2, 4.0Hz, 1H), 2.20-2.13 (m, 1H), 2.08- 1.97 (s + 5H), 1.78-1.75 (m, H); MS m / e 599 (31.5, M +), 251 (33.0), 235 (100), 207 (84.1), 114 (73.3).

EXAMPLE 7
N- [3-phenyl-4- [L-methionine] carbonyl] phenyl] -N- [1H-imidazol-5-ylmethyl]
4-bromobenzenesulfonamide &alpha; D = -29.5 (c = 0.20, MeOH), 1H NMR (400MHz, CD30D) δ 8.78 (m, 1H), 7.80 (d, J = 8.4Hz, 2H), 7.58 (d, J = 8.4Hz, 2H), 7.47 (d, J = 8.2Hz, 1H), 7.40-7.25 (m, 6H), 7.17 (dd, J); = 7.4, 1.4Hz, 1H), 7.07 (se, 1H), 5.03 (AB, 2H), 4.47 (dd, J = 9.2, 4.0Hz, 1H), 2 , 20-2.13 (m, 1H), 2.08-1.97 (s + m, H), 1.78-1.75 (m, 1H), MS m / e 645 (100), 644. (25, Mit), 267 (65.9), 107 (46.3).

EXAMPLE 8
N- [3-phenyl-4 - [(L-methionine) carbonyl] phenyl] -N- [1H-imidazol-5-ylmethyl) 2-bromobenzene sulfonamide
1H NMR (400MHz, CD30D) δ 8.71 (s, 1H), 8.05 (dd, J = 7.0, 1.6Hz, 0.33H), 7.92 (dd,
J = 7.0, 1.6Hz, 0.76H), 7.87 (d, J = 7.0Hz, 0.76H), 7.65 (d, J = 7.0Hz, 0.33H), 7.517; , 42 (m, 3H), 7.37-7.34 (m, 4H), 7.30-7.10 (m, 4H), 5.29 (AB, 2H), 4.47 (dd, J), = 9.2, 4, OH 1H), 2.20-2.13 (m, 1H), 2.08-1.97 (s + m, 5H), 1.78-1.75 (m, 1H) ).

EXAMPLE 9
N- [3-phenyl-4 - [(L-methionine) carbonyl] phenyl] -N- [1H-imidazol-5-ylmethyl]
4-methoxybenzenesulfonamide &alpha; D = -33.0 (c = 0.22, MeOH); 1H NMR (400MHz, CD 30D) δ 8.74 (s, 1H), 7.67 (d, J = 8.8Hz, 2H), 7.45 (d, J = 8.2Hz, 1H), 7, 37-7.24 (m, 6H), 7.15 (d, J = 7.8Hz, 1H), 7.13 (d, J = 8.8Hz, 2H), 7.09 (se, 1H), 4.95 (AB, 2H), 3.89, (s, 3H), 4.47 (dd, J = 9.2, 4.0Hz, 1H), 2.20-2.13 (m, 1H) , 2.08-1.97 + m, 5H), 1.78-1.75 (m, 1H), MS m / e 595 (100, m.p.
MH +), 235 (17.1), 207 (26.6), 115 (5.2).

EXAMPLE 10
N- [3-phenyl-4 - [(L-methionine) carbonyl] phenyl] N- [1H-imidazol-5-ylmethyl] -
4-cyanobenzenesulfonamide aD = -35.1 (c = 0.17, MeOH); 1H NMR (400MHz, CD3OD) δ 8.83 (s, 1H), 8.00 (AB, 2H), 7.83 (AB, 2H), 7.47 (d, J = 8.2 Hz, 1H), 7.40-7.85 (m, 6H), 7.17 (dd, J = 8.2, 2.0Hz, 1H), 7.15 (d, J = 2.0Hz, 1H), 5.06 (AB, 2H), 4.47 (dd, J = 9.2, 4.0Hz, 1H), 2.202.13 (m, 1H), 2.08-1.97 (s + m, H), 1 , 78-1.75 (m, 1H), MS m / e 590 (100, M e), 441 (5.6), 361 (4.5).

EXAMPLE 11
N- [3-phenyl-4 - [(L-methionine) carbonyl] phenyl-N- [1 H -imidazol-5-ylmethyl] 4-trifluoromethylbenzenesulfonamide oLD = - 20.2 (c = 0.24, MeOH), 1H NMR (400MHz, CD30D) δ 8.58 (s, 1H), 7.94 (d, J = 8.4Hz, 2H), 7.87 (d, J = 8.4Hz, 2H), 7.47; (d, J = 8.2Hz, 1H), 7.38-7.34 (m, 3H), 7.277.24 (m, 3H), 7.18 (dd, J = 8.2, 2.1Hz, 1H), 7.03 (d, J = 2.1Hz, 1H), 5.01 (AB, 2H), 4.47 (dd, J = 9.2, 4.0Hz, 1H), 2.13 (m, 1H), 2.08-1.97 (s + m, 5H), 1.78-1.75 (m, 1H), MS m / e 633 (100, M e), 235 (m.p. 45.2), 207 (43.2).

