FR2774987A1 - New 4-amino chroman or thiochroman 8-carboxamide derivative farnesyl transferase inhibitors, used as antiproliferative agents, e.g. for treating cancer - Google Patents

Abstract

4-Amino-chroman (or thiochroman) 8-carboxamide derivatives (I) are new. Novel intermediates are also claimed. (Thio)chromans of formula (I), in racemic or stereoisomeric form, and their salts are new. R1 = (i) -COCH(NH2)CH2SH, (ii) -CH2CH(NH2)CH2SH or (iii) -CH(R11)(R12); R2 = H, alkyl, aralkyl, aryl, alkylcarbonyl, aralkylcarbonyl, arylcarbonyl or heteroarylalkyl; R3 = H, halo, alkyl, aryl or aralkyl; R4 = -CH(R13)(R14); R5 = H or -C(O)-R15; R6-R8, R12 = H, alkyl, aryl or aralkyl; X = O, S, SO or SO2; R11 = heterocyclyl (optionally substituted by one or more of halo, alkyl (optionally mono- or disubstituted by phenyl), alkoxy, alkylthio, cycloalkylalkyl, or aralkyl or heteroarylalkyl (both optionally ring substituted by one or more of halo, alkyl, alkoxy, CN, NO2, amino (optionally substituted by alkylcarbonyl), alkylsulfonyl, polyfluoroalkyl, polyfluoroalkoxy, polyfluoroalkylthio, aryl or heteroaryl (optionally substituted by one or more of halo, alkyl or alkoxy), aralkyl or aryloxy)); R13, R14 = H; or aryl or heteroaryl (both optionally substituted by one or more of halo, alkyl, alkoxy, OH, NO2, NH2, polyfluoroalkoxy or aralkoxy); provided that R13 and R14 are not both H; R15 = OH, alkoxy, amino, aralkylamino, alkylamino or -NHCH(COOR16)(CH2)2SCH3; R16 = H or alkyl. Independent claims are included for the novel intermediates of formula (II) and (XIV); and for the preparation of (I), (II) (or their protected derivatives) and esters of (XIV).

Description

NOVEL DERIVATIVES OF CONDENSED HETEROCYCLIENT SYSTEMS

  THEIR PREPARATION, THE PHARMACEUTICAL COMPOSITIONS WHICH THEY

  CONTAIN AND THEIR USE FOR THE PREPARATION OF

DRUGS

  The present invention relates to novel 4-amino-8-carboxy derivatives.

  (thio) chromanes of general formula (I) -N

4

6x

3 R

X x, R6 R4 Rs

R4 R (I)

  their preparation, the pharmaceutical compositions which contain them and their

  use for the preparation of drugs.

  Farnesyl transferase protein is an enzyme that catalyzes the transfer of the farnesyl moiety from farnesyl pyrophosphate (FPP) to the terminal cysteine residue of the CAAX tetrapeptide sequence of a number of proteins and

  p1 1 Ras protein, expressing the ras oncogene.

  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 p2 1 Ras 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).

  Inhibition of farnesyl transferase and therefore farnesylation of the p21Ras protein blocks the ability of the mutated p21Ras 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 signaling pathway uses the farnesylation of a protein, such as a normal p21Ras protein (Nagasu et al., Cancer Research 55, 5310-5314,

  1995; Sepp-Lorenzino et al., Cancer Research 55, 5302-5309, 1995).

  Inhibitors of farnesyl transferase may therefore be inhibitors of

  cell proliferation and therefore antitumor and anti-tumor agents.

  leukemic. 1,5-disubstituted tetrahydronaphthyl derivatives have been described in WO 96/22278 as having an in vitro enzyme inhibitory activity of famesyl transferase at concentrations greater than 1 OnM, as well as

  1,2,3,4-tetrahydroisoquinoline derivatives, 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 means 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 or sulfur-containing heterocyclic system, distinct from that of the compounds of the art. previous cited, show their inhibitory activity both enzymatically (of the order of 10-9M) at the cellular level, and this at concentrations quite significant. Because of this activity, the compounds of general formula (I) are therefore agents

  anti-tumor and anti-leukemic drugs.

  Nothing in the prior art suggested making such a change in the chemical structure and did not predict advantageous anti-cancer properties.

  manifested by the present compounds.

  In addition, according to the invention, the novel products of general formula (I), farnesyl transferase inhibitors, can be competitive with respect to a substrate of the Alesyl Transferase, such as those described by ADCox and CJDer, Biochimica and Biophysica acta, 1333 (1997), 51-71 and in particular the protein p21, Rho, H-Ras, Ki-Ras, N-Ras; this feature allows them to act specifically at the substrate. The present invention relates to new derivatives of general formula (I)

4

Y N / R6

-C *

R4 R5 (I)

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

  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: 2 diastereoisomers, and 2 enantiomers, the enantiomers possibly being in the form of a racemic mixture. All the stereoisomeric forms of the compounds of the general formula (I)

also part of the invention.

  Particularly advantageously, C * has the configuration (S).

  In what precedes and what follows, the expression "stereoisomer", defines the pure form

  of said stereoisomer or optionally the mixture of "enriched" stereoisomers, that is,

  that is, containing predominantly said stereoisomer or said form.

  In the foregoing definitions and those which follow, and unless otherwise specified: the radicals and alkyl portions contain 1 to 6 carbon atoms in a straight or branched chain, and especially include methyl, ethyl, propyl, butyl and pentyl radicals and portions; , hexyl and their isomers iso, sec., tert, - the term halogen defines the fluorine, chlorine, bromine and iodine atoms, - the term aryl defines a 6 to 10 membered aromatic system, and in the definitions of R1, R2, R3, R5 and R6, and unless otherwise stated, aryl radicals, and aryl portions, especially in aralkyl, such as benzyl, may optionally be substituted by one or more atoms or radicals, selected from halogen atoms or alkyl, alkoxy, cyano, nitro, amino, alkylthio, alkylsulfonyl, polyfluoroalkyl radicals, such as trifluoroalkyl, such as trifluoromethyl, polyfluoroalkoxy, such as trifluoroalkoxy, such as trifluoromethoxyv preferentially aryl represents the phenyl radical the term BOC defines the tert.butoxycarbonyl radical, - the term Ph defines the phenyl radical, - the term Hal defines a halogen atom such as Fluorine, Chlorine, Bromine, Iodine, in the general formula (I ): RI represents a radical chosen from the radicals -CO-CH (NH2) -CH2SH, or

-CH2-CH (NH2) -CH2SH,

  optionally of racemic configuration or that of their stereoisomers, and more particularly of the configuration of the natural amino acids, or the radicals of formula R 1 R 1, R 2 represents a hydrogen atom, an alkyl, aralkyl, aryl, alkylcarbonyl, aralkylcarbonyl or arylcarbonyl radical, heterocyclylalkyl; R3 represents a hydrogen atom or a halogen atom or an alkyl, aryl or aralkyl radical; R4 represents a radical R13 CH4 R14 R5 represents a hydrogen atom, or a radical -C (O) -Ris, or a radical -NH-CH (CO2Ri6) (CH2) 2 -S-CH3, R6 represents an atom of hydrogen or an alkyl, aryl, aralkyl radical; R7, R8 independently represent a hydrogen atom or an alkyl, aryl, aralkyl radical; X represents an oxygen atom or a radical -S (O) 1, for which I is equal to 0, 1 or 2; R 1, represents an optionally substituted heterocyclyl radical, the term heterocyclyl defining here a cyclic radical, saturated or unsaturated, of 5 to members and containing 1, 2, 3 or 4 nitrogen atoms, and optionally another heteroatom selected from the atoms oxygen or sulfur; Said radical may in particular be chosen from pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indolizinyl, isoindolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl radicals. , pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl, triazolyl, tetrazolyl, thiazolyl, thiazolidinyl, oxazolyl, oxazolinyl, isothiazolyl, isoxazolyl, each heterocycle being optionally substituted on any one or more of atoms or heteroatoms which constitute it, with one or more atoms or radicals chosen from halogen atoms and alkoxy, alkyl, aralkyl or aryl radicals, the portions or aryl radicals of which are themselves optionally substituted by one or more atoms or radicals, chosen from halogen atoms and / or alkyl, alkoxy, cyano, nitro, amino, alkylthio, alkylsulfonyl, polyfluoroalkyl, such as polyfluoroalkyl, such as trifluoromethyl, polyfluoroalkoxy, such as trifluoroalkoxy, such as trifluoromethoxy, polyfluorothioalkyl; preferably, R 1, represents a heterocyclyl radical optionally substituted with one or more atoms or radicals chosen from halogen atoms and / or alkoxy, alkyl or aralkyl radicals, advantageously substituted by aralkyl, such as benzyl; R12 represents a hydrogen atom, or a radical chosen from alkyl, aryl or aralkyl, R13, R14, which may be identical or different, independently represent a hydrogen atom, or an aryl radical, with for these radicals, aryl defining an aromatic system of 6; 10-membered ring, optionally consisting of a single ring or of two fused rings, said system possibly being optionally heteroaromatic and in this case containing a

  or a plurality of heteroatoms selected from oxygen, nitrogen or sulfur atoms.

  Preferably, said aryl radical may be chosen from naphthyl radicals, such as 2-naphthyl, indolyl, such as 3-indolyl, or phenyl; it may optionally be substituted with one or more substituents chosen from halogen atoms, and alkyl, hydroxy, nitro, amino, alkoxy or aralkoxy radicals, it being understood that R13 and R14 do not each simultaneously represent a hydrogen atom; R 1 is a radical selected from hydroxy, alkoxy, amino, aralkylamino, alkylamino; or a radical -NH-CH (CO2Ri6) - (CH2) 2 -S-CH3

  R16 represents a hydrogen atom or an alkyl radical.

  Among the products of general formula (I), those for which R 1 represents a radical -CO-CH (NH 2) -CH 2 SH, or -CH 2 -CH (NH 2) -CH 2 SH, preferably of configuration of the natural amino acid, are preferred, or an optionally substituted heterocyclylalkyl radical; more particularly, RI represents a 4 (5) -inmidazolylmethyl radical, optionally substituted by an aralkyl radical; among the radicals R2, it is preferred to choose a hydrogen atom, an acetyl or alkyl radical, and more particularly, R2 represents a hydrogen atom or an alkyl radical; preferably, R3 represents a hydrogen or fluorine atom, and in particular advantageously substituted on the benzo ring at the 6-position; advantageously, R 3 represents a hydrogen atom;

  preferably, R4 may represent a radical chosen from the following radicals -

  CH 2 - (2-naphthyl), -CH 2 - (3-indolyl), -CH- (phenyl) 2, -CH 2 (phenyl) with the phenyl ring being optionally substituted, preferably in position 3 and / or 4, by a or more substituents independently selected from halogen atoms, or alkyl, hydroxy, nitro, amino, alkoxy, or aralkoxy radicals; advantageously, R 4 represents a radical -CH 2 (phenyl), with phenyl substituted with halogen or alkoxy at the 4-position; preferably, Rs represents a radical -C (O) -Ris for which Ris represents a

  hydroxy, methoxy, ethoxy, or amino radical, or a -NH-CH (CORi6) (CH2) radical;

  S-CH3, for which R16 represents a hydrogen atom or an alkyl radical; advantageously, R 5 represents a -C (O) NH 2 radical; preferentially, R6 represents a hydrogen atom; preferably, R7 and R8 each represent a hydrogen atom; preferably, X represents an oxygen atom, a sulfur atom or -SO2;

  advantageously, X represents an oxygen atom.

  As preferred compounds according to the invention, mention will be made especially of those represented in general formula (I) in which: R1 represents a radical -CO-CH (NH2) -CH2SH, or -CH2-CH (NH2) -CH2SH, preferentially of configuration of the natural amino acid, or a 4 (5) -imidazolylmethyl radical, of which the 4-imidazolyl radical is optionally substituted; R2 represents a hydrogen atom or an alkyl radical; R3 represents a hydrogen or fluorine atom; ,

  R4 represents a radical chosen from the following radicals: -CH2- (2naphthyl), -CH2-

  (3-indolyl), -CH- (phenyl) 2, -CH 2 (phenyl) with the phenyl ring being optionally substituted, preferably in position 3 and / or 4, with one or more substituents chosen independently from halogen atoms or by the radicals alkyl, hydroxy, nitro, amino, alkoxy, or aralkoxy, R5 represents a radical -C (O) -Ris for which R15 represents a hydroxyl, alkoxy or amino radical, or a radical -NHCH (CO2Ri6) - (CH 2) 2 -S-CH 3, for which R 6 represents a hydrogen atom or an alkyl radical, R 6 represents a hydrogen atom, R 7 and R 8 each represent a hydrogen atom, X represents an oxygen atom; , a sulfur atom, or -SO,

  in racemic form or their stereoisomers as well as their salts.

  By way of nonlimiting illustration of the claimed compounds, mention may be made especially of any compound of general formula (I), selected individually from:

  N- (1 - (S) -carbamoyl-2-phenyl-ethyl) -4- (2- (R) -amino-3-mercaptopropylamino)

chroman-8-carboxamide

  N- (1 - (S) -carbamoyl-2-phenyl-ethyl) -4- (2- (R) amino-3- ethyl ester of ethyl ester

  mercapto-propylamino) -chroman-8-carboxylic acid

  N- (1 (S) -carboxy-2-phenyl-ethyl) -4- (2 (R) -amino-3-mercaptopropylamino) chroman-

  N- (2-phenyl-ethyl) -4- (2 (R) -amino-3-mercaptopropylamino) chroman-8-carboxamide 8-carboxamide

  [4- (2 (R) -amino-3-mercapto-propylamino) -chromane] -8-carbonyl-L-Lphénylalanyl

methionine

  N- (I (S) -benzylcarbamoyl-2-phenyl-ethyl) -4- (2 (R) -amino-3-mercaptopropylamino)

chroman-8-carboxamide

  N- (1 (S) -N-butylcarbamoyl-2-phenylethyl) -4- (2 (R) -amino-3-mercaptopropylamino)

chroman-8-carboxamide

  N- (1 (S) -carbamoyl-2-phenyl-ethyl) -4- (2 (R) -amino-3-mercaptopropylamino) -6-

fluoro-chroman-8-carboxamide

  N - ((S) -carbamoyl-2-phenyl-ethyl) -4- (2 (R) -amino-3-mercaptopropylamino) 6-

fluoro-chroman-8-carboxamide

  N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- (2 (R) -amino-3-mercapto

propylamino) -chroman-8-carboxamide

  N- [1 (S) -carbamoyl-2- (4-methoxyphenyl) ethyl] -4- (2 (R) -amino-3-mercapto

propylamino) -chroman-8-carboxamide

  N- [I (S) -carbamoyl-2- (4-fluorophenyl) ethyl] -4- (2 (R) -amino-3-mercapto)

propylamino) -chroman-8-carboxamide

  N- [1 (S) -carbamoyl-2- (4-nitrophenyl) ethyl] -4- (2 (R) -amino-3-mercapto

propylamino) -chroman-8-carboxamide

  N- [I (S) -carbamoyl-2- (4-hydroxyphenyl) ethyl] -4- (2 (R) -amino-3-mercapto)

propylamino) -chroman-8-carboxamide

  N- [1 (S) -carbamoyl-2- (3,4-dichlorophenyl) ethyl] -4- (2 (R) -amino-3-mercapto

propylamino) -chroman-8-carboxamide

  N- [1 (S) -carbamoyl-2- (4-methylphenyl) ethyl] -4- (2 (R) -amino-3-mercapto

propylamino) -chroman-8-carboxamide

  N- [1 (S) -carbamoyl-2- (4-bromophenyl) ethyl] -4- (2 (R) -amino-3-mercapto

propylamino) -chroman-8-carboxamide

  N- [1 (R) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- (2 (R) -amino-3-mercapto

propylamino) -chroman-8-carboxamide

  N- [2- (4-aminophenyl) -1 (S) -carbamoyl-ethyl] -4- (2 (R) -amino-3-mercapto)

propylamino) -chroman-8-carboxamide

  N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-cyanobenzyl) -1H-imidazol-4-

  yl] methylamino-chroman-8-carboxamide

  N- [I (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- (1-methyl-1H-imidazole)

  yl) méthylamnno-chroman-8-carboxamide

  N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-cyanobenzyl) -1H-imidazol-5-

  yl] methylamino-chroman-8-carboxamide

  N- [1 (S) -carbamoyl-2- (4-chlorophenyl) -ethyl] -4- {N-acetyl- [1- (4-cyanobenzyl) -1H-

  imidazol-5-yl-methyl] amino} -chroman-8-carboxamide

  N- [1 (S) -carbamoyl-2- (4-benzyloxyphenyl) -ethyl] -4- [1 - (4-cyanobenzyl) imidazole)

  yl] methylamino-chroman-8-carboxamide

  N- (1 - (S) -carbamoyl-2-phenyl-ethyl) -4- (2- (R) -amino-3-mercaptopropionylamino)

chroman-8-carboxamide

  N- (I - (S) -carbamoyl-2- (indol-3-yl) ethyl) -4- (2- (R) -amino-3-mercapto)

  propionylamino) -chroman-8-carboxamide

  N- [I - (S) -carbamoyl-2- (4-hydroxyphenyl) ethyl] -4- (2- (R) -amino-3-mercapto)

  propionylamino) -chroman-8-carboxamide

  N- [1 - (S) -carbamoyl-2- (2-naphthyl) ethyl] -4- (2- (R) -amino-3-mercapto)

  propionylamino) -chroman-8-carboxamide

  N- [1 - (R) -carbamoyl-2- (2-naphthyl) ethyl] -4- (2- (R) -amino-3-mercapto)

  propionylamino) -chroman-8-carboxamide

  N- [1 (S) -methoxycarbonyl-2- (4-chlorophenyl) ethyl] -4- [1 - (4cyanobenzyl) -1H-

  imidazol-5-yl] methylamino-thiochroman-8-carboxamide

  N- [I (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1 - (4-cyanobenzyl) -1H-imidazol-5-one.

  yl] methylamino-thiochroman-8-carboxamide

  (N- [I (S) -methoxycarbonyl-2- (4-chlorophenyl) ethyl] -4- [1 - (4cyanobenzyl) -1H-

  imidazol-5-yl] methylamino-1,1-dioxothiochroman-8-carboxamide

  N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-cyanobenzyl) -1H-imidazol-5-

  yl] methylamino-1,1-dioxothiochroman-8-carboxamide 11

  N- [I (S) -carbamoyl-2- (4-bromophenyl) ethyl] -4- [1- (4-cyanobenzyl) -1 Himidazol-5-

  yl] methylamino-chroman-8-carboxamide

  N- [1 (S) -carbamoyl-2- (4-fluorophenyl) ethyl] -4- [1- (4-cyanobenzyl) -1H-imidazol-5-

  yl] methylamino-chroman-8-carboxamide

  N- [1 (S) -carbamoyl-2- (4-methoxyphenyl) ethyl] -4- [1- (4-cyanobenzyl) -1H-imidazol-5-

  yl] méthylanino-chroman-8-carboxamide

  N- [1 (S) -carbamoyl-2- (4-benzyloxyphenyl) -ethyl] -4- [1- (4-cyanobenzyl) -1H-imidazole-

  yl] methylamino-chroman-8-carboxamide

  N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- {N- [I - (4-cyanobenzyl) H-imidazol)

  yl-methyl] ethylamino-chroman-8-carboxamide

  N- [I (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-chlorobenzyl) -1H-imidazol-5-

  yl] methylamino-chroman-8-carboxamide

  N- [I (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-nitrobenzyl) -1H-imidazol-5-

  yl] methylamino-chroman-8-carboxamide

  N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-trifluoromethoxybenzyl) -1H-

  imidazol-5-yl] methylamino-chroman-8-carboxamide

  N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-trifluoromethylbenzyl) -1H-

  imidazol-5-yl] methylamino-chroman-8-carboxamide

  N- [1 (S) -carbamoyl-2- (4-chlorophenyl) -ethyl] -4- [1-benzyl-I Himidazol-5-

  yl] methylamino-chroman-8-carboxamide

  N- [1I (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-methoxybenzyl) -1H-imidazole)

  yl] methylamino-chroman-8-carboxamide

  N- [I (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-fluorobenzyl) -1H-imidazol-5-

  yl] methylamino-chroman-8-carboxamide

  N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1 - (4-methanesulfonylbenzyl) -1H-

  imidazol-5-yl] methylamino-chroman-8-carboxamide

  or their other stereoisomers, or in racemic form as well as their salts.

  More preferentially, mention may be made, according to the invention, of any compound of general formula (I) selected individually from:

  N- [I (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- (2 (R) -armino-3-mercapto)

propylamino) -chroman-8-carboxamide

  N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-cyanobenzyl) -1H-imidazol-5-

  yl] methylamino-chroman-8-carboxamide

  N- [1 (S) -carbamoyl-2- (4-bromophenyl) ethyl] -4- [1 - (4-cyanobenzyl) -1 Himidazol-5-

  yl] methylamino-chroman-8-carboxamide

  N- [I (S) -carbamoyl-2- (4-fluorophenyl) ethyl] -4- [1- (4-cyanobenzyl) -1H-imidazol-5-

  yl] methylamino-chroman-8-carboxamide

  N- [I (S) -carbamoyl-2- (4-methoxyphenyl) ethyl] -4- [1- (4-cyanobenzyl) -1H-imidazol-5-

  yl] methylamino-chroman-8-carboxamide

  N- [I (S) -carbamoyl-2- (4-benzyloxyphenyl) ethyl] -4- [I - (4-cyanobenzyl) -1H-imidazole;

  yl] methylamino-chroman-8-carboxamide

  N- [I (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- {N- [1H- (4cyanobenzyl) -1H-imidazol-

  yl-methyl] ethylamino-chroman-8-carboxamide

  N- [I (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-chlorobenzyl) -1H-imidazol-5-

  yl] methylamino-chroman-8-carboxamide

  N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-trifluoromethoxybenzyl) -1H-

  imidazol-5-yl] methylamino-chroman-8-carboxamide

  or their other stereoisomers, or in racemic form as well as 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 general formula (I) are proposed. Of course, are included in the present invention the

  analogous processes to lead to these same compounds.

  According to the present invention, the products of general formula (I) in which R1, R2, R3, R4, R5, R6, R7, R8 and X are as defined in general formula (I), can be obtained from the product of general formula (IIa) HN-G1

R3 / R7

R 7s X8

O N6

  In which R3, R4, R5, R6, R7, R8, X are as defined in general formula (I) and G1 represents a hydrogen atom, ie, when Ri represents the radical -CO -CH (NH2) -CH2SH, by action of a protected amino acid of general formula

HO2C-CH (NHG2) -CH2SG3 (III)

  wherein G2 represents a protecting group of an amino function such as a benzyloxycarbonyl, tert.butoxycarbonyl or vinyloxycarbonyl radical, and G3 represents a mercapto protecting group such as for example triphenylmethyl. Advantageously, according to the invention, G 2 represents a radical BOC and G 3 represents

  a triphenylmethyl radical (-CPh3).

  Generally, this reaction is carried out by coupling the amino acid

  suitably protected, in the presence of 2- (1H-benzotriazol-1-yl) -, 1,3,3-

  tetramethyluronium hexafluorophosphate (HBTU), N-hydroxybenzotriazole (HOBT) and diisopropylethylamine in an organic solvent for example consisting of a mixture of N-methylpyrrolidone (NMP) and dimethylformamide (DMF), followed by a deprotection reaction of the protecting groups amino groups and

mercapto, described below.

  In particular, this reaction can be carried out by solid phase synthesis, according to which the products are synthesized under the conditions described above, but

  operating from protected amino acids, advantageously by the grouping 9-

  fluorenylmethoxycarbonyl (Fmoc) and grafted onto resin, then finally cleaved from the

  resin in an acid medium, such as trifluoroacetic acid, after the coupling reaction.

  or when R1 represents the -CH2-CH (NH2) -CH2SH radical, by the action of a reagent of general formula H

O '"SG3

NHG,

NHG, (IV),

  in which G 2 and G 3 are defined as above, followed by a deprotection reaction of the amino and mercapto radicals by cleavage of the protecting groups G,

and G3, described below.

  Generally, the reaction of the product of general formula (IV) with the product of general formula (II) is carried out under reducing amination conditions, in particular by operating, for example, in an organic solvent such as acetonitrile or methanol, the presence of acid, such as acetic acid, on 3 A molecular sieves, then by the action of a reducing compound, such as in particular sodium cyanoborohydride (NaBH3CN) or sodium triacetoxyborohydride (NaBH (OCOCH3) 3) or BH3.pyridine complex, operating in an organic solvent such as ethanol, at a temperature preferably between 0 C and the reflux temperature of the solvent. The product of general formula (IV) can be obtained from the product of general formula Me-N fOMe

O '/ \ SG3

  NHG, in which G2 and G3 are defined as above, according to the described method

  in the patent application EP 0 618 221.

  Generally, the deprotection reaction of the amino and thiol radicals by cleavage of the G2 and G3 groups is carried out according to the known deprotection methods described by T.W.Greene, Protective groups in organic chemistry, Wiley-interscience (1991); it will be preferred in particular to operate in an organic solvent such as a halogenated aliphatic hydrocarbon such as dichloromethane, in the presence of trifluoroacetic acid (TFA) and optionally triethylsilane and at room temperature preferably, or, when R1 represents a radical of formula R12 R i for which R 1 and R 2 are as defined in general formula (I), by action of a reagent of general formula R 1] 0 = C R 1 (V)

  for which Ril and Ri are defined as before.

  The reaction of the product of general formula (V) 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 acidetel than acetic acid, on 3 A molecular sieve, then by action of a reducing compound, such as sodium cyanoborohydride (NaBH3CN) or sodium triacetoxyborohydride (NaBH (OCOCH3) 3) or BH3 pyridine complex, by operating in an organic solvent such as ethanol, at a temperature preferably between

  0 C and the reflux temperature of the solvent.

  The product of general formula (V) 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.

  And, in the case where: a) Rs represents a -CORis radical, where Ris represents an amino radical, the products of general formula (I) can be obtained from the products of general formula (I) for which Ris represents a alkoxy radical by action of ammonia in an organic solvent such as toluene or methanol; b) Ri5 represents a hydroxyl radical, the products of general formula (I) can be obtained by saponification of the compounds of formula (I) for which Rs = - CORi5 and

R15 represents an alkoxy radical.

  c) R2 represents an alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical, the products of general formula (I) in which R1, R3, R4, R5, R6, R7, R8 and X are as defined in general formula (I) can be obtained from the corresponding compounds of general formula (I) in which R 2 represents a hydrogen atom, by the action of the corresponding acid of formula R 2 OH, in which R 2 represents an alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical, or of an activated form of this acid, such as an acyl halide, or the anhydride of this acid, optionally in the presence of an organic base, such as a triethylamine, or a mineral base such as potassium carbonate, in a solvent organic

as dichloromethane.

  d) R2 represents an alkyl, aryl, aralkyl, heterocyclylalkyl radical, the products of general formula (I) in which R1, R3, R4, R6, R6, R7, Rs and X are as defined in general formula (I) may be obtained from the corresponding compounds of general formula (1) in which R2 represents a hydrogen atom, by action of the corresponding aldehyde, generally 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, preference will be given to high-performance liquid chromatography on a silica column: normal phase, reverse phase Cis 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.

  Compounds of general formula (IIa) in which R 3, R 4, R 5, R 6, R 7, R 4, X are as defined in general formula (I) also form part of the present invention.

  G1 represents a hydrogen atom.

  The products of general formula (IIa) in which R3, R4, R5, R6, R7, R8 are defined as above, X represents an oxygen atom, and G1 represents a hydrogen atom can be obtained from compounds of general formula (lIb) HN-Gl

R R7

  Wherein R3, R4, R6, R6, R7, R8 are defined as above, X represents an oxygen atom 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 T; W.Greene, Protective groups in organic chemistry, Wileyinterscience (1991), and more particularly by hydrogenolysis in the presence of a catalyst such as palladium on coal, when Gl 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, at a temperature preferably close to 20 C.

  The products of general formula (IIb) in which R3, R4, R6, R6, R7, R8 are defined as above, X represents an oxygen atom and Gj represents a protective group defined as above can be obtained from compounds of general formula (VI) HN-G

R''R7

Ri i

CO, H (VI)

  in which R3, R7, R8 and G1 are defined as above and X represents an oxygen atom, by action of a compound of general formula (VII) corresponding HN R6

R 'R.

4 (VII),

  wherein R4 R5, R6 are as defined above, operating according to the methods of amidification. 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 an agent of

  condensation such as 1-ethyl-3- [3-hydrochloride]

  (1,2-dimethylamino) propyl] carbodiimide, benzotriazol-1-oxytris (dimethylamino) phosphonium-1,1-dicyclohexylcarbodiimide or hexafluorophosphate, optionally in the presence of an activating agent such as hydroxybenzotriazole, at a temperature preferably between 0 C and the reflux temperature of the solvent. The compound of general formula (VII) can be obtained commercially or by functionalization of commercially available amino acids according to the methods described by Larock, Comprehensive Organic Transformations, VCH, New York, 1989. Preferably, when R5 represents a radical-C ( O) -Ri5 for which Ri5 is as defined in the general formula (I), 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 during the amidification reaction and that several

  Stereoisomers can then be obtained at the end of this reaction.

  Optionally, when R5 represents the -CORi5 radical for which R15 represents an amino, alkylamino or aralkylamino radical as defined in the general formula (I), or -NHCH (CO2Ri6) - (CH2) 2 -S-CH3 for which R16 is defined as in general formula (I), the products of general formula (IIb) can also be obtained from compounds of general formula (VI) by action of a compound of general formula (VII) HNR6

4 (VII),

  in which R4 and R6 are as defined in general formula (I) and R5 represents the -CORi5 radical for which R15 represents an alkoxy radical, under the same conditions as those used for the previous amidification, and then is followed by the action ammonia, in an organic solvent such as an alcohol, methanol preferably, optionally in the presence of catalytic amounts of sodium cyanide, at a temperature preferably between 0 C and the reflux temperature of the solvent, while operating optionally in autoclave, or is followed, after hydrolysis of the -CORi5 radical to the carboxy radical, of the action of an alkylamine, an aralkylamine (with the alkyl radical corresponding to the radical Ris

  desired) or methionine, under the coupling conditions described above.

  The compounds of general formula (VI) in which R 3, R 7, R 8 and G are defined as above and X represents an oxygen atom may in particular be obtained from the compounds of general formula (VIII): HN-G1

R3- R7

R3

NR8 (VIII)

  wherein R3, R7, R8 and G, are defined as above, and X represents an oxygen atom by 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

  an ether such as diethyl ether, at a temperature preferably between

  78 C and the temperature preferably ambient, followed by carboxylation carried out for example by means of carbon dioxide,

  for example in the form of dry ice or CO2 gas.

  The compounds of general formula (VIII) in which R3, R7, R8 and G are defined as above and X represents an oxygen atom may be obtained from compounds of general formula (IX):

R3 R7

R (IX)

  in which R3, R7, R8 are defined as above and X represents an oxygen atom, by action of an ammonia salt such as ammonium acetate, in the presence of sodium cyanoborohydride, in particular by operating in a 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 T. W.Greene, Protective groups in organic chemistry, Wileyinterscience (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 temperature

boiling solvent.

  The products of general formula (IX) are commercially available or can be obtained by application or adaptation of the methods described by IM LOCKHART, The chemistry of heterocyclic compounds, chromenes, chromanones and chromones, 5, 207-428, 1977. According to another embodiment of use, the products of general formula (IIa) in which R3, R4, R5, R6, R7 and R8 are defined as above, X represents a radical S (O) I with I defined as in general formula (I) and Gi represents a hydrogen atom can be obtained from compounds of general formula (X) o R3XR7

O NR6

R4 R (X)

  in which R 3, R 4, R 5, R 6, R 7, R 8 are as defined in general formula (I), X represents a radical S (O), with 1 defined as in general formula (I), proceeding as described below. above for obtaining the products of general formula (VIII)

  from the products of general formula (IX).

  The products of general formula (X) in which R 3, R 4, R 5, R 6, R 7 and R 8 are as defined in general formula (I), and X represents an S (O) I radical with 1 defined as in the general formula ( I), can be obtained from the compounds of general formula (XI) O x

R3 R7

xrg

COOH (XI)

  in which R3, R7 and R8 are as defined above and X represents a radical S (O) I with I defined as in general formula (I), by action of the compounds of general formula (VII), operating under the conditions of amidation

  described above.

  The compounds of general formula (XI) in which R 3, R 7 and R 8 are as defined above and X represents an S (O) I radical with 1 = 1 or 2, can be obtained by oxidation of the compounds of general formula (XI) in which X represents a sulfur atom, by oxidation, in particular by the action of oxygenated water in an organic acid, such as acetic acid, at a temperature preferably between 0 ° C. and the boiling point of the acid or by the action of a peracid, such as m-chloroperbenzoic acid, in an organic solvent, such as chloroform, at a temperature preferably between 0 ° C. and the boiling point of the solvent. The compounds of general formula (XI) in which R 3, R 7 and R 8 are as defined above and X represents a sulfur atom, can be obtained from compounds of general formula (XII) O

R 3 7

EXX

COOH (XII)

  in which R3, R7 and R8 are as defined above and X represents a sulfur atom by action of an acid, such as sulfuric acid, at a temperature of

  preferably between 0 C and the boiling temperature of the reaction mixture.

  The compounds of general formula (XII) can be obtained from the compounds of general formula (XIII) R 3 R 3 -SH COOH (xm) by the action of the corresponding acid (Hal) -C 2 H 4 (R 7) (R 5) -COOH , for which R7, Rs are defined as above and Hal is preferably a bromine atom. This reaction can be carried out by operating in an aqueous medium, in the presence of a mineral base, such as sodium carbonate, preferably at room temperature.

  boiling the reaction mixture.

  In addition, according to another embodiment of the invention, the novel products of general formula (I), in which R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8 and X are defined as above, can be obtained from the product of general formula (XIV) RN / R

R2, N, RI

R3z R7

X R8

O OH (XIV),

  in which R 1, R 1, R 3, R 4, R 8 and X are defined as above, by the action of a compound of general formula (VII) HNR 6

R41 R.

R R (VII),

  wherein R4 R6, R6 are as defined above, 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

  account of the same stereochemical considerations.

  Also included in the present invention are the compounds of general formula (XIV) wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8 and X are as defined in formula

General (I).

  Generally, the new products of general formula (I) in which R 1, R 2, R 3, R 4, R 6, R 6, R 7, R 8 and X are defined as above can be obtained after

  a subsequent deprotection reaction, preferably at the end of the process.

  Generally, the acids of general formula (XIV) in which R 1, R 2, R 3, R 7, R 5, X are defined as above can be obtained from the corresponding esters of general formula (XV): R 2 N / R 1 R 3 R1 -N

R3 IR7

XRs

O OR (XV)

  in which R1, R2, R3, R7, R8, X are defined as above and R 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 (XV) may be carried out in an organic solvent such as an alcohol such as methanol or ethanol, which may be aqueous, by means of a

  mineral base such as soda or potash or sodium carbonate.

  Generally, the compounds of general formula (XV) in which R, R 1, R, R 3, R 2, R 8 and X are defined as above can be obtained from compounds of general formula (XVI): NH 2

R3 R7

O OR (XVI)

  in which R, R3, R7, R8 and X are defined as above, * or, when R1 represents the radical -CO-CH (NH2) -CH2SH, by action of a reagent of general formula

HO2C-CH (NHG2) -CH2SG3 (IID,

  when R1 represents the -CH2-CH (NH2) -CH2SH radical, by the action of a reagent of general formula H

O SG3

NHG,

NHG2 (IV),

  or, when R 1 represents a radical of formula R 1, R 1 by the action of a reagent of general formula R 1, OC Ril (V)

  for which Ril and Ri2 are defined as before.

  These reactions using the compounds of general formula (III), (IV) and (V) can be carried out under the same corresponding experimental conditions, relating to the compounds of general formulas (III), (IV), (V) and described

  previously for the preparation of the compounds of general formula (I).

  Generally, the esters of general formula (XVI) can be obtained from the corresponding acids of general formula (VI): HN-Gl

R3 R7

TX R8

CO2H (VI)

  wherein R3, R7, R8 and X are defined as above and G, represents a protecting group defined as above, by esterification and deprotection of the amino group; the esterification can be affected according to any known method of esterification, 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 T; W.Greene, Protective groups in organic chemistry, Wiley-interscience (1991), and more particularly by hydrolysis in acidic medium when G1 represents a radical tert. butoxycarbonyl; advantageously according to the invention, these reactions can be carried out simultaneously, by operating in acidic medium, preferably in the presence of hydrochloric acid, using as solvent the alcohol of general formula R-OH in which R is defined as above, and at a temperature of preference

  between 20 C and the reflux of the solvent.

  For X = O, the compounds of general formula (VI) can be prepared as

described above.

  For X = S (O) i with I defined as in general formula (I), the compounds of general formula (VI) can be prepared from compounds of general formula (XI) in which R3, R7 and R8 are such that defined above and X represents a radical S (O) I with I defined as in general formula (I), according to the same process as that used to prepare the compounds of general formula (VIII) from

  compounds of general formula (IX).

  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; in particular, the products of general formula (I)

  can be in the form of ditrifluoroacetate.

  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 which 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, methylene-bis-

  b-oxynaphthoate, hydrochloride, sulfate, nitrate and phosphate.

  The present invention relates to the use of compounds of general formula (I) 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.

  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 the oncogene ras.

  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 H-Ras, N-Ras or K-Ras oncoproteins, 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 organs, including muscle, bone or connective tissue, skin, brain, lungs, sexual organs, lymphatic or renal systems, breast or blood cells, liver, digestive tract, colon, pancreas and thyroid or adrenal glands, and including the following pathologies: psoriasis, restenosis, solid tumors, Kaposi's sarcoma, carcinomas, cholangiocarcinoma, choriocarcinoma, neuroblastoma, tumor of Wilms, Hodgkin's disease, melanoma, teratocarcinoma, glioma, multiple myeloma, chronic lymphocytic leukemia, acute or chronic granulocytic lymphoma, and cancers such as pancreatic, colon, lung, cancerous tumors. ovary, breast,

  brain, prostate, liver, stomach, bladder or testes.

  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, lung, ovary, breast, brain, prostate, liver, stomach, bladder or testes, and more preferably colon and pancreatic cancer,

particular of the colon.

  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 growth of tumors expressing the activated ras oncogene.

  Therapeutic treatment may also be performed concurently with other therapeutic treatments including 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 (ct, 3 or 6) 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 analogs such as fluorouracil and cytarabine, purine analogues such as mercaptopurine and thioguanine, natural products such as vinca alkaloids such as vinblastine, vincristine and vendesine, epipodophyllotoxins such as etoposide and teniposide, antibiotics such as dactinomycin , daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin, enzymes such as L-asparaginase, various agents such as platinum coordination complexes such as cisplatin, substituted ureas such as hydroxyurea, methylhydrazine derivatives such as procarbazine, adrenocorticoid suppressors such as mitotane and aminoglutethymide, hormones and antagonists such as adrenocorticosteroids such as prednisone, progestins such as hydroxyprogesterone caproate, methoxyprogesterone acetate and megestrol acetate, estrogens such as diethylstilbestrol and ethynylestradiol, antiestrogens such as tamoxifen,

  androgens such as testosterone propionate and fluoxymesterone.

  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 in order to obtain a synergistic therapeutic effect, said compounds being preferentially principles active agents 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 the compounds

  cytotoxic agents usually used in the treatment of cancer.

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

pathological conditions.

  The products according to the invention can be administered orally, parenterally or

  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.

  These compositions may also include substances other than

  diluents, for example wetting, sweetening or flavoring products.

  The compositions according to the invention for parenteral administration may be

  aqueous or nonaqueous sterile 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 can

  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 for as long

  than 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, preferably orally. It is understood that, to choose the most appropriate dosage, should be taken into account the route of administration, the weight of the patient, his state of health

  age, and all factors that may affect the effectiveness of the treatment.

  In general, the doctor will determine the appropriate dosage according to

  age, weight and all other factors specific to the subject to be treated.

  Example 36 illustrates compositions according to the invention.

  The following examples are presented for illustrative and non-limiting purposes

present invention.

  EXAMPLE 1 Preparation of Diastereoisomers of N- (1- (S) -carbamoyl-2-phenyl)

  ethyl) -4- (2- (R) -amino-3-mercaptopropylamino) -chroman-8-carboxamide 262 g (3.4 moles) of ammonium acetate are added to 550 ml of a methanolic solution 4-chromanone (50 g, 0.337 mol) at a temperature in the region of 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 II of distilled water brought to pH = 10 by addition of O10N sodium hydroxide and the organic phase extracted with 3 times 300 ml of dichloromethane, then washed with distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 mmHg, 2.6 kPa) at C. crude product (46 g) is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (95/5 by volume). We

  25.3 g (50.4%) of 4-amino-chroman is thus obtained in the form of a brown oil.

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

  beige powder form melting at 113-114 C.

  A solution consisting 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 cyclohexane of sec-butyl-

  lithium (0.11 moles). 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) using 4N hydrochloric acid. The precipitate obtained is filtered, washed with water and then dried under reduced pressure at 50 ° C. 7.8 g (53.2%) of 4-tert-butoxycarbonylarmino-chroman-8-carboxylic acid are obtained in the form of

beige powder melting at 185-187 C.

  To a solution composed of 3 g (10.2 mmol) of 4-tert-

  butoxycarbonylamino-chroman-8-carboxylic acid, 1.85 g (11.3 mmol) of (S) -

  phenylalanine carboxamide, 1.52 g (11.3 mmol) of 1-hydroxybenzotriazole and 1.5 ml (10.2 mmol) of triethylamine in 100 ml of dichloromethane are added

  2.16 g (11.3 mmol) of 1- (3-dimethylaminopropyl) hydrochloride

  ethylcarbodiirmide at a temperature of 20 C. The reaction is continued for hours at the same temperature. The reaction medium is then washed with 2 times ml of distilled water, then 40 ml of a saturated aqueous solution of sodium hydrogen carbonate and finally 50 ml of a saturated aqueous sodium chloride solution. After drying over magnesium sulphate, the organic solution is filtered and then concentrated to dryness under reduced pressure to yield

  4.2 g (93%) of N- (I (S) -carbamoyl-2-phenyl-ethyl) -4-tertbutoxycarbonylamino

  chroman-8-carboxamide as a white meringue. Spectrum of R.M.N. IH

  (300 MHz, (CD3) 2SO, d in ppm). The description is made on the mixture of

  two diastereoisomers 50-50: 1.43 (s, 9H: COOC (CH 3) 3); from 1.85 to 2.15 (mt, 2H: chromanyl CH 2) 2.98 and 3.13 (2 dd, respectively J = 13.5 and 9 Hz and J = 13.5 and 5 Hz, 1H each: ArCH2) 4.30 (mt, 2H: CH2O of chromanyl); from 4.60 to 4.80 (mt, 2H NCHCON and chromanyl CHN); 6.96 (t, J = 7.5 Hz, 1H: chromanyl H6); 7.15 and 7.55 (2s wide, 1H each: CONH,); from 7.15 to 7.35 (mt, 6H: aromatic H of phenyl and H5 of chromanyl); 7.45 (d, J = 9 Hz, 1H: CONH)

  7.67 (mt, 1H: H7 chromanyl); 8.25 (d, J = 7.5 Hz, 1H: ArCONH).

  40 ml of trifluoroacetic acid are added dropwise to a solution of 4.2

  N- (I (S) -carbamoyl-2-phenyl-ethyl) -4-tert-butoxycarbonylamino- (9.57 mmol)

  chroman-8-carboxamide in 40 ml of chloroform cooled at 0 C. The reaction mixture is stirred for 1.5 hours at a temperature of 20 C and then diluted with 100 ml of a saturated solution of sodium bisulfite. The organic phase is decanted, washed with water and discarded. The aqueous phase is alkalinized to pH = 14 and the organic phase extracted with 3 times 50 ml of dichloromethane, then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. 0.91 g (28%) of N- (1 (S) -carbamoyl-2-phenyl-ethyl) -4-aminochroman-8-carboxamide in the form of

white meringue.

  Spectrum of R.M.N. 1H (300 MHz, (CD3) 2SO, d in ppm). The description is

  performed on the mixture of the two diastereoisomers 50-50: 1.80 and from 1.95 to 2.20 (2 mts, 1H each: CH 2 of chromanyl); from 1.95 to 2.20 (mt, 2H: NH 2) 2.99 and 3.12 (2 dd, respectively J = 14 and 7.5 Hz and J = 14 and 4.5 Hz, each IH: ArCH, ); 3.93 (t, J = 6 Hz, 1H: chromanyl CHN); from 4.20 to 4.45 (mt, 2H: CH 2 O of chromanyl); 4.68 (mt, 1H: NCHCON); 6.95 (t, J = 7.5 Hz, 1H: chromanyl H6); 7.16 (brs, 1H: 1H from CONH 2); from 7, 20 to 7.40 (mt, 5H: aromatic H of phenyl); from 7.50 to 7.60 (mt, 1H: the other H of CONH2); 7.50 to 7.60 and 7.67 (2 mts, 1H each: H5 and H7 chromanyl); 8.30 (d, J = 7.5 Hz, 1H: ArCONH).)

  A mixture of N- (1 (S) -carbamoyl-2-phenyl-ethyl) -4-amino-chroman-8-

  carboxamide (0.91 g, 2.68 mmol) and S-triphenylmethyl-N-tertbutoxycarbonyl-L-

  cysteine (2.52 g, 5.64 mmol, prepared according to the process described in patent EP 0618221) in solution in acetonitrile (45 ml) in the presence of acetic acid (0.5 ml) and 3A sieve is It is stirred for 5 hours at a temperature in the region of 20 ° C. Sodium cyanoborohydride (0.51 g, 8.05 mmol) is then added and stirring is continued for 15 hours at the same temperature. The precipitate formed is filtered, washed with dichloromethane and the filtrate concentrated to dryness under reduced pressure. The crude product thus obtained in the form of brown meringue is purified by flash chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (95/5 and then 90/10 by volume). We obtain 1.84 g

  (87%) N- (1 (S) -carbamoyl-2-phenyl-ethyl) -4- (2 (R) -tertbutoxycarbonylamino-3-

  triphenylmethylthio-propylamino) -chroman-8-carboxamide in the state of meringue cream. Spectrum of R.M.N. JH (250 MHz, (CD3) 2SO at a temperature of 383

  K, d in ppm). The description is made on the mixture of the two

  diastereoisomers 50-50: 1.41 (s, 9H: COOC (CH 3) 3); from 1.75 to 2.00 (mt, 2H: CH 2 of chromanyl); 2.39 (mt, 2H: CH 2 S); 2.61 (broad d, J = 6 Hz, 2H: CH 2 N); 3.03 and 3.17 (2 dd, respectively J = 14 and 7.5 Hz and J = 14 and 5 Hz, 1H each: ArCH2); 3.53 (mt, 1H: propylamine CHN); 3.67 (mt, 1H: chromanyl CHN); from 4.10 to 4.35 (mt, 2H: chromanyl CHO); 4.75 (mt, 1H: NCHCON); 6.24 (mt, 1H: exchangeable); from 6.80 to 7.10 (mf, 2H: CONH2); 6.89 (mt, 1H: chromanyl H6); from 7.10 to 7.45 (mt, 21H: aromatic H of triphenylmethyl - aromatic H of phenyl and H5 of chromanyl); 7.68 (mt, 1H: chromanyl H7); 8.14 (d, J = 7.5 Hz, 1H ArCONH).

  To a pale yellow solution of N- (1 (S) -carbamoyl] -2-phenyl-ethyl) -4- (2 (R) tert-

  butoxycarbonylamino-3-triphenylmethylthio-propylamino) -chroman-8-carboxamide (1.84 g, 2.39 mmol) and triethylsilane (0.5 ml, 3.11 mmol) in 13 ml of dichloromethane, 9 ml are added dropwise. 1 ml (0.119 mol) of trifluoroacetic acid. The reaction mixture is stirred for 1 hour at a temperature in the region of 20 ° C. and then concentrated under reduced pressure. The residue is triturated 3 times with ml of pentane and then 3 times with 15 ml of diisopropyl ether. After dry drying, the crude product is purified by high performance liquid chromatography (C18 phase) eluting with a gradient of a water / acetonitrile mixture containing 0.07% trifluoroacetic acid. We obtain:

  0.26 g of the diastereoisomer A of N- (1 (S) -carbamoyl-2-phenyl-ethyl) -4 (2 (R) -

  amino-3-mercaptopropylamino) -chroman-8-carboxamide in the form of ditrifluoroacetate in the form of white lyophilizate, the characteristics of which are as follows: NMR spectrum. 1H (300 MHz, (CD3) 2SO, d in ppm): from 2.20 to 2.40 (mf, 2H CH 2 of chromanyl); 2.84 (mt, 2H: CH 2 S); 2.99 and 3.13 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH2); from 3.30 to 4.00 (mt: the 4H corresponding to CH2N-CHN of chromanyl and CHN of propylamrnine); from 4.25 to 4.50 (mt, 2H: CH 2 O of chromanyl); 4.68 (mt, 1H NCHCON); 7.07 (t wide, J = 7.5 Hz, 1H H6 chromanyl); 7.17 and 7.62 (2s wide, 1H each: CONH2); from 7.20 to 7.35 (mt, 5H: aromatic H of phenyl); 7.55 to 7.70 and 7, 81 (respectively mt and d wide, J = 7.5 Hz, 1H each: H5 and H7 chromanyl)

8.23 (d, J = 6.5 Hz, 1H: ArCONH).

  Mass spectrum: DCI (NH3), rm / z = 429, (M + H) + elemental analysis. C22H28N4O3S, 2CF3CO2, H, 1, 6Hf0 ', Calculated (% o) AT: C = 45.56, H = 4.88 F = 16.63, N = 8.17 S = 4.68 Found (%)) : C, 45.13; H = 4.45; F = 16.88, N = 8, 21 'S = 4.39 rotatory power. D 0 = + 40.8 0.6 (CH 3 OH, c = 1)

  0.19 g of N- (1 (S) -carbamoyl-2-phenyl-ethyl) -4 (2 (R)) diastereoisomer B

  amino-3-mercaptopropylamino) -2,3-dihydro-4H-chroman-8-ylcarboxamide in the form of ditrifluoroacetate in the form of white lyophilizate, the characteristics of which are as follows: Mass spectrum: DCI (NH 3) , m / z = 429, (M + H) + elemental analysis: C2211H28N4O535, 2CF3CO2H, 1.5H2O: Calcd. (%): C = 45.68; H = 4.87: mp = 16.67; N, 8.20; S = 4.69 Found (%): C = 45.61, H = 4.54. F = 16.91; N = 8.04, S = 4.61 rotatory power: ctD0 = -43.3 + 0.7 (CH30 H, c = 1)

  EXAMPLE 2 Preparation of Diastereoisomers of the Ethyl Ester of N-Acid

  (1- (S) -carbamoyl-2-phenyl-ethyl) 4- (2- (R) -amino-3-mercapto-propylamino) -

chroman-8-carboxylic acid

  To a solution consisting of 4.1 g (0.014 mol) of 4-tert-

  butoxycarbonylamino-chroman-8-carboxylic acid, 3.54 g (0.015 mol) of hydrochloride

  of the L-phenylalanine ethyl ester, 2.08 g (0.015 mol) of

  benzotriazole, 4 ml (0.028 mol) of triethylamine in 140 ml of dichloromethane,

  2.95 g (0.015 mole) of 1- (3-dimethylaminopropyl) hydrochloride are added.

  ethylcarbodiimnide. The reaction medium is stirred for 15 hours at a temperature in the region of 20 ° C., then washed with 50 ml of water, then successively, with 2 times 50 ml of hydrochloric acid N, 2 times 50 ml of sodium hydrogencarbonate, and finally 50 ml of a saturated solution of sodium chloride. The organic phase is then dried over magnesium sulphate, filtered and then concentrated to dryness under pressure.

  reduced to yield 6.55 g of N- (1 (S) -ethoxycarbonyl-2-phenyl-ethyl) 4-tert-

  butoxycarbonylamino-chroman-8-carboxamide in the form of white meringue

  used without further purification in subsequent steps.

  Spectrum of R.M.N. 1H (300 MHz, (CD3) 2SO, d in ppm). The description is

  performed on the mixture of the two diastereoisomers 50-50: 1.20 (t, J = 7.5 Hz, 3H: CH 3 of ethyl); 1.44 (s, 9H: COOC (CH 3) 3); from 1.85 to 2.15 (mt, 2H: CH 2 of chromanyl); 3.14 (AB limit, 2H: ArCH); 4.14 (q, J = 7.5 Hz, 2H: COOCH 2 ethyl); 4.31 (mt, 2H: CH 2 O of chromanyl); from 4.65 to 4.85 (mt, 2H: NCHCOO and chromanyl CHN); 7.00 (t, J = 7.5 Hz, I H: H 6 chromanyl); from 7.20 to 7.40 (mt, 6H: aromatic H of phenyl and H5 of chromanyl); 7.46 (d, J = 9 Hz, I H: CONH); 7.69 (d wide, J = 7.5 Hz, 1H: H7 from

chromanyl); 8.38 (mt, 1H: ArCONH).

  6.5 g (0.0139 mol) of N- (1 (S) -ethoxycarbonyl-2-phenylethyl) -4-tert-

  butoxycarbonylamino-chroman-8-carboxamide dissolved in 30 ml of dichloromethane are stirred for 15 hours at a temperature of 20 C after addition of 17.4 ml of 4N hydrochloric isopropanol (0.069 mol). The reaction medium is then concentrated under reduced pressure, then washed with 1N sodium hydroxide and the organic phase concentrated to dryness. The crude product obtained is purified by chromatography on a silica column using dichloromethane and then a mixture of dichloromethane and methanol (95/5 by volume) as eluent. We

  4.8 g (94.1%) of N- (I (S) -ethoxycarbonyl-2-phenyl-ethyl) -4-aminochroman-

  8-carboxamide as a yellow oil.

  Spectrum of R.M.N. 1H (250 MHz, (CD3) 2SO d6, d in ppm). The description

  is carried out on the mixture of the two diastereoisomers 50-50: 1.20 (t, J = 7.5 Hz, 3H: CH 3 of ethyl); 1.80 and 2.05 (2 mts, 1H each CH 2 of chromanyl); 2.16 (mf, 2H: NH 2); 3.14 (AB limit, 2H: ArCH2); 3.94 (t, J = 5 Hz, 1H: chromanyl CHN); 4.14 (q, J = 7.5 Hz, 2H: COOCH 2 ethyl); from 4.15 to 4.45 (mt, 2H: CH 2 O of chromanyl); 4.70 (q, J = 7 Hz, 1H: NCHCOO); 6.96 (t, J = 7.5 Hz, 1H: chromanyl H6); from 7.20 to 7, 40 (mt, 5H: aromatic H of phenyl); 7.55 and 7.68 (2 d wide, J = 7.5 Hz, 1H each: H5

  and H7 chromanyl); 8.40 (d, J = 7 Hz, 1H: ArCONH).

  The procedure is as in Example 1 for the preparation of N- (I (S) -carbamoyl-

  2-phenyl-ethyl) -4 - [(2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthio) -

  propylamino] -chroman-8-carboxamide, but from N- (1 (S) ethoxycarbonyl-2-

  phenyl-ethyl) -4-amino-chroman-8-carboxamide (4.8 g, 0.0131 mol). The crude product is purified by flash chromatography on a silica column, eluting with a mixture of cyclohexane and ethyl acetate (80/20 by volume). We obtain 5.9 g (56.4%) of

  N- (I (S) -ethoxycarbonyl-2-phenyl-ethyl) -4- (2 (R) -tertbutoxycarbonylamino-3-

  triphenylmethylthio-propylamino) -chroman-8-carboxamide in the state of white meringue. Spectrum of R.M.N. IH (250 MHz, (CD3) 2SO at a temperature of 393

  K, d in ppm). The description is made on the mixture of the two

  diastereoisomers 50-50: 1.22 (t, J = 7.5 Hz, 3H: ethyl CH3); 1.42 (s, 9H: COOC (CH 3) 3) from 1.80 to 2.00 (mt, 2H: CH 2 of chromanyl); 2.42 (mt, 2H: CH 2 S); 2.64 (bd, J = 6 Hz, 2H: CH2N) from 3.10 to 3.25 (mt, 2H: ArCH2); 3.56 (mt, 1H NMR of propylamine); 3.71 (mt, 1H: chromanyl CHN); 4.17 (q, J = 7.5 Hz, 2H: COOCH 2 ethyl) 4.20 to 4.40 (mt, 2H: CH 2 O of chromanyl) 4.83 (mt, 1H: NCHCOO); 6.10 (mt, 1H: exchangeable); 6.92 (t wide, J = 7.5 Hz, 1H: chromanyl H6) from 7.15 to 7.45 (mt, 21H: aromatic H) of the aromatic trifluoromethyl phenyl and H5 of chromanyl); 7.73 (d

  broad, J = 7.5 Hz, 1H: H7 chromanyl); 8.17 (d, J = 7 Hz, 1H: ArCONH).

  The procedure is as in Example 1 for the preparation of N- (1 (S) -carbamoyl-

  2-phenyl-ethyl) 4- (2 (R) -amino-3-mercaptopropylamino) -chroman-8-carboxamide, but from N- (1 (S) -ethoxycarbonyl-2-phenyl-ethyl) -4- (2-phenylethyl) -4- (R) -tert

  butoxycarbonylamino-3-triphenylmethylthiopropylamino) -chroman-8carboxamide (0.72 g, 0.9 mmol), triethylsilane (0.2 ml, 1.17 mmol), trifluoroacetic acid (3.45 ml, 45 mmol). ) and dichloromethane (12 ml). The crude product is purified by high performance liquid chromatography (phase C1 8) eluting with a gradient

  a water / acetonitrile mixture containing 0.07% trifluoroacetic acid. 0.13 g of the diastereoisomere A of N- (1 (S) ethoxycarbonyl-2-phenyl-ethyl) are obtained.

  (2 (R) -amino-3-mercaptopropylamino) -chroman-8-carboxamide in the form of ditrifluoroacetate in the form of white lyophilizate, the characteristics of which are as follows: NMR spectrum. 1H (400MHz, (CD3) 2SO, d in ppm): 1.20 (t, J = 7.5Hz, 3H: ethyl CH3); from 1.90 to 2.30 (mf spread, 2H: CH 2 chromanyl); from 2.70 to 2.90 (mt, 2H: CH 2 S); from 2.80 to 3.90 (mt: the 4H corresponding to the CH2N -CHN of the chromanyl and CHN of the propylamine) 3.10 and 3.17 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each ArCH,); 4.13 (mt, 2H: COOCH 2 ethyl); 4.34 (mt, 2H: CH-, O from chromanyl); 4.69 (mt, 1H: NCHCOO); 7.05 (mt, 1H: chromanyl H6); from 7.20 to 7.40 (mt, 5H: aromatic H of phenyl); 7, 60 and 7.76 (2 d wide, J = 7.5 Hz, 1H each: H5 and H7 chromanyl) 8, 36 (d, J = 7 Hz, 1H: ArCONH). Mass Spectrum: DCI (NH3), m / z = 458, (M + H) + elemental analysis: C, 4H31N3O4S, 2CF3CO: H, O, 2H: O: Calculated (%): C = 48.79, H = 4.89; N = 6.10, S = 4.65 Found (%: C = 48.71, H = 4.57, N = 6.11, S = 4.24 rotatory power:? 2 × O = +41.3 + 0) , 8 (CH30H, c = 0.5)

mIIIm '', ....

  0.09 g of N- (1 (S) -ethoxycarbonyl-2-phenylethyl) diastereoisomer B -4

  (2 (R) -amino-3-mercaptopropylamino) -chroman-8-carboxamide in the form of ditrifluoroacetate in the form of white lyophilizate, the characteristics of which are as follows: NMR spectrum. H (400 MHz, (CD 3) 2 SO, d in ppm): 1.20 (t, J = 7.5 Hz, 3H: ethyl CH 3); from 1.85 to 2.10 (mf, 2H: CH 2 of chromanyl); from 2.70 to 2.85 (mrt, 2H: CH 2 S); from 2.80 to 3.60 (mt: the 3H corresponding to CH2N and CHN of propylamine); 3.15 (AB limit, 2H: ArCH2); 3.79 (mt, 1H: chromanyl CHN); 4.13 (mt, 2H: COOCH 2 ethyl); 4.28 and 4.39 (2 mts, 1H each: chromanyl CH 2 O); 4.74 (mt, 1H: NCHCOO); 7.01 (mt, 1H: H6 of chromanyl); from 7.20 to 7.40 (mt, 5H: aromatic H of phenyl); 7.58 and 7.75 (2 mts, 1H each: H5 and

  H7 chromanyl); 8.35 (d, J = 7 Hz, 1H: ArCONH).

  Mass spectrum. IE, m / z = 457 (M +), m / z = 381 (M-C 2 H 6 NS) + ', m / z = 353 (M +);

  C3H8N2S), m / z = 176 (m / z = 353-C21H302) +, m / z = 159 (ClOH702), m / z = 132 (m / z = 159-CO + H), m / z = 69 (CF3 +), m / z = 45 (CO2H +) base peak elemental analysis. C24H31N3O4S, 2CF3C021H, I.6,%, O: Calculated (%): C, 48.29, H = 4.95; N = 6.03; S = 4.60 Found (% o): C = 48.78, H = 4.52; N = 6.11: S = 4. 34 rotatory power: 2 = -40.8 + 0.9 (CHiOH, c = 0.5)

  Example 3: Preparation of N- (I (S) -carboxy-2-phenyl-diastereoisomers

  ethyl) 4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8-carboxamide

  N- (1 (S) -ethoxycarbonyl-2-phenyl-ethyl) -4- (2 (R) -tert-

  butoxycarbonylamino-3-triphenylmethylthiopropylamino) -chroman-8carboxamide (5.9 g, 7.38 mmol) dissolved in a mixture of methanol (120 ml) and distilled water (40 ml) is stirred in the presence of potassium hydroxide ( 0.5 g, 8.86 mmol) at a temperature in the region of 20 C for 15 hours. The methanol is then distilled under reduced pressure and the aqueous phase washed with 50 ml of diethyl ether and then acidified to pH = 1 with 6N hydrochloric acid. Extraction of the organic phase by 3 times 150 ml of a mixture of dichloromethane and methanol (90/10 by volume), drying over magnesium sulphate and dry concentration under presion

  reduced to 5.3 g of N- (1 (S) -carboxy-2-phenyl-ethyl) -4- (2 (R) -tert-

  butoxycarbonylamino-3-triphénylrnéthylthio-propylamnino) -chroman-8carboxamide

in the form of white meringue.

  Mass Spectrum: DCI (NH3), m / z = 772 (M + H), m / z = 672 (m / z = 772-C5H802), m / z = 530 (m / z = 772-C10H10 + H) ) +, m / z = 430 (min / z-530-CsH80s2) +, m / z = 262 (C9H16 + NH4) + base peak, m / z = 243 C19H15 +

  The procedure is as in Example I for the preparation of N- (1 (S) carbamoyl

  2-phenyl-ethyl) -4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8carboxamide,

  but from N- (1 (S) -carboxy-2-phenyl-ethyl) -4 - [(2 (R) -terbutoxycarbonylamino)

  3-triphenylmethylthio) -propylamino] -chroman-8-carboxamide (0.87 g, 1.13 mmol), triethylsilane (0.32 ml, 1.47 mmol), trifluoroacetic acid (4.3 ml, 56%). , 4 mmol) and dichloromethane (15 ml). The crude product is purified by high performance liquid chromatography (phase C1 8) eluting with a gradient of a water / acetonitrile mixture containing 0.1% trifluoroacetic acid. We obtain:

  0.16 g of the diastereoisomer A of N- (1 (S) -carboxy-2-phenyl-ethyl) -4 (2 (R) -

  amino-3-mercaptopropylamino) -chroman-8-carboxamide in the form of ditrifluoroacetate in the form of white lyophilizate, the characteristics of which are as follows: NMR spectrum. 1H (400 MHz, (CD3) 2 SO, d in ppm): from 2.00 to 2.30 (mf spread, 2H: CH 2 of chromanyl); from 2.75 to 2.90 (mt, 2H: CH 2 S); from 2.80 to 4.10 (mt: the 3H corresponding to CH2N and CHN of propylamine); 3.10 and 3.20 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH2) from 3.60 to 4.10 (mf spread: I'H corresponding to the CHN of chromanyl); 4.33 (mt, 2H: CH 2 O of chromanyl); 4.67 (mt, 1H: NCHCOO); 7.06 (t wide, J = 7.5 Hz, 1H: chromanyl H6); from 7.20 to 7.40 (mt, 5H: aromatic H of phenyl); 7.60 and 7.80 (2 d wide, J = 7.5 Hz, I H each: H5 and H7 from

  chromanyl); 8.28 (d, J = 7 Hz, 1H: ArCONH).

  Rotatory power: (lD20 = +52.9 + 1.0 (CH30H, c = 0.5)

  0.10 g of N- (1 (S) -carboxy-2-phenyl-ethyl) -4 (2 (R)) diastereoisomer B

  amino-3-mercaptopropylamino) -chroman-8-carboxamide in the form of ditrifluoroacetate in the form of white lyophilizate, the characteristics of which are as follows: NMR spectrum. tH (400 MHz, (CD3) 2SO, d in ppm): from 2.00 to 2.30 (mf, 2H CH 2 of chromanyl); from 2.70 to 2.90 (mt, 2H: CH 2 S); from 2.80 to 3.60 (mt: the 3H corresponding to CH2N and CHN of propylamine); 3.12 and 3.19 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH2); from 3.60 to 4.45 (mf spread: H corresponding to chromanyl CHN); 4.25 to 4.45 (mt, 2H: CH 2 O of chromanyl); 4.72 (mt, I H: NCHCOO); 7.05 (mt, 1H: chromanyl H6); from 7.20 to 7.40 (mt, 5H: aromatic H of phenyl); 7.60 and 7.81 (2 d wide, J = 7.5 Hz, 1H each: H5 and H7 chromanyl); 8.27 (d, J = 7 Hz, 1H: ArCONH). Rotatory power: CD 1o = -36.4 + 0.8 (CI-H30H, c = 0.5)

  EXAMPLE 4 Preparation of Diastereoisomers of N- (2-phenyl-ethyl) -4 (2 (R) -

  amino-3-mercapto-propylamino) -chroman-8-carboxamide

  The procedure is as in Example 2 for the preparation of N- (1 (S) -

  ethoxycarbonyl-2-phenyl-ethyl) -4-tert-butoxycarbonylamino-chroman-8-

  carboxamide, but from 4.0 g (0.0136 mole) of 4-tert-

  butoxycarbonylamino-chroman-8-carboxylic acid, 1.9 ml (0.015 mol) of 2-phenyl-

  ethylamine, 2.02 g (0.015 mol) of 1-hydroxybenzotriazole, 2.1 ml (0.015 mol) of

  triethylamine, 2.88 g (0.015 mole) of 1- (3-dimethylaminopropyl) -hydrochloride

  ethylcarbodiimide and 120 ml of dichloromethane. 5.49 g of N (2-phenyl-

  ethyl) -4-tert-butoxycarbonylamino-chroman-8-carboxamide as a solid

  white used without further purification in subsequent steps.

* Spectrum of R.M.N. 1 H (300 MHz, (CD 3) 2 SO, d in ppm): 1.45 (s, 9H COOC (CH 3) 3); from 1.85 to 2.15 (mt, 2H: CH 2 of chromanyl); 2.85 (t, J = 7.5 Hz 2H: ArCH2); 3.54 (mt, 1H: CH 2 N); 4.28 (mt, 2H: CH 2 O of chromanyl); 4.77 (mt, 1H: chromanyl CHN); 6.97 (t, J = 7.5 Hz, I H: H 6 of chromanyl) from 7.20 to 7.40 (mt, 6H: aromatic H of phenyl and H5 of chromanyl); 7.44 (broad, J = 9 Hz, 1H: CONH); 7.66 (d wide, J = 7.5 Hz, 1H: H7 from

  chromanyl); 8.16 (t, J = 6.5 Hz, 1H: ArCONH).