EXAMPLE 12
N- [3-phenyl-4- [(L-methionine) carbonyl] phenyl-N- [1H-imidazol-5-ylmethyl]
4-tert-butylbenzenesulfonamide = 37.8 (0.13, MeOH); 1H NMR (400MHz, CD3OD) δ 8.80 (s, 1H), 7.65 (d, J = 8.4Hz, 1H), 7.58 (d, J = 8.4Hz, 1H), 7, 48-7.45 (m, 2H), 7.36-7.20 (m, 8H), 6.91 (d, J = 2.1Hz, 1H), 5.01 (AB, 2H), 4, 48 (dd, J = 9.2, 4.0Hz, 1H), 2.20-2.13 (m, 1H), 2.08-1.97 (s + m, 5H), 1.78-1. 75 (m, 1H), 1.35 (s, 9H); MS m / e 621 (100, MH +), 392 (17.2), 267 (16.3), 143 (15.5), 115 (13.6).

EXAMPLE 13
N- [3-phenyl-4 - [(L-methionine) carbonyl] phenyl] -NH-imidazol-5-ylmethyll
4-nitrobenzenesulfonamide &alpha; D = -35.8 (c = 0.157, MeOH); 1H NMR (400MHz, CD30D) δ 8.83 (s, 1H), 8.46 (AB, 2H), 7.91 (AB, 2H), 7.47 (d, J = 8.2Hz, 1H) 7.11 (dd, J = 8.2, 2.0Hz, J = 2.0Hz, 1H), 5.05 (AB, 2H), 4.47 (dd, J = 9.2, 4.0Hz, 1H), 2.20-2.13 (m, 1H), 2.08-1.97 (s + m, 5H), 1.78-1.75 (m, 1H), 1.35 (s, 9H);
MS m / e 610 (100, M e), 381 (4.1), 181 (3.4).

EXAMPLE 14
N- [3-phenyl-4 - [(L-methionine) carbonyl] phenyl] -N- [1H-imidazol-5-ylmethyl] -
1H-NMR 2-methylbenzenesulfonamide (400MHz, CD30D) δ 8.80 (s, 1H), 7.86 (d, J = 7.9Hz, 0.5H), 7.54 (d, J = 7.9Hz, 1H NMR (400 MHz, CDCl3):? , 5H), 7.48-7.10 (m, 10H), 7.03 (salt, 1H), 5.10 (s, 1H), 5.06 (s, 1H), 4.47 (dd, J = 9.2, 4.0Hz, 1H), 2.40 (s, 3H), 2.20-2.13 (m, 1H), 2.08-1.97 (s + m, 5H), 1.78-1.75 (m, 1H), MS m / e 579 (100, MH +), 499 (14.0), 430 (21.4), 350 (44.08).

EXAMPLE 15
N- [3-phenyl-4 - [(L-methionine) carbonyl] phenyl] -N- [1H-imidazol-5-ylmethyl]
2-naphthalenesulfonamide = 37.3 (0.104, MeOH); 1H NMR (400MHz, CD30D) δ 8.83 (s, 1H), 8.33 (s, 1H), 8.10 (d, J = 8.6Hz, 1H), 8.03 (d, J = 8); , 6Hz, 1H), 7.77-7.65 (m, 2H), 7.44 (d, J = 8.2Hz, 1H), 7.34 (s, 1H), 7.28-7.12 (m, 8H), 7.00 (s, 1H), 5.04 (AB, 2H), 4.47 (dd, J = 9.2, 4.0Hz, 1H), 2.20-2.13 (m, 1H), 2.08-1.97 (s + m, 5H), 1.78-1.75 (m, 1H); MS m / e 615 (100, M e), 386 (7.7), 267 (11.5), 207 (15.2), 115 (11.8).

EXAMPLE 16
N- [3-phenyl-4- [(L-methionine) carbonyl] phenyl] -N- [1H-imidazol-5-ylmethyl]
1-naphthalenesulfonamide &alpha; D = -21.8 (0.114, MeOH); 1H NMR (400MHz, CD3OD) δ 8.81 (s, 1H), 8.34 (d, J = 8.6Hz, 1H), 8.24 (t, J = 7.7Hz, 2H), 8.02 (d, J = 7.7Hz, 1H), 7.58-7.51 (m, 3H), 7.41 (d, J = 8.2Hz, 1H), 7.30-7.25 (m, 4H), 7.18 (dd, J = 8.2, 2.0Hz, 1H), 7.10-7.07 (m, 2H), 6.90 (d, J = 2.0Hz, 1H), 5.04 (s, 2H), 4.47 (dd, J = 9.2, 4.0Hz, 1H), 2.20-2.13 (m, 1H), 2.08-1.97 (s). + m, 5H), 1.78-1.75 (m, 1H).