  The procedure is as in Example 2 for the preparation of N- (I (S) -

  ethoxycarbonyl-2-phenyl-ethyl) -4-amino-chroman-8-carboxamide, but from 2 g (0.0136 mol) of N- (2-phenyl-ethyl) -4-tertbutoxycarbonylamino-chroman-8 carboxamide, 17.1 ml of 4N hydrochloric isopropanol (0.068 mol) and 25 ml of dichloromethane. After concentration of the reaction medium to dryness, the residue is taken up in diisopropyl ether, filtered on sintered glass and then dried under reduced pressure to give

  yield 4.4 g (97.1%) of N- (2-phenyl-ethyl) -4-aminochroman hydrochloride.

  carboxamide as a white solid. (IR 378291, FGU 1302)

  The procedure is as in Example I for the preparation of N- (I (S) carbamoyl-

  2-phenyl-ethyl) -4- (2 (R) -tert-butoxycarbonylamino-3-triphénylméthylthio-

  propylamino) -chroman-8-carboxamide, but from N (2-phenylhydrochloride)

  ethyl) -4-amino-chroman-8-carboxamide (4.4 g, 0.0132 mol) The crude product is purified by flash column chromatography on silica eluting with a mixture of

  cyclohexane and ethyl acetate (80/20 by volume). 2.2 g (22.9%) of N-

  (2-phenylethyl) -4- (2 (R) -tert-butoxycarbonylamino-3-triphénylméthylthio-

  propylamino) -chroman-8-carboxamide in the state of white meringue.

  Spectrum of R.M.N. H (250 MHz, (CD3) 2 SO, d in ppm). The description

  is carried out on the mixture of the two diastereoisomers 50-50: from 1.30 to 1.50 (mt, 9H: COOC (CH3) 3); from 1.70 to 1.90 (mt, 2H: chromanyl CH 2) from 2.20 to 2.35 (mt, 2H: CH 2 S); from 2.40 to 2.60 (mt: the 2H corresponding to the CH 2 N of propylamine); 2.83 (t, J = 7 Hz, 2H: ArCH 2); 3.45 to 3.65 (mt, 2H: propylamine CHN and chromanyl CHN); 3.51 (q, J = 7 Hz, 2H: CH 2 NCO) from 4.10 to 4.30 (mt, 2H: CH 2 O of chromanyl); 6.80 (mt, 1H: exchangeable); 6.90 (mt, 1H H6 chromanyl); from 7.15 to 7.40 (mt, 21H: aromatic Hs of triphenylmethyl - aromatic H of phenyl and H5 of chromanyl); 7.65 (mt, 1H: chromanyl H7);

8.14 (mt, 1H: ArCONH).

  The procedure is as in Example 1 for the preparation of N- (1 (S) -carbamoyl-

  2-phenyl-ethyl) -4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8carboxamide,

  but from N- (2-pbenyl-ethyl) -4- (2 (R) -tert-butoxycarbonylamino-3-

  triphenylmethylthio-propylamino) -chroman-8-carboxamide (2.2 g, 3.03 mmol), triethylsilane (0.62 ml, 3.93 mmol), trifluoroacetic acid (11.6 ml, 15.1 mmol ) and dichloromethane (45 ml). The crude product is purified by high performance liquid chromatography (phase C1 8) eluting with a gradient of a water / acetonitrile mixture containing 0.1% trifluoroacetic acid. We obtain:

  0.16 g of the diastereoisomer A of N- (2-phenyl-ethyl) -4- (2 (R) -amino-3-

  mercapto-propylamino) -chroman-8-carboxamide in the form of ditrifluoroacetate in the form of white lyophilizate, the characteristics of which are as follows: NMR spectrum. 1H (250 MHz, (CD3) 2SO with addition of a few drops of CD3COOD at a temperature of 373 K, d in ppm): from 1.90 to 2.20 (mt, 2H: CH 2 of chromanyl); from 2.80 to 3.20 (mt, 4H: CH 2 S and CH 2 N of propylamine); 2.88 (t, J = 7 Hz, 2H: ArCH2); 3.46 (mt, 1H: CI-HN propylamine); 3.59 (t, J = 7Hz, 2H: CH2NCO); 3.88 (t, J = 5 Hz, 1H: chromanyl CHN); 4.20 to 4.40 (mt, 2H chromanyl CH 2 O) 6.96 (t, J = 7.5 Hz, 1H: chromanyl H 6); from 7.40 to 7.40 (mt, 5H: aromatic H of phenyl); 7.50 and 7.75 (2 d wide, J = 7.5 Hz, 1H each

: H5 and H7 chromanyl).

  Mass Spectrum: DCI (NH3), m / z = 386 (M + H) +

  elemental analysis. C21H27N3O2S, 2CF3CO2H.

  Calculated (%) o. C, 48.93; H = 4.76: M = 18.58, N = 6.85; S = 5.23 Found (% o): C = 48.9; H = 4.3, F = 18.2, N = 6.9; S = 4.8 rotatory power: otoD20 O (CH30H, c = 0.5)

  0.18 g of N- (2-phenyl-ethyl) -4- (2 (R) -amino-3- diastereoisomer B

  mercapto-propylamino) -chroman-8-carboxamide in the form of ditrifluoroacetate in the form of white lyophilizate, the characteristics of which are as follows: NMR spectrum. 1H (250 MHz, (CD3) 2SO with addition of a few drops of CD3COOD at a temperature of 373 K, d in ppm): 2.05 (mt, 2H: CH 2 of chromanyl); from 2.80 to 3.20 (mt, 4H: CH 2 S and CH 2 N of propylamine); 2.89 (t, J = 7 Hz, 2H: ArCH2); 3.52 (mt, 1H: propylamine CHN); 3.60 (t, J = 7 Hz, 2H: CH2NCO); 3.94 (t, J = 5 Hz, 1H: chromanyl CHN); 4.20 to 4.45 (mt, 2H CH 2 O of chromanyl); 6.97 (t, J = 7.5 Hz, 1H: chromanyl H6): 7.15 to 7.40 (mt, 5H: aromatic H of phenyl); 7.52 and 7.76 (2 d wide, J = 7.5 Hz, 1H each

: H5 and H7 chromanyl).

  Mass spectrum. DCI (NH3), m / z = 386 (M + H) + elemental analysis: C21H127N3O, S, 2CF3COeH: Calculated (%) C = 48.93; HI = 4.76 F = 18.58, N = 6.85: S = 5.23 Found (OO): C = 48.6; H = 4.4; F =], 1: N = 6.9: S = 4.9 rotatory power: cD- -1 + 0.4 (CH.OH, c = 0.5)

  Example 5: Preparation of diastereoisomers of 14- (2 (R) -amino-3-mercapto

  propvlamino) -chromanl-8-carbonyl-L-phenylalanyl-L-methionine

  1.5 g (1.95 mmol) of N- (1 (S) -carboxy-2-phenyl-ethyl) -4 - [(2 (R) -tert-

  butoxycarbonylamino-3-triphenylmethylthio) -propylamino] -chroman-8carboxamide, 0.43 g (2.14 mmol) of L-methionine methyl ester hydrochloride, 0.29 g (2.14 mmol) of benzotriazole, 0.6 ml (4.28 mnoles) of triethylamine,

  0.41 g (2.14 mmol) of 1- (3-dimethylaminopropyl) hydrochloride

  ethylcarbodiimide dissolved in 20 ml of dichloromethane are stirred at a temperature of 20 C for 15 hours. After dilution of the reaction medium with an additional 80 ml of dichloromethane, the organic phase is washed with 25 ml of distilled water, then successively with 2 times 25 ml of 1N sodium hydroxide, 25 ml of water, twice 25 ml of hydrochloric acid. 1N and finally 25 ml of a saturated solution of sodium chloride. Then, after drying over magnesium sulfate, filtration and

  dry concentration under reduced pressure, 1.75 g (98%) of methyl ester of

  (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) chroman] -8-

  carbonyl-L-phenylalanyl-L-methionine as a pale yellow meringue.

  Spectrum of R.M.N. IH (400 MHz, (CD3) 2SO with addition of some

  drops of CD3COOD at a temperature of 343 K, d in ppm). The description

  is carried out on the mixture of the two diastereoisomers 50-50: 1.42 (s, 9H: COOC (CH3) 3); from 1.85 to 2.10 (mt, 2H: methyl-thioethyl CH 2) 2.06 (s, 3H: methyl-thioethyl-SCH 3); 2.23 (mt, 2H: CH 2 S of propylamine);

  from 2.25 to 2.60 (mt: the 4H corresponding to CH 2 of chromanyl and CH 2 S of methyl-

  thio-ethyl); from 2.85 to 3.00 (mt, 2H: propylamine CH 2 N); 3.02 and 3.17 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH2); 3.69 (mt 3H: COOCH3); 3.81 (mt, 1H: propylamine CHN); from 4.20 to 4.55 (mt, 4H: chromanyl CHO - chromanyl CHN and methyl-thioethyl CHN); 4.86 (mt, 1H: NCHCON); 7.03 (t, J = 7.5 Hz, 1H: chromanyl H6); from 7.15 to 7.40 (mt, 20H aromatic Hs of triphenylmethyl and aromatic H of phenyl); 7.63 and 7.80 (2

  mts, 1H each: H5 and H7 chromanyl).

  To a solution consisting of 1.75 g (1.91 mmol) of methyl ester of

  (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthio-propylamino) chroman] -8

  carbonyl-L-phenylalanyl-L-methionine in a mixture of tetrahydrofuran (40 ml) and distilled water (4 ml) is added 0.1 g (2.29 mmol) of lithium hydroxide hydrate. The reaction medium is stirred for 15 hours at a temperature in the region of 20 ° C. and then concentrated to dryness under reduced pressure. The crude product thus obtained (1.9 g) in the form of pale yellow meringue is solubilized in dichloromethane (35 ml), treated with 0.39 ml (2.48 mmol) of triethylsilane and then with 7.3 ml (9, 53 mmol) of trifluoroacetic acid. The reaction mixture is stirred for 2 hours at a temperature in the region of 20 ° C. and then concentrated to dryness under reduced pressure. The residue is washed with 3 times 30 ml of pentane and then 3 times 30 ml of petroleum ether before being purified by high performance liquid chromatography (C18 phase) eluting with

  a gradient of a water / acetonitrile mixture containing 0.07% trifluoroacetic acid.

We obtain:

  0.20 g of diastereoisomer A of [4- (2 (R) -amino-3-mercaptopropylamino) -

  chroman] -8-carbonyl-L-phenylalanyl-L-methionine in the form of ditrifluoroacetate in the form of white lyophilizate, the characteristics of which are as follows: NMR spectrum. 1H (250 MHz, (CD3) 2SO, d in ppm): from 1.85 to 2.10 (mt, 2H CH 2 methyl-thioethyl); 2.07 (s, 3H: SCH3); from 2.05 to 2.25 (mt, 2H: CH 2 of chromanyl); 2.40 to 2.60 (mt, 2H: SCH 2 methyl-thioethyl); 2.84 (mt, 2H: CH 2 S); 2.85 to 3.35 (mt, 2H: CH2N); 3.00 and 3.18 (2 dd, respectively J = 14 and 8.5 Hz and J = 14 and 5 Hz, each IH: ArCH2); 3.47 (mt, 1H: propylamine CHN); from 3.70 to 4.50 (mt: 1'H corresponding to the chromanyl CHN); 4.25 to 4.50 (mt, 3H: CH 2 O of chromanyl and CH of methylthioethyl); 4.81 (mt, 1H: NCHCON); 7.04 (t, J = 7.5 Hz, 1H: chromanyl H6); from 7.15 to 7.40 (mt, aromatic HH of phenyl); 7.60 and 7.78 (2 d broad, J = 7.5 Hz, 1H each: H5 and H7 chromanyl); 8.23 and 8.42 (2 d, respectively J = 7.5 Hz and J = 8 Hz, I H

each: 2 CONH).

  Mass Spectrum: LSIMS, m / z = 561 (M + H) + elemental analysis: C27H31V40525, 2CF3CO7H, 1.3H, O: Calcd (C) = 45.84: H = 5.04: F14.03 N = 6.90 S = 7.90 Found (% O): C 46.28: H = 5.12; F 13.50 N 7.01 S = 7.63 rotatory power. cD20 = +37.0 + 0.7 (CH3OH = 0.5)

  0.24 g of [4- (2 (R) -amino-3-mercaptopropylamino) diastereoisomer B

  chroman] -8-carbonyl-L-phenylalanyl-L-methionine trifluoroacetate in the form of white lyophilizate, the characteristics of which are as follows: 1 H NMR spectrum (250 MHz, (CD3) 2 SO, d in ppm) 1.85 to 2.10 (mt, 2H: CH 2 methyl-thioethyl) 2.07 (s, 3H: SCH 3); from 2.00 to 2.25 (mt, 2H: CH 2 of chromanyl); from 2.45 to 2.60 (mt, 2H: methyl-thioethyl SCH2) 2.82 (mt, 2H: CH2S) 2.99 and 3.17 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH2); from 2.95 to 3.75 (mt: the 4H corresponding to CH2N-CHN of propylamine and CHN of chromanyl); 4.20 to 4.50 (mt, 3H: CH, O of chromanyl and CH of methyl-thioethyl); 4.83 (mt, 1H: NCHCON); 7.03 (t, J = 7.5 Hz, 1H H6 chromanyl); from 7.15 to 7.35 (mt, 5H: aromatic H of phenyl); 7.59 and 7.76 (2 d wide, J = 7.5 Hz, 1H each: H5 and H7 chromanyl); 8.23 and 8.51 (2 d,

J = 8 Hz, 1H each: the 2 CONH).

  Mass spectrum: LSIMS, m / z = 561 (M + H) + elemental analysis :. C27H36N4O5S2, 1, 7CF3CO2H1, 1, OH20: Calculated (% O). C = 47.26; H = 5.18, F = 12.54 N = 7.25; S, 8.30 Found (% O): C = 47.07; H, 4.92; F = 12.35; N = 7.19, S = 7.93 rotary power: aD '= -40.3 + 1.2 (CH 3 OH, c = 0.5)

  Example 6 Preparation of N- (1 (S) -benzylcarbamoyl) -2 Diastereoisomers

  phenyl-ethyl) -4- (2 (R) -amino-3-mercaptopropylamino) -chroman-8-carboxamide By operating as in Example 5 for the preparation of the methyl ester

  [4- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino)

  chroman] -8-carbonyl-L-phenylalanyl-L-methionine, but starting from 1.8 g (2.33

  mmol) of N- (I (S) -carboxy-2-phenyl-ethyl) -4- (2 (R) -tertbutoxycarbonylamino-3-

  triphenylmethylthio-propylamino) -chroman-8-carboxamide, 0.18 ml (2.57 mmol), benzylamine, 0.35 g (2.57 mmol) 1-hydroxybenzotriazole, 0.36 ml (2.57 mmol).

  mmol) of triethylamine, 0.49 g (2.57 mmol) of 1- (3-

  dimethylaminopropyl) -3-ethylcarbodiimide and 25 ml of dichloromethane,

  2.1 g of N- (I (S) -benzylcarbamoyl-2-phenyl-ethyl) -4- (2 (R) -tert-

  butoxycarbonylamino-3-triphenylmethylthio-propylamino) -chroman-8carboxamide

in the form of yellow meringue.

  Spectrum of R.M.N. IH (250 MHz, (CD3) 2SO with the addition of a few

  drops of CD3COOD at a temperature of 343 K, d in ppm). The description

  is carried out on the mixture of the two diastereoisomers 50-50: 1.40 (s, 9H: COOC (CH3) 3); 2.24 (mt, 2H: CH 2 S); from 2.25 to 2.50 (mt, 2H: CH, chromanyl); from 2.90 to 3.00 (mt, 2H: propylamine CH 2 N); 3.03 and 3, 15 (respectively mt and dd, J = 14 and 5 Hz, 1H each: ArCH2); 3.81 (mt, 1H: propylamine CHN); 4.20 to 4.40 (mt, 4H: CH 2 O of chromanyl and ArCH 2 NCO); 4.48 (mt, 1H: chromanyl CHN); 4.84 (mt, 1H: NCHCON); 7, 03 (t, J = 8 Hz, 1H: H6 of chromanyl); from 7.15 to 7.40 (mt, 25H: aromatic H of aromatic triphenylmethyl-H of the two phenyls); 7.53 and 7.82 (2 mts, 1H

each: H5 and H7 chromanyl).

  The procedure is as in Example 1 for the preparation of N- (1 (S) -carbamoyl-

  2-phenyl-ethyl) -4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8carboxamide,

  but from N- (1 (S) -benzylcarbamoyl-2-phenyl-ethyl) -4- (2 (R) -tert-

  butoxycarbonylamino-3-triphenylmethylthiopropylamino) -chroman-8carboxamide (2.0 g, 2.32 mmol), triethylsilane (0.5 mL, 3.02 mmol), trifluoroacetic acid (8.9 mL, 0.116 moles ) and dichloromethane (40 ml). The crude product is purified by high performance liquid chromatography (phase C1 8) eluting with a gradient of a water / acetonitrile mixture containing 0.07% of acid

  trifluoroacetic. 1.05 g of the 50/50 mixture of the two diastereoisomers of N-

  (1 (S) -benzylcarbamoyl-2-phenyl-ethyl) -4- (2 (R) -amino-3-mercaptopropylamino)

  chroman-8-carboxamide in the form of trifluoroacetate in the form of white lyophilisate, the characteristics of which are as follows:

  Spectrum of R.M.N. 1H (300 MHz, (CD3) 2SO, d in ppm). The description is

  performed on the mixture of the two diastereoisomers 50-50: 2.26 (mf.2H: CH 2 chromanyl); 2.85 (mt, 2H: CH: S); 3.03 and 3.13 (respectively mt and dd, J = 13.5 and 7 Hz, 1 H each: ArCH2); from 3.00 to 4.00 (mt 4H corresponding to CH2N-CHN propylamine and chromanyl CHN) from 4.25 to 4.50 (mt, H: NCH2 benzyl and CH20 chromanyl); 4.80 (mt, 1H: NCHCON); 7.07 (t, J = 7.5 Hz, 1H: chromanyl H6) of 7.15 to 7.40 (mt, 10H aromatic H 2 of the phenyls); 7.64 and 7.81 (respectively broad, J = 7.5 Hz and mt, 1H each: H5 and H7 chromanyl); 8,33 and 8, 67 (2 mts, 1H each: the 2

CONH).

  Mass spectrum :. DCI (NH3), m / z = 519 (M + H) + elemental analysis: C9H3. V403S, 1, 9CF3COH, 1. OH-O:

III'111 111 -,

  Calculated (0%): C = 52.29; H, 5.07; F = 14.37; N, 7.44; S = 4.26 Found (%): C = 52.29; H, 5.05; F = 14.32: N = 7.54, S = 4.25 rotatory power: ct2d = +3.8 + 0.4 (CH3OH, c = 0.5)

  EXAMPLE 7 Preparation of Diastereoisomers of N- (1 (S) -n-butylcarbamoyl)

  phenyi-ethyl) -4- (2 (R) -amino-3-mercaptopropylamino) -chroman-8-carboxamide By operating as in Example 5 for the preparation of the methyl ester

  [4- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino)

  chroman] -8-carbonyl-L-phenylalanyl-L-methionine, but starting from 1.8 g (2.33

  mmol) of N- (1 (S) -carboxy-2-phenyl-ethyl) -4- (2 (R) -terbutoxycarbonylamino)

  3-triphenylmethylthio-propylamino) -chroman-8-carboxamide, 0.25 ml (2.57 mmol), n-butylamine, 0.35 g (2.57 mmol) 1-hydroxybenzotriazole, 0.36 ml (2 57

  mmol) of triethylamine, 0.49 g (2.57 mmol) of 1- (3-

  (dimethylaminopropyl) -3-ethylcarbodiimide and 25 ml of dichloromethane,

  1.97 g of N- (1 (S) -n-butylcarbamoyl-2-phenyl-ethyl) -4- (2 (R) -tert-

  butoxycarbonylamino-3-triphenylmethylthio-propylamino) -chroman-8carboxamide

in the form of yellow meringue.

  Spectrum of R.M.N. IH (250 MHz, (CD3) 2SO with the addition of a few

  drops of CD3COOD at a temperature of 343 K, d in ppm). The description

  is carried out on the mixture of the two diastereoisomers 50-50: 0.87 (t, J = 7 Hz, 3H butyl CH 3); from 1.15 to 1.50 (mt, 4H: the 2 central CH2 butyl); 1.41 (s, 9H: COOC (CH 3) 3); from 2.15 to 2.35 (mt, 2H: CH 2 S); from 2, 30 to 2.55

  (mt, 2H: CH 2 of chromanyl); 2.90 to 3.20 (mt, 6H: CH 2 N propylamine -

  Butyl CH2N and ArCH2); 3.83 (mt, 1H: propylamine CHN); from 4.25 to 4.45 (mt, 2H: CH 2 O of chromanyl); 4.51 (mt, 1H: chromanyl CHN); 4.76 (mt, 1H: NCHCON); 7.04 (t, J = 7.5 Hz, 1H: CH at 6); from 7.15 to 7.40 (mt, 20H: aromatic H of triphenylmethyl and aromatic H of phenyl); 7.56 and 7.83 (2 mts,

1H each: H5 and H7 chromanyl).

  The procedure is as in Example I for the preparation of N- (1 (S) -carbamoyl-

  2-phenyl-ethyl) -4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8carboxamide,

  but from N- (1 (S) -n-butylcarbamoyl-2-phenyl-ethyl) -4- (2 (R) -tert-

  butoxycarbonylamino-3-triphenylmethylthiopropylamino) -chroman-8carboxamide (1.96 g, 2.34 mmol), triethylsilane (0.47 ml, 2.99 mmol), trifluoroacetic acid (8.8 ml, 0.115 moles). ) and dichloromethane (40 ml). The crude product is purified by high performance liquid chromatography (C18 phase) eluting with a gradient of a water / acetonitrile mixture containing 0.07% of acid

  trifluoroacetic. 1.12 g of the 50/50 mixture of the two diastereoisomers of N-

  (1 (S) -N-butylcarbamoyl-2-phenylethyl) -4- (2 (R) -amino-3-mercaptopropylamino)

  chroman-8-carboxamide in the form of trifluoroacetate in the form of white lyophilisate, the characteristics of which are as follows:

  Spectrum of R.M.N. 1H (300 MHz, (CD3) 2SO, d in ppm). The description is

  performed on the mixture of the two diastereoisomers 50-50: 0.87 (t, J = 7.5 Hz, 3H: butyl CH 3); from 1.15 to 1.45 (mt, 4H: the 2 central CH2 of butyl); from 2.10 to 2.35 (mf, 2H: CH 2 of chromanyl); 2.75 to 2.90 (mrt, 2H: CH 2, S); from 2.90 to 3.20 (mt, 2H: ArCH2); from 2.90 to 3.90 (mt: 6H corresponding to butyl CH2N-CH2N - propylamine CHN and chromanyl CHN); 4.25 to 4.50 (mt, 2H: CH 2 O of chromanyl); 4.71 (mt, 1H: NCHCON); 7.05 (t, J = 7.5 Hz, 1H: chromanyl H6); from 7.15 to 7.35 (mt, 5H: aromatic H of phenyl) 7.62 and 7.79 (respectively broad, J = 7.5 Hz and mt, 1H each: H5 and H7 from

  chromanyl); 8,08 and 8,29 (2 mts, 1H each: the 2 CONH).

  Mass Spectrum: DCI (NI-IH3), m / z = 485 (M + H) +

  Elemental analysis: C-6H31, N403S, 1.7CF3CO: H, 1.4I-1.0.

  Calc'd (%): C = 50.18; H = 5.80; F = 13.77: N = 7.96; S = 4.56 Found (%): C = 50.18, H, 5.64; F = 13.81, N = 7.92, S = 4.28 rotatory power: aD = +4, 0.4 (CH3OH, c = 0.5)

  EXAMPLE 8 Preparation of N- (l) (S) -carbamoyl-2-phenyl) diastereoisomers

  ethyl) -4- (2 (R) -amino-3-mercapto-propylamino) -6-fluoro-chroman-8-

carboxamide

  By operating as in Example 1 for the preparation of 4-amino

  chromane, but from 77 g (1 mole) of ammonium acetate, 16.6 g (0.1 mol) of 6-fluoro-chroman-4-one, 5.7 g (0.09 mole) of sodium cyanoborohydride and 300 ml of methanol, 11 g (55%) of 4-amino-6-fluoro-chroman in the form of

pale yellow oil.

  By operating as in Example I for the preparation of 4-tert-

  butoxycarbonylamino-chroman, but from 11 g (0.066 mole) of 4 amino-6-

  fluoro-chromane, 8.3 g (0.099 mol) of sodium hydrogen carbonate, 16.6 g (0.076 g)

  mole) of di-tert-butyl-dicarbonate and 130 ml of ethanol gives 18.3 g (100%) of 4-

  tert-butoxycarbonylamino-6-fluoro-chroman in the form of a white powder melting at

123-125 C.

  By operating as in Example I for the preparation of 4-tert-

  butoxycarbonylamino-chroman-8-carboxylic acid, but from 18 g (0.066 mol) of

  4-tert-butoxycarbonylamino-6-fluoro-chroman, 13.8 g (0.12 mol) of N, N'-

  tetramethylethylenediamine, 112 ml of a 1.3 M solution in sec-butyllithium cyclohexane (0.146 mol) and 350 ml of anhydrous diethyl ether give 17.3 g (84.4%) of 4-tertbutoxycarbonylamino-6-fluoro-chroman-8-carboxylic acid

  in the form of a white powder melting at 182-185 C.

  By operating as in Example 1 for the preparation of N- (1I (S) -

  carbamoyl-2-phenyl-ethyl) -4-tert-butoxycarbonylamino-chroman-8carboxamide,

  but from 4.7 g (0.015 mole) of 4-tert-butoxycarbonylamino-fluorinated

  chroman-8-carboxylic acid, 2.7 g (0.0165 mol) of (S) -phenylalaninecarboxamide, 2.25 g (0.0165 mol) of 1-hydroxy-benzotriazole. 3.2 g (0.0165 mol) of I - (3- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 2.1 ml (0.015

  mole) of triethylamine and 150 ml of dichloromethane, 6.4 g (93.3%) of

  (1 (S) -carbamoyl-2-phenyl-ethyl) -4-tert-butoxycarbonylamino-6-fluorochroman-8-

  carboxamide in the form of beige meringue.

  Spectrum of R.M.N. 1 H (300 MHz, (CD3) 2 SO, d in ppm). The description is

  performed on the mixture of the two diastereoisomers 50-50: 1.46 (s, 9H: COOC (CH3) 3); from 1.95 to 2.20 (mt, 2H: chromanyl CH 2); 3.02 and 3.15 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH2); from 4.15 to 4.40 (mt, 2H: CH 2 O of chromanyl); from 4.65 to 4.85 (mt, 2H: NCHCON and chromanyl CHN); 7.13 and 7.44 (2 mts, 1H each: H5 and H7 chromanyl); from 7.15 to 7.40 (mt, 6H: 1H of CONH 2 and aromatic H of phenyl); 7.55 (d = J = 8 Hz, 1H: CONH); 7.64 (s wide, 1H: the other H of CONH2); 8.37 (d, J = 7.5 Hz, 1H

: ArCONH).

  To 6.3 g (0.0137 moles) of N- (1 (S) -carbamoyl-2-phenyl-ethyl) -4-tert-

  butoxycarbonylamino-6-fluoro-chroman-8-carboxamide dissolved in 50 ml of dichloromethane, 17 ml of a 4N solution of hydrogen chloride in 2-propanol are added. The reaction is continued for 5 hours at a temperature in the region of C, then the reaction medium is concentrated to dryness under reduced pressure at 50 ° C., the residue is taken up in 100 ml of diethyl ether and the insoluble material is filtered off and dried under reduced pressure at room temperature. C. The crude product thus obtained (4.8 g) is taken up in 300 ml of distilled water, this aqueous phase washed with diethyl ether and then basified with 1N sodium hydroxide. Extraction of the organic phase with twice 150 ml of dichloromethane leads to the formation of 0.42 g of an insoluble material which proves to be the

  N- (I (S) -carbamoyl-2-phenyl-ethyl) -4-amino-6-fluorinated diastereoisomer A

  chroman-8-carboxamide in the form of a beige powder melting at 110 ° -113 ° C. The chloromethylenic phase is dried over magnesium sulphate and then concentrated to dryness under reduced pressure at 50 ° C. to yield 2.9 g of purified crude product by chromatography on silica column using a mixture of dichloromethane and methanol (94/6 by volume) as eluent. 0.45 g of N- (I (S) carbamoyl-2-phenyl-ethyl) -4-amino-6-fluoro-chroman-8-carboxamide diastereoisomer A are obtained in the form of an amorphous white solid: NMR spectrum. 1H (300 MHz, (CD3) 2SO, d in ppm): 1.78 and 2.07 (2 mts, 1H each: CH 2 of chromanyl); 2.14 (mf, 2H: NH 2); 2.99 and 3.11 (2 dd, respectively J = 14 and 9 Hz and J = 14 and 5 Hz, 1H each: ArCH2); 3.92 (t, J = 6 Hz, 1H: chromanyl CHN); 4.27 (mt, 2H: chromanyl CH 2 O); 4.66 (mt, 1H: NCHCON); 7.19 and 7.62 (2s wide, 1H each: CONH 2); from 7.20 to 7.50 (mt, 7H: aromatic H of phenyl - H5 and H7 of chromanyl); 8.38 (d, J = 7.5

Hz, 1H: ArCONH).

  and 0.90 g of N- (1- (S) -carbamoyl-2-phenyl-ethyl) -4-amino-6 diastereoisomer B

  fluoro-chroman-8-carboxamide as beige meringue MR spectrum 1H (300 MHz, (CD3) 2SO, d in ppm): 1.77 and 2.03 (2 mts each, 1H: chromanyl CH 2); 2.12 (mf, 2H: NH 2); 2.98 and 3.11 (2 dd, respectively J = 13.5 and 8.5 Hz and J = 13.5 and 5 Hz, 1H each: ArCH); 3.90 (t, J = 6 Hz, 1H: chromanyl CHN); from 4.10 to 4.40 (mt, 2H: CH 2 O of chromanyl); 4.66 (mt, 1H: NCHCON); 7.18 and 7.59 (2s wide, 1H each: CONH 2); from 7, 20 to 7.35 (mt, 5H: aromatic H of phenyl); 7.37 and 7.43 (2 dd, J = 9, 5 and 3 Hz, 1H

  each: H5 and H7 chromanyl); 8.37 (d, J = 8 Hz, 1H: ArCONH).

  By operating as in Example I for the preparation of N- (I (S) -

  carbamoyl-2-phenyl-ethyl) -4 - [(2 (R) -tert-butoxycarbonylamino-3-

  triphenylmethylthio) -propylamino] -chroman-8-carboxamide, but from 0.85 g

  (2.4 mmol) of N- (1 (S) -carbamoyl-2-phenyl-ethyl) -4-amino-diastereoisomeric

  6-fluoro-chroman-8-carboxamide, 1.18 g (2.65 mmol) of striphenylmethyl-N-tert-

  butoxycarbonyl-L-cysteine, 0.45 g (7.2 mmol) of sodium cyanoborohydride, sieve 3A, 0.5 ml of acetic acid and 50 ml of acetonitrile, 0.87 g (46, 3%)

  of N- (1 (S) -carbamoyl-2-phenyl-ethyl) -4 (2 (R) -tert- diastereoisomeric

  butoxycarbonylamino-3-triphenylmethylthio-propylamino) -6-fluoro-chroman8-

  carboxamide in the state of white meringue.

  Spectrum of R.M.N. H (400 MHz, (CD 3) 2 SO at 373 K, d in ppm) 1.43 (s, 9H: COOC (CH 3) 3); 1.82 and 1.98 (2 mts, 1H each: chromanyl CH 2) from 2.35 to 2.50 (mt, 2H: CH 2 S); from 2.55 to 2.70 (mt, 2H: CH 2 N); 3.05 and 3.18 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH2); 3.55 (mt, 1H propylamine CHN); 3.71 (mt, 1H: chromanyl CHN); from 4.15 to 4.30 (mt, 2H: CH 2 O of chromanyl); 4.75 (mt, 1H: NCHCON); 6.15 (mt, 1H: exchangeable) 6.90 (mf, 2H: CONH2); from 7.15 to 7.45 (mt, 22H: aromatic H of triphenylmethyl - aromatic H of phenyl H5 and H7 of chromanyl); 8,18 (d, J =

7.5 Hz, 1H: ArCONH).

  The procedure is as in Example I for the preparation of N- (1 (S) -carbamoyl-

  2-phenyl-ethyl) -4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8carboxamide,

  but from the diastereoisomer A of N- (1 (S) -carbamoyl-2-phenyl-ethyl) 4- (2 (R) -

  tert-butoxycarbonylamino-3-triphenylmethylthio-propylamino) -6-fluorochroman-8-

  carboxamide (0.83 g, 1 mmol), triethylsilane (0.2 mL, 1.25 mmol), trifluoroacetic acid (1.9 mL, 25 mmol) and dichloromethane (15 mL). The crude product is taken up in 30 ml of a mixture of diisopropyl ether and dichloromethane (2/1 by volume), the precipitate filtered on sintered glass and dried. 0.48 g is obtained

  (68.6%) ditrifluoroacetate of N- (i) S-carbamoyl-2-phenyl-diastereoisomeric

  ethyl) -4 - [(2 (R) -amino-3-mercaptopropylamino] -6-fluoro-chroman-8carboxamide as a white solid melting at 125-130 ° C and having the following characteristics: NMR spectrum 1H (400 MHz, (CD3) 2SO at a temperature of 373 K, d in ppm) 2.00 and 2.13 (2 mts, 1H each: chromanyl CH 2), 2.75 to 3.15 (mt, 4H: CH, S and CH 2 N); 3.05 and 3.18 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, each IH: ArCH 2); 3.34 (mt, 1H: CHN); propylamine) 3.92 (t, J = 5 Hz, 1H: chromanyl CHN) 4.20 to 4.40 (mt, 2H: chromanyl CHO) 4.76 (mt, 1H: NCHCON) from 6.80 to 7.05 (mf, 2H: CONH), from 7.15 to 7.50 (mt, 7H: H5 and H7)

  chromanyl and phenyl aromatic H) 8.19 (d, J = 7 Hz, 1H: ArCONH).

  Mass Spectrum: DCI (NfH3), m / z = 447 (M + H) + Elemental Analysis: C22H27FN4O3S, 2CF3CO2H. 2H-20, 0.2iPrO Calculated (%) J C = 44.69; H = 4.94, M = 18.19, N = 7.66; S = 4.39 Found (0). C = 44.64, H 4.51; F = 18.14; N = 8.08; S = 4.08 rotatory power - +19.9 0.7 CH30H, c =, rotatory power. ctD = +19.9 + 0.7 (CH3OH- c = 0.5)

  Example 9 Preparation of N- (1 (S) -carbamoyl-2-phenyl) diastereoisomers

  ethyl) -4- (2 (R) -amino-3-mercapto-propylamino) -6-fluoro-chroman-8-

carboxamide

  By operating as in Example 1 for the preparation of N- (I1 (S) -

  carbamoyl-2-phenyl-ethyl) -4- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthio)

  propylamino) -chroman-8-carboxamide, but from 0.85 g (2.4 mmol) of

  N- (1 (S) -carbamoyl-2-phenyl-ethyl) -4-amino-6-fluoromeric diastereoisomer B

  chroman-8-carboxamide, 1.18 g (2.65 mmol) of S-triphenylmethyl-N-tert-

  butoxycarbonyl-L-cysteine, 0.45 g (7.2 mmol) of sodium cyanoborohydride, sieve 3A, 0.5 ml of acetic acid and 50 ml of acetonitrile give 0.85 g (45% )

  N- ((S) -carbamoyl-2-phenyl-ethyl) -4- (2 (R) tert-diastereoisomer B

  butoxycarbonylamino-3-triphenylmethylthio) propylamino) -6-fluoro-chroman8-

  carboxamide in the state of white meringue.

  Spectrum of R.M.N. H (400 MHz, (CD 3) 2 SO at 373 K, d in ppm): 1.42 (s, 9H: COOC (CH 3) 3); 1.82 and 1.98 (2 mts, 1H each: chromanyl CH 2) from 2.30 to 2.45 (mt, 2H: CH: S); from 2.50 to 2.70 (mt, 2H: CH 2 N); 3.05 and 3.18 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH.); 3.55 (mt, 1H: propylamine CHN); 3.70 (mt, 1H: chromanyl CHN); 4.17 and 4.27 (2 mts, 1H each: CH 2 O of chromanyl); 4.75 (mt, 1H: NCHCON); 6.14 (mt, 1H: exchangeable); from 6.80 to 7.00 (mf, 2H: CONH2); from 7,15 to 7,45 (mt, 22H: aromatic H of triphenylmethyl - aromatic H of phenyl - H5 and H7 of

  chromanyl); 8.19 (d, J = 6 Hz, 1H: ArCONH).

  The procedure is as in Example 1 for the preparation of N- (1 (S) carbamoyl-

  2-phenyl-ethyl) -4- (2 (R) -amino-3-mercapto) propylamino) -chroman-8carboxamide,

  but from the N- (1 (S) -carbamoyl-2-phenyl-ethyl) 4- (2 (R)) diastereoisomer B

  tert-butoxycarbonylanmino-3-triphenylmethylthio-propylamino) -6-fluorochroman-8-

  carboxamide (0.82 g, 1 mmol), triethylsilane (0.2 mL, 1.25 mmol), trifluoroacetic acid (1.9 mL, 25 mmol) and dichloromethane (15 mL). The crude product is taken up in 35 ml of a mixture of diisopropyl ether and dichloromethane (2/1 by volume), the precipitate filtered on sintered glass and dried. We obtain 0.62 g

  (88.6%) ditrifluoroacetate of N- (i) (S) carbamoyl-2-phenyl-diastereoisomeric B

  ethyl) 4- (2 (R) -arnino-3-mercaptopropylamino) -6-fluoro-8-aminocarboxamide as a white solid, m.p. 110-115 ° C, and having the following characteristics: NMR spectrum. 1H (400 MHz, (CD3) 2SO at a temperature of 373 K, d in ppm): 2.01 and 2.13 (2 mts, 1H each: chromanyl CH 2); from 2.75 to 3.10 (mt, 4H: 4H corresponding to CH2N and CH2S); 3.05 and 3.18 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5.5 Hz, 1H each: ArCH2); 3.33 (mnt, 1H: CHN); 3.83 (t, J = 5 Hz, 1H: chromanyl CHN); from 4.15 to 4.45 (mt, 2H: chromanyl CHO); 4.78 (tnt, 1H: NCHCON); 6.96 (mf, 2H: CONH2); from 7.10 to 7.50 (mt, 7H: H5 and H7 from

  chromanyl and aromatic H of phenyl); 8.19 (d, J = 7 Hz, 1H: ArCONH).

  Mass spectrum: DCI (NH 3), m / z = 447 (M + H) + rotatory power: a D = 20, 7 + 0.6 (CH 3 OH = 0.5)

  Example 10: Preparation of N- [1 (S) -carbamoyl-2- (4-) 4- diastereoisomers

  chlorophenyl) -ethyl-4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8-

  carboxamide 6 g (0.02 mol) of 4-tert-butoxycarbonylamino-chroman-8-carboxylic acid dissolved in 70 ml of saturated methanol in hydrogen chloride are refluxed for 15 hours. The reaction mixture is then concentrated to dryness under reduced pressure and the residue taken up in petroleum ether. The insoluble material is filtered on sintered glass, washed with the same solvent and then dried. 5 g of 4-amino-chroman-8-carboxylic acid methyl ester hydrochloride are obtained in the form of a cream solid. Spectrum of R.M.N. 1H (300 MHz, (CD3) 2SO, d in ppm): 2, 14 and 2.28 (2 mts, 1H each: chromanyl CH 2); 3.79 (s, 3H: COOCH 3); 4.33 (t, J = 6 Hz, 2H: CH 2 O of chromanyl); 4.55 (t, J = 5.5 Hz, 1H: chromanyl CHN); 7.05 (t, J = 7.5 Hz, 1H: chromanyl H6); 7.63 and 7.71 (2 d wide, J = 7.5 Hz, 1H each: H5 and H7

  chromanyl); 8.62 (solid, 3H: NH3 +).

  The procedure is as in Example I for the preparation of N- (1 (S) -carbamoyl-

  2-phenyl-ethyl) -4- (2 (R) -tert-butoxycarbonylamino-3-triphénylméthylthio-

  propylamino) -chroman-8-carboxamide, but from the ester hydrochloride

  4-amino-chroman-8-carboxylic acid methyl ester (5 g, 0.021 mol),

  triphenylmethyl-N-tert-butoxycarbonyl-L-cysteine (10.10 g, 0.023 mol), sodium cyanoborohydride (3.84 g, 0.062 mol), acetic acid (3.5 ml), sieve 3A and acetonitrile (350 ml). The crude product is purified by flash chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (98/2

  in volumes). 8.45 g (64.5%) of methyl ester of 4 (2 (R) -tert-

  Butoxycarbonylamino-3-triphenylmethylthio-propylamino) -chroman-8-carboxylic

the state of yellow meringue.

  Spectrum of R.M.N. H (250 MHz, (CD3) 2 SO, d in ppm). The description

  is carried out on the mixture of the two diastereoisomers 50-50: 1.40 (s, 9H: COOC (CH3) 3); from 1.70 to 1.95 (mf, 2H: CH 2 of chromanyl); from 2.20 to 2.60 (mt: the 4H corresponding to CHS and CH2N); from 3.30 to 3.65 (mt, 2H: propylamine CHN and chromanyl CHN); 3.78 (s, 3H: COOCH3); from 4. 10 to 4.30 (mt, 2H: CHO 2 0 of chromanyl); 6.80 (mt, I H: exchangeable); 6, 90 (mt, I H: H6 chromanyl); from 7.15 to 7.45 (mt, 16H: aromatic H) of triphenylmethyl and H5 of

  chromanyl); 7.51 (d wide, J = 7.5 Hz, 1H: chromanyl H7).

  To 8.45 g (0.013 mole) of 4- (2 (R) -tert-

  butoxycarbonylamino-3-triphenylmethylthio-propylamino) -chroman-8-carboxylic acid in solution in a mixture consisting of 175 ml of methanol and 40 ml of distilled water, 1.11 g (0.020 mol) of potassium hydroxide and agitation is continued for 48 hours at a temperature in the region of 20 ° C. The reaction medium is then concentrated to dryness and the residue taken up in 200 ml of distilled water and then the acidified solution to pH = 1 using 1N hydrochloric acid. . The precipitate formed is filtered on sintered glass, washed with water and then with pentane. Purification by flash chromatography on a silica column using a mixture of dichloromethane and methanol (95/5

  in volume) as eluent gives 6.16 g (74.2%) of 4- (2 (R) -

  tert-butoxycarbonylamino-3-triphénylmnéthylthio-propylamino) -chroman-8-

  carboxylic acid as pale yellow meringue.

  Spectrum of R.M.N. H (300 MHz, (CD3) 2SO at a temperature of 373

  K, d in ppm). The description is made on the mixture of the two

  diastereoisomers 50-50: 1.41 (s, 9H: COOC (CH 3) 3); from 1.70 to 2.00 (mt, 2H: CH, chromanyl); from 2.30 to 2.50 (mt, 2H: CH 2 S); from 2.55 to 2.65 (mt, 2H: CH 2 N); from 3.40 to 3.60 (mt, 1H: propylamine CHN); from 3.60 to 3.75 (mt, 1H: chromanyl CHN); from 4.10 to 4.35 (mt, 2H: CH 2 O of chromanyl); 6.31 (mf, 1H: exchangeable); 6.85 (mt, 1H: chromanyl H6); from 7.15 to 7.45 (mt, 16H: aromatic aromatics of triphenylmethyl and H5 of chromanyl); 7.48 (d wide,

J = 7.5 Hz, 1H H7 chromanyl).

  LSIMS mass spectrum, m / z = 625 (M + H), m / z = 581 (m / z = 625-CO2), m / z = 381 (m / z = 625-C19H16) +, m / z = 243 (C19H15 +) base peak

  1.25 g (5 mmol) of the methyl ester hydrochloride of (S) -4-

  Chlorophenylalanine are heated at 40 ° C. in a mixture of toluene (30 ml) and 30% ammonia (15 ml). The reaction is continued overnight at the same temperature, then after cooling the reaction medium is concentrated to dryness under reduced pressure, the residue taken up in ethyl acetate, filtered on sintered glass and then

  dried. 1 g (85%) of (S) -4-chlorophenylalanine hydrochloride are obtained.

  carboxamide in the form of a cream solid.

  DCI mass spectrum (NH3), m / z = 216 (M + NH4), m / z = 199 (M + H) + base peak

III - - - - -.

  To a solution consisting of 1.2 g (2 mmol) of 4- (2 (R) - (tert-

  butoxycarbonylamino-3-triphenylmethylthio-propylamino) -chroman-8-

  carboxylic acid, 0.52 g (2.2 mmol) of (S) -4-hydrochloride.

  chlorophenylalanine carboxamide, 0.30 g (2.2 mmol) of 1-hydroxy

  benzotriazole and 0.62 ml (4.4 mmol) of triethylamine in 20 ml of

  dichloromethane, 0.42 g (2.2 mmol) of

  dimethylaminopropyl) -3-ethylcarbodiimide at a temperature in the region of 20 C.

  The reaction is continued for 15 hours at the same temperature. After dilution with ml of dichloromethane, the reaction medium is washed 3 times with 20 ml of 0.1N hydrochloric acid, then twice with a 0.1N sodium hydroxide solution and finally with 20 ml of a saturated aqueous solution of sodium chloride. sodium. After drying over magnesium sulphate, the organic solution is filtered and then concentrated to dryness. The crude product (1.5 g) is purified by flash chromatography on a silica column, eluting with a mixture of dichloromethane and

  methanol (98/2 by volume) to yield 0.95 g (59.4%) of N- [1 (S) -

  carbamoyl-2- (4-chlorophenyl) -ethyl] -4- (2 (R) -tert-butoxycarbonylamino-3-

  triphenylmethylthio-propylamino) -chroman-8-carboxamide in the form of

cream meringue.

  Spectrum of R.M.N. 1H (250 MHz, (CD3) 2SO at a temperature of 383

  K, d in ppm). The description is made on the mixture of the two

  diastereoisomers 50-50: 1.41 (s, 9H: COOC (CH 3) 3); from 1.75 to 2.05 (mt, 2H: CH 2 of chromanyl); 2.40 (mt, 2H: CH 2 S); 2.62 (broad d, J = 6 Hz, 2H: CH 2 N); 3.03 and 3.16 (2 dd, respectively J = 14 and 7.5 Hz and J = 14 and 5.5 Hz, each IH: ArCH,); 3.55 (mt, 1H: propylamine CHN); 3.68 (mt, 1H: chromanyl CHN); from 4.10 to 4.35 (mt, 2H: CH 2 O of chromanyl); 4.75 (mrt, 1H: NCHCON); 6.18 (mt, I H: exchangeable); from 6.80 to 7.05 (mf, 2H: CONH2); 6.89 (mt, 1H: chromanyl H6); from 7.10 to 7.45 (mt, 20H: Aromatic aromatic triphenylmethyl H-4-chloro-phenyl and H5 chromanyl) 7.67 (mt, 1H: H7 chromanyl) 8.12 (d wide, J = 8 Hz, 1H: ArCONH).

  The procedure is as in Example I for the preparation of N- (1 (S) -carbamoyl-

  2-phenyl-ethyl) -4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8-carboxamide,

  but from N- [1 (S) -carbamoyl-2- (4-chlorophenyl) -ethyl] -4 (2 (R) -tert-

  butoxycarbonylamino-3-triphenylmethylthiopropylamino) -chroman-8carboxamide (0.95 g, 1.18 mmol), triethylsilane (0.24 ml, 1.53 mmol), trifluoroacetic acid (4.51 ml, 59 mmol). ) and dichloromethane (60 ml). The crude product is purified by high performance liquid chromatography (C18 phase) eluting with a gradient of a water / acetonitrile mixture containing 0.07% trifluoroacetic acid. We obtain:

0.21 g of the 50/50 mixture of the two diastereoisomers A and B of N- [I (S)]

  carbamoyl-2- (4-chlorophenyl) -ethyl] -4- (2 (R) -amino-3-mercaptopropylamino) -

  chroman-8-carboxamide in the form of ditrifluoroacetate in the form of a cream lyophilisate, the characteristics of which are as follows:

  Spectrum of R.M.N. 1H (400MHz, (CD3) 2SO, d in ppm). The description is

  performed on the mixture of the two 50-50 diastereoisomers of 2.05 to 2.35 (mf, 2H: CH 2 chromanyl); from 2.75 to 2.95 (mt, 2H: CH 2 S); 2.99 and 3.16 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, each IH: ArCH2); from 3.00 to 3.90 (mt: the 4H corresponding to CH2N-CHN of chromanyl and CHN of propylamine) from 4.25 to 4.50 (mt, 2H: CH 2 O of chromanyl); from 4.60 to 4.80 (mt, 1H: NCHCON); 7.07 (t wide, J = 7.5 Hz, 1H: chromanyl H6); from 7.15 to 7.40 (mt, 5H: 1H of CONH 2 and aromatic H of 4-chlorophenyl); 7.55 to 7.70 and 7.78 (2 mts, 1H each: H5 and H7 chromanyl); from 7.55 to 7.70 (mt, 1H: the other

  H of CONH2); 8.25 (mrt, 1H: ArCONH).

  Mass spectrum: DCI (NH 3), m / z = 463 (M + H) + rotatory power: cD 2 = -3, 4 + 0.4 (CH 3 OH = 0.5)

  0.09 g of N- [1 (S) -carbamoyl-2- (4-chlorophenyl) diastereoisomer B

  ethyl] -4- (2 (R) -amino-3-mercaptopropylamino) -chroman-8-carboxamide in the form of ditrifluoroacetate in the form of a cream lyophilizate, the characteristics of which are as follows: NMR spectrum. 1H (400 MHz, (CD3) 2SO, d in ppm): from 2.10 to 2.35 (mf, 2H CH 2 of chromanyl); from 2.75 to 2.90 (mt, 2H: CH 2 S); 2.98 and 3.11 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH2); from 3.00 to 3.95 (mt: 4H corresponding to CH2N-CHN of chromanyl and CHN of propylamine); 4.38 (mt, 2H: CH 2 O of chromanyl); 4.71 (mt, 1H: NCHCON); 7.06 (t wide, J = 7.5 Hz, 1H: chromanyl H6); 7.21 and 7.63 (2s wide, 1H each

  : CONH2); 7.26 and 7.36 (2 d, J = 8 Hz, 2H each: aromatic H of 4-chloro

  phenyl); 7.60 and 7.77 (respectively d, J = 7.5 Hz and mt, 1H each: H5 and H7 from

  chromanyl); 8.23 (d, J = 7.5 Hz, 1H: ArCONH).

  Mass Spectrum: DCI (NH3), m / z = 463 (M + H) + Rotation: COD20 = 40.4 + 0.8 (CHI OH, c = 0.5)

  Example 11 Preparation of Diastereoisomers of N-II (S) -carbamoyl-2- (4-

  methoxyphenyl) -ethyl-4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8-

  carboxamide The procedure is as in Example 10 for the preparation of (S) -4-chlorophenylalanine-carboxamide hydrochloride, but starting from 1.17 g (4.7 mmol) of the methyl ester hydrochloride (S). ) -4méthoxyphénylalanine. 1.05 g (95%) of (S) -4-methoxyphenylalanine carboxamide hydrochloride is obtained in the form of a light-brick solid. Mass Spectrum: DCI (NH 3), m / z = 212 (M + NH 4) +, m / z = 195 (M + H) + base peak

  The procedure is as in Example 10 for the preparation of N-

  [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- (2 (R) -terbutoxycarbonylamino)

  3-triphenylmethylthio-propylamino) -chroman-8-carboxamide, but from

  1.25 g (2 mmol) of 4- (2 (R) -tert-butoxycarbonylamino-3- acid

  triphenylmethylthio-propylamino) -chroman-8-carboxylic acid, 0.51 g (2.2 mmol) of (S) -4-methoxyphenylalanine-carboxamide hydrochloride, 0.30 g

6 3 2774987

  (2.2 mmol) of 1-hydroxy-benzotriazole, 0.62 ml (4.4 mmol) of

  triethylamine, 0.42 g (2.2 mmol) of 1- (3-chlorohydrate)

  dimethylaminopropyl) -3-ethylcarbodiimide and 20 ml of dichloromethane. The crude product (1.39 g) is purified by flash chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (98/2).

  volumes) to yield 0.9 g (56.2%) of N- [1 (S) -carbamoyl-2- (4-

  methoxyphenyl) -ethyl] -4- (2 (R) -tert-butoxycarbonylamino-3-

  triphenylmethylthio-propylamino) -chroman-8-carboxamide in the form of

cream meringue.

  Spectrum of R.M.N. H (250 MHz, (CD3) 2SO at a temperature of 383

  K, d in ppm). The description is made on the mixture of the two

  diastereoisomers 50-50: 1.41 (s, 9H: COOC (CH 3) 3); from 1.80 to 2.05 (mt, 2H: CH 2 of chromanyl); 2.39 (mt, 2H: CH 2 S); 2.61 (broad d, J = 6 Hz, 2H: CH, N); 2.97 and 3.09 (2 dd, respectively J = 14 and 7 Hz and J = 14 and 5.5 Hz, 1H each: ArCH2); 3.54 (mt, 1H: propylamine CHN); 3.68 (mt, 1H: chromanyl CHN); 3.74 and 3.75 (2 s, 3H in all ArOCH3); from 4.15 to 4.35 (mt, 2H: CH 2 O of chromanyl); 4.69 (mt, 1H NCHCON); 6.20 (mt, 1H: exchangeable); from 6.75 to 7.00 (mf, 2H: CONH2); 6.85 (d, J = 9 Hz, 2H: H3 and H5 from 4-methoxyphenyl); 6.89 (mt, 1H: H 6 of chromanyl);

  from 7.10 to 7.45 (mt, 18H: aromatic H of triphenylmethyl - H3 and H5 from 4-

  methoxyphenyl and H5 chromanyl) 7.69 (d wide, J = 7.5 Hz, I H: H7 from

  chromanyl); 8.10 (broad d, J = 7.5 Hz, 1H: ArCONH).

  The procedure is as in Example I for the preparation of N- (1 (S) -carbamoyl-

  2-phenyl-ethyl) -4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8-carboxamide,

  but from N- [1 (S) -carbamoyl-2- (4-methoxyphenyl) -ethyl] -4 (2 (R) -tert-

  butoxycarbonylanmino-3-triphenylmethylthiopropylamino) -chroman-8carboxamide (0.9 g, 1.12 mmol), triethylsilane (0.23 ml, 1.46 mmol), trifluoroacetic acid (4.3 ml, 56 mmol). ) and dichloromethane (50 ml). The crude product is purified by high performance liquid chromatography (C18 phase) eluting with a gradient of a water / acetonitrile mixture containing 0.07% trifluoroacetic acid. We obtain:

  0.25 g of diastereoisomer A of N- [((S) -carbamoyl-2- (4-methoxyphenyl)]

  ethyl] -4- (2 (R) -amino-3-mercaptopropylamino) -chroman-8-carboxamide in the form of ditrifluoroacetate in the form of a cream lyophilisate, the characteristics of which are as follows: Spectrum of R.M.N. 1H (400 MHz, (CD3) 2SO, d in ppm): from 2.00 to 2.35 (mf, 2H CH 2 of chromanyl); from 2.75 to 2.90 (mt, 2H: CH 2 S) 2.93 and 3.06 (2dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH 2); from 3.00 to 4.00 (mt: 4H corresponding to CH2N-CHN of chromanyl and CHN of propylamine); 3.73 (s, 3H: ArOCH3) 4.25 to 4.50 (mt, 2H: CH2O chromanyl); 4.62 (mt, 1H: NCHCON); 6.87 and 7.20 (2 d, J = 8 Hz, 2H each: aromatic H of 4-methoxyphenyl); 7.06 (t wide, J = 7.5 Hz, I H: H 6 chromanyl); 7.14 and 7.57 (2s wide, 1H each: CONH,); 7.60 and 7.82 (2 d wide,

  J = 7.5 Hz, 1H each: H5 and H7 chromanyl); 8.20 (mt, 1H: ArCONH).

  Mass Spectrum: DCI (NH 3), m / z = 459 (M + H) + Elemental Analysis: C, 3H 10 N 4 O 4 S, 2.2CF · COH 1, OHI: Calculated (%). C = 45.24; H, 4.74; M = 17.24 N = 7.70: S = 4.41 Found (%): C = 45.37; H, 4.10. M = 17.41; N, 7.64; S = 3.97 rotatory power. aD2 = +48.0 + 0.9 (CHI OH, c = 0.5)

  0.23 g of N- [1 (S) -carbamoyl-2- (4-methoxyphenyl) diastereoisomer B

  ethyl] -4- (2 (R) -amino-3-mercaptopropylamino) -chroman-8-carboxamide in the form of ditrifluoroacetate in the form of a cream lyophilizate, the characteristics of which are as follows: NMR spectrum. 1H (400 MHz, (CD3) 2SO, d in ppm): from 2.10 to 2.35 (mt, 2H: CH 2 of chromanyl); from 2.75 to 2.90 (mt, 2H: CH 2 S); 2.93 and 3.06 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH2); from 3.00 to 4.00 (mt: the 4H corresponding to CH2N-CHN of chromanyl and CHN of propylamine) 3, 73 (s, 3H: ArOCH3) from 4.30 to 4.50 (mt, 2H: CH20 of

2774987

  chromanyl); 4.67 (mt, 1H: NCHCON); 6.87 and 7.10 to 7.20 (respectively d, J = 8 Hz and mt, 2H each: aromatic H of 4-methoxyphenyl); 7.07 (t, J = 7.5 Hz, 1H: chromanyl H6); from 7.10 to 7.20 and from 7.55 to 7.65 (2 mts, 1H each: CONH2); from 7.55 to 7.65 and 7.81 (respectively mt and d wide, J = 7.5 Hz, 1H each

  : H5 and H7 chromanyl); 8.21 (d, J = 7 Hz, 1H: ArCONH).

  Mass Spectrum: DCI (NH3), m / z = 459 (M + H) + Elemental Analysis: C2JH3ON4O4S, 2,2CF3CO2H1, 1,4H, O: Calculated (%): C, 44.80; H, 4.80; F = 17.07; N = 7.63, S = 4.36 Found (OO) 2: C, 44.78, H = 3.78; M = 17.17; N, 7.44; S 3.83 rotatory power: oD2 = -45.0 + 0.8 (CH30H, c = 0.5)

  Example 12: Preparation of N- [JI (S) -carbamoyl-2- (4-) 4- diastereoisomers

  fluorophenyl) -ethyl-4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8-

  Carboxamide is carried out as in Example 10 for the preparation of (S) -4-chlorophenylalanine-carboxanamide hydrochloride, but starting from 1.26 g (5.4 mmol) of the methyl ester hydrochloride (S). ) -4fluorophénylalanine. 1.22 g (100%) of (S) -4-fluorophenylalanine-carboxamide hydrochloride are obtained in the form of

solid pink brown.

  Mass Spectrum: DCI (NH), m / z = 200 (M + NH4) +, m / z = 183 (M + H) + base peak

  The procedure is as in Example 10 for the preparation of N- [1 (S) -

  carbamoyl-2- (4-chlorophenyl) ethyl] -4- (2 (R) -tert-butoxycarbonylamino-3 -

  triphenylmethylthio-propylamino) -chroman-8-carboxamide, but starting from 1.25 g (2

  mmol) of 4- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthio-

  propylamino) -chroman-8-carboxylic acid, 0.48 g (2.2 mmol) of (S) -4-hydrochloride.

  fluorophenylalanine carboxamide, 0.30 g (2.2 mmol) of 1-hydroxybenzotriazole,

  0.62 ml (4.4 mmol) of triethylamine, 0.42 g (2.2 mmol) of 1- (3-

-. - --I>

66 2774987

  dimethylaminopropyl) -3-ethylcarbodiimide and 20 ml of dichloromethane. The crude product is purified by flash chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (99/1 by volume) to yield 0.82 g.

  (51.9%) N- [1 (S) -carbamoyl-2- (4-fluorophenyl) -ethyl] -4- (2 (R) -tert-

  butoxycarbonylamino-3-triphenylmethylthio-propylamino) -chroman-8-carboxamide

in the form of cream meringue.

  Spectrum of R.M.N. H (250 MHz, (CD3) 2 SO, d in ppm). The description

  is carried out on the mixture of the two diastereoisomers 50-50: 1.40 (br s, 9H: COOC (CH 3) 3); from 1.70 to 1.95 (mt, 2H: CH 2 of chromanyl); of

  2.20 to 2.40 (mt, 2H: CH 2 S); from 2.70 to 3.70 (mt: the 6H corresponding to CH2N -

  ArCH2 - propylamine CHN and chromanyl CHN); from 4.10 to 4.40 (mt, 2H CH 2 O of chromanyl); from 4.40 to 4.75 (mt, 1H: NCHCON); from 6.75 to 6.95 (mt, 2H: NHCOO and H6 from chromanyl); from 6.95 to 7.40 (mt, 21H: aromatic Hs of triphenylmethyl - aromatic H 4-fluoro-phenyl - H5 from chromanyl and IH from CONH2); from 7.40 to 7.75 (mt, 2H: H7 of chromanyl and the other H of CONH2); of

8.20 to 8.35 (mt, 1H: ArCONH).

  The procedure is as in Example I for the preparation of N- (1 (S) -carbamoyl-

  2-phenyl-ethyl) -4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8carboxamide,

  but from N- [1 (S) -carbamoyl-2- (4-fluorophenyl) -ethyl] -4 (2 (R) -tert-

  butoxycarbonylamino-3-triphenylmethylthiopropylamino) -chroman-8carboxamide (0.8 g, 1.01 mmol), triethylsilane (0.21 ml, 1.32 mmol), trifluoroacetic acid (3.88 ml, 50, 7 mmol) and dichloromethane (50 ml). The crude product is purified by high performance liquid chromatography (C18 phase) eluting with a gradient of a water / acetonitrile mixture containing 0.1% trifluoroacetic acid. We obtain:

  0.11 g of the diastereoisomer A of N- [1 (S) -carbamoyl-2- (4-fluorophenyl) -

  ethyl] -4- (2 (R) -amino-3-mercaptopropylamino) -chroman-8-carboxamide in the form of ditrifluoroacetate in the form of a cream lyophilizate, the characteristics of which are as follows: NMR spectrum. 1H (400 MHz, (CD3) 2SO, d in ppm): from 2.10 to 2.35 (mf, 2H CH 2 of chromanyl); from 2.75 to 2.95 (mt, 2H: CH 2 S); from 2.90 to 3.90 (mt: the 4H corresponding to CH2N CHN of chromanyl and CHN of propylamine); 2.98 and 3.11 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH2); from 4.30 to 4.45 (mt, 2H: CH 2 O of chromanyl); 4.66 (mt, 1H: NCHCON); 7.06 (t wide, J = 7.5 Hz, 1H: chromanyl H6); 7.13 and 7.31 (2 dd, respectively J = 9 and 8 Hz and J = 8 and 6 Hz, 2H each: aromatic H 4-fluoro-phenyl); 7.18 and 7.61 (2s wide, 1H each: CONH2); from 7, 55 to 7.65 and 7.78 (respectively mt and d

  broad, J = 7.5 Hz, 1H each: H5 and H7 chromanyl); 8.22 (mt, 1H: ArCONH).

  Mass spectrum: IS, m / z = 447 (M + H) + peak base, m / z = 341 (M-C 3 H 9 N 2 S) + rotatory power: aD20 = +43.1 + 0.9 (CHI30H, c = 0.5)

  0.14 g of N- [1 (S) -carbamoyl-2- (4-fluorophenyl) diastereoisomer B

  ethyl] -4- (2 (R) -amino-3-mercaptopropylamino) -chroman-8-carboxamide in the form of ditrifluoroacetate in the form of a cream lyophilizate, the characteristics of which are as follows: NMR spectrum. 1H (400 MHz, (CD3) 2SO, d in ppm): from 2.10 to 2.35 (mf, 2H: CH 2 of chromanyl); from 2.75 to 2.95 (mt, 2H: CH 2 S); from 2.95 to 3.90 (mt: the 4H corresponding to CH2N CHN of chromanyl and CHN of propylamine); 2.98 and 3.12 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH2); 4.30 to 4.50 (mt, 2H: CH 2 O of chromanyl); 4.71 (mt, 1H: NCHCON); 7.06 (t wide, J = 7.5 Hz, 1H: chromanyl H6); 7.13 and 7.27

  (respectively t, J = 8 Hz and dd, J = 8 and 6 Hz, 2H each: aromatic H of 4-

  fluoro-phenyl); 7.20 and 7.62 (2s wide, 1H each: CONH2); from 7.55 to 7.65 and 7.77 (respectively mt and d wide, J = 7.5 Hz, 1H each: H5 and H7 from

  chromanyl); 8.23 (d, J = 8 Hz, 1H: ArCONH).

  IS mass spectrum, m / z = 447 (M + H) + peak base, m / z = 341 (M-C3H9N2S) + rotational power: loD20 = -41.2 + 0.8 (CH30H, c = 0) , 5)

68 2774987

  EXAMPLE 13 Preparation of Diastereoisomers of N- [1 (S) -carbamoyl-2- (4-

  nitrophenyl) -ethyl-4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8-

  Carboxamide is carried out as in Example 10 for the preparation of (S) -4-chlorophenylalanine-carboxamide hydrochloride, but from 1.29 g (4.95 mmol) of the methyl ester hydrochloride (S). ) -4nitrophénylalanine. 1.05 g (86%) of (S) -4-nitrophenylalanine carboxamide hydrochloride is obtained in the form of a brick solid. Mass Spectrum: DCI (NH3), m / z = 227 (M + NH4) + peak base, m / z-210 (M + H) +

  The procedure is as in Example 10 for the preparation of N- [1 (S) -

  carbamoyl-2- (4-chlorophenyl) -ethyl] -4- (2 (R) -tert-butoxycarbonylamino-3-

  triphenylmethylthio-propylamino) -chroman-8-carboxamide, but starting from 1.25 g (2

  mmol) of 4- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthio-

  propylamino) -chroman-8-carboxylic acid, 0.54 g (2.2 mmol) of (S) -4-hydrochloride.

  nitrophenylalanine carboxamide, 0.30 g (2.2 mmol) of 1-hydroxybenzotriazole,

  0.62 ml (4.4 mmol) of triethylamine, 0.42 g (2.2 mmol) of 1- (3-

  (dimethylaminopropyl) -3-ethylcarbodiimide and 20 ml of dichloromethane. The crude product is purified by flash chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (98/2 by volume) to yield 0.75 g.

  (46%) N- [I (S) -carbamoyl-2- (4-nitrophenyl) -ethyl] -4- (2 (R) -tert-

  butoxycarbonylamino-3-triphenylmethylthio-propylanmino) -chroman-8carboxamide

in the form of cream meringue.

  Spectrum of R.M.N. 1H (250 MHz, (CD3) 2SO d6, d in ppm). The

  description is made on the mixture of the two diastereoisomers 50-50:

  1.40 (bs, 9H: COOC (CH 3) 3); from 1.70 to 1.95 (mt, 2H: CH 2 of chromanyl); from 2.20 to 2.40 (mt, 2H: CH 2 S); from 2.95 to 3.70 (mt: 6H corresponding to CH2N - ArCH2 - propylamine CHN and chromanyl CHN); from 4.10 to 4.35 (mt, 2H: CH 2 O of chromanyl); from 4.50 to 4.85

69 2774987

  (mt, I H: NCHCON); from 6.75 to 7.00 (mt, 2H: NHCOO and chromanyl H6) from 7.15 to 7.40 (mt, 17H: aromatic Hs of triphenylmethyl - H5 from

  chromanyl and 1H of CONH2); from 7.50 to 7.75 (mt, 4H: H2 and H6 from 4-nitro-

  phenyl - H7 of chromanyl and the other H of CONH2); from 8.05 to 8.45 (mt, 1H:

  ArCONH); 8.18 (mt, 2H: H3 and H5 4-nitro-phenyl).