EXAMPLE 17
N- [3-phenyl-4 - [(L-methionine) carbonyl] phenyl] -N- [1H-imidazol-5-ylmethyl]
2-thiophenesulfonamide aD = -28.1 (0.128, MeOH), 1H NMR (400MHz, CD3OD) δ 8.75 (s, 1H), 7.92 (dd, J = 5.0, 1.1Hz, 1H) ), 7.54 (dd, J = 3.8, 1.1Hz, 1H), 7.42 (d, J = 8.2Hz, 1H), 7.38-7.28 (m, 5H), 7.24 (dd, J = 5.0, 3.8Hz, 1H), 7.20 (dd, J = 8.2, 2.0Hz, 1H), 7.13 (d, J = 2.0Hz, 1H), 5.01 (s, 2H), 4.47 (dd, J = 9.2, 4.0Hz, 1H), 2.20-2.13 (m, 1H), 2.08-1.97 (s). +5H), 1.78-1.75 (m, 1H); MS m / e 571 (100, MH +), 422 (5.8), 342 (8.0).

EXAMPLE 18
N- [3-phenyl-4 - [(1-methionine) carbonyl] phenyl] -N-1H-imidazol-5-ylmethyl]
3-thiophenesulfonamide α = 23.5 (0.110, MeOH), 1H NMR (400MHz, CD3OD) δ 8.79 (s, 1H), 8.04 (d, J = 1.8Hz, 1H), 7.71 -7.69 (m, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.38-7.30 (m, 6H), 7.22 (d, J = 3.4 Hz, 1H), 7.18 (dd, J = 8.2, 2.0Hz, 1H), 7.10 (d, J = 2.0Hz, 1H), 5.00 (AB, 2H), 4.47 ( dd, J = 9.2, 4.0Hz, 1H), 2.20-2.13 (m, 1H), 2.08-1.97 (s + m, 5H), 1.78-1.75 (m, 1H)
MS m / e 571 (100, M e), 251 (13.9), 115 (15.9).

EXAMPLE 19
N- [3-phenyl-4 - [(1-methionine) carbonyl] phenyl] -N- [1H-imidazol-5-ylmethyl] -5-chloro-2-thiophenesulfonamide 1H NMR (400MHz, CD30D) δ 8.81 (s, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.40-7.33 (m, 7H), 7.24 (dd, J = 8.2, 2.0 Hz, 1H), 7.21-7.19 (m, 2H), 5.03 (s, 2H), 4.47 (dd, J = 9.2, 4.0Hz, 1H), 2.20-2, 13 (m, 1H), 2.08-1.97 (s + m, 5H), 1.78-1.75 (m, 1H).

EXAMPLE 20
N- [3-phenyl-4 - [(L-methionine) carbonyl] phenyl] -N- [1H-imidazol-5-ylmethyl] -5-bromo-2-thiophenesulfonamide aD = -32.3 (c = 0, 3, MeOH), 1H NMR (400MHz, CD30D) δ 8.81 (s, 1H), 7.50 (d, J = 8.2Hz, 1H), 7.39-7.32 (m, 8H), 7.25 (d, J = 8.2Hz, 1H), 7.17 (s, 1H), 5.02 (AB, 2H), 4.47 (dd, J = 9.2, 4.0Hz, 1H). ), 2.20-2.13 (m, 1H), 2.08-1.97 (s + m, 5H), 1.78-1.75 (m, 1H), MS m / e 651 (100); , Mit), 650 (42.3, Mit), 207 (15.7), 177 (42.6), 115 (19.2).

EXAMPLE 21
N- [3-phenyl-4 - [(1-methionine) carbonyl] phenyl] -N- [1 H -imidazol-5-ylmethyl] -1-methyl-4-imidazolesulfonamide 1H NMR (400MHz, CD 30D) 68, 83 (s, 1H), 7.88 (s, 1H), 7.53 (s, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.39-7.30 (m, 6H), 7.18 (dd, J = 8.2, 2.0Hz, 1H), 7.14 (d, J = 2.0Hz, 1H), 5.14 (s, 2H), 4.46 ( dd, J = 9.2, 4.0Hz, 1H), 3.76 (s, 3H), 2.20-2.13 (m, 1H), 2.08-1.97 (s + m, 5H) , 1.78-1.75 (m, 1H), MS m / e 569 (100, MH +), 340 (61.1), 223 (30.4), 191 (40.1).

EXAMPLE 22
N- [3-phenyl-4- [(Irmethionine) carbonyl] phenyl] -N- [1H-imidazol-5-ylmethyl]
3,5-dimethyl-4-isoxazolinesulfonamide = = 25.6 (c = 0.288, MeOH); 1H NMR (400MHz, CD30D) δ 8.83 (s, 1H), 7.53 (d, J = 8.2Hz, 1H), 7.40-7.32 (m, 9H), 5.11 (AB); , 2H), 4.49 (dd, J = 9.2, 4.0Hz, 1H), 2.40 (s, 3H), 2.23-2.15 (m, 1H), 2.11 (s). , 3H), 2.08-2.00 (s + m, 5H), 1.84-1.75 (m, 1H); MS m / e 584 (100, M e), 435 (11.4), 355 (12.1), 230 (31.0), 207 (43.2).