  The procedure is as in Example 1 for the preparation of N- (1 (S) carbamoyl-

  2-phenyl-ethyl) -4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8carboxamide,

  but from N- [1 (S) -carbamoyl-2- (4-nitrophenyl) -ethyl] -4 (2 (R) -tert-

  butoxycarbonylamino-3-triphenylmethylthiopropylamino) -chroman-8carboxamide (0.75 g, 0.92 mmol), triethylsilane (0.19 ml, 1.19 mmol), trifluoroacetic acid (3.52 ml, 46 mmol ) and dichloromethane (50 ml). The crude product is purified by high performance liquid chromatography (phase C1 8) eluting with a gradient of a water / acetonitrile mixture containing 0.07% trifluoroacetic acid. We obtain:

  0.18 g of the diastereoisomer A of N- [(S) -carbamoyl-2- (4-nitrophenyl)]

  ethyl] -4- (2 (R) -amino-3-mercaptopropylamino) -chroman-8-carboxamide in the form of ditrifluoroacetate in the form of yellow lyophilizate, the characteristics of which are as follows: NMR spectrum. 1H (400 MHz, (CD3) 2SO, d in ppm): from 2.10 to 2.35 (mt, 2H: CH 2 of chromanyl); from 2.75 to 2.95 (mrt, 2H: CH 2 S); from 2.95 to 3.90 (mt: the 4H corresponding to CH2N CHN of chromanyl and CHN of propylamine); 3.14 and 3.28 (2 dd, respectively J = 14 and 9 Hz and J = 14 and 5 Hz, 1H each: ArCH,); 4.25 to 4.50 (mt, 2H: CH 2 O of chromanyl); 4.77 (mt, 1H: NCHCON); 7.05 (t wide, J = 7.5 Hz, 1H: chromanyl H6); 7.25 and 7.67 (2s wide, 1H each: CONH2); 7.58 and 8.19 (2 dd, J = 8 Hz, 2H each: aromatic H of 4-nitro-phenyl); 7.50 to 7.65 and 7.74 (respectively mt and d wide, J = 7.5 Hz, 1H each: H5 and H7 chromanyl); 8.29 (mt, 1H ArCONH). Mass spectrum: IS, m / z = 474 (M + H) +

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  Elemental analysis: C22H27N5O5S, 2.5CF3CO2H, 1.5H2O1 Calcd. (%): C, 41.28H, 4.17; F = 18.14, N = 8.91 S = 4.08 Found (%): C 41.58; H, 3.84; F = 17.81 N = 8.77 S = 3.65 rotatory power: oD 20 = +25.7 + O.7 (CH30H, c = 0.5)

  0.15 g of N- [1 (S) -carbamoyl-2- (4-nitrophenyl) ethyl] diastereoisomer B

  4- (2 (R) -amino-3-mercaptopropylamino) -chroman-8-carboxamide in the form of ditrifluoroacetate in the form of yellow lyophilisate, the characteristics of which are as follows: NMR spectrum. 1H (400 MHz, (CD3) 2SO, d in ppm): from 2.10 to 2.35 (mf, 2H: CH 2 of chromanyl); from 2.75 to 2.95 (mt, 2H: CH2S) from 2.95 to 3.90 (mt: the 4H corresponding to CH2N CHN of chromanyl and CHN of propylamine); 3.13 and 3.28 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH2) 4.39 (mt, 2H: CH 2 O of chromanyl); 4.81 (mt, 1H: NCHCON); 7.05 (t wide, J = 7.5 Hz, 1H: chromanyl H6); 7.28 and 7.69 (2s wide, 1H each: CONH,); 7.53 and 8.18 (2 dd, J = 8 Hz, 2H each: aromatic H 4-nitrophenyl); 7.61 and 7.74 (2 d wide, J = 7.5 Hz, 1H each

  H5 and H7 chromanyl); 8.31 (mt, 1H: ArCONH).

  Mass spectrum: IS, m / z = 474 (M + H) + elemental analysis: C2, H27NO5S5, 2, 5CF3CO2I-I, H, 1.5H, O. Calculated (1o, C = 41.28, H = 4.17, F = 18.14, N = 8.91, S = 408, Found (%), C 41.55, H = 3.58; , F = 17.60, N = 8.93 S = 3.62 rotatory power O (D0 = -54.7 1.0 (CH3OH, c = 0.5)

  Example 14: Preparation of N- [1 (S) -carbamoyl-2- (4-) 4- diastereoisomers

  hydroxyphenyl) ethyl-4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8-

  Carboxamide is used as in Example 10 for the preparation of (S) -4-chlorophenylalanine-carboxamide hydrochloride, but from 2 g (8.6 mmol) of the hydrochloride of the methyl ester of (S) - 4hydroxyphénylalanine. 1.9 g is obtained

71 2774987

  (100%) (S) -4-hydroxyphenylalanine-carboxamide hydrochloride in the form of

white solid.

  Mass Spectrum: DCI (NH 3), m / z = 198 (M + NH 4) +, m / z = 181 (M + H) + basic peak

  The procedure is as in Example 10 for the preparation of N- [I (S) -

  carbamoyl-2- (4-chlorophenyl) ethyl] -4- (2 (R) -tert-butoxycarbonylamino-3-

  triphenylmethylthio-propylamino) -chroman-8-carboxamide, but starting from 1.0 g

  (1,6 mmol) 4- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthio-

  propylamino-chroman-8-carboxylic acid, 0.38 g (2.2 mmol) of (S) -4-hydrochloride.

  hydroxyphenylalanine carboxamide, 0.24 g (1.76 mmol) of 1-hydroxy-

  benzotriazole, 0.50 ml (3.53 mmol) of triethylamine, 0.34 g (1.76 mmol) of I - (3- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 15 ml of dichloromethane The crude product is purified by flash column chromatography on silica eluting with a mixture of dichloromethane and methanol (95/5

  volumes) to yield 0.46 g (36.5%) of N- [1 (S) -carbamoyl-2- (4hydroxyphenyl) -

  ethyl] -4- (2 (R) -tert-butoxycarbonylamino-3-triphénylméthylthiopropylamino) -

  chroman-8-carboxamide in the form of cream meringue.

  Spectrum of R.M.N. H (400 MHz, CDCl3 at a temperature of 333 K,

  d in ppm). The description is made on the mixture of the two

  diastereoisomers 50-50: 1.44 (s, 9H: COOC (CH 3) 3); from 1.80 to 2.00 (mt, 2H: CH 2 of chromanyl); 2.37 and 2.47 (2dd, J = 12 and 5.5 Hz, 2H: CH 2 S); from 2.60 to 2.85 (mt, 2H: CH 2 N); 3.09 and 3.25 (2 mts, 2H: ArCH2); 3.60 to 3.75 (mt, 2H propylamine CHN and chromanyl CHN); from 4.05 to 4.35 (mt, 2H CH2O of chromanyl); from 4.50 to 4.70 (mt, 1H: NHCOO); 4.85 (mt, 1H: NCHCON); from 5.00 to 5.50 and from 5.80 to 6.30 (2 mfs spread, 1H each CONH2); 6.76 (mt, 2H: H3 and H5 of 4-hydroxy-phenyl); 7.04 (mt, 1H: H6

  chromanyl); from 7.10 to 7.50 (mt, 18H: aromatic aromatics of triphenylmethyl)

  H2 and H6 of 4-hydroxy-phenyl and H5 of chromanyl); 8.05 (mt, 1H: H7 from

  chromanyl); from 8.10 to 8.25 (mt, 1H: ArCONH).

72 2774987

  The procedure is as in Example 1 for the preparation of N- (I (S) carbamoyl)

  2-phenyl-ethyl) -4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8carboxamide,

  but from N- [1 (S) -carbamoyl-2- (4-hydroxyphenyl) -ethyl] -4 (2 (R) -tert-

  butoxycarbonylamino-3-triphenylmethylthiopropylamino) -chroman-8carboxamide (0.46 g, 0.59 mmol), triethylsilane (0.12 ml, 0.76 mmol), trifluoroacetic acid (2.24 ml, 29 mmol) ) and dichloromethane (30 ml). The crude product is purified by high performance liquid chromatography (phase C1 8) eluting with a gradient of a water / acetonitrile mixture containing 0.07% trifluoroacetic acid. We obtain:

  0.13 g of the diastereoisomer A of N- [1 (S) -carbamoyl-2- (4-hydroxyphenyl) -

  ethyl] -4- (2 (R) -amino-3-mercaptopropylamino) -chroman-8-carboxamide in the form of ditrifluoroacetate in the form of white lyophilizate, the characteristics of which are as follows: NMR spectrum. 1H (400 MHz, (CD3) 2SO, d in ppm): from 2.00 to 2.30 (mf, 2H: CH 2 of chromanyl); 2.80 (mt, 2H: CH 2 S); 2.87 and 3.00 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH,); from 3.00 to 4.00 (mt: 4H corresponding to CH2N-CHN of chromanyl and CHN of propylamine); 4.37 (mt, 2H: CH 2 O of chromanyl); 4.58 (mt, 1H: NCHCON); 6.68 and 7.06 (2 d, J = 8 Hz, 2H each: aromatic H of 4-hydroxy-phenyl); from 7.00 to 7.10 (mt, 1H: chromanyl H6); 7.12 and 7.54 (2s wide, 1H each: CONH2); 7.58 and 7.80 (respectively d, J = 7.5 Hz and mt, 1H each: H5 and H7

  chromanyl); 8.19 (mt, 1H: ArCONH); 9.23 (mf, 1H: ArOH).

  Mass Spectrum: DCI (NH3), m / z = 445 (M + H) + Elemental Analysis: C22H28N4O4, 2CF3CO2H, 2H2O: Calcd (Io) C = 44.06; H = 4.84; F = 16.09; N = 7.91: S = 4.52 Found (%): C = 44.13; H, 4.35; F = 16.05; N, 7.78; S = 4.56 rotatory power. D2 = +51.2 + 0.9 (CH30H, c = 0.5)

  0.12 g of N- [1 (S) -carbamoyl-2- (4-hydroxyphenyl) diastereoisomer B

  ethyl] -4- (2 (R) -amino-3-mercaptopropylamino) -chroman-8-carboxamide in the form of ditrifluoroacetate in the form of white lyophilizate, the characteristics of which are as follows:

73 2774987

  Spectrum of R.M.N. 1H (400MHz, (CD3) 2SO, d in ppm): from 1.95 to 2.30 (mf spread, 2H: CH 2 of chromanyl); from 2.70 to 2.85 (mt, 2H: CH 2 S); 2.87 and 3.00 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each ArCH2); from 3.00 to 4.00 (mt: 4H corresponding to CH2N-CHN of chromanyl and CHN of propylamine); 4.25 to 4.50 (mt, 2H: CH 2 O of chromanyl); 4.62 (mt, 1H)

  : NCHCON); 6.67 and 7.03 (2 d, J = 8.5 Hz, 2H each: aromatic H of 4-

  hydroxy-phenyl); from 7.00 to 7.10 (mt, 1H: chromanyl H6); 7.13 and 7.55 (2s wide, 1H each CONH 2); 7.58 and 7.78 (respectively d, J = 7.5 Hz and mt, 1H each: H5 and H7 chromanyl); 8.20 (mt, 1H: ArCONH); 9, 22 (massive, I H ArOH). Mass Spectrum: DCI (NH3), m / z = 445 (M + H) +

  elemental analysis. C22H28N4O5, 2.5CF.COH, 2.41.

  Calculated (% O) C = 41.96; H, 4.60; Mp 18.44; N = 7.25 S = 4.15 Found (% o): C = 41.84; H, 4.07; F = 18.42; N = 6.92; S = 3.92 rotatory power: o.D2 = -41.7 + 0.8 (CH301-1, c = 0.5) J

  Example 15: Preparation of diastereoisomers of N- [1 (S) -carbamoyl-2- (3,4)

  dichlorophenyl) -ethyl-4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8-

  Carboxamide is carried out as in Example 10 for the preparation of (S) -4-chlorophenylalanine-carboxamide hydrochloride, but from 1 g (3.5 mmol) of the hydrochloride of the methyl ester of (S) - 3,4dichlorophénylalanine. 0.7 g (74%) of (S) -3,4-dichlorophenylalanine-carboxamide hydrochloride are obtained in the form of

solid yellow ocher.

  Mass spectrum. DCI (NH3), m / z = 250 (M + NH4) + base peak, m / z = 233 (M + H) +

  The procedure is as in Example 10 for the preparation of N- [1 (S) -

  carbamoyl-2- (4-chlorophenyl) -ethyl] -4- (2 (R) -tert-butoxycarbonylamrnino-3-

  triphenylmethylthio-propylamino) -chroman-8-carboxamide, but starting from 0.7 g

74 2774987

  (1.12 mmol) 4- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthio)

  propylamino) -chroman-8-carboxylic acid, 0.33 g (1.23 mmol) of (S) -hydrochloride

  3,4-dichlorophenylalanine carboxamide, 0.16 g (1.23 mmol) of 1-hydroxy-

  benzotriazole, 0.35 ml (2.47 nmol) of triethylamine, 0.24 g (1.23 mmol) of 1- (3- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 15 ml of

  dichloromethane. 1.0 g of N- [1 (S) -carbamoyl-2- (3,4-dichlorophenyl) -

  ethyl] -4- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino)

  chroman-8-carboxamide as a pale yellow meringue used without purification

  additional in the subsequent steps.

  Spectrum of R.M.N. IH (400 MHz, CDCl3, d in ppm). The description is

  carried out on the mixture of the two diastereoisomers 50-50: 1.43 (s, 9H: COOC (CH 3) 3) of 1.75 to 2.10 (mt, 2H: CH 2 of chromanyl); from 2.25 to 2.85 (mt, 4H: CH 2 S and CH 2 N); from 3.00 to 3.30 (mt, 2H: ArCH2); from 3.60 to 3.80 (mt, 2H: propylamine CHN and chromanyl CHN); from 4.15 to 4.40 (mt, 2H: CH 2 O of chromanyl); from 4.55 to 4.70 (mt, 1H: NHCOO) 4.91 (mt, 1H: NCHCON); 5.31 and 6.26 (2 mfs, 1H each: CONH2) 6.97 (mt, 1H: chromanyl H6); from 7.10 to 7.50 (mt, 19H: aromatic H) of aromatic triphenylmethyl H of 3-4-chloro-phenyl and H5

  chromanyl); 8.05 (mt, 1H: chromanyl H7); 8.30 (mt, 1H: ArCONH).

  The procedure is as in Example 1 for the preparation of N- (1 (S) -carbamoyl-

  2-phenyl-ethyl) -4- (2 (R) -amino-3-mercaptopropylamino) -chroman-8-carboxamide,

  but from N- [1 (S) -carbamoyl-2- (3,4-dichlorophenyl) -ethyl] -4 (2 (R) -tert-

  butoxycarbonylamino-3-triphenylmethylthiopropylamino) -chroman-8carboxamide (0.5 g, 0.60 mmol), triethylsilane (0.12 ml, 0.77 mmol), trifluoroacetic acid (2.28 ml, 30 mmol). ) and dichloromethane (30 ml). The crude product is purified by high performance liquid chromatography (IC phase 8) eluting with a gradient of a water / acetonitrile mixture containing 0.07% trifluoroacetic acid. We obtain:

  0.03 g of N- [1 (S) -carbamoyl-2- (3,4-dichlorophenyl) diastereoisomer A

  ethyl] -4- (2 (R) -arnino-3-mercaptopropylamino) chroman-8-carboxamide in the form of ditrifluoroacetate in the form of white lyophilizate, the characteristics of which are as follows:

2774987

  Spectrum of R.M.N. 1H (400 MHz, (CD3) 2SO, d in ppm): from 1.90 to 2.20 (mt, 2H: CH 2 of chromanyl); from 2.70 to 2.90 (mt, 2H: CH 2 S); 3.00 and 3.13 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH); from 3.15 to 4.00 (mt: the 4H corresponding to CH2N-CI-HN of propylamine and CHN of chromanyl); 4.36 (mt, 2H: CH 2 O of chromanyl); 4.70 (mrt, 1H: NCHCON); 7.01 (mf, 1H: chromanyl H6); 7.21 (brs, 1H: 1H of CONH 2) 7.28 (broad d, J = 8 Hz, 1H: 1H of 3,4-dichlorophenyl); 7.50 to 7.65 (mt, 3H: the other H of CONH2 and 2H of 3,4-dichlorophenyl); 7.50 to 7.65 and 7.71 (respectively mt and d wide, J = 8 Hz, 1H each: H5 and H7 chromanyl)

  8.25 (broad, J = 7.5 Hz, 1H: ArCONH).

  Mass Spectrum: DCI (NH3), m / z = 497 (M + H) + Elemental Analyte: CeH1.6ClN4O3S, 2.5CF3CO: H: Calcd (%): C = 41.44; H = 3.67: N = 7.16, S = 4.10 Found (%): C, 41.41; H, 3.35; N, 7.25; S = 4.07 rotatory power: aD = +26.0 0.9 (CH301-H, c = 0.5J

  0.04 g of the 65/35 mixture of the two diastereoisomers A and B of N- [1 (S) -

  carbamoyl-2- (3,4-dichlorophenyl) -ethyl] -4- (2 (R) -amino-3-mercaptopropylamino) -

  chroman-8-carboxamide in the form of ditrifluoroacetate in the form of white lyophilisate, the characteristics of which are as follows:

  Spectrum of R.M.N. 1H (400MHz, (CD3) 2SO, d in ppm). The description is

  carried out on the mixture of the two diastereoisomers 65-35: from 1.90 to 2.25 (mt, 2H: CH 2 of chromanyl); 2.70 to 2.90 (mt, 2H CH 2 S); 2.99 and 3.05 to 3.20 (respectively dd, J = 14 and 8 Hz and mt, 1H each ArCH2); from 3.15 to 4.10 (mt: 4H corresponding to CH2N-CHN of propylamine and chromanyl CHN) from 4.25 to 4.50 (mt, 2H: CH 2 O of chromanyl); from 4.65 to 4.80 (mt, 1H: NCHCON); 7.02 (mt, 1H: H6 from

  chromanyl); from 7.20 to 7.75 (mt, 7H: aromatic H) of 3,4-dichlorophenyl -

  H5 and H7 chromanyl and CONH2); 8.26 and 8.31 (2d, J = 7Hz, 1H: ArCONH).

  Mass spectrum: DCI (NH), m / z = 497 (M + H) + rotatory power: ctD '= 16.2 + 0.7 (CH 3 OH, c = 0.5)

76 2774987

  Example 16: Preparation of diastereoisomers of N-il (S) -carbamoyl-2- (4-

  methylphenyl) -ethyl-4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8-

carboxamide

  The procedure is as in Example 10 for the preparation of N- [1 (S) -

  carbamoyl-2- (4-chlorophenyl) -ethyl] -4- (2 (R) -tert-butoxycarbonylamino-3-

  triphenylmethylthio-propylamino) -chroman-8-carboxamide, but starting at 0.54 g

  (0.87 mmol) 4- (2- (R) -tert-butoxycarbonylamino-3-triphenylmethylthio)

  propylamino) -chroman-8-carboxylic acid, 0.20 g (0.87 mmol) of hydrochloride

  (S) -4-methylphenylalanine methyl ester, 0.12 g (0.87 mmol) of 1-hydroxy-

  benzotriazole, 0.25 ml (1.74 mmol) of triethylamine, 0.17 g (0.87 mmol) of I - (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 10 ml of dichloromethane. The crude product (0.68 g) is purified by flash chromatography on a silica column, eluting with dichloromethane to yield 0.58 g (84%) of

  N- [1 (S) -methoxycarbonyl-2- (4-methylphenyl) -ethyl] -4- (2 (R) -tert-

  butoxycarbonylamino-3-triphenylmethylthio-propylamino) -chroman-8carboxamide

in the form of meringue.

  Spectrum of R.M.N. IH (400 MHz, CDCl3, d in ppm). The description is

  performed on the mixture of the two diastereoisomers 50-50: 1.44 (s, 9H: COOC (CH3) 3); 1.84 and 1.96 (2 mts, 1H each: CH 2 of chromanyl); from 2.30 to 2.85 (mt, 4H: CH 2 S and CH 2 N); 2.32 (s, 3H: CH 3 of tolyl); 3.18 (d, J = 6 Hz, ArCH2); from 3.60 to 3.80 (mt, 2H: propylamine CHN and chromanyl CHN); 3.74 (mt, 3H: COOCH3); from 4.10 to 4.30 (mrt, 2H: CH 2 O of chromanyl); 4.64 (mt, 1H: NHCOO); 5.05 (mt, 1H: NCHCOO); 6.95 (mt, 1H: chromanyl H6); from 7.00 to 7.50 (mt, 20H: aromatic H of triphenylmethyl - aromatic H of tolyl and H5 of chromanyl); 8.08 (mt, 1H: chromanyl H7); 8.37 (d wide, J = 7 Hz, 1H ArCONH).

77 2774987

  0.58 g (0.73 mmol) of N- [1 (S) -methoxycarbonyl-2- (4-methylphenyl) -ethyl] -

  4- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthio-propylamino) chroman-8-

  carboxamide dissolved in 1.2 ml of 6N ammonia methanol are heated in an autoclave at 50 ° C. for 48 hours. After cooling to a temperature in the region of 20 ° C., the reaction medium is concentrated to dryness under reduced pressure and the residue is purified by flash chromatography on a silica column using a mixture of dichloromethane and methanol (98/2 by volume) as eluent. . We obtain

  0.17 g (30%) of N- [I (S) -carbamoyl-2- (4-methylphenyl) -ethyl] -4 (2 (R) -tert-

  butoxycarbonylamino-3-triphenylmethylthio-propylamino) -chroman-8carboxamide

in the form of yellow meringue.

  Mass Spectrum: LSIMS, m / z = 785 (M + H) +, m / z = 541 (M-C19H16) +, m / z = 243 (C10H15 +) base peak

  The procedure is as in Example I for the preparation of N- (1 (S) -carbamoyl-

  2-phenyl-ethyl) -4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8carboxamide,

  but from N- [1 (S) -carbamoyl-2- (4-methylphenyl) -ethyl] -4 (2 (R) -tert-

  butoxycarbonylamino-3-triphenylmethylthiopropylamino) -chroman-8carboxamide (0.17 g, 0.22 mmol), triethylsilane (0.05 ml, 0.28 mmol), trifluoroacetic acid (0.83 ml, 10.8 mmol) and dichloromethane (10 ml). The crude product is purified by high performance liquid chromatography (C18 phase) eluting with a gradient of a water / acetonitrile mixture containing 0.07% trifluoroacetic acid. We obtain:

  0.03 g of the diastereoisomer A of N- [1- (S) -carbamoyl-2- (4-methylphenyl) -

  ethyl] -4- (2- (R) -amino-3-mercaptopropylamino) -chroman-8-carboxamide in the form of ditrifluoroacetate in the form of white lyophilizate, the characteristics of which are as follows: NMR spectrum. 1H (400 MHz, (CD3) 2SO, d in ppm): from 2.00 to 2.35 (mf, 2H: CH 2 of chromanyl); 2.28 (s, 3H: ArCH3); from 2.70 to 2.90 (mt, 2H: CH 2 S); 2.95 and 3.07 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH2); from 3, 10 to 4.00 (mt: the 4H corresponding to CH2N-CHN of chromanyl and CHN of propylamine); 4.37 (mt, 2H: CH 2 O of chromanyl);

78 2774987

  4.64 (mt, 1H: NCHCON); 7.06 (t wide, J = 7.5 Hz, 1H: chromanyl H6); 7.11 and 7.17 (2 d, J = 8 Hz, 2H each: aromatic H of tolyl); 7.15 and 7.59 (2s wide, 1H each: CONH 2); 7.60 and 7.81 (respectively mt and d wide, J = 7.5

  Hz, 1H each: H5 and H7 chromanyl); 8.21 (mt, 1H: ArCONH).

  Mass spectrum: DCI (NH 3), m / z = 443 (M + H) + rotatory power. cD 2 = + 14.8 + 0.8 (CH 3 OH, c = 0.5)

  0.03 g of N- [1 (S) -carbamoyl-2- (4-methylphenyl) diastereoisomer B

  ethyl] -4- (2 (R) -amino-3-mercaptopropylamino) -chroman-8-carboxamide in the form of ditrifluoroacetate in the form of white lyophilizate, the characteristics of which are as follows: NMR spectrum. 1H (400 MHz, (CD3) 2SO, d in ppm): from 1.95 to 2.35 (mf, 2H: CH 2 of chromanyl); 2.27 (s, 3H: ArCH3); from 2.70 to 2.90 (mt, 2H: CH 2 S); 2.94 and 3.07 (2 dd, respectively J = 13.5 and 7.5 Hz and J = 13.5 and 5 Hz, 1H each: ArCH2); from 3.10 to 4.00 (mt: 4H corresponding to CH2N-CHN of chromanyl and CHN of propylamine); 4.25 to 4.50 (mt, 2H: CH 2 O of chromanyl); 4.68 (mt, 1H: NCHCON); 7.05 (mf, 1H: chromanyl H6); from 7.05 to 7.20 (mt, 5H: 1H of CONH 2 and aromatic H of tolyl); 7.55 to 7.65 and 7.78 (2 mts, 1H each: H5 and H7 chromanyl); 7.59 (s wide, 1H: the other H

  CONH2); 8.22 (d, J = 7 Hz, 1H: ArCONH).

  DCI mass spectrum (NHq), m / z = 443 (M + H) + rotational power ctD = -34.9 + 0.9 (CH3OH, c = 0.5)

  Example 17: Preparation of N- [1 (S) -carbamoyl-2- (4-) 4- diastereoisomers

  bromophenyl) ethyl] -4- (2 (R) -amino-3-mercaptopropylamino) -chroman-8-

  carboxamide The procedure is as in Example 10 for the preparation of (S) -4-chlorophenylalanine-carboxamide hydrochloride, but starting from 0.78 g (2.65 mmol) of the methyl ester hydrochloride (S). ) -4bromophénylalanine. We obtain 0.72 g

79 2774987

  (97%) of (S) -4-bromophenylalanine-carboxamide hydrochloride in the form of

yellow solid.

  Mass Spectrum: DCI (NH 3), m / z = 260 (M + NH 4) + base peak, min / z = 243 (M + H) +

  The procedure is as in Example 10 for the preparation of N- [1 (S) -

* Carbamoyl-2- (4-chlorophenyl) -ethyl] -4- (2 (R) -tert-butoxycarbonylamino-3-

  triphenylmethylthio-propylamino) -chroman-8-carboxamide, but starting at 0.9 g

  (1.44 mmol) 4- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthio)

  propylamino) -chroman-8-carboxylic acid, 0.44 g (1.59 mmol) of (S) -hydrochloride

  4-bromophenylalanine carboxamide, 0.21 g (1.59 mmol) of 1-hydroxy-

  benzotriazole, 0.45 ml (3.17 mmol) of triethylamine, 0.30 g (1.59 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 15 ml of

  dichloromethane. 1.04 g of N- [1 (S) -carbamoyl-2- (4-bromophenyl) -ethyl] are obtained.

  4- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthio-propylamino) chroman-8-

  carboxamide in the form of cream meringue used without further purification

in the later stages.

  Spectrum of R.M.N. H (250 MHz, (CD3) 2 SO d6 at a temperature of

  383 K, d in ppm). The description is made on the mixture of the two

  diastereoisomers 50-50: 1.42 (s, 9H: COOC (CH 3) 3); from 1.80 to 2.00 (mt, 2H: chromanyl CH 2) 2.40 (mt, 2H: CHS); 2.63 (d, J = 6 Hz, 2H: CH 2 N propylamine); 3.02 and 3.16 (2 dd, respectively J = 4 and 7.5 Hz and J = 14 and 5 Hz, each IH ArCH2); 3.56 (mt, 1H: propylamine CHN); 3.69 (mt, 1H: chromanyl CHN); from 4.10 to 4.35 (mrt, 2H: CH 2 O of chromanyl); 4.76 (mt, 1H: NCHCON); 6.21 (mt, 1H: exchangeable); from 6.80 to 7.05 (mf, 2H: CONH2); 6.90 (mt, 1H: chromanyl H6); from 7.10 to 7.50 (mt, 21H: aromatic H of triphenylmethyl - aromatic H of phenyl and H5 of chromanyl); 7.68 (d wide, J = 7.5 Hz, 1H: chromanyl H7); 8.13 (broad, J = 7.5 Hz, 1H: ArCONH).

2774987

  The procedure is as in Example I for the preparation of N- (1 (S) -carbamoyl-

  2-phenyl-ethyl) -4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8carboxamide,

  but from N- [1 (S) -carbamoyl-2- (4-bromophenyl) -ethyl] -4 (2 (R) -tert-

  butoxycarbonylamino-3-triphenylmethylthio-propylamino) -chroman-8-carboxamide (1.04 g, 1.2 mmol), triethylsilane (0.25 mL, 1.59 mmol), trifluoroacetic acid (4.68 mL, 61, 2 mmol) and dichloromethane (50 ml). The crude product is purified by high performance liquid chromatography (C18 phase) eluting with a gradient of a water / acetonitrile mixture containing 0.07% trifluoroacetic acid. We obtain:

  0.05 g of N- [1 (S) -carbamoyl-2- (4-bromophenyl) diastereoisomer A

  ethyl] -4- (2 (R) -amino-3-mercaptopropylamino) -chroman-8-carboxamide in the form of ditrifluoroacetate in the form of white lyophilizate, the characteristics of which are as follows: NMR spectrum. 1H (400MHz, (CD3) 2SO, d in ppm): 1.85 to 2.15 (mf, 2H: CH 2 of chromanyl); from 2.70 to 2.90 (mt, 2H: CH 2 S); 2.98 and 3.11 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH2); from 3.10 to 4.00 (mt: 4H corresponding to CH2N-CHN of chromanyl and CHN of propylamine); 4.35 (mt, 2H: chromanyl CHO); 4.68 (rnt, 1H: NCHCON); 7.02 (solid, 1H: chromanyl H6); 7.19 and 7.62 (2s wide, 1H each

  CONH2); 7.24 and 7.50 (2 d, J = 8 Hz, 2H each: aromatic H of 4-bromine

  phenyl); 7.58 and 7.74 (respectively d, J = 7.5 Hz and mt, 1H each: H5 and H7

  chromanyl); 8.25 (mt, 1HH: ArCONH).

  Mass spectrum. DCI (NH3), m / z = 296 (M + H) + elemental analysis. C22H27BrN4O3S, 2,4CF3CO2H, 0.8H2O: Calcd. (% O): C = 40.46; H = 3.93; F 17.20, N = 7.04, S = 4.03 Found (%): C = 40.42; H = 3.72; F 17.20; N = 7.01: S 3.83 rotatory power: iD) 2 = +36.7 + 0.7 (CH30H, c = 0.5)

  0.06 g of N- [1 (S) -carbamoyl-2- (4-bromophenyl) diastereoisomer B

  ethyl] -4- (2 (R) -amino-3-mercaptopropylamino) -chroman-8-carboxamide in the form of ditrifluoroacetate in the form of white lyophilizate, the characteristics of which are as follows:

81 2774987

  Spectrum of R.M.N. 1H (400MHz, (CD3) 2SO, d in ppm): from 1.90 to 2.20 (mf, 2H: CH 2 of chromanyl); from 2.70 to 2.90 (mt, 2H: CH 2 S); 2.97 and 3.10 (2 dd, respectively J = 13 and 8 Hz and J = 13 and 5 Hz, 1H each: ArCH2); from 3.10 to 4.00 (rmt: 4H corresponding to CH2N-CHN of chromanyl and CHN of propylamine); from 4.25 to 4.45 (mt, 2H: CH 2 O of chromanyl); 4.71 (mt, 1H: NCHCON); 7.01 (mf, 1H: chromanyl H6); 7.20 and 7.49 (2 d, J = 8 Hz, 2H each: aromatic H of 4-bromo-phenyl); 7.21 and 7.62 (2s wide, 1H each: CONH2); 7.58 and 7.74 (respectively d, J = 7.5 Hz and mt, 1 H each: H5 and H7

  chromanyl); 8.25 (broad, J = 7.5 Hz, 1H: ArCONH).

  Mass Spectrum: DCI (NH3), m / z = 296 (M + H) + Elemental Analysis: C22H, 7BrN4O3S, 2.3CF3CO2H, 0.61-20: Calcd (%): C = 40.93, H = 3.94; F = 16.80: N 7.18; S, 4.11 Found (%): C, 40.90; H = 3.56; F = 16.61, N = 7.14. S 3.96 rotatory power: cD20 = -42.0 + 0.9 (CH30OH, c = 0.5)

  Example 18: Preparation of Diastereoisomers of N- [1 (R) -carbamoyl-2- (4-

  chlorophenyl) -ethyl] -4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8-

  Carboxamide is carried out as in Example 10 for the preparation of (S) -4-chlorophenylalanine-carboxamide hydrochloride, but starting from 1.03 g (4.12 mmol) of the methyl ester hydrochloride (R). ) -4chlorophénylalanine. 0.97 g (100%) of (R) -4-chlorophenylalanine-carboxamide hydrochloride are obtained in the form of

white solid.

  Mass Spectrum: DCI (NH 3), m / z = 216 (M + NH 4) + base peak, m / z = 199 (M + H) +

  The procedure is as in Example 10 for the preparation of N- [1 (S) -

  carbamoyl-2- (4-chlorophenyl) -ethyl] -4- (2 (R) -tert-butoxycarbonylamino-3-

  triphenylmethylthio-propylamino) -chroman-8-carboxamide, but starting from 0.7 g

  (1.12 mmol) 4- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthio)

82 2774987

  propylamino) -chroman-8-carboxylic acid, 0.29 g (1.23 mmol) of (R) -hydrochloride

  4-chlorophenylalanine carboxamide, 0.16 g (1.23 mmol) of 1-hydroxy-

  benzotriazole, 0.35 ml (2.47 mmol) of triethylamine, 0.24 g (1.23 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 15 ml of

  dichloromethane. 0.76 g of N- [1 (R) -carbamoyl-2- (4chlorophenyl) -ethyl] are obtained.

  4- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) chroman-8-

  carboxamide as a pale yellow meringue used without purification

  additional in the subsequent steps.

  Spectrum of R.M.N. H (400 MHz, CDCl3, d in ppm). The description is

  performed on the mixture of the two diastereoisomers 50-50: 1.46 (s, 9H: COOC (CH3) 3); from 1.80 to 2.05 (mt, 2H: CH 2 of chromanyl); from 2.30 to 2.85 (mt, 4H: CH 2 S and CH 2 N); 3.15 and 3.26 (respectively dd, J = 14 and 7 Hz and mt, 1H each: ArCH2); from 3.60 to 3.80 (mt, 2H: propylamine CHN and chromanyl CHN); from 4.05 to 4.35 (mt, 2H: CH 2 O of chromanyl); from 4.55 to 4.70 (mt, 1H: NHCOO); 4.92 (mt, 1H: NCHCON); from 5.25 to 5.35 and 6.18 (2 mfs, 1H each: CONH2); 6.88 (mt, 1H: chromanyl H6); from 7.10 to 7, 50 (mt, 20H: aromatic H of triphenylmethyl - aromatic H 4 -chlorophenyl and H5 chromanyl);

  8.06 (mt, 1H: chromanyl H7); 8.31 (mt, 1H: ArCONH).

  The procedure is as in Example I for the preparation of N- (1 (S) carbamoyl-

  2-phenyl-ethyl) -4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8carboxamide,

  but from N- [1 (R) -carbamoyl-2- (4-chlorophenyl) -ethyl] -4 (2 (R) -tert-

  butoxycarbonylamino-3-triphenylmethylthiopropylamino) -chroman-8carboxamide (0.76 g, 0.94 mmol), triethylsilane (0.19 ml, 1.23 mmol), trifluoroacetic acid (3.61 ml, 47, 2 mmol) and dichloromethane (35 ml). The crude product is purified by high performance liquid chromatography (C18 phase) eluting with a gradient of a water / acetonitrile mixture containing 0.07% trifluoroacetic acid. We obtain:

  0.03 g of N- [1 (R) -carbamoyl-2- (4-chlorophenyl) diastereoisomer A

  ethyl] -4- (2 (R) -amino-3-mercaptopropylamino) -chroman-8-carboxamide in the form of

83 2774987

  ditrifluoroacetate in the form of white lyophilizate, the characteristics of which are as follows: Spectrum of R.M.N. 1H (400 MHz, (CD3) 2SO, d in ppm): from 1.95 to 2.10 (mt, 2H: CH 2 of chromanyl); 2.78 (mt, 2H: CH 2 S); 3.00 and 3.13 (2 dd, respectively J = 13.5 and 8 Hz and J = 13.5 and 5 Hz, 1H each: ArCH.); from 3.15 to 3.90 (mt: the 4H corresponding to CH2N-CHN of chromanyl and CHN of propylamine); 4.36 (mt, 2H: CH 2 O of chromanyl); 4.69 (mt, 1H: NCHCON); 7.01 (mf, 1H: chromanyl H6); 7.18 and 7.60 (broad 2s, 1H each: CONH 2) 7.29 and 7.37 (2 d, J = 8 Hz, 2H each: aromatic H of 4-chlorophenyl) 7.57 and 7 , 74 (2 d wide, J = 7.5 Hz, 1H each: H5 and H7 chromanyl); 8.25

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

  Mass Spectrum: DCI (NH 3), m / z = 463 (M + H) + elemental analysis: C 22 H 27 ClN 4 O 3 S, 2.2CF 3 CO 2 H: Calculated (%) o: C = 44.42 H = 4.12; N = 7.85. S = 4.49 Found (%) C = 44.55; H = 3.7, N = 8.24; S = 4.09 rotatory power: OtD = -39.2 + 1.2 (CH30H, c = 0.5)

  0.05 g of N- [1 (R) -carbamoyl-2- (4-chlorophenyl) diastereoisomer B

  ethyl] -4- (2 (R) -amino-3-mercaptopropylamino) -chroman-8-carboxamide in the form of ditrifluoroacetate in the form of white lyophilizate, the characteristics of which are as follows: NMR spectrum. 1H (400 MHz, (CD3) 2SO, d in ppm): from 1.90 to 2.20 (mt, 2H: CH 2 of chromanyl); from 2.70 to 2.85 (mt, 2H: CH 2 S); 2.99 and 3.12 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH2); from 3.15 to 4.00 (mt: the 4H corresponding to CH2N-CHN of chromanyl and CHN of propylamine); 4, 43 and 4.52 (2 mts, 1H each: CH 2 O of chromanyl); 4.73 (mt, 1H: NCHCON); 7.02 (mf, 1H: chromanyl H6); 7.19 and 7.61 (2s wide, 1H

  each: CONH2); 7.27 and 7.36 (2 d, J = 8 Hz, 2H each: aromatic H from 4-

  chloro-phenyl); 7.59 and 7.74 (respectively broad, J = 7.5 Hz and mt, IH

  each: H5 and H7 chromanyl); 8.26 (d, J = 7.5 Hz, 1H: ArCONH).

  Mass Spectrum: DCI (NH3), m / z = 463 (M + H) + Elemental Analysis: C22H17CIN403S, 2, 2CF3CO2H, O, 2H2O.0

84 2774987

  Calculated (%). C, 44.20; H, 4.16; CI = 4.94; N = 7.81, S 4.47 Found (%): C = 44.00; H = 3.71; Cl = 5.28; N = 7.90; S = 4.83 rotatory power: cD 2 = +35.8 + 1.0 (CH30H, c = 0.5)

  EXAMPLE 19 Preparation of Diastereoisomers of N- [2- (4-aminophenyl) 1 (S)]

  -ethyl-carbamoyl-4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8-

  carboxamide 0.5 g (2 mmol) of (S) -4-nitrophenylalanine carboxamide in solution in ethanol at a temperature in the region of 20 ° C. are hydrogenated in the presence of 10% palladium on carbon. After consumption of the theoretical amount of hydrogen, the reaction medium is filtered on celite and the filtrate concentrated on

  dry under reduced pressure to yield 0.36 g (82%) of (S) -4-hydrochloride.

  aminophenylalanine carboxamide in the form of a caramel solid.

  Mass spectrum :. IE, m / z = 179 M + ', m / z = 162 (M-NH3) +, mnz = 135 (M-CONH2) + base peak, m / z = 106 (m / z = 135-CH3N) + , m / z = 36 HICI +

  The procedure is as in Example 10 for the preparation of N- [1 (S) -

  carbamoyl-2- (4-chlorophenyl) -ethyl] -4- (2 (R) -tert-butoxycarbonylamino-3-

  triphenylmethylthio-propylamino) -chroman-8-carboxamide, but starting at 0.95 g

  (1.52 mmol) 4- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthio-

  propylamino) -chroman-8-carboxylic acid, 0.36 g (1.67 mmol) of (S) -hydrochloride

  4-aminophenylalanine carboxamide, 0.23 g (1.67 mmol) of I-hydroxy

  benzotriazole, 0.47 ml (3.34 mmol) of triethylamine, 0.32 g (1.67 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 20 ml of dichloromethane. The crude product (0.75 g) is purified by flash chromatography on a silica column, eluting with a mixture of dichloromethane and methanol.

  (90/10 by volume) to give 0.46 g (38.3%) of N- [2- (4-aminophenyl) -1 (S) -

  carbamoyl-ethyl] -4- (2 (R) -tert-butoxycarbonylamino-3-triphenylméthylthio-

propylamino) -chroman-8-carboxamide.

2774987

  Spectrum of R.M.N. H (250 MHz, (CD3) 2SO at a temperature of 383

  K, d in ppm). The description is made on the mixture of the two

  diastereoisomers 50-50: 1.42 (s, 9H: COOC (CH 3) 3); from 1.75 to 2.05 (mt, 2H: CH, chromanyl) 2.41 (mt, 2H: CH 2 S); 2.63 (mt, 2H: CH2N) from 2.80 to 3.05 (mt: the 2H corresponding to ArCH2); 3.55 (mt, 1H: propylamine CHN); 3.69 (mt, 1H: chromanyl CHN) from 4.15 to 4.40 (mt, 2H: CH 2 O of chromanyl); from 4.40 to 4.70 (mt, 1H: NCHCON); 6.14 (mt, 1H: exchangeable); 6.54 (d, J = 8 Hz, 2H: H 3 and H 5 of 4-amino-phenyl); from 6.70 to 6.85 (mf, 2H: CONH2)

  6.90 (mt, 1H: chromanyl H6); 6.90 (d wide, J = 8 Hz, 2H: H2 and H6 from 4-

  amino-phenyl); from 7.15 to 7.45 (mt, 16H: aromatic aromatics of triphenylmethyl and H5 of chromanyl); 7.70 (broad, J = 7.5 Hz, 1H: chromanyl H7); 8.04

(broad d, J = 7 Hz, 1H: ArCONH).

  The procedure is as in Example 1 for the preparation of N- (1 (S) -carbamoyl-

  2-phenyl-ethyl) -4- (2 (R) -amino-3-mercapto-propylamino) -chroman-8carboxamide,

  but from N- [2- (4-aminophenyl) -1 (S) -carbamoyl-ethyl] -4 (2 (R) -tert-

  butoxycarbonylamino-3-triphenylmethylthiopropylamino) -chroman-8carboxamide (0.46 g, 0.57 mmol), triethylsilane (0.12 ml, 0.77 mmol), trifluoroacetic acid (2.24 ml, 29, 3 mmol) and dichloromethane (30 ml). The crude product is purified by high performance liquid chromatography (C18 phase) eluting with a gradient of a water / acetonitrile mixture containing 0.07% trifluoroacetic acid. We obtain:

  0.03 g of mixture of diastereoisomers A and B (dia A / dia B = 70/30) of N-

  [2- (4-aminophenyl) -1 (S) -carbamoyl-ethyl] -4- (2 (R) -amino-3-mercaptopropylamino)

  chroman-8-carboxamide in the form of ditrifluoroacetate in the form of white lyophilisate, the characteristics of which are as follows:

  Spectrum of R.M.N. 1H (400MHz, (CD3) 2SO, d in ppm). The description is

  carried out on the mixture of the two diastereoisomers 70-30: from 2.00 to 2.25 (mf, 2H: CH 2 of chromanyl); 2.75 to 2.85 (mt, 2H CH 2 S); 2.88 and 3.03 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H

86 2774987

  each: ArCH2); from 3.00 to 4.00 (mt: the 4H corresponding to CH2N-CHN of chromanyl and CHN of propylamrin); from 4.25 to 4.50 (mt, 2H: CH 2 O of chromanyl); 4.65 (mt, 1H: NCHCON); 6.85 and 7.10 (respectively mf and broad, J = 7.5 Hz, 2H each: aromatic H of 4-amino-phenyl); 7, 03 (mt, 1H: chromanyl H6); 7.15 and 7.58 (2s wide, 1H each: CONH 2); 7.58 and 7.77

  (2 mts, 1H each: H5 and H7 chromanyl); 8.24 (mt, 1H: ArCONH).

  Mass Spectrum: DCI (NH3), m / z = 444 (M + H) *

  0.04 g of mixture of diastereoisomers A and B (dia A / dia B = 30/70) of N-

  [2- (4-aminophenyl) -1 (S) -carbamoyl-ethyl] -4- (2 (R) -amino-3-mercaptopropylamino)

  chroman-8-carboxamide in the form of ditrifluoroacetate in the form of white lyophilisate, the characteristics of which are as follows:

  Spectrum of R.M.N. 1H (400MHz, (CD3) 2SO, d in ppm). The description is

  performed on the mixture of the two diastereoisomers 30-70: 2.00 to 2.30 (mf, 2H: CH 2 chromanyl); 2.75 to 2.85 (mt, 2H CH 2 S); 2.90 and 3.05 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH2); from 3.00 to 4.00 (mt: 4H corresponding to CH2N-CHN of chromanyl and CHN of propylamine); from 4.30 to 4.50 (mt, 2H: CH 2 O of chromanyl); 4.67 (mt, 1H: NCHCON) 6.89 and 7.13 (respectively mf and d broad, J = 7.5 Hz, 2H each: aromatic H of 4-amino-phenyl); 7.04 (t wide, J = 7.5 Hz, 1H: chromanyl H6); 7.16 and 7.59 (2s wide, 1H each: CONH 2); 7.60 and 7.77 (respectively mt and d wide, J = 7.5 Hz, 1H each: H5

  and H7 chromanyl); 8.25 (mt, 1H: ArCONH).

  Mass spectrum. DCI (NH 3), m / z = 444 (M + H)

  Example 20: Preparation of N- [li (S) -carbamoyl-2- (4-chlorophenyl) -ethyl] -11-

  (4-cyanobenzyl) -1H-imidazol-4-yl] methylamino-chroman-8-carboxamide

  To a solution of 5 g of 1 H-imidazol-4-yl-carboxaldehyde and 11.17 g of 4-

  bromomethyl-benzonitrile in 500 cm3 of acetonitrile is added 14.37 g of potassium carbonate. The reaction mixture is stirred for 2 hours under reflux.

87 2774987

  acetonitrile, filtered, and then concentrated under reduced pressure. The residue is taken up in 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 2.5% methanol. We obtain 4.15 g (27%) of 1- (4-

  cyano-benzyl) -1H-imidazol-5-yl-carboxaldehyde and 5.6g (35%) of 1- (4-cyano)

  benzyl) -1H-imnidazol-4-ylcarboxaldehyde as yellow solids.

  I - (4-cyanobenzyl) -1H-imidazol-5-yl-carboxaldehyde has the following characteristics: proton nuclear magnetic resonance spectrum (400 MHz, (CD3) 2SO

  d6, d in ppm): 5.62 (s, 2H: CHAr); 7.33 (d, J = 8 Hz, 2H: H2 and H6 4cyano-

  phenyl); 7.83 (d, J = 8 Hz, 2H: H 3 and H 5 of 4-cyano-phenyl); 7.99 and 8, 30 (2 s,

  Each of them: aromatic H imidazolyl); 9.71 (s, 1H: CHO).

  I - (4-cyanobenzyl) -1H-imidazol-4-yl-carboxaldehyde has the following characteristics: proton nuclear magnetic resonance spectrum (400 MHz, (CD3) 2SO

  d6, d in ppm): 5.43 (s, 2H: CH 2 Ar); 7.50 (d, J = 8 Hz, 2H: H2 and H6 4cyano-

  phenyl); 7.88 (d, J = 8 Hz, 2H: H 3 and H 5 of 4-cyano-phenyl); 8.03 and 8.16 (2 s.

  1H each: aromatic H of imidazolyl); 9.73 (s, 1H: CHO).

  By operating as in Example I for the preparation of N- (I (S) -

  carbamoyl-2-phenyl-ethyl) -4 - [(2 (R) -tert-butoxycarbonylamino-3-

  triphenylmethylthio) -propylamino] -chroman-8-carboxamide, but from N- [I (S) -

  carbamoyl-2- (4-chlorophenyl-ethyl) -4-amino-chroman-8-carboxamide (0.43 g, 1.10 mmol), 1- (4-cyanobenzyl) -1H-imidazol-4- γ-carboxaldehyde (0.268 g, 1.27 mmol), sodium cyanoborohydride (0.216 g, 3.45 mmol), acetic acid (0.5 ml) and acetonitrile (20 ml) in the presence of molecular sieves 4A, after purification by flash chromatography on a silica column, eluting with dichloromethane:

  0.15 g of a diastereoisomer of N- [1 (S) -carbamoyl-2- (4-chlorophenyl) -

  ethyl)] - 4- [1- (4-cyanobenzyl) -1H-imidazol-4-yl] methylamino-chroman-8-carboxamide in the form of a cream meringue having the following characteristics: Spectrum of R.M.N. 1H (400MHz, (CD3) 2SO, d in ppm) from 1.85 to 2.05 (mt, 2H CH 2 of chromanyl); 2.97 and 3.09 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH2); 3.66 (AB, J = 14 Hz, 2H: CH 2 N); 3.77 (mt, 1H: chromanyl CHN); from 4.20 to 4.40 (mt, 2H: CH 2 O of chromanyl); 4.66 (mt, 1H: NCHCON); 5.28 (s, 2H: ArCH2N); 6.92 (t, J = 8 Hz, 1H: H 6 chromanyl); 7.08 and 7.74 (broad 2s, 1H each: aromatic H of imidazolyl); 7.17 and 7.57 (2s wide, 1H each: CONH2); 7.26 and 7.36 (2 d, J = 8 Hz, 2H each: aromatic H 4-chloro-phenyl) from 7.30 to 7.40 (mt, 1H: H5 chromanyl); 7.41 (d, J = 8 Hz, 2H: H 2 and H 6 of 4-cyano-phenyl); 7.65 (dd, J = 8 and 2 Hz, 1H: H7 chromanyl); 7.84 (d, J = 8 Hz, 2H: H3 and H5 4-cyano-phenyl) 8.28 (d, J = 8 Hz, 1H ArCONH). Mass Spectrum DCI (NH3), m / z = 569 (M + H) +

  elemental analysis. C31HR: CIN60.1, 1.31-1.0.

  Calculated%). C = 62.85 H = 538; N = 14.18 Found (%: C = 62.81H = 4.97, N = 13.76 rotatory power: CLD20 = +29, .2 + 0.6 (CH30H, c = O5)

  Example 21: Preparation of N- [1 (S) -carbamoyl-2- (4-) 4- diastereoisomers

  chlorophenyl) -ethyl] -4- (1-methyvl-imidazol-5-yl) methylamino-chroman-8-

carboxamide

  By operating as in Example 1 for the preparation of N- (I1 (S) -

  carbamoyl-2-phenyl-ethyl) -4-tert-butoxycarbonylamino-chroman-8carboxamide,

  but from 5.87 g (0.020 mole) of 4-tert-butoxycarbonylaminochroman-8-

  carboxylic acid, 5.5 g (0.022 mol) of the (S) -4-methyl ester hydrochloride

  chlorophenylalanine, 2.97 g (0.022 mole) of 1-hydroxybenzotriazole, 4.22 g (0.022 mole) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 4.55 g (0.045 mole) of triethylamine and 200 ml of dichloromethane is obtained after chromatography on a silica column, eluting with a mixture of dichloromethane

  and methanol (99/1 by volume), 8.35 g (87.6%) of N- [1 (S) methoxycarbonyl-2- (4-

  chlorophenyl) -ethyl] -4-tert-butoxycarbonylamino-chroman-8-carboxarmide under

pale yellow lacquer form.

  Mass spectrum: EI, mnn / z = 488 (M +), m / z = 415 (M-C4H9O) +, m / z = 372 (m / n / z = 415).

  CHON) +, m / z = 292 (M-C 10 H 10 OO Cl) + ', m / z = 276 (M-C 10 H 11 O 2 NCl) + peak base,

  m / z = 236 (m / z = 292-C 4 H 5) +, m / z = 220 (m / z = 276-C 4 H 5) +, m / z = 175 (m / z = 220).

  CO2H) +, m / z = 148 (m / z = 175-CO + H) + ', m / z = 57 (C4H9 +)

  By operating as in Example 16 for the preparation of N- [1 (S) -

  carbamoyl-2- (4-methylphenyl) -ethyl] -4 - [(2 (R) -tert-butoxycarbonylamino-3-

  triphenylmethylthio) -propylamino] -chroman-carboxamide, but starting at 8.0 g

  (0.016 moles) N- [I (S) -methoxycarbonyl-2- (4-chlorophenyl) -ethyl] -4-tert-

  butoxycarbonylamino-chroman-8-carboxamide and 30 ml of ammonia methanol

  6N, 6.8 g (90%) of N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4-tert-

  butoxycarbonylamino-chroman-8-carboxamide as a white powder

at 187-190C.

  Mass spectrum: EI, m / z = 473 (M + '), m / z = 429 (M-CH2ON) +, m / z = 292 (M-

  C9H8ONCI) +, m / z = 276 (M-C9HIoON2Cl) + peak base, m / z = 236 (m / z = 292-C4Hs8) +,

  m / z = 220 (m / z = 276-C4Hg) +, m / z = 175 (m / z = 220-CO2H) +, m / z = 148 (m / z = 175-

CO + H) +, m / z = 57 (C4H9 +)

  A suspension of N- [1- (S) -carbamoyl-2- (4-chlorophenyl) -ethyl] -4-tert-

  butoxycarbonylamino-chroman-8-carboxamide (6.4 g, 0.0135 mol) in an IN solution of hydrogen chloride in diethyl ether (300 ml) is stirred for 48 hours at a temperature in the region of 20 ° C. this suspension are then added 20 ml of methanol and the ether phase removed. The methanol residue is taken up in a mixture of 1N aqueous sodium hydroxide (150 ml), distilled water (250 ml) and dichloromethane (200 ml), then the organic phase decanted, washed with water, dried over magnesium sulphate. filtered and concentrated to dryness under reduced pressure at 50 ° C. 5.2 g of crude product are thus obtained, purified by chromatography on a silica column using a mixture of dichloromethane and methanol (90/10 by volume).

  as an eluent to yield 2.9 g (58%) of N- [1 (S) -carbamoyl-2- (4chlorophenyl) -

  ethyl] -4-amino-chroman-8-carboxamide as pale yellow meringue.

  Spectrum of R.M.N. 1H (300 MHz, (CD3) 2SO, d in ppm). The description is

  performed on the mixture of the two diastereoisomers 50-50: 1.81 and 2.06 (2 mts, 1H each: chromanyl CH 2) 2.98 and 3.11 (2 dd, respectively J = 13.5 and 8 Hz and J = 13.5 and 5 Hz, 1H each: ArCH2); 3.94 (t, J = 5 Hz, 1H: chromanyl CHN); from 4.15 to 4.40 (mt, 2H: CH 2 O of chromanyl); 4.69 (mt, 1H: NCHCON): 6.95 (t, J = 7.5 Hz, 1H: chromanyl H6); 7.18 and 7.58 (2s wide, 1H each: CONH 2); from 7.20 to 7.45 (mt, 4H: aromatic H of 4-chlorophenyl); 7.54 and 7.66 (2 mts, 1H each: H5 and

  H7 chromanyl); 8.31 (d, J = 7.5 Hz, 1H: ArCONH).

  By operating as in Example 20 for the preparation of 1- (4-cyano-

  benzyl) -1H-imidazol-5-ylcarboxaldehyde and 1- (4-cyano-benzyl) -H-imidazol-4-yl;

  carboxaldehyde, but from 3.6 g (0.037 mole) of 1H-imidazol-4-yl-

  carboxaldehyde and 2.56 ml (0.041 mole) of methyl iodide, 0.81 g (19%) of 1-methyl-1H-imidazol-5-yl-carboxaldehyde is obtained in the form of a white solid, the characteristics of which are 1H NMR Spectrum (300 MHz, (CD3) 2SO d6, d in ppm): 3.87 (s, 3H)

  NCH3); 7.88 (s, 1H: N = CH-N); 8.01 (s, 1H: N-CH =); 9.75 (s, 1H: CHO).

  After stirring for 4 hours at a temperature of 20 C

  mixture consisting of N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] 4-amino-

  chroman-8-carboxamide (0.4 g, 1.07 mmol), 1-methyl-1H-imidazol-5-yl-

  carboxaldehyde (0.115 g, 1.18 mmol) and acetic acid (0.5 mL) in acetonitrile (20 mL) in the presence of 4A molecular sieve, sodium cyanoborohydride (0.2 g, 21 mmol) and stirring is continued overnight. The reaction medium is filtered through Celite and the filtrate concentrated to dryness under reduced pressure. The residue is taken up in 100 ml of dichloromethane. The organic phase is washed with ml of a saturated solution of sodium hydrogencarbonate, then with 2 times 20 ml of distilled water, 20 ml of a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated at room temperature. dry. After purification by flash chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (100/0 to 90/10 by volume), the following are obtained:

  0.11 g of N- [1 (S) -carbamoyl-2- (4-chlorophenyl) diastereoisomer A

  ethyl] -4- (1-methyl-1H-imidazol-5-yl) methylamino-chroman-8-carboxamide in the form of a white meringue having the following characteristics: Spectrum of R.M.N. H (400 MHz, (CD3) 2 SO, d in ppm): 2.02 (mt, 2H: CH 2 of chromanyl); 2.29 (mf, 1H: NH); 2.98 and 3.11 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH2); 3.66 (s, 3H: NCH3): 3.70 to 3.90 (mt, 3H: chromanyl CHN and CH2N); 4.25 to 4.40 (mt, 2H: CH 2 O of chromanyl); 4.68 (mt, 1H: NCHCON); 6.81 and 7.54 (2 s, 1H each: aromatic H of imidazolyl); 6.94 (t, J = 7.5 Hz, 1H: chromanyl H6); 7.16 and 7.57 (2s wide, 1H each: CONH 2); 7.27 and 7.36 (2 d, J = 8 Hz, 2H each: aromatic 4-chlorophenyl); 7.42 (d, J = 7.5 Hz, 1H: chromanyl H5); 7.67 (d, J = 7.5 Hz, 1H: H7 chromanyl); 8.28

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

  Mass spectrum. DCI (NH3), m / z = 468 (M + H) + elemental analysis. C, 4H26ClNIO3, 1.3H2O, O. Calc'd (% o): C = 58.66; H = 5.87, Cl = 7.22 N = 14, Found (% 2: C = 58.43, H = 5.25, Cl = 7.49, N = 14.34 Rotatory power: aD 2 = +36, 7 + 0.9 (CH30H, c = 0.5)

  0.19 g of N- [1 (S) -carbamoyl-2- (4-chlorophenyl) diastereoisomer B

  ethyl] -4- (1-methyl-1H-imidazol-5-yl) methylamino-chroman-8-carboxamide in the form of a white meringue having the following characteristics: Spectrum of R.M.N. H (400 MHz, (CD3) 2 SO, d in ppm): 2.02 (mt, 2H: CH 2 of chromanyl); 2.27 (mf, 1H: NH); 2.98 and 3.11 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH2) 3.66 (s, 3H: NCH3); from 3.70 to 3.90 (mt, 3H: chromanyl CHN and CH2N); 4.26 and 4.40 (2 mts, 1H

92; 12,774,987

  each: CH2O of chromanyl); 4.68 (mt, 1H NCHCON); 6.82 and 7.54 (2 s, 1H each: aromatic H of imidazolyl); 6.95 (t, J = 7.5 Hz, 1H: H 6 chromanyl); 7.16 and 7.56 (2 s wide, 1H each: CONH 2); 7,27 and 7,36 (2d, J = 8Hz, 2H each: aromatic H of 4-chlorophenyl); 7.44 (dd, J = 7.5 and 2 Hz, 1H: chromanyl H5); 7.66 (dd, J = 7.5 and 2 Hz, 1H: H7 from

  chromanyl); 8.29 (d, J = 8 Hz, 1H: ArCONH).

  Mass Spectrum: DCI (NH3), m / z = 468 (M + H) + rotatory power: ED20 = 56.4 + 1.1 (CH3OHI-I, c = 0.5)

  EXAMPLE 22 Preparation of Diastereoisomers of N-Fl (S) -carbamoyl-2- (4-

  chlorophenyl) ethyl-4- [1- (4-cyanobenzyl) -1H-imidazol-5-ylmethylamino)

chroman-8-carboxamide

  Operating as in Example 21 for the preparation of N- [I (S) -

  carbamoyl-2- (4-chlorophenyl) ethyl] -4- (1-methyl-1H-imidazol-5-yl) methylamino-

  chroman-8-carboxamide, but from N - [] (S) -carbamoyl-2- (4chlorophenyl) -

  ethyl] -4-amino-chroman-8-carboxamide (0.43 g, 1.10 mmol), I- (4-

  cyanobenzyl) -IH-imidazol-5-yl-carboxaldehyde (0.268 g, 1.27 mmol), sodium cyanoborohydride (0.216 g, 3.45 mmol), acetic acid (0.5 ml) and acetonitrile (20 ml) in the presence of molecular sieve 4A, after purification by flash chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (100/0 to 95/5 by volume):

  0.22 g of N- [1 (S) -carbamoyl-2- (4-chlorophenyl) diastereoisomer A

  ethyl] -4- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methylamino-chroman-8-yl

  carboxamide in the form of a cream meringue, the characteristics of which are as follows: Spectrum of R.M.N. 1H (400MHz, (CD3) 2SO, d in ppm): from 1.80 to 2.00 (mt, 2H: CH 2 of chromanyl); 2.28 (mt, 1H: NH); 2.98 and 3.12 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH2); 3.55 and 3.60 to 3.75 (respectively dd, J = 14 and 6.5 Hz and mt, 1H each: CH2N); of

93 2774987

  3.60 to 3.75 (mt, 1H: chromanyl CHN); 4.20 to 4.40 (mt, 2H: CH 2 O of chromanyl); 4.69 (mt, 1H: NCHCON); 5.43 (s, 2H: ArCH2N); 6.85 (t, J = 7.5 Hz, 1H: H6 chromanyl); 6.91 (s, 1H: 1H aromatic imidazolyl)

  from 7,15 to 7,40 (mt, 7H: aromatic H of 4-chloro-phenyl - H2 and H6 from 4-

  cyano-phenyl and H5 chromanyl); 7.16 and 7.56 (2s wide, 1H each CONH 2); 7.67 (dd, J = 7.5 and 2 Hz, 1H: H7 chromanyl); from 7,70 to 7,85 (mt, 3H: H3 and H5) of 4-cyano-phenyl and the other aromatic H of

  imidazolyl); 8.26 (d, J = 8 Hz, 1H: ArCONH).

  Mass spectrum: DCI (NH 3), m / z = 569 (M + H) + elemental analysis: C 31 H 29 ClN 6 O 3, 0.66H 2 O: Calculated (%): C = 64.22; H, 5.25: Cl = 6.11, N = 14.49 (%). C, 64.03; H 4.78, Cl = 5.61: N = 14.73 Rotation: DC '= + 26.8 + 0.9 (CH 3 OH, c = 0.5)

  0.16 g of N- [1 (S) -carbamoyl-2- (4-chlorophenyl) diastereoisomer B

  ethyl] -4- [1- (4-cyanobenzyl) imidazol-5-yl] methylamino-chroman-8-carboxamide in the form of a cream meringue having the following characteristics: Spectrum of R.M.N. 1H (400MHz, (CD3) 2SO, d in ppm): from 1.80 to 2.00 (mt, 2H: CH 2 of chromanyl); 2.25 (mt, 1H: NH); 2.98 and 3.11 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH2); 3.56 and 3.60 to 3.75 (respectively dd, J = 14 and 6 Hz and mt, 1H each: CH2N); from 3.60 to 3.75 (mt, 1H: chromanyl CHN); 4.21 and 4.33 (2 mts, 1H each CH 2 O of chromanyl); 4.69 (mt, 1H: NCHCON); 5.43 (s, 2H: ArCH2N) 6.85 (t, J = 7.5 Hz, 1H: chromanyl H6); 6.91 and 7.76 (2 s, 1H each: aromatic H of imidazolyl); 7.17 and 7.56 (2 s wide, 1H each: CONH 2); 7.20 (dd, J = 7.5 and 2 Hz, 1H: H5 chromanyl); from 7.20 to 7.40 (mt, 6H: aromatic Hs of 4-chloro-phenyl-H2 and H6 of 4cyano-phenyl); 7.64 (dd, J =

  7.5 and 2 Hz, 1H: H7 chromanyl); 7.81 (d, J = 8 Hz, 2H: H3 and H5 from 4-

  cyano-phenyl); 8.27 (d, J = 8 Hz, 1H: ArCONH).

  Mass spectrum: DCI (NH3), m / z = 569 (M + H) + elemental analysis. C31H29ClN5O3, 0.9H2O, 0.1 CH2Cl2: Calculated (%). C, 62.91; H = 5.26; Cl = 7.16, N = 14.15 Found (%,): C, 62.95; H = 4.82; Cl = 7.12: N = 13.94 Rotatory power: CXD20 = -48.5 + 1.0 (CH30H, c = 0.5)

  Example 23: Preparation of N- [1 (S) -carbamoyl-2- (4-chlorophenyl) -ethyl-4 {N-

  acetyl- [1- (4-cyanobenzyl) -1H-imidazol-5-yl-methyl] amino} -chroman-8-

carboxamide

  0.20 g (0.35 mmol) of N- [1 (S) -carbamoyl-2- (4-) diastereoisomeric

  chlorophenyl) ethyl] -4- [1- (4-cyanobenzyl) -1H-imidazol-5yl] methylamino chroman

  8-carboxamide in solution in 15 ml of dichloromethane are treated with 0.03 ml

  (0.38 mmol) of acetyl chloride and then with 0.05 ml (0.38 mmol) of triethylamine.

  The reaction is continued overnight at a temperature in the region of 20 ° C. and then for another 24 hours after the addition of a new equivalent of acetyl chloride and triethylamine. The reaction medium is concentrated to dryness under reduced pressure, and then the crude product purified by flash chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (90/10 by volume). We

  0.04 g (19%) of N- [1 (S) -carbamoyl-2- (4-chlorophenyl) -ethyl] -4 {N-acetyl- [1 -

  (4-cyanobenzyl) -1H-imidazol-5-yl-methyl] amino} -chroman-8-carboxamide as a cream solid having the characteristics as follows NMR Spectrum. H (400 MHz, (CD 3) 2 SO 4, at a temperature of 403 K, d in ppm): 2.07 (s, 3H: CH 3 CO); 2.12 (mt, 2H: chromanyl CH 2) 3.08 and 3, 20 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 6 Hz, 1H each ArCH 2); 4.09 and 4.44 (2d, J = 17Hz, 1H each CH2N); 4.26 (mt, 2H chromanyl CH 2 O); 4.78 (mt, 1H: NCHCON); 5.21 (s, 2H: ArCH2N)), 45 (t, J = 8 Hz, 1H: chromanyl CHN); 6.72 (mf, 2H: CONH2); 6.83 and 7.59 (broad 2s, 1H each: aromatic H of imidazolyl); 6.91 (t, J = 8 Hz, 1H: chromanyl H6); 7.06 (d, J = 8 Hz, 1H: chromanyl H5); 7, 22 (d, J = 8 Hz, 2H: H 2 and H 6 of 4-cyano-phenyl); 7.30 (AB limit, 4H: aromatic H of 4-chlorophenyl); from 7.65 to 7.75 (mt, 1H: chromanyl H7) 7.69 (d, J = 8 Hz, 2H: H3 and H5 from 4-cyano-phenyl); 7.95 (d wide, J = 7.5

Hz, 1H: ArCONH).

  Mass Spectrum: DCI (NH3), m / z = 61 (M + H) + Elemental Analysis: C33H31ClN6O4, 3.6H2O, 0.1 CH2Cl2: Calculated (o). C 58.08 H = 5.66; Cl = 6.22; N = 12.28 Found (): C = 58.13 H = 5.30; Cl, 6.19; N = 11.88 IO0 rotatory power: ctD = +19.1 + 0.7 (DMSO, c = 0.5)

  EXAMPLE 24 Preparation of diastereoisomers of N-il (S) -carbamoyl-2- (4-

  benzyloxyphenyl) ethyl] -4-11- (4-cyanobenzyl) imidazol-5-yl] methylamino

chroman-8-carboxamide

  By operating as in Example I for the preparation of N- (I (S) -

  carbamoyl-2-phenyl-ethyl) -4-tert-butoxycarbonylamino-chroman-8carboxamide,

  but starting from 2.2 g (7.5 mmol) of 4-tert-butoxycarbonylaminochroman-8-

  carboxylic acid, 2.41 g (7.5 mmol) of (S) -4-methyl ester hydrochloride

  benzyloxyphenylalanine, 1.01 g (7.5 mmol) of 1-hydroxybenzotriazole, 1.44 g (7.5 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1.67 g (16.5 g). mmol) of triethylamine and 200 ml of dichloromethane are obtained after chromatography on a silica column, eluting with a mixture of dichloromethane

  and methanol (95/5 by volume), 3.85 g (91.7%) of N- [1 (S) methoxycarbonyl-2- (4-

  benzyloxyphenyl) -ethyl] -4-tert-butoxycarbonylamino-chroman-8-carboxamide under

beige meringue shape.