EXAMPLE 23
N- [3-phenyl-4- [(L-methionine) carbonyl] phenyl] -N- [1H-imidazol-2.0Hz, 1H), 5.05 (AB, 2H), 4.47 (dd, J); = 9.2, 4.0Hz, 1H), 2.20-2.13 (m, 1H), 2.08-1.97 (s + m, 5H), 1.78-1.75 (m, 1H); MS m / e 566 (100, MH +), 417 (47.6), 337 (20.1), 223 (10.2), 191 (51.5).

EXAMPLE 24
N- [3-phenyl-4 - [(L-methionine methyl ester) carbonyl] phenyl] -N- [1H-imidazol-S-
ylmethyl] benzenesulfonamide
To a solution of compound 1F (238 mg, 0.35 mmol) in CH 2 Cl 2 (3 mL) is added dropwise trifluoroacetic acid (0.8 mL) and the medium is stirred for 1 hour at room temperature. Triethylsilane is then added until complete disappearance of the intense yellow coloring. The resulting solution is co-evaporated with toluene and the resulting solid residue is filtered or triturated with Et2O to remove residual triphenylmethane. The product obtained is purified by preparative reverse phase HPLC under the following conditions: column C-18> 220 nM, UV detector, flow rate 50 mL / m, gradient of 10% acetonitrile and 90% water (0.1% TFA) at 70% acetonitrile (0.1% TFA) in 40 minutes. Fractions of> 98% purity are pooled and lyophilized to yield the desired product (145 mg). an = - 28.4 (c = 0.23, MeOH). H
NMR (400MHz, CD3OD) δ 8.82 (s, 1H), 7.74 (t, J = 7.4Hz, 1H), 7.69 (d + s, J = 7.4Hz, 2H), 7, 63-7.60 (m, 2H), 7.43 (d, J = 8.2 Hz, 1H), 7.38-7.35 (m, 3H), 7.28-7.26 (m, 2H) ), 7.16 (dd, J = 8.2, 2.0Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 5.00 (AB, 2H), 4.50 (dd). , J = 9.6, 4.0Hz, 1H), 3.68 (s, 3H), 2.18-2.11 (m, 1H), 2.05-1.93 (s + m, 4H) , 1.77-1.73 (m, 1H).

EXAMPLE 25 N- [3-phenyl-4 - [(D-methionine) carbonyl-phenyl]
N- [1H-imidazol-5-ylmethyl] benzenesulfonamide
This compound was prepared following the sequence of reactions described for Example 2, with L-methionine being replaced by D-methionine. aD = + 22.9 (0.16, MeOH).

EXAMPLE 26
N - [(3-pyridyl) methyl] -N- [3-phenyl-4
[(L-Methionine) carbonyl] phenyl] benzenesulfonamide
EXAMPLE 26A
4 - [(3-pyridyl) methyl] amino-2-phenylbenzoyl-L-methionine methyl ester
To a solution of the de-qualified 2D compound (500 mg, 1.4 mmol) in dichloromethane is added 3-pyridine-carbaldehyde (132 l, 1.4 mmol) and acetic acid (437 ass, 8.4 mmol). ). After 15 minutes, NaBH (OAc) 3 is added and the resulting medium is stirred for 2 hours at room temperature. The reaction medium is diluted in AcOEt and washed with a saturated solution of NaHCO3. The organic phases are dried over MgSO 4, filtered and evaporated and the residue obtained is purified by flash chromatography on a silica column with a CH 2 Cl 2 / MeOH / NH 4 OH mixture in the proportions 95 / 4.5 / 0.5 to yield a yellowish solid. (524 mg, 84%). H
NMR (400 MHz, CDCl 3) δ 8.62 (d, J = 1.8 Hz, 1H), 8.55 (dd, J = 4.7, 1.8 Hz, 1H), 7.717.67 (m, 2H), 7.43-7.33 (m, 4H), 7.30-7.28 (m, 1H), 6.65 (dd, J = 8.2, 2.0Hz, 1H), 6.49 (d. , J = 2.0Hz, 1H), 5.68 (d, J = 7.6Hz, 1H), 4.62 (dd, J = 9.4, 4.0Hz, 1H), 4.44-4, 37 (m, 2H), 3.61 (s, 3H), 2.11-2.07 (m, 2H), 1.92 (s, 3H), 1.92-1.83 (m, 1H) 1.70-1.61 (m, 1H).