  Spectrum of R.M.N. 1H (400MHz, (CD3) 2SO, d in ppm). The description is

  performed on the mixture of two diastereoisomers 50-50: 1.45 (s, 9H: OC (CH3) 3); 1.95 and 2.07 (2 mts, 1H each: chromanyl CH 2); 3.07 (mt, 2H: ArCH2); 3.68 (s, 3H: COOCH3); 4.27 (mt, 2H: CH 2 O of chromanyl); 4.68 (mt, 1H: NCHCON); 4.77 (mt, 1H: chromanyl CHN); 5.10 (s, 2H: OCH 2 benzyloxy); from 6.95 to 7.05 (mt, 3H: H3 and H5 phenoxy and H6 chromanyl); from 7.15 to 7.25 (mt, 2H: H 2 and H 6 of phenoxy); from 7.25 to 7, 50 (mt, 6H: aromatic H of benzyloxy and H5 of chromanyl); 7.70 (mt, 1H: chromanyl H7); 8.32 and 8.34 (2 d, J = 8 Hz, 1H

in full: ArCONH).

  By operating as in Example 16 for the preparation of N- [I (S) -

  carbamoyl-2- (4-methylphenyl) -ethyl] -4- (2 (R) -tert-butoxycarbonylamino-3-

  triphenylmethylthio) -propylamino-chroman-8-carboxamide, but starting at 3.8 g

  (6.8 mmol) N- [1 (S) -methoxycarbonyl-2- (4-benzyloxyphenyl) -ethyl] -4-tert-

  butoxycarbonylamino-chroman-8-carboxamide and 20 ml of ammoniacal methanol

  6N, 3.5 g (94.6%) of N- [1 (S) -carbamoyl-2- (4-benzyloxyphenyl) ethyl] -4- are obtained.

tert-butoxycarbonylamino-chroman-8-carboxamide in the form of beige meringue.

  Spectrum of R.M.N. 1H (400MHz, (CD3) 2SO, d in ppm). The description is

  performed on the mixture of two diastereoisomers 50-50: 1.45 (s, 9H: OC (CH3) 3); 1.95 and 2.08 (2 mts, 1H each: CH, chromanyl); 2.93 and 3.05 (respectively mt and dd, J = 14 and 4 Hz, 1H each: ArCH2); 4.28 (mt, 2H: chromanyl CH 2 O); 4.63 (mt, 1H: NCHCON); 4.78 (mt, 1H: chromanyl CHN); 5.08 (s, 2H: OCH 2 benzyloxy); from 6.90 to 7.05 (mt, 3H: H3 and H5 phenoxy and H6 chromanyl); from 7.10 to 7.20 (mt, 3H: H 2 and H 6 of phenoxy and H 5 of chromanyl); from 7.25 to 7.50 (mt, 6H: aromatics of benzyloxy and 1H of CONH2); 7.58 (s wide, 1H: the other H of CONH2); 7, 70 (mt, I H: H7 chromanyl); 8.24 (broad d, J 8 Hz, 1H ArCONH).

  By operating as in Example 21 for the preparation of N- [1 (S) -

  carbamoyl-2- (4-chlorophenyl) ethyl] -4-amino-chroman-8-carboxamide, but from

  3.5 g (6.4 mmol) of N- [1 (S) -carbamoyl-2- (4-benzyloxyphenyl-ethyl)] -4-tert-

  butoxycarbonylammino-chroman-8-carboxamide, 2.25 g (78.9%) of N-

  [(S) -carbamoyl-2- (4-benzyloxyphenyl-ethyl)] - 4-amino-chroman-8-carboxamide

in the form of beige meringue.

  Spectrum of R.M.N. 1H (400MHz, (CD3) 2SO, d in ppm). The description is

  performed on the mixture of two diastereoisomers 50-50: 1.79 and 2.03 (2 mts, 1H each: CH 2 of chromanyl); from 1.95 to 2.35 (mf spread: the 2H corresponding to NH2); 2.92 and 3.04 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5 Hz, 1H each: ArCH2); 3.93 (mt, 1H: chromanyl CHN) from 4.15 to 4.40 (mt, 2H: CH 2 O of the chromanyl); 4.62 (mt, 1H: NCHCON); 5.07 (s, 2H: OCH 2 benzyloxy); from 6.90 to 7.00 (mt, 3H: H3 and H5 phenoxy and H6 chromanyl); 7.10 and 7.51 (2s wide, 1H each: CONH2); from 7. 10 to 7.20 (mt, 2H: H 2 and H 6 of phenoxy); from 7.30 to 7.50 (mt, 5H: aromatic H of benzyloxy); 7.50 to 7.60 and 7.67 (2 mts, 1H each: H5 and H7 chromanyl);

8.26 (d, J = 8 Hz, 1H: ArCONH).

  By operating as in Example 20 for the preparation of N- [1 (S) -

  carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-cyanobenzyl) -1H-imidazole)

  yl] methylamino-chroman-8-carboxamide, but from N- [1 (S) -carbamoyl] -2-

  benzyloxyphenyl) -ethyl] -4-amino-chroman-8-carboxamide (1.56 g, 3.5 mmol), I- (4-cyanobenzyl) -1H-imidazol-5-yl-carboxaldehyde (0.813 g, 3.85 mmol), sodium cyanoborohydride (0.44 g, 7 mmol), acetic acid (1.3 ml) and acetonitrile (50 ml) in the presence of molecular sieve 4A, are obtained after purification with chromatography on a silica column eluting with a mixture of dichloromethane and methanol (98/2 by volume):

  0.25 g of diastereoisomer A of N- [1 (S) -carbamoyl-2- (4-benzyloxyphenyl) -

  ethyl] -4- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methylamino-chroman-8-carboxamide in the form of a white meringue having the following characteristics: Mass spectrum.DCI: m / z = 641 (M + H) +

  elemental analysis. C38H36N6O4, 0.2H2O. 0,2CH2Cl.

  Calculated (%): C, 69.38; H, 5.61; N = 12.71 Found (%): C, 69.03; H, 5.61; N = 12.88 rotatory power: aD20 = +17.2 + 0.7 (CH30H, c0.5)

  0.16 g of N- [1 (S) -carbamoyl-2- (4-benzyloxyphenyl)) diastereoisomer B

  ethyl] -4- [1- (4-cyanobenzyl) imidazol-5-yl] methylamino-2,3-dihydro-4Hchroman-8-

  MTIlI, i. Y-carboxamide in the form of a white meringue, the characteristics of which are as follows: Mass spectrum: DCI m / z = 641 (M + H) + elemental analysis: C38H36N6O4, 0.2H, 0.3CH2Cl: Calculated (% ): C, 68.68H, 5.57; N = 12.55 Found (%): C = 68.87, H = 5.40: N 12.43 Rotatory: At D 2 = -39.3 + 0.8 (CH 3 OH, c = 0.5) Examples The compounds are synthesized in the solid phase from amino acids protected by the Fmoc (9-fluorenylmethoxycarbonyl) group. The syntheses are carried out in 3 cc polypropylene syringes equipped with a teflon sinter, a 2-way valve and closed with a finned cap. The agitation of the syringes is carried out at

  using a stirrer for hemolysis tube (syringes plugged, valves closed).

  The elimination of the liquid phases of the syringes is carried out by means of an enclosure

  empty equipped with luer tips (plugs removed, valves open).

  All operations are conducted at room temperature.

  The syntheses are carried out on 50 gimoles of Rink resin (substitution 0.48 mmol / g Novabiochem). The coupling of amino acids protected by the Fmoc group is carried out by treating for 1 hour the resin with 250 pmol of the amino acid in the presence of 250 Mmoles of 2 (1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium, hexafluorophosphate (HBTU), 250 gmoles of N-hydoxybenzotriazole and 750 ug of diisopropylethylamine in 1.075 cm 3 of N-methylpyrrolidone-2 (NMP) / dimethylformamide (DMF) (52.5 / 55 by volume). For the coupling of 4- (9-fluorenylmethoxycarbonylamino) -chroman-8-carboxylic acid, 200 imoles are

  used the other reagents are added in proportion.

  The deprotection of the FMOC group is carried out by 3 successive treatments of the resin during, I min., I min. and 20 min. respectively, with 2 cm of piperidine

% in the NMP (in volumes).

  The compounds are cleaved from the resin by a treatment of 1 h. 30 min. with 0.5 cm3 of a mixture of trifluoroacetic acid / phenol / ethanedithiol / thioanisole / water (40/3/1/2/2 v / p / v / v / v) with stirring at room temperature. The resin is then removed by filtration and the filtrate is condensed for 1 hour using a Jouan RC-10-10 centrifugal evaporator fitted with a cold trap at -90 ° C. and a vane pump (empty about 100 g). of Hg). The temperature of the evaporation tank is set at 40 ° C. The concentrates are then precipitated by adding 8 cm 3 of a mixture of methyl tert-butyl ether and petroleum ether (6/2). The products are collected by centrifugation, resolubilized in 0.5 cm3 of trifluoroacetic acid precipitated again by adding 6 ml of a mixture of methyl-tert-butyl ether and petroleum ether (6/2). The precipitates are collected again by centrifugation

  then washed with 6 ml of a mixture of methyl tert-butyl ether and petroleum ether (6/2).

  The products are then dried under vacuum (26 mm Hg).

  EXAMPLE 25 Preparation of Diastereoisomers of N- (1- (S) -carbamoyl-2-

  phenyl-ethyl) -4- (2- (R) -amino-3-mercapto-propionylamino) -chroman-8-

  carboxamide The assembly is carried out as follows: - starting 50 pmol of Rink resin - deprotection of the Fmoc group - washing of the resin with 4 x 2 cm3 of NMP - coupling of Fmoc-L-phenylalanine - washing the resin by 4 x 2 cm3 of NMP - Fmoc group deprotection - washing of the resin with 4 x 2 cm3 of NMP

  coupling of 4- (9-fluorenylmethoxycarbonylamino) -chroman-8-

  carboxylic acid - washing of the resin with 4 x 2 cm3 of NMP - deprotection of the Fmoc group - washing of the resin with 4 x 2 cm3 of NMP - coupling of (S-trityl) -Fmoc-L-cysteine - washing of the resin by 4 x 2 cm3 of NMP deprotection of the Fmoc group - washing of the resin with 4 x 2 cm3 of NMP

  -cleavage of the resin and precipitation of the final product.

  The crude product is solubilized in 4.5 cm 3 of an acetonitrile / acetic acid / water 0.5 / 1/3 mixture and injected onto a RS8 BioRad 100 A (RS8) column (10 × 250 mm) eluted by a linear gradient of water / trifluoroacetic acid (100 μl). /0.07) to water / acetonitrile / trifluoroacetic acid (75/25 / 0.07) in 30 minutes at a flow rate of 6 cm3 / min. The presence of the products is detected by their absorbance at 235 nm. 2 fractions are isolated:

  - 2.9 mg (10% yield); Diastereoisomer A of N- (1- (S) -carbamoyl-2-

  phenyl-ethyl) -4- (2- (R) -amino-3-mercapto-propionylamino) -chroman-8carboxamide. - 3.6 mg (13% yield); Perkin-Elmer Sciex API-III electrospray mass spectrometry; [M + H] + = 443.1 (theoretical: 443). Diastereoisomer B

  N- (1- (S) -carbamoyl-2-phenyl-ethyl) -4- (2- (R) -amino-3-mercaptopropionylamino) -

chroman-8-carboxamide

  Example 26: Preparation of diastereoisomers of N- (1- (S) -carbamoyl-2 (indole)

  3-yl) ethyl) -4- (2- (R) -amino-3-mercapto-propionylamino) -chroman-8-

  carboxamide The assembly is carried out as follows: - starting 50 pmol of Rink resin - deprotection of the Fmoc group - washing of the resin with 4 x 2 cm 3 of NMP - coupling of the Fmoc-L-tryptophan - washing the resin by 4 x 2 cm3 of NMP - deprotection of the Fmoc group - washing of the resin with 4 x 2 cm3 of NMP

  coupling of 4- (9-fluorenylmethoxycarbonylamino) -chroman-8-

  carboxylic acid - washing of the resin with 4 x 2 cm3 of NMP - deprotection of the Fmoc group - washing of the resin with 4 x 2 cm3 of NMP - coupling of the (S-trityl) -Fmoc-L-cysteine - washing of the resin with 4 x 2 cm3 of NMP deprotection of the Fmoc group - washing of the resin with 4 x 2 cm3 of NMP

  -cleavage of the resin and precipitation of the final product.

  The crude product is solubilized in 4.5 cm 3 of acetonitrile / acetic acid / water 0.5 / 1/3 and injected onto a C18 RSL BioRad 100 A column (10 × 250 mm) eluted by a linear gradient of water / trifluoroacetic acid (100 μl). /0.07) to water / acetonitrile / trifluoroacetic acid (75/25 / 0.07) in 30 minutes at a flow rate of 6 cm3 / min. The presence of the products is detected by their absorbance at 280 nm. 2 fractions - 2.7 mg (9% yield) are isolated; Perkin-Elmer Sciex API-III electrospray mass spectrometry; [M + H] + = 482.1 (theoretical: 482). Diastereoisomere A

  N- (I - (S) -carbamoyl-2- (indol-3-yl) ethyl) -4- (2- (R) -amino-3-mercapto)

  propionylamino) -chroman-8-carboxamide - 1.2 mg (4% yield); Perkin-Elmer Sciex APIIII electrospray mass spectrometry; [M + H] + = 482.1 (theoretical: 482). Diastereoisomer B

  N- (1 - (S) -carbamoyl-2- (indol-3-yl) ethyl) -4- (2- (R) -amino-3-mercapto-

  propionylamino) -chroman-8-carboxamide

  EXAMPLE 27 Preparation of Diastereoisomers of N-11- (S) -carbamoyl-2- (4-

  hydroxyphenyl) ethyl-4- (2- (R) -amino-3-mercapto-propionylamino) -chroman-8-

  carboxamide The assembly is carried out as follows: - starting 50 pmol of Rink resin - deprotection of the Fmoc group

102; 2,774,987

  washing of the resin with 4 × 2 cm 3 of NMP - coupling of (O-tertbutyl) -Fmoc-L-tyrosine - washing of the resin with 4 × 2 cm 3 of NMP deprotection of the Fmoc group - washing of the resin with 4 x 2 cm3 of NMP

  coupling of 4- (9-fluorenylmethoxycarbonylamino) -chroman-8-

  carboxylic acid - washing of the resin with 4 x 2 cm3 of NMP - deprotection of the Fmoc group - washing of the resin with 4 x 2 cm3 of NMP - coupling of the (S-trityl) -Fmoc-L-cysteine - washing of the resin with 4 x 2 cm3 of NMP deprotection of the Fmoc group - washing of the resin with 4 x 2 cm3 of NMP

  -cleavage of the resin and precipitation of the final product.

  The crude product is solubilized in 4.5 cm 3 of acetonitrile / acetic acid / water 0.5 / 1/3 and injected onto a C1s RSL BioRad 100 A column (10 × 250 mm) eluted by a linear gradient of water / trifluoroacetic acid (100 μl). /0.07) to water / acetonitrile / trifluoroacetic acid (75/25 / 0.07) in 30 min at a flow rate of 6 cm3 / min. The presence of the products is detected by their absorbance at 280 nm. 2 fractions are isolated: 2 mg (yield 7%); Perkin-Elmer Sciex API-III electrospray mass spectrometry; [M + H] + = 459.1 (theoretical: 459). Diastereoisomere A

  N- [1 - (S) -carbamoyl-2- (4-hydroxyphenyl) ethyl] -4- (2- (R) -amino-3-mercapto)

  propionylamino) -chroman-8-carboxamide - 4.1 mg (14% yield); Perkin-Elmer Sciex APIiI electrospray mass spectrometry; [M + H] + = 459.2 (theoretical: 459). Diastereoisomer B

  N- [1 - (S) -carbamoyl-2- (4-hydroxyphenyl) ethyl] -4- (2- (R) -amino-3-mercapto)

  propionylamino) -chroman-8-carboxamide

103 -2774987

  Example 28: Preparation of N- [1- (S) -carbamoyl-2- (2-) diastereoisomers

  naphthyl) ethyl-4- (2- (R) -amino-3-mercapto-propionylamino) -chroman-8-

  carboxamide The assembly is carried out as follows: - starting 50 pmol of Rink resin - deprotection of the Fmoc group - washing of the resin with 4 × 2 cm 3 of NMP - coupling of Fmoc-L-3- (2-naphthyl) - alanine - washing of the resin with 4 x 2 cm3 of NMP - deprotection of the Fmoc group - washing of the resin with 4 x 2 cm3 of NMP

  coupling of 4- (9-fluorenylmethoxycarbonylamino) -chroman-8-

  carboxylic acid - washing of the resin with 4 x 2 cm 3 of NMP - deprotection of the Fmoc group - washing of the resin with 4 x 2 cm 3 of NMP - coupling of (S-trityl) -Fmoc-L-cysteine - washing of the resin with 4 x 2 cm3 of NMP deprotection of the Fmoc group - washing of the resin with 4 x 2 cm3 of NMP

  -cleavage of the resin and precipitation of the final product.

  The crude product is solubilized in 4.5 cm 3 of an acetonitrile / acetic acid / water 0.5 / 1/3 mixture and injected onto a C18 RSL BioRad 100 A column (10 × 250 mm) eluted by a linear gradient of water / acetonitrile / trifluoroacetic acid. (95/5 / 0.07) to water /

  acetonitrile / trifluoroacetic acid (70/30 / 0.07) in 30 minutes at a rate of 6 cm3 / min.

  The presence of the products is detected by their absorbance at 235 nm. 2 fractions are isolated: 5.9 mg (yield 19%); Perkin-Elmer Sciex API-III electrospray mass spectrometry; [M + H] + = 493.1 (theoretical: 493). Diastereoisomere A

  N- [1 - (S) -carbamoyl-2- (2-naphthyl) ethyl] -4- (2- (R) -amino-3-mercapto-

  propionylamino) -chroman-8-carboxamide - 3.9 mg (13% yield); Perkin-Elmer Sciex APIIfI electrospray mass spectrometry; [M + H] + = 493.1 (theoretical: 493). Diastereoisomere B

  N- [I - (S) -carbamoyl-2- (2-naphthyl) ethyl] -4- (2- (R) -amino-3-mercapto)

  propionylamino) -chroman-8-carboxamide

  Example 29: Preparation of diastereoisomers of N- [1- (R) -carbamoyl-2- (2-

  naphthyl) ethyl] 4- (2- (R) -amino-3-mercapto-propionylamino) -chroman-8-

  carboxamide The assembly is carried out as follows: - starting 50 grmol of Rink resin - deprotection of the Fmoc group - washing of the resin with 4 × 2 cm 3 of NMP - coupling of Fmoc-D-3- (2-naphthyl) - alanine - washing of the resin with 4 x 2 cm3 of NMP - deprotection of the Fmoc group - washing of the resin with 4 x 2 cm3 of NMP

  coupling of 4- (9-fluorenylmethoxycarbonylamino) -chroman-8-

  carboxylic acid - washing of the resin with 4 x 2 cm3 of NMP - deprotection of the Fmoc group - washing of the resin with 4 x 2 cm3 of NMP - coupling of the (S-trityl) -Fmoc-L-cysteine - washing of the resin by 4 x 2 cm3 of NMP deprotection of the Fmoc group - washing of the resin with 4 x 2 cm3 of NMP

  -cleavage of the resin and precipitation of the final product.

  The crude is solubilized in 4.5 cm3 of an acetonitrile / acetic acid / water 0.5 / 1/3 mixture and injected onto a C18 RSL BioRad 100 column (10 × 250 mm) eluted by a linear gradient of water / acetonitrile / trifluoroacetic acid ( 95/5 / 0.07) with water /

  acetonitrile / trifluoroacetic acid (70/30 / 0.07) in 30 minutes at a rate of 6 cm3 / min.

  The presence of the products is detected by their absorbance at 235 nm. 2 fractions are isolated: - 3.1 mg (10% yield); no analytical data. Diastereoisomere A of

  N- [1 - (R) -carbamoyl-2- (2-naphthyl) ethyl] -4- (2- (R) -amino-3-mercapto)

  propionylamino) -chroman-8-carboxamide - 5.3 mg (13% yield); no analytical data. Diastereoisomer B of

  N- [1 - (R) -carbamoyl-2- (2-naphthyl) ethyl] -4- (2- (R) -amino-3-mercapto)

  propionylamino) -chroman-8-carboxamide

  Example 30: Preparation of N- [i (S) -methoxycarbonyl-2- (4-chlorophenyl)]

  Ethyl-4- (4-cyanobenzyl) -1H-imidazol-5-ylmethylamino-thiochroman-8-

  carboxamide 42 g (0.4 mole) of sodium carbonate are added in small portions to a mixture of 14.5 g (0.094 mole) of 2thiosalicylic acid, 14.5 g (0.094 mole) of 3-bromoacidic acid, 1-propionic and 300 ml of water. After the end of the addition, the reaction mixture is refluxed for 24 hours. After cooling, the reaction medium is acidified to pH = 2-3 with 4N hydrochloric acid. The solid formed is filtered, dried and then taken up in 350 ml

  After cooling, the solid is filtered and dried.

  17 g (80%) of 2- (2-carboxyethylthio) benzoic acid are obtained in the form of a yellow solid melting at 194 ° C. Spectrum of R.M.N. 1H (400MHz, (CD3) 2SO, d in ppm): 2.60 (t, J = 7Hz, 2H: CH2CO); 3.13 (t, J = 7 Hz, 2H: SCH 2); 7.24 (t, J = 7.5 Hz, 1H: H5); 7.43 (d, J = 7.5 Hz, 1H: H3); 7.55 (td, J = 7.5 and 1.5 Hz, 1H: H4); 7.89 (dt, J = 7.5 and 1.5 Hz, 1H: H6); from 12.20 to 13.20 (spread mf, 2H: the 2

COOH).

  A mixture of 20 g (0.088 mole) of 2- (2-carboxyethylthio) benzoic acid

  in 500 ml of sulfuric acid is stirred at 20 C for 48 hours.

  The reaction medium is poured on ice, the solid formed is filtered, washed with water,

  then dried under vacuum to give 13.7 g (74.4%) of 4-oxothiochroman acid.

  carboxylic acid as a yellow solid melting at 220 ° C. 1 H NMR spectrum (300 MHz, (CD 3) 2 SO, d in ppm): 2.92 (t, J = 6.5 Hz, 2H: CH 2 CO): 3, 20 (t, J = 6.5Hz, 2H: SCH2): 7.34 (t, J = 7.5Hz, 1H: H6 benzothiopyranyl); 8.10 and 8.23 (2

  dd, J = 7.5 and 2 Hz, 1H each: H5 and H7 benzothiopyranyl).

  2.76 g (144 mmol) of 1- (3-dimethylaminopropyl) hydrochloride

  ethylcarbodiimide are added to a solution composed of 3 g (144 mmol) of 4-oxo-2,3-dihydro-4H-thiochroman-8-yl carboxylic acid, 3.08 g (144 mmol) of the methyl ester of (S) -4-chlorophenylalanine, 1.94 g (144 mmol) of 1-hydroxybenzotriazole and 2.2 ml of triethylamine in 30 ml of chloroform. The reaction is stirred at 20 ° C. for 24 hours. The reaction medium is washed twice with 20 ml of water, the organic phase is dried over MgSO 4, filtered, concentrated under vacuum and then purified by flash chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (97 / 3 in volume). 5.55 g (95.4%) of

  N- [1 - (S) -methoxycarbonyl-2- (4-chlorophenyl) ethyl] -4-oxo-thiochroman-8-

  carboxamide as a beige solid melting at 174 ° C. NMR spectrum H (300 MHz, (CD3) 2 SO, d in ppm): 2.91 (mt, 2H: CH2CO); 3.03 and 3.10 to 3.25 (respectively dd, J = 14 and 10 Hz, and mt, 1H each: ArCH2); from 3.10 to 3.25 (mt, 2H: SCH2); 3.69 (s, 3H: COOCH3); 4.67 (mt, 1H: NCHCON); 7.31 (t, J = 7.5 Hz, 1H: H6 benzothiopyranyl); 7.36 (AB, J = 8.5 Hz, 4H: aromatic H of 4-chlorophenyl); 7.49 and 8.09 (2 dd, J = 7.5 and 2.5 Hz, 1H each: H5 and H7

  benzothiopyranyl); 9.00 (d, J = 7.5 Hz, I H: ArCONH).

  mg (0.95 mmol) of sodium cyanoborohydride are added on a

  solution composed of 0.5 g (1.24 mmol) of N- [1- (S) -methoxycarbonyl-2 (4-

  chlorophenyl) ethyl] -4-oxo-thiochroman-8-carboxamide and 0.95 g (12.3 mmol) of ammonium acetate in 30 ml of methanol. The reaction is stirred at 20 ° C. The reaction is monitored by thin layer chromatography. After 24 hours at 20 ° C., the reaction having not evolved, 0.1 ml of acetic acid, 3 A molecular sieve is added and the mixture is refluxed for 48 hours. After cooling, the reaction medium is filtered on celite, concentrated under vacuum, taken up in 30 ml of distilled water brought to pH = 10 by addition of 2N sodium hydroxide, and extracted with twice 30 ml of dichloromethane. The organic phase is dried over MgSO 4, filtered, concentrated in vacuo and then purified by chromatography on a silica column, eluting with a mixture of dichloromethane and sodium hydroxide.

  methanol (90/10 by volume). 250 mg (50%) of N- [1- (S) -

  methoxycarbonyl-2- (4-chlorophenyl) ethyl] -4-amino-thiochroman-8-carboxamide as beige meringue. Spectrum of R.M.N. 1H (400MHz, (CD3) 2SO, d

  ppm). The description is made on the mixture of two diastereoisomers 50-50:

  from 1.90 to 2.25 (mf spread, 2H: NH 2); 1.95 (mt, 2H: CH, benzothiopyranyl) 2.79 and 3.00 to 3.10 (2 mts, 1H each: SCH2 benzothiopyranyl); 3.02 and 3.15 (2 dd, respectively J = 14 and 10 Hz and J = 14 and Hz, 1H each: ArCH2); 3.67 (s, 3H: COOCH3); 3.91 (mt, 1H: CHN from

  benzothiopyranyl); 4.63 (mt, 1H: NCHCON); 7.08 (mt, 2H: H2 and H6 from 4-

  chloro-phenyl); from 7.30 to 7.40 (mt, 2H: H 3 and H 5 of 4-chlorophenyl); from 7.30 to 7.40 and 7.47 (2 mts, respectively 2H and 1H: H5 - H6 and H7 from

  benzothiopyranyl); 8.66 and 8.68 (2d, J = 7.5 Hz, 1H in total: ArCONH).

  A mixture of 220 mg (0.54 mmol) of N- [1- (S)]

  methoxycarbonyl-2- (4-chlorophenyl) -ethyl] -4-amino-thiochroman-8-

  carboxamide, 138 mg (0.65 mmol) of 1- (4-cyanobenzyl) -1H-imidazol-5-yl-

  carboxaldehyde, 0.3 ml of acetic acid, in 10 ml of methanol, in the presence of molecular sieve 3, is stirred at 20 ° C. for two

  hours. 51 mg (0.81 mmol) of sodium cyanoborohydride are added.

  After stirring for 24 hours at 20 ° C., the reaction medium is filtered through celite, concentrated under vacuum, taken up with saturated NaHCO 3 solution and extracted twice with 20 ml of dichloromethane. The organic phase is dried over MgSO 4, filtered, concentrated under vacuum and then purified by flash chromatography on a silica column, eluting with a mixture of dichloromethane and sodium hydroxide.

  methanol (96.5 / 3.5 by volume). 290 mg (88.8%) of N- [1- (S) -

  methoxycarbonyl-2- (4-chlorophenyl) ethyl] -4- [1 - (4-cyanobenzyl) -1 Himidazol

  -yl] methylamino-thiochroman-8-carboxamide as beige meringue.

  Spectrum of R.M.N. H (400 MHz, (CD3) 2 SO, d in ppm). The description is

  performed on the mixture of two diastereoisomers 50-50: 1.73 and 2.00 to 2.20 (2 mts: the 2H corresponding to the CH2 of benzothiopyranyl) 2.73 and 2.95 to 3.10 (2 mts , 1H each: benzothiopyranyl CH2S); from 2.95 to 3.10 and 3.16 (2 mts, 1H each: ArCH2); 3.42 and 3.55 to 3.75 (2 mts, 1H each: CH2N); from 3.55 to 3.75 (mt, 1H: benzothiopyranyl CHN); 3.67 (s, 3H: COOCH3); 4.64 (mt, 1H: NCHCON); 5.39 and 5.40 (2 s, 2H in total: ArCHN); 6.89 (s, 1H: aromatic H of imidazolyl); 6.98 (2 t, J = 7.5 Hz, 1H in total: H6 benzothiopyranyl); from 7.05 to 7.20 (mt, 4H: H2 and H6 from 4-cyano-phenyl-H5 and H7 from benzothiopyranyl); 7, 34 and 7.37 (2 d, J = 8 Hz, 2H each: aromatic H of 4-chloro-phenyl); 7.70 to 7.80 (mt, 2H: H3 and H5 4-cyano-phenyl); 7.76 (s, 1 H: aromatic H of imidazolyl) 8.69 and 8.71 (2 d, J = 8 Hz, I H

totality: ArCONH).

  Example 31: Preparation of N- [1 (S) -carbamoyl-2- {4-chlorophenyl) -

  ethyl] -4- [1- (4-cyanobenzyl) -1H-imidazol-5-yl methylamino-thiochroman-8-

carboxamide

  In an autoclave, a mixture of 180 mg (0.3 mmol) of N- [1 -

  (S) -methoxycarbonyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-cyanobenzyl) -1H-

  imidazol-5-yl] methylamino-thiochroman-8-carboxamide and 30 ml of 6N ammonium methanol are heated at 60 ° C. for 4 hours. After cooling,

  The reaction medium is concentrated under vacuum to give 172 mg (98%) of N-

  [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-cyanobenzyl) -1Heididazole-

  -yl] methylamino-thiochroman-8-carboxamide as beige meringue.

  Spectrum of R.M.N. 1H (400MHz, (CD3) 2SO, d in ppm). The description is

  performed on the mixture of two diastereoisomers 50-50: 1.74 and 2.08 (2 mts, 1H each: benzothiopyranyl CH 2); 2.72 and 3.03 (2 mts, 1H each: benzothiopyranyl CH 2 S); 2.90 and 3.10 (2 mts, 1H each: ArCH,); 3.43 and 3.60 (2 mts, 1H each: CH 2 N); 3.64 (mt, 1H: benzothiopyranyl CHN) 4.61 (mt, 1H: NCHCON); 5.38 and 5.40 (2 s, 2H in total: ArCH 2 N); 6.88 (s, 1H: aromatic H of imidazolyl); 6.96 (2 t, J = 7.5 Hz, all of H: benzothiopyranyl H6); from 7.05 to 7.20 (mt, 5H: 1H of CONH, H 2 and H 6 of 4-cyano-phenyl-H 5 and H 7 of benzothiopyranyl); 7.34 (AB limit, 4H: aromatic H of 4-chlorophenyl); from 7.35 to 7.45 (mt,

  1H: the other H of CONH2); from 7.70 to 7.80 (mt, 2H: H3 and H5 from 4-cyano-

  phenyl); 7.75 (s, 1H: aromatic H of imidazolyl); 8.24 and 8.26 (2d, J = 8

Hz, 1H in total: ArCONH).

  Example 32 Preparation of N- [1 (S) -methoxycarbonyl-2- (4-

  chlorophenyl) ethyl-4-1- (4-cyanobenzyl) -1H-imidazol-5-yl] methylamino1,1-

dioxo-thiochroman-8-carboxamide

  A mixture of 5 g (0.024 mole) of 4-oxo-2,3-dihydro-4H-thiochroman-

  8-yl carboxylic acid, 100 ml of chloroform, 50 ml of acetic acid, and 10 g (0.058 mol) of 3-chloroperbenzoic acid are stirred at 20 ° C. for 24 hours. The reaction medium is evaporated to dryness, taken up with 100 ml of

  dichloromethane, and then filtered to give 4.2 g (72.8%) of 4-oxo-1,1-dioxoic acid.

  thiochroman-8-carboxylic acid as a yellow solid melting at 207 ° C. Spectrum of R.M.N. 1H (300 MHz, (CD3) 2SO d6, d in ppm) 3.28 (broad t, J = 6.5 Hz, 2H: CH2CO); 3.98 (broad t, J = 6.5 Hz, 2H: SO 2 CH 2); 7.90 (t, J = 8 Hz, 1H: H6 benzodioxothiopyranyl); 7.98 and 8.14 (2 dd, J = 8 and 2 Hz, 1H each: H5 and H7 from

  benzodioxothiopyranyle); from 13.20 to 14.20 (mf very spread, I H: COOH).

  By operating as in Example 30 for the preparation of N- [I- (S) -

  methoxycarbonyl-2- (4-chlorophenyl) ethyl] -4-oxo-thiochroman-8-carboxamide, but starting from 4-oxo-1,1-dioxo-thiochroman-8-carboxylic acid (3 g, 12.5 mmol) , (S) -4chlorophenylalanine methyl ester (2.65 g, 12.5 mmol), 1-hydroxy-benzotriazole (1.68 g, 12.5 mmol), triethylamine (1.9 ml), ), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and chloroform (100 ml), is obtained after purification by flash column chromatography on silica eluting with a mixture of dichloromethane and methanol.

  (98/2 by volume), 4.1 g (75%) of N- [1 (S) -methoxycarbonyl-2- (4chlorophenyl) -

  ethyl] -4-oxo-1,1-dioxothiochroman-8-carboxamide as beige meringue. Spectrum of R.M.N. 1H (400 MHz, (CD3) 2SO, d in ppm) 3.07 and 3.13 (2 dd, respectively J = 14 and 8 Hz and J = 14 and 5.5 Hz, 1H each ArCH,); 3.26 (t, J = 6.5 Hz, 2H: CH 2 CO); 3.66 (s, 3H: COOCH3); 3.91 (t, J = 6.5 Hz, 2H: SO2CH2); 4.68 (mrt, 1H: NCHCON); 7.35 (AB, J = 8 Hz, 4H: aromatic H of 4-chlorophenyl); 7.63 and 8.10 (2dd, J = 8 and 1.5Hz, each IH: H5 and H7 benzodioxothiopyranyl); 7,87 (t, J = 8 Hz, 1H: H6 benzodioxothiopyranyl)

9.09 (d, J = 8 Hz, 1H: ArCONH).