EXAMPLE 26B
N - [(3-pyridyl) methyl] -N- [3-phenyl-4 - [(L-methionine methyl)
ester) carbonyl] phenyl] -benzenesulfonamide
This compound is prepared from the derivative 26A using the procedure described in Example 1D. The residue is purified by flash chromatography on a silica column with a CH 2 Cl 2 / MeOH / NH 4 OH mixture in the proportions 90/9/1 to yield the expected product (163 mg). 1H NMR (400MHz, CDCl3) δ 8.48 (dd, J = 4.7, 1.8Hz, 1H), 8.38 (d, J = 1.8Hz, 1H), 7.72-7.63 ( m, 4H), 7.57-7.48 (m, 3H), 7.39-7.37 (m, 3H), 7.25-7.21 (m, 2H), 7.05-7, (M, 2H), 5.85 (d, J = 7.6Hz, 1H), 4.77 (AB, 2H), 4.62 (dd, J = 9.4, 4.0Hz, 1H), 3.66 (s, 3H), 2.11-2.07 (m, 2H), 1.92 (s, 3H), 1.92-1.83 (m, 1H), 1.70-1, 61 (m, 1H).

EXAMPLE 26
A solution of compound 26B (160 mg, 0.44 mmol) and LiOH (1 M in H 2 O, 880 l, 0.88 mmol) in THF (2 mL) is stirred for 2 hours at room temperature and the resulting solution is concentrated. The residue is purified by a rapid filtration on a thin layer of silica with the mixture CH 2 Cl 2 / MeOH in the proportions 90/10. The product obtained is purified by preparative reverse phase HPLC column C18, 220 nM, UV detector, flow rate 50 mL / m; gradient of 10% acetonitrile and 90% water (0.1% TFA) to 70% acetonitrile (0.1% TFA) in 40 minutes. Fractions> 98% purity are pooled and lyophilized to yield the desired product. 1H NMR (400MHz, CD30D) δ 8.72 (s, 1H), 8.63 (d, J = 5.3Hz, 1H), 8.42 (d, J = 8.1Hz, 1H), 7.80. (dd, J = 8.1, 5.3Hz, 1H), 7.74-7.70 (m, 3H), 7.64-7.60 (m, 2H), 7.44 (d, J = 8.2 Hz, 1H), 7.37-7.20 (m, 5H), 7.18 (dd, J = 8.2, 2.0Hz, 1H), 7.10 (d, J = 2.0 Hz , 1H), 5.06 (s, 2H), 4.47 (dd, J = 9.2, 4.0Hz, 1H), 2.20-2.13 (m, 1H), 2.08-1. , 97 (s + m, H), 1.78-1.75 (m, 1H).

EXAMPLE 27
N- [2- (R) -amino-3-mercaptopropyl] -N- [3-phenyl-4 - [(L-methionine) carbonyl] -
phenyl] benzenesulfonamide
EXAMPLE 27A
To a solution of 4- [2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropyl] amino-2-phenylbenzoyl- (S) -methionine methyl ester (250 mg, 0.32 mmol) prepared by reductive amination of 2D compound with N-BOC-S-tritryl- (R) -cysteine in the presence of acetic acid and NaBH3CN, in pyridine (3 mL) is added phenylsulfonyl chloride (100 l, 0.075 mmol). The resulting yellow solution is stirred for 24 hours at room temperature then the pyridine is co-evaporated with toluene and the residue is diluted in dichloromethane and washed with saturated NaCl solution until neutral. The organic phase is dried over MgSO4> filtered, evaporated and the crude product obtained is used as in the next reaction.

EXAMPLE 27
This compound is obtained using the same sequence of reactions used in Example 1 for the synthesis of Example 1. = 17.8 (c = 0.22, MeOH); 1H NMR (400MHz, CD3OD)? 7.77-7.70 (m, 1H), 7.66-7.58 (m, 4H), 7.55 (d, J = 8.6Hz, 1H), 7H NMR (400 MHz, CD? , 40-7.34 (m, 5H), 7.26 (dd, J = 8.2, 2.0Hz, 1H), 7.16 (d, J = 2.0Hz, 1H), 4.50 ( dd, J = 9.2, 4.0Hz, 1H), 4.00-3.88 (m, 2H), 3.39-3.35 (m, 1H), 2.81-2.78 (m). , 2H), 2.20-2.13 (m, 1H), 2.08-1.97 (s + m, 5H), 1.78-1.75 (m, 1H).

 The following examples illustrate compositions according to the invention. In these examples, the term "active component" refers to one or more (generally one) of the compounds of formula (I) according to the present invention.

tablets
They can be prepared by direct compression or by wet granulation. The direct compression procedure is preferred but may not be suitable in all cases depending on the doses and physical properties of the active component.

A - By direct compression
mg per 1 tablet active component 10.0 microcrystalline cellulose B P. C 89.5 magnesium stearate 0 5
100.0
The active component was passed through a sieve of 250 mesh size, mixed with the excipients and compressed with 6.0 mm punches. Tablets having other mechanical strengths can be prepared by modifying the compression weight and using appropriate punches.