  A mixture of 1 g (2.29 mmol) of N- [1 (S) -methoxycarbonyl-2- (4-

  chlorophenyl) ethyl] -4-oxo-1,1-dioxothiochroman-8-carboxamide, 2 g (26.6 mmol) of ammonium acetate, 110 mg (1.70 mmol) sodium cyanoborohydride, 1 1 ml of acetic acid in 50 ml of methanol in the presence of 3 A molecular sieve is stirred at 20 ° C. for 3 hours and then at reflux for 24 hours. After cooling, the reaction medium is filtered on celite, concentrated under vacuum, taken up in 30 ml of distilled water brought to pH = 10 by addition of 2N sodium hydroxide, and extracted with twice 50 ml of dichloromethane. The organic phase is dried over MgSO 4, filtered, concentrated under vacuum and then purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (94/6 by volume). 420 mg (42%) of

  N- [1 - (S) -methoxycarbonyl-2- (4-chlorophenyl) ethyl] -4-amino-1,1-dioxo

  thiochroman-8-carboxamide as beige meringue. Spectrum of R.M.N. 1 H

  (300 MHz, CDCl3, d in ppm). The description is made on the mixture of two

  diastereoisomers 50-50: 2.40 and 2.76 (2 mts, 1H each: benzodioxothiopyranyl CH 2); from 3.20 to 3.40 and from 3.65 to 3.85 (2 mts, respectively 3H and 1H: SO2CH2 of benzodioxothiopyranyl and ArCH2); 3, 71 and 3.73 (2 s, 3H in total: COOCH 3): 4.27 (mt, 1H: benzodioxothiopyranyl CHN); 5.10 (mt, 1H: NCHCON); 6.87 (mt, 1H: ArCONH); from 7.15 to 7.35 (mt, 4H: aromatic H of 4-chlorophenyl):

  7.45 to 7.70 (mt, 3H in total: H5 - H6 and H7 benzodioxothiopyranyl).

  By operating as in Example 30 for the preparation of N-

  [1 - (S) -methoxycarbonyl-2- (4-chlorophenyl) ethyl] -4- [1 - (4cyanobenzyl) -1H-

  imidazol-5-yl] methylamino-thiochroman-8-carboxamide, but from N [1 -

  (S) -methoxycarbonyl-2- (4-chlorophenyl) ethyl] -4-amino-1,1-dioxo

  thiochroman-8-carboxamide (0.40 g, 0.9 mmol), 1- (4-cyanobenzyl) -1H-

  imidazol-5-yl-carboxaldehyde (0.232 g, 1.1 mmol), sodium cyanoborohydride (0.086 g, 1.36 mmol), acetic acid (0.5 ml) and methanol (10 ml) in the presence of molecular sieve 3A, after purification by flash chromatography on a silica column, eluting with a mixture of

  dichloromethane and methanol (96/4 by volume), 0.515 g (89%) of N [1 (S) -

  methoxycarbonyl-2- (4-chlorophenyl) ethyl] -4- [f] - (4-cyanobenzyl) -1 Himidazol

  -yl] methylamino-1,1-dioxo-thiochroman-8-carboxamide as beige meringue. Spectrum of R.M.N. H (400 MHz, (CD3) 2 SO, d in ppm). The

  description is carried out on the mixture of two diastereoisomers 50-50:

  2.32 and 2.43 (2 mts: 2H corresponding to CH, benzodioxothiopyranyl); 2.61 (mt, 1H: NH); 3.07 (mt, 2H: ArCH 3) 3.25 to 3.40 and 3.45 to 3.70 (2 mts: 4H corresponding to SO 2 CH 2 of benzodioxothiopyranyl and CH 2 N); 3.64 (s, 3H COOCH3); 3.88 (mt, 1H: benzodioxothiopyranyl CHN); 4.63 (mt, 1H: NCHCON); 5.42 (s, 2H ArCH2N); 6.91 (s, 1H: aromatic H of imidazolyl); 7.20 to 7.30 and 7.44 (respectively mt and d, J = 8 Hz, 1H each: H5 and H7 benzodioxothiopyranyl); 7.22 (d, J = 8 Hz, 2H: H 2 and H 6 of 4-cyanophenyl) 7.30 and 7.35 (2 d, J = 8 Hz, 2H each: aromatic H 4-chlorophenyl); 7.52 (t, J = 8 Hz, 1H: H 6 benzodioxothiopyranyl); 7, 76 (s, 1H: H

  aromatic imidazolyl); 7.80 (d wide, J = 8 Hz, 2H: H3 and H5 from 4-

  cyano-phenyl); 8.66 (d, J = 8 Hz, 1H: ArCONH).

  Example 33: Preparation of N- [1 (S) -carbamoyl-2- (4-chlorophenyl) -

  Ethyl-4- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methylamino-1,1-dioxoethyl

thiochroman-8-carboxamide

  By operating as in Example 31 for the preparation of N-

  [1 - (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-cyanobenzyl) -1H-imidazole;

  -yl] methylamino-thiochroman-8-carboxamide, but from N- [1 (S) -

  methoxycarbonyl-2- (4-chlorophenyl) ethyl] -4- [1 - (4-cyanobenzyl) -1 Himidazol

  -yl] methylamino-1,1-dioxothiochroman-8-carboxamide (0.40 g, 0.63 mmol), and 6N ammonia methanol (20 ml). 0.37 g (94.7%) of

  N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1 - (4-cyanobenzyl) -1H-

  imidazol-5-yl] methylamino-1,1-dioxothiochroman-8-carboxamide as beige meringue. Spectrum of R.M.N. H (400 MHz, (CD3) 2 SO, d in ppm). The

  description is carried out on the mixture of two diastereoisomers 50-50:

  2.25 to 2.50 (mt, 2H: CH 2 benzodioxothiopyranyl); 2.57 and 2.71 (2 mts, 1H in total: NH); 2.85 and 3.15 to 3.40 (2 mts, 1H each: ArCH 3) from 3.20 to 3.75 (mt: 4H corresponding to SO 2 CH 2 of benzodioxothiopyranyl and CH 2 N); 3.89 (mrt, 1H: benzodioxothiopyranyl CHN); 4.59 (mt, 1H: NCHCON); 5.41 and 5.43 (2 s, 2H in total: ArCH 2 N); from 6.85 to 7.00 (mt, 2H: aromatic H of imidazolyl and H5 of benzodioxothiopyranyl); from 7.15 to 7.45 (mt, 9H: H7 from

  benzodioxothiopyranyl - H2 and H6 4-cyano-phenyl - aromatic H 4-

  chlorophenyl and CONH2); 7.52 (mt, 1H: H6 benzodioxothiopyranyl); from 7.75 to 7.90 (mt, 2H: H3 and H5 4-cyano-phenyl); 7.77 (s, 1H: aromatic H of imidazolyl); 8.51 and 8.57 (2d, J = 9Hz, 1H in total ArCONH).

EXAMPLE 34

  Evaluation of the farnesyl transferase activity of compounds according to the invention The farnesyl transferase activity is measured by the farnesylated amount of K-ras substrate or of substrate derived from the peptide corresponding to its C-terminal part,

  the farnesyl group being provided by farnesyl pyrophosphate (FPP).

  Specifically, the biotinylated substrate used, representative of K-ras: BIOT (13A) 3 -S-K-D-G- (K) 6 -S-K-T-K-C-V-I-M, is [3H] famesylated on its cysteine C. by farnesyl transferase in the presence of [3H] FPP. It is then contacted with PVT * -streptavidin beads (AMERSHAM), and quantified by proximity scintillation (SPA assay) between tritium and PVT beads, through 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 μl in a final volume of 100 μl of the HEPES 50 buffer-based reaction mixture. mM pH 7.5, 5 mM MgCl 2, 40 mM KCl,

  dithiothreitol 5 mM, Triton X100 0.01%.

  The inhibitors to be tested, dissolved initially at 1 mM in a suitable solvent (DMF or DMSO) are diluted in the assay buffer and are added in the form of gl, in triplicate, in the reaction mixture at a concentration 10 times higher.

to 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. , 2M, 1.5mM MgCl2, 0.5% (w / v) BSA, 0.05% (w / v) sodium azide containing 200g of PVT-streptavidin beads. After stirring slowly for 30 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 colored agent attenuating the

scintillation ("quenching").

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

substrates and buffer.

  IC50's are calculated or measured from the inhibitions obtained at nine different concentrations with Enzfitter or Grafit software. Products

  according to the invention have IC50o between 0.1 nM and 100 gM.

EXAMPLE 35 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 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. The 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, are 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% CO2.

  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 the formation of clones by 50% at

  concentrations between 0.1 nM and 100 tM.

EXAMPLE 36

EXAMPLE A

  The capsules are prepared, according to the usual technique, at 50 mg of active product having the following composition: active ingredient .............

  .................................................. ...... 50 mg Cellulose ......................................... ........................ .DTD: ......... 18 mg Lactose ........... .................................... DTD: ............ ................... 55 mg - Colloidal Silica ............... DTD: ......... .............................................. Img Sodium carboxymethyl starch. ............................................ 10 mg - Talc .. .................................................. .......... DTD: ......................... 10 mg - magnesium stearate ....... .......... DTD: ...................................... I mg..DTD: EXAMPLE B

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

  .................................................. ...... 50 mg Lactose ......................................... .......................... .DTD: ............. 104 mg Cellulose ..... .................................. DTD: .............. ......................... 40 mg - Polyvidone .............. DTD: ..... .................................................. ....... 10 mg - Sodium carboxymethyl starch ...................................... ..... 22 mg - Talc ......................................... ................. DTD: .......................... 10 mg - Stearate magnesium ................ DTD: ............................... ......... 2mg - Colloidal silica ....... DTD: ............................ ................................... 2mg Mixture of hydroxymethylcellulose, glycerin, titanium oxide (72-3 , 5-24, 5) qs 245 mg film-coated tablet..DTD: EXAMPLE C

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

  ......................................... 50 mg - Benzoic acid .... .. DTD: .............................................. ............... 80 mg Benzyl alcohol ............................... .......................... .DTD: ..... 0.06 ml - Sodium Benzoate ........ .............................. DTD: .................. .... 80 mg - 95% Ethanol ........................... DTD: .......... ................................. 0.4 ml - Sodium hydroxide ......... .................................................. 24 mg Propylene glycol .............................................. .......... .DTD: .......... 1.6 ml Water ...................... .......................... DTD: ...................... ... qsp 4 ml..DTD:

Claims (23)

  1 - Compounds of general formula (I) C * R ", R 4 WE R4 R5 (I)   in which: R 1 represents a radical chosen from the radicals -COCH (NH 2) -CH 2 SH, or -CH2-CH (NH2) -CH2SH,   or the radicals of formula R 1, R 2 represents a hydrogen atom, an alkyl radical or an aralkyl radical. aryl. alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, heterocyclylalkyl; R3 represents a hydrogen atom or a halogen atom or an alkyl, aryl or aralkyl radical; R4 represents a radical / R13 -CH R14 R5 represents   a hydrogen atom, or a radical -C (O) -Ris, or a radical -NHCH (CO2Ri6) - (CH2) 2-S-CH3,   R6 represents a hydrogen atom or an alkyl, aryl or aralkyl radical; R7, R8 independently represent a hydrogen atom or an alkyl, aryl, aralkyl radical; X represents an oxygen atom or an S (O) I radical, for which 1 is equal to 0, 1 or 2; R 1 represents an optionally substituted heterocyclyl radical, R 12 represents a hydrogen atom, or a radical chosen from alkyl, aryl or aralkyl, R 13, R 14, which may be identical or different, independently represent a hydrogen atom, or an aryl radical, it being understood that R13 and R14 do not each simultaneously represent a hydrogen atom,   Ris represents a radical chosen from hydroxyl, alkoxy and amino radicals.   araikylamino, alkylamino; or a radical -NH-CH (CO2Ri6) - (CH2) 2 -S-CH3   R16 represents a hydrogen atom or an alkyl radical.   in racemic form, or their stereoisomers as well as in the form of salts.   2 - Compounds according to claim I for which RI represents a radical -CO-CH (NH2) -CH2SH, or   -CH 2 -CH (NH 4) -CH 2 S, or an optionally substituted heterocyclylalkyl radical.   3 - Compounds according to any one of the preceding claims for which   R. represents a hydrogen atom, an acetyl or alkyl radical   4 - Compounds according to any one of the preceding claims for which   Ril represents a heterocyclyl radical optionally substituted with one or more atoms or radicals chosen from halogen atoms and / or alkoxy, alkyl or aralkyl radicals   Compounds according to any one of the preceding claims for which   R3 represents a hydrogen or fluorine atom   6 - Compounds according to any one of the preceding claims for which   R4 represents a radical chosen from the following radicals: -CH2- (2naphthyl), -CH2-   (3-indolyl), -CH- (phenyl) 2, -CH 2 (phenyl) with the phenyl ring being optionally substituted   7 - Compounds according to any one of the preceding claims for which   R5 represents a radical -C (O) -Ris for which R15 represents a hydroxyl, methoxy, ethoxy or amino radical, or a radical -NH-CH (CO2Ri6) - (CH2) 2S-CH3, for which R16 represents a hydrogen atom or an alkyl radical   8 - Compounds according to any one of the preceding claims for which   R6 represents a hydrogen atom   9 - Compounds according to any one of the preceding claims for which   R7 and R8 each represents a hydrogen atom;   Compounds according to any one of the preceding claims for which   X represents an oxygen atom, a sulfur atom or -SO, 1 l - Compound of general formula (I) characterized in that it is a compound selected individually from:   N- (I - (S) -carbamoyl-2-phenyl-ethyl) -4- (2- (R) -amino-3-mercaptopropylamino) chroman-8-carboxamide   N- (1- (S) -carbamoyl-2-phenyl-ethyl) -4- (2- (R) -amino-3- ethyl ester of ethyl ester   mercapto-propylamino) -chroman-8-carboxylic acid   N- (1 (S) -carboxy-2-phenyl-ethyl) -4- (2 (R) -amino-3-mercaptopropylamino) chroman-   N- (2-phenyl-ethyl) -4- (2 (R) -amino-3-mercaptopropylamino) chroman-8-carboxamide 8-carboxamide   [4- (2 (R) -amino-3-mercapto-propylamino) -chromane] -8-carbonyl-L-Lphénylalanyl methionine   N- (1 (S) -benzylcarbamoyl-2-phenyl-ethyl) -4- (2 (R) -amino-3-mercaptopropylamino) chroman-8-carboxamide   N- (1 (S) -N-butylcarbamoyl-2-phenyl-ethyl) -4- (2 (R) -amino-3-mercaptopropylamino) chroman-8-carboxamide   N- (I (S) -carbamoyl-2-phenyl-ethyl) -4- (2 (R) -amino-3-mercaptopropylamino) -6- fluoro-chroman-8-carboxamide   N- (I (S) -carbamoyl-2-phenyl-ethyl) -4- (2 (R) -amino-3-mercaptopropylamino) -6- fluoro-chroman-8-carboxamide   N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- (2 (R) -amino-3-mercapto propylamino) -chroman-8-carboxamide   N- [1 (S) -carbamoyl-2- (4-methoxyphenyl) ethyl] -4- (2 (R) -amino-3-mercapto propylamino) -chroman-8-carboxamide   N- [1 (S) -carbamoyl-2- (4-fluorophenyl) ethyl] -4- (2 (R) -amino-3-mercapto propylamino) -chroman-8-carboxamide   N- [1 (S) -carbamoyl-2- (4-nitrophenyl) ethyl] -4- (2 (R) -amino-3-mercapto propylamino) -chroman-8-carboxamide   N- [I (S) -carbamoyl-2- (4-hydroxyphenyl) ethyl] -4- (2 (R) -amino-3-mercapto) propylamino) -chroman-8-carboxamide   N- [I (S) -carbamoyl-2- (3,4-dichlorophenyl) ethyl] -4- (2 (R) -amino-3-mercaptopropanol propylamino) -chroman-8-carboxamide   N- [1 (S) -carbamoyl-2- (4-methylphenyl) ethyl] -4- (2 (R) -amino-3-mercapto propylamino) -chroman-8-carboxamide   N- [1 (S) -carbamoyl-2- (4-bromophenyl) ethyl] -4- (2 (R) -amino-3-mercapto propylamino) -chroman-8-carboxamide   N- [I (R) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- (2 (R) -amino-3-mercapto propylamino) -chroman-8-carboxamide   N- [2- (4-aminophenyl) -1 (S) -carbamoyl-ethyl] -4- (2 (R) -amino-3-mercapto) propylamino) -chroman-8-carboxamide   N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-cyanobenzyl) -1H-imidazol-4-   yl] methylamino-chroman-8-carboxamide   N- [I (S) -carbamoyl-2- (4-chlorophenyl) -ethyl] -4- (1-methyl-1-Himidazol-5-   yl) méthylamnino-chroman-8-carboxamide   N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-cyanobenzyl) -1H-imidazol-5-   yl] methylamino-chroman-8-carboxamide   N- [1 (S) -carbamoyl-2- (4-chlorophenyl) -ethyl] -4- {N-acetyl- [1- (4-cyanobenzyl) -1H-   imidazol-5-yl-methyl] amino} -chroman-8-carboxamide   N- [I (S) -carbamoyl-2- (4-benzyloxyphenyl) -ethyl] -4- [1- (4-cyanobenzyl) imidazol-5-   yl] methylamino-chroman-8-carboxamide   N- (1- (S) -carbamoyl-2-phenyl-ethyl) -4- (2- (R) -amino-3-mercaptopropionylamino) - chroman-8-carboxamide   N- (I - (S) -carbamoyl-2- (indol-3-yl) ethyl) -4- (2- (R) -amino-3-mercapto)   propionylamino) -chroman-8-carboxamide   N- [I - (S) -carbamoyl-2- (4-hydroxyphenyl) ethyl] -4- (2- (R) -amino-3-mercapto)   propionylamino) -chroman-8-carboxamide   N- [1 - (S) -carbamoyl-2- (2-naphthyl) ethyl] -4- (2- (R) -amino-3-mercapto)   propionylamino) -chroman-8-carboxamide   N- [1 - (R) -carbamoyl-2- (2-naphthyl) ethyl] -4- (2- (R) -amino-3-mercapto)   propionylamino) -chroman-8-carboxamide   N- [1 (S) -methoxycarbonyl-2- (4-chlorophenyl) ethyl] -4- [1 - (4cyanobenzyl) -1H-   imidazol-5-yl] methylamino-thiochroman-8-carboxamide   N- [I (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-cyanobenzyl) -1H-imidazol-5-   yl] methylamino-thiochroman-8-carboxamide   (N- [1H (S) -methoxycarbonyl-2- (4-chlorophenyl) ethyl] -4- [1 - (4cyanobenzyl) -1H-   imidazol-5-yl] methylamino-1,1-dioxothiochroman-8-carboxamide   N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-cyanobenzyl) -1H-imidazol-5-   yl] methylamino-1,1-dioxothiochroman-8-carboxamide   N- [1 (S) -carbamoyl-2- (4-bromophenyl) ethyl] -4- [1 - (4-cyanobenzyl) -1 Himidazol-5-   yl] methylamino-chroman-8-carboxamide   N- [I (S) -carbamoyl-2- (4-fluorophenyl) ethyl] -4- [1- (4-cyanobenzyl) -1H-iminazol-5-   yl] methylamino-chroman-8-carboxamide   N- [1 (S) -carbamoyl-2- (4-methoxyphenyl) ethyl] -4- [1- (4-cyanobenzyl) -1H-imidazol-5-   yl] methylamino-chroman-8-carboxamide   N- [I (S) -carbamoyl-2- (4-benzyloxyphenyl) -ethyl] -4- [1- (4-cyanobenzyl) -1H-imidazole-   yl] methylamino-chroman-8-carboxamide   N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- {N- [1- (4-cyanobenzyl) H-imidazol)   yl-methyl] ethylamino-chroman-8-carboxamide   N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-chlorobenzyl) -1H-imidazol-5-one   yl] methylamino-chroman-8-carboxamnide   N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [I - (4-nitrobenzyl) -1H-imidazol-5-   yl] methylamino-chroman-8-carboxamide   N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-trifluoromethoxybenzyl) -1H-   imidazol-5-yl] methylamino-chroman-8-carboxamide   N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-trifluoromethylbenzyl) -1H-   imidazol-5-yl] methylamino-chroman-8-carboxamide   N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1-benzyl-1-Himidazol-5-   yl] methylamino-chroman-8-carboxamide   N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-methoxybenzyl) -1H-imidazole)   yl] methylamino-chroman-8-carboxamide   N- [11 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-fluorobenzyl) -1H-imidazol)   yl] methylamino-chroman-8-carboxamide   N- [1 (S) -carbamoyl-2- (4-chlorophenyl) ethyl] -4- [1- (4-methanesulfonylbenzyl) -1H-   imidazol-5-yl] methylamino-chroman-8-carboxamide   or their other stereoisomers, or in racemic form as well as their salts.   12 - Process for the preparation of the compounds of general formula (I) according to one   any of the preceding claims, wherein R2, R3, R4, R6, R6, R7, R8 and   X are as defined in general formula (I) and R 1 represents the radical -CO-CH (NH 2) -CH 2 SH, characterized in that the product of general formula (IIa) HN-G is condensed. 3 R 7 R3 A8 O <6   R5 (IIa) wherein R3, R4, R5, R6, R7, R5, X are as defined in the general formula (I) and G1 represents a hydrogen atom, with a protected amino acid of the general formula HO2C- CH (NHG2) -CH2SG3 (Ia) wherein G2 is a protecting group of an amino function and G3 is a mercapto protecting group, then removing the protecting groups of the amino and mercapto groups; 13 - Process for the preparation of the compounds of general formula (I) according to one   any of claims 1 to 11, wherein R2, R3, R4, R6, R6, R7, R8 and X   are as defined in general formula (I) and R1 represents the radical -CH2-CH (NH2) -CH2SH, characterized in that the product of general formula (IIa) in which R3, R3, R5 is condensed. R6. R7, Rs, X are as defined in general formula (I) and G1 represents a hydrogen atom, with a reagent of general formula H O '"SG3 NHG. NH- (IV),   in which G 1 and G 3 are defined as above, and then the amino and mercapto radicals are removed by cleavage of the protective groups G 2 and G 3, 14 - Process for the preparation of the compounds of the general formula (I) according to one of   any of claims 1 to 11, wherein R2, R3, R4. R5, R6, R7, R8 and X   are as defined in general formula (I) and RI represents the radical Ri Ri, for which Ril and Ri2 are as defined in general formula (I), characterized in that the product of general formula (IIa) in which R 3, R 4, R 5, R 6, R 7, R 5, X are as defined in general formula (I) and G 1 represents a hydrogen atom, with a reagent of general formula R 1 (R)   for which Ril and Ri2 are defined as before.   - Process for the preparation of the compounds of general formula (1) according to one   any of claims 1 to 11, wherein R, R2, R3, R4, R6, R7, Rs and X   are as defined in general formula (I) and R5 represents a -CORi5 radical, o Ris represents an amino radical, characterized in that one proceeds from the products of general formula (I) for which Ris represents an alkoxy radical by Ammonia action 16 - Process for the preparation of the compounds of general formula (I) according to one   any of claims 1 to 1 1, for which R 1, R 2, R 3, R Re, R 6, 7, R 8 and X   are as defined in general formula (I) and R5 represents a -CORi5 radical, where R15 represents a hydroxyl radical, characterized in that saponification is carried out by   compounds of formula (I) for which R5 = -CORi5 and Ris represents an alkoxv radical.   17 - Process for the preparation of the compounds of general formula (I) according to one   any of claims 1 to 11, wherein R1, R3, R4, R, R6, R7, Rs and X   are as defined in general formula (I) and R2 represents an alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical, characterized in that one proceeds from the corresponding compounds of general formula (I) in which R2 represents a hydrogen atom, by action of the corresponding acid of formula R 2 OH, in which R 2 represents an alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical, or of an activated form of this acid 18 - Process for the preparation of the compounds of general formula (I) according to one of   any of claims I to 11, wherein R1, R3, R4, R6, R6, R7, R8 and X   are as defined in general formula (I) and R2 represents an alkyl, aryl, aralkyl, heterocyclylalkyl radical, characterized in that one proceeds from the corresponding compounds of general formula (I) in which R2 represents a hydrogen atom by the action of the corresponding aldehyde 19 - Process for the preparation of the compounds of general formula (I) according to one of   any of claims 12 to 13 characterized in that G2 represents a radical   benzyloxycarbonyl, tert.butoxycarbonyl or vinyloxycarbonyl, and G3 represents a triphenylmethyl radical.   - Process for the preparation of the compounds of general formula (I) according to claim 12, characterized in that the reaction of the compound of general formula   (III) on the compound of general formula (IIa) is carried out in the presence of 2- (H-   benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), N-   hydroxybenzotriazole (HOBT) and diisopropylethylamine in an organic solvent. 21 - Process for the preparation of the compounds of general formula (I) according to one of   any of claims 13 or 14, characterized in that the reaction of the product   of general formula (IV) on the product of general formula (IIa) or the reaction of the product of general formula (V) with the product of general formula (IIa) is carried out under reducing amination conditions. compounds of general formula (I) according to claim 21, characterized in that the reaction of the product of general formula (IV) with the product of general formula (IIa) or the reaction of the product of general formula (V) with the product of formula (IIa) is carried out by operating in an organic solvent in the presence of acid and then by action of a reducing compound 23 - Process for the preparation of the compounds of general formula (I) according to claim 22, characterized in that the reducing compound is sodium cyanoborohydride (NaBH3CN) or sodium triacetoxyborohydride (NaBH (OCOCH3) 3 or BH3 pyridine complex 24-Compounds of general formula (IIa) HN-G O / NR6   Wherein R 3, R 4, R 1, R 6, R 7, R 5, X are as defined in general formula (I) and   G1 represents a hydrogen atom.   - Process for the preparation of the compounds of general formula (IIa) according to claim 24 wherein R3, R4, Ri, R6, R7, R8 are as defined in general formula (Ha), X represents an oxygen atom and G, represents a hydrogen atom, characterized in that the compounds of general formula (IIb) HN-GI R7 R3 XR8 are deprotected O NR6   R4 (IIb) wherein X, R3, R4, R6, R6, R7, R8 are defined as above, and G1 represents a group protecting an amino function, the compounds of general formula (IIb) being obtained from compounds of general formula (VI) HN-Gl Ra <R R7 XR8 CO, H (VI)   in which X, R3, R7, R8 and G are defined as above, by the action of a compound of general formula (VII) corresponding R R I * R4 R5 (VII),   in which R4 R5, R6 are as defined above, under the amidification conditions 26 - Process for the preparation of the compounds of general formula (IIb) according to claim 25 for which R3, R4, R6, R7, R8 are as defined in the general formula (IIa), X represents an oxygen atom, Gl represents a group protecting an amino function and Rs represents the -CORis radical for which Ris represents an amino, alkylamino radical. aralkylamino as defined in the general formula (1), or -NHCH (CO2Ri6) - (CH2) rS-CH3 for which R16 is defined as in general formula (I), characterized in that the products of general formula (lib) are obtained from compounds of general formula (VI) by action of a compound of general formula (VII) HNR6 R4 R5 (VII),   in which R4 and R6 are as defined in general formula (I) and R5 represents the -CORi5 radical for which R15 represents an alkoxy radical, under the previous amidification conditions, and then is followed by the action of ammonia, or is followed, after hydrolysis of the radical - CORi5 to the carboxy radical, of the action of an alkylamine, an aralkylamine (with the alkyl radical corresponding to the radical Ris   desired) or methionine, under the coupling conditions described above.   27 - Preparation process according to any one of claims 25 or 26,   characterized in that G. represents a protecting group of an amino function selected from benzyloxycarbonyl radicals, tert. butoxycarbonyl or vinyloxycarbonyl.   28 - Preparation process according to any one of claims 25 or 26,   characterized in that the reaction of the products (VII) with the compounds of the general formula (IIb) is carried out in the presence of a condensing agent, and optionally in the presence of an activating agent. 28, characterized in that the agent of   condensation is selected from 1-ethyl-3- [3-hydrochloride]   (1,2-dimethylamino) propyl] carbodiimide, benzotriazol-1-oxytris (dimethylamino) phosphonium-1-dicyclohexylcarbodiimide or hexafluorophosphate, - Process for the preparation according to claim 28, characterized in that the activating agent is hydroxybenzotriazole   31 - Preparation process according to any one of claims 25 or 26,   characterized in that the compounds of general formula (VI) used in which R3, R7, R8 and G1 are defined as above and X represents an oxygen atom are obtained from the compounds of general formula (VIII): HN -gl R3 R7 X R8 (VIII)   in which R3, R7, R8, X and G, are defined as previously, by action of a base, followed by carboxylation, the compounds of general formula (VIII) wherein R3, R7, R8, X and G, are defined as previously obtainable from compounds of general formula (IX): R R 7 XR (LX)   in which R3, R7, R8, X 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 32 - Preparation process according to claim 31, characterized in what the base   used is an alkali metal salt.   33 - Process for the preparation of the compounds of general formula (IIa) according to claim 24 wherein R3, RF, Rs, R6, R7, R8 are as defined in general formula (fia), X represents a radical S (O) I with 1 defined as in general formula (I), and G1 represents a hydrogen atom, characterized in that one proceeds from compounds of general formula (X) R3 I R7 R RX) O <6x 0 N, R R4- R "RI (X)   in which R3, R4, R5, R6, R7, R8, X are as defined above, by the action of an ammonia salt, in the presence of sodium cyanoborohydride, the products of general formula (X) being obtainable at from compounds of general formula (XI) o R3, R7 } XR8 COOH (XI)   wherein R3, R7, R8, X are as previously defined, by action of   compounds of general formula (VII), operating according to the conditions of amidification.   34 - Preparation process according to claim 33 characterized in that the   amidification conditions are as claimed in any of the claims 28, 29 or 30.   - Preparation process according to claim 33, characterized in that the compounds of general formula (XI) implemented wherein R3, R ,, RN are defined as above, X represents a radical S (O) I with I = 1 or 2 are obtained from compounds of general formula (XI) in which X represents a sulfur atom, by oxidation, the compounds of general formula (XI) in which R3, R7 and R8 are as defined above and X represents a sulfur atom, obtainable from the compounds of general formula (XII) wherein R3, R7 and R8 are as defined above and X represents a sulfur atom by action of an acid, and the compounds of general formula (XII) obtainable from compounds of general formula (XIII) R3 SH COOH (XIII)   by the action of the corresponding acid (Hal) -C2H4 (R7) (Rs) -COOH, for which R7, Rs are defined as above 36 - Preparation process according to Claim 35, characterized in that the oxidation is carried out by action of oxygenated water in an organic acid, or by action of a peracid, such as m-chloroperbenzoic acid, in an organic solvent 37 - Process for the preparation of the compounds of general formula (I) according to one of   any of claims 1 to 11, wherein R1, R2, R3, R4 R1, R6, R7, R8 and X   are as defined in general formula (I), characterized in that one proceeds from the product of general formula (XIV) - tR Ri R7 XR8 O OH (XIV),   in which R1, R1, R3, R7, R8 and X are defined as above, by the action of a compound of general formula (VII) HN / R6 R4 R5 (VII),   in which R4, R5, R6 are as defined above, by operating according to the amidation methods, the acids of general formula (XIV) in which R1, R2, R3, R7, R8, X are defined as previously obtainable from the corresponding esters of general formula (XV): R2.N / RI R3 R7 XR8 O OR (XV)   in which R 1, R 2, R 3, R 7, R 6, X are defined as above and R represents an alkyl radical, preferably methyl, by saponification 38. Preparation process according to claim 37, characterized in that the   amidification conditions are as claimed in any of the claims 28, 29 or 30.   39 - Compounds of general formula (XIV) R2N CRI R3 R? X R8 O OH (XIV)   in which R1, R2, R3, R4, R6, R6, R7, R8 and X are defined as in general formula (I) - Process for the preparation of compounds of general formula (XV) according to claim 37 in which R2, R3, R7 , Rs, X, R are defined as in general formula (XV) and Rl represents the radical -CO-CH (NH2) -CH2SH, characterized in that one proceeds from compounds of general formula (XVI) NH, -xvi I R, R34XR8 O OR (XVI)   in which R, R3, R7, R8 and X are defined as above, by the action of a reagent of general formula HO2C-CH (NHG2) -CH2SG3 (III),   in which G. and G3 are defined as in claim 19, under the conditions of claim 12.   41. Process for the preparation of the compounds of general formula (XV) according to claim 37, in which R 1, R 3, R 7, R 8, X, R are defined as in general formula (XV) and R 1 represents the radical -CH 2 -CH ( NH, CH2SH, characterized in that   that one proceeds from compounds of general formula (XVI) in which R, R3.   R-, R8 and X are defined as above by the action of a reagent of general formula H O SG3 NHG. 1).   in which G2 and G3 are defined as in claim 19. under the conditions dz claim 1'3.   42 - Process for the preparation of the compounds of general formula (XV) according to claim 37 wherein R2, R3, R7, R8, X, R are defined as in general formula (XV) and RI represents a radical of formula R1, Ril characterized in that one proceeds from compounds of general formula (XVI) wherein R, R3, R7, R8 and X are defined as previously by action of a reagent of general formula R1 o- -   R 1 (V) for which R 1 and R 2 are defined as in general formula (I), under the conditions * of claim 14.   43 - Preparation process according to any one of claims 40 to 42 of the   compounds of general formula (XV) in which R2, R3, R7, R8, X, R are defined as in claim 37, characterized in that the esters of general formula (XVI) used are obtained from the corresponding acids of general formula (VI): HN-Gl R R- R CO, H VI)   in which R3. R. R 1 and X are defined as above and G represents a protecting group of the amino function. by esterification and protection of ammo group.   44 - Pharmaceutical composition containing at least one product of general formula (I) in combination with one or more pharmaceutically acceptable diluents or adjuvants   acceptable whether inert or biologically active.   Use of Compounds of General Formula (I) for the Preparation of Pharmaceutical Compositions for the Treatment and / or Prevention of Pathological Conditions Associated with Cellular Signaling Pathways   farnesyl transferase, or their consequences or symptoms.   46 - Use of the compounds of general formula (I) according to the invention for the preparation of pharmaceutical compositions useful for inhibiting famresvle transferase. 47 - 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 proliferations.   48 - Use of the compounds of general formula (I) according to the invention for the   preparation of pharmaceutical compositions useful for the treatment of cancers.   49 - Association of a product of general formula (I) with one or more compatible and pharmacologically active compounds and / or radiotherapy treatment so   to obtain a synergistic therapeutic effect.