B - By gram
mg for one active component tablet 10.0 lactose Codex 74.5 starch Codex 10.0 pregelatinized maize starch Codex 5.0
magnesium stearate 0 5
Compression weight 100.0
The active component is passed through a 250 μm mesh screen and mixed with lactose, starch and pregelatinized starch. The mixed powders are moistened with purified water, granulated, dried, sieved and mixed with magnesium stearate. The lubricated granules are tableted as for the direct compression formulas. A film of coating can be applied to the tablets by means of suitable film-forming materials, for example methylcellulose or hydroxypropyl methylcellulose, according to conventional techniques. The tablets can also be coated with sugar.

capsules
mg for one capsule active ingredient 10.0 starch 1500 89.5 magnesium stearate Codex 0.5
Filling weight 100.0
The starch used is a directly compressible starch form from Colorcon Ltd., Orpington, Kent, United Kingdom.

 The active component is passed through a 250 μm mesh sieve and mixed with the other substances. The mixture is introduced into hard gelatin capsules No. 2 on a suitable filling machine Other dosage units can be prepared by changing the filling weight and, when necessary, changing the size of the capsule .

Syrup
mg per dose of 5 ml active ingredient 10.0 sucrose Codex 2750.0 glycerin Codex 500.0 buffer) aroma dye) qs

preservative) distilled water 5.0
The active ingredient, buffer, flavor, color and preservative are dissolved in part of the water and the glycerin is added. The remainder of the water is heated to 80 ° C. and the sucrose is dissolved therein, then cooled, the two solutions are combined, the volume is adjusted and the mixture is mixed in. The syrup obtained is clarified by filtration.

suppositories
Active component 10.0 mg
Witepsol H15 (E) supplement to 1.0 g
Witepsol H15 (g) is a brand marketed by Adeps Solidus of the
European Pharmacopoeia.

 A suspension of the active component in Witepsol H15 is prepared and introduced into a suitable machine with 1 g suppository molds.

Liquid for administration by intravenous injection
g / l active component 2.0 water for injection Codex supplement to 1000.0
Sodium chloride can be added to control the tonicity of the solution and adjust the pH to maximum stability and / or to facilitate the dissolution of the active component by means of a dilute acid or alkali or by adding buffer salts appropriate. The solution is prepared, clarified and filled into ampoules of appropriate size which is sealed by melting the glass. The liquid for injection can also be sterilized by autoclaving in one of the acceptable cycles. It is also possible to sterilize the solution by filtration and to introduce sterile ampoule under aseptic conditions. The solution can be introduced into the ampoules in a gaseous atmosphere.

Inhalation cartridges
g / micronized active ingredient cartridge 1.0 lactose Codex 39.0
The active component is micronized in a fluid energy mill and placed in the form of fine particles before mixing with lactose for tablets in a high energy mixer. The powder mixture is introduced into hard gelatin capsules No. 3 on a suitable encapsulating machine The contents of the cartridges are administered by means of a powder inhaler.

Aerosol under pressure with metering valve
mg / dose per micronized active ingredient box 0.500 120 mg oleic acid Codex 0.050 12 mg trichlorofluoromethane for pharmaceutical use 22.25 5.34 g dichlorodifluoromethane for pharmaceutical use 60.90 14.62 g
The active component is micronized in a fluid energy mill and placed in the form of fine particles. The oleic acid is mixed with trichlorofluoromethane at a temperature of 10-15 ° C. and the micronised drug is introduced into the solution using a high-shear mixer. aluminum aerosol cans on which appropriate dosing valves are fixed, delivering a dose of 85 mg of the suspension, the dichlorodifluoromethane is introduced into the cans by injection through the valves.

 The derivatives of the present invention are inhibitors of prenylation of proteins and more particularly of farnesylation of Ras proteins as shown by the inhibition studies of farnesyl transferase protein and geranylgeranyl protein transferase.

A) Evaluation of the inhibition of Farnesyl Protein Transferase
Principle
Farnesylation of the inylated peptide GCVLS, catalyzed by the Protein enzyme
Farnesyl transferase causes a change in the emission spectrum of the dansyl group, and in particular an increase in the emission at 505 nm when the molecule is excited at 340 nm. Measured by spectrofluorometer, this emission is proportional to the activity of the enzyme (Pompliano et al., J. Am Chem Chem S 1992, 114: 7945-7946).

Equipment
Reaction buffer: 55 mM TRIS / HCI Ph 7.5; 5.5 mM DTT; 5.5 mM MgCl 2; 110 ', 1M ZnCl 2, 0.22% N octyl-ss-D-glucopyranoside.

substrates
Farnesyl pyrophosphate (FPP) provided by Sigma.

Peptide dansylé GCVLS provided by the company Neosystem, Strasbourg, France.

Enzyme:
Protein Farnesyl Transferase is partially purified from beef brain by Q-Sepharose ion exchange chromatography, provided by the company
Pharmacia, following the protocol described by Moores et al., J. Biol. Chem. 1991, 266 14603-14610, Reiss et al., Cell 1990, 62: 81-88).

Method
The reaction mixture containing 2.2 μM FPP and 2.2 μM dansyl-GCVLS was prepared on ice with or without the amount of enzyme giving an intensity of 100 to the spectrofluorimtre after incubation for 10 minutes at 37 ° C.

In an Eppendorf tube, 360 CIL of reaction mixture is mixed with 40 μl of a compound according to the invention concentrated ten times, or 40 μl of a solvent. The whole is incubated for 10 minutes at 37 ° C. The reaction is stopped on ice and the intensity of the fluorescence is measured under the following conditions: excitation 340 nm, slit 4 nm, emission 505 nm, slit 10 nm. The results are expressed as percent inhibition, in which case the derivatives of the present invention have been identified as potent inhibitors of Farnesyl Protein.
Transferase. Indeed IC50 <10, uM is found.

B) Evaluation of the Inhibition of Geranslgeranyl Protein Transferase I
Equipment
Reaction buffer: 55 mM TRIS / HCI Ph 7.5; 5.5 mM DTT; 5.5 mM MgCl 2, 110 zM ZnCl 2, 0.22% N octyl-s-D-glucopyranoside.

Substrates 3H-geranylgeranyl pyrophosphate (GGPP), 66, μM, C1 / mmol provided by the company
Isotopchim.

Recombinant Rho-GST protein
Enzyme:
GGTase is partially purified from beef brain by Q-Sepharose ion exchange chromatography provided by Pharmacia and then eluted at 0.23 and 0.4 M NaCl following the protocol described by Moores et al. J. Biol.

 Chem. 1991, 266: 14603-14610; Reiss et al., Cell 1990, 62: 81-88).

Method
The reaction mixture containing 220 nM of 3H-GGPP, 0.5 μM Rho-GST with or without 5 μL of GGTase per assay is prepared on ice.

 In an Eppendorf tube, 45 μl reaction mixture is mixed with 5 μl of a compound of the invention concentrated ten times or with 5 μl of solvent. The whole is incubated for 45 min at 37 ° C. An aliquot of 45 μl is deposited on a numbered P81 phosphocellulose filter, washed in a mixture of 95% ethanol and 75 mM phosphoric acid in the proportions 1/1. The aliquot is counted by scintillation.

 The tests are performed in duplicate.

 The results are expressed as percent inhibition. By way of illustration, the compound of Example 15 of the present invention inhibits 50% of GGTase activity at 10J.

The derivatives of the present invention are inhibitors of enzymes which catalyze the prenylation of proteins and more particularly of PFTase enzymes and
GGTase. They are distinguished from the closest derivatives of the prior art, not only by their original chemical structure but also by their biological activity and more particularly by their effectiveness in inhibiting prenylation enzymes such as
PFTase.

dans laquelle A est le résidu SO2(2-thiényl) s'avère être, de façon tout à fait inattendue, un bien meilleur inhibiteur de la PFTase que les dérivés les plus proches de l'art antérieur de formule (VIII) dans laquelle A est l'hydrogène ou le résidu CO(2-thiényl) comme l'indiquent les résultats rassemblés dans le tableau suivant.

Thus, as an illustrative example, the compound of Example 17 of the present invention of Formula VIII

in which A is the residue SO2 (2-thienyl) turns out to be, quite unexpectedly, a much better inhibitor of the PFTase than the closest derivatives of the prior art of formula (VIII) in which A is hydrogen or the residue CO (2-thienyl) as indicated by the results summarized in the following table.

<Tb>

<SEP> A <SEP> Reference <SEP> 1C50 <SEP> (PFTase, <SEP> nM)
<tb> H <SEP> Request <SEP> of <SEP> Patent <SEP> WO <SEP> 97/17070 <SEP> 1500
<tb> CO (2-thienyl) <SEP> Application <SEP> of <SEP> Patent <SEP> WO <SEP> 96/30015 <SEP> 500
<tb> SO2 (2-thienyl) <SEP> Example <SEP> 17 <SEP> of <SEP> the <SEP> present <SEP> invention <SEP> 29
<Tb>

Claims (19)

 benzoisoxazole, benzimidazole, chroman.  benzothiophene, indole, indoline, benzothiazole, benzopyran, benzoxazole,  pyrimidine, quinazoline, quinoline, quinoxaline, tetraphydroquinoline, benzofuran, CH2CH = CH2, CH2SH, CH2SCH3, CH2SCH2C6H5, CH2CH2SC6H5, CH2CH2S (2thienyl) and m represents an integer between 1 and 4 Rs represents a hydrogen or a linear or branched alkyl chain comprising from 1 to 6 carbon atoms or a benzyl, their salts, hydrates and solvates physiologically acceptable for therapeutic use, in the above definitions, aryl represents phenyl, naphthyl, tetrahydronaphthyl, indanyl, and heteroaryl represents a residue selected from a furan, pyrrole, thiophene, thiazole, isothiazole, oxadiazole , imidazole, oxazole, isoxazole, pyridine, R1 is CH2CH2SCH3, CH2CH2S (O) CH3, CH2CH2SO2CH3, (CH2) mNHCOCH3, CH2OH, CH2CH2OH, CH2CH (CH3) 2, (CH2) mCONH2, (CH2) mCONHCH3, (CH2) mCONMe2, (CH2) 3 CH3, CH2OCH3, CH2CH20CH3, R3, which may be at any of the free positions of the aromatic ring to which it is attached, represents H, Cl, CF3, Br, I, F, SiMe3 or an aryl or heteroaryl residue; R2 represents a saturated or unsaturated, linear or branched alkyl residue comprising from 1 to 20 carbon atoms, an aryl, alkylaryl, heteroaryl or alkylheteroaryl residue, which may be variously substituted with one or more residues chosen from Rg, OH, OR9, SH; , SRs, NHR9Rlo, CORs, CONR9R10, COOLS, NHCOR9, CF3, NO2, CN, Cl, F, Br, OCF3 in which Rg and Rlo, which may be identical or different, represent an alkyl radical comprising from 1 to 5 carbon atoms in chain straight or branched, an aryl or heteroaryl residue; OCH3, CN, NO2; Y represents O, S or NR6; R6 is hydrogen, R'6 or SO2R'6; R7, Rg and R'8, which may be identical or different, represent a hydrogen, a linear or branched alkyl residue comprising from 1 to 6 carbon atoms, a phenyl, thienyl, benzyl or phenethyl residue in which the aromatic ring may optionally be substituted by a linear or branched alkyl radical containing from 1 to 6 carbon atoms or else Cl, Br, F, CF 3, OCH 3, CN, NO 2; R'6 represents a linear or branched alkyl radical containing from 1 to 6 carbon atoms, a phenyl, thienyl, benzyl or phenethyl radical in which the aromatic nucleus may optionally be substituted by a linear or branched alkyl radical containing from 1 to 6 atoms carbon, or by Cl, Br, F, CF3, Z represents CH or N;  wherein,

R1 represents a residue selected from X represents (CH2) n, CO, (CH2) nCO, CO (CH2) n, where n represents an integer between 1 and 5,  in which

 1. Compounds corresponding to the general formula (I) 2. Compounds according to claim 1, characterized in that the asymmetric carbon  carrying the substituent R4 is of (R) configuration. 3. Compounds according to claim 1, characterized in that the asymmetric carbon  carrying the substituent R4 is of (S) configuration. 4. Compounds according to claim 1, characterized in that R3 represents a residue  phenyl. 5. Compounds according to claim 1, characterized in that R1 represents a residue  pyridyl or imidazolyl. 6. Compounds according to claim 1, characterized in that R4 represents  CH 2 CH 2 CH 3, CH 2 CH 2 SCH 3, CH 2 CH 2 SO 2 CH 3, CH 2 CH 2 CONH 2 or CH 2 CH 2 CON (CH 3) 2. 7. Compounds according to claim 1, characterized in that R4 represents  CH 2 CH (CH 3) 2 or (CH 2) 3 CH 3. 8. Compounds according to claim 1, characterized in that R5 represents a  methyl or isopropyl. 9. Compounds according to claim 1, characterized in that R1 represents CH (NE6) CH2SH. 10. Compounds according to claim 1, characterized in that R5 represents a  hydrogen. 11. Process for the preparation of the compounds of general formula (I) according to one of the  claim 1 and wherein R5 represents an alkyl or benzyl residue,  characterized in that an intermediate of general formula (II) is condensed

 wherein R1, R2, X and R3 are as previously defined and L represents OH, Cl, imidazole, or the group C (= O) L represents the activated form of a carboxylic acid, which is conducive to the formation of an amide after reaction with an amine, with an amine or the hydrochloride derivative an amine of general formula (III)

 the general formula (I).  wherein R5 represents an alkyl or benzyl residue and R4 is defined as in 12. The method of preproduction of the compounds according to claim 10, characterized in that  a compound of the general formula (I) in which R5 is  remain alkyl or benzyl with lithium hydroxide, potassium hydroxide or sodium hydroxide. 13. Process for the preparation of the compounds of general formula (I) according to one of the  Claims 1 to 10, characterized in that an intermediate of  general formula (VII)

 requiring activation during condensation.  as Br, Cl, I, OMes, OTos, OTf or a precursor of a leaving group  R1, R2 and X are defined as before and L 'represents a leaving group  with successively two electrophiles which are L'-X-R1 and ClSO2R2 in which  in which R ;, R4 and R5 are defined as above, 14. Compounds according to one of claims 1 to 10 for their application as  therapeutically active substances. Compounds according to claim 14 for the treatment or prevention of  cancers. 16. Compounds according to claim 14 for both curative and preventive treatment  disorders related to farnesylation and geranylgeranylation of proteins. 17. Compounds according to claim 14 for the treatment or prevention of  restenosis or atherosclerosis. 18. Compounds according to claim 14 for the treatment or prevention of  viral infections due to the delta liver virus. 19. Pharmaceutical compositions containing as an active ingredient a compound  according to one of claims 1 to 18 or a salt thereof and an excipient  pharmaceutically acceptable.