CA2241788C - Novel n-(arylsulphonyl)amino acid derivatives, their preparation process and pharmaceutical compositions containing them - Google Patents

Abstract

Compounds of formula (I), wherein R1 to R9, R16 and R17 are as defined in claim 1, are disclosed. The compounds are pharmacologically active.

Description

NOVEL DERIVATIVES OF N- (ARYLSULFONYL) AMINOACIDES, THEIR
PROCESS FOR PREPARATION AND COMPOSITIONS
PHARMACEUTICALS CONTAINING
The subject of the present invention is new derivatives of N- (arylsulfonyl) amino acids, their preparation, the compositions pharmaceuticals container.
These compounds have an affinity for the bradykinin receptors (BK). Bradykinin is a nonapeptide belonging as the decapeptide kallidine to the class of kinins and which shows a physiological activity in the cardiovascular field and as a mediator in inflammation and pain. We distinguishes several receptors for bradykinin: the B1 and B receptors (D.
Regoli et al., Pharmacol. Rev., 1980, 32, 1-46). Specifically, B2 receivers are receptors for bradykinin and kallidin: they are predominant and is the normally found in most tissues; the Bl receivers are the receptors specific for [des-Arg9] bradykinin and [des-ArglO] kallidine: they are induced during inflammatory processes.
The bradykinin receptors have been cloned for different species, especially for the human species: B1 receptor: JG Menke et al.,). Biol.
Chem., 1994, 269 (34) 21583-21586; B2 receiver: JF Hess, Biochem.
Biophys.
Res. Commun., 1992, 184, 260-268.
Reviews: Drug News and Perspectives, 1994, 7 (10), 603-611 and Exp. Opin.
Ther. Patents, 1995, 5 (4), 331-340, review the antagonists of receptors of bradykinin. Many antagonists described oht structures peptide.
As antagonists of the bradykinin receptors, mention may be made in especially the HOE-140 (F.1 Hock, Brit J. Pharmacol 1991, 102, 769-773) for the receptor and [des-Arg9, LeuBJ bradykinin for the B1 receptor (MN Perkins et al., Bread.
1993, 53, 191-197). Recently a non structural B2 receptor antagonist Peptide SR 173657 has been described in Archiv Pharmacol., 1996, Suppl. 1 {4), R6.
According to the present invention, a new family of compounds with affinity for the bradykinin receptors, it is acts of N- (arylsulfonyl) amino acid derivatives.
Of the N- (arylsulfonyl) amino acid derivatives, some are known and present different pharmacological activities. Thus compounds to activity antithrombotic are described. in patents or patent applications European

2 EP 558 961, EP 236 163, EP 236 164, German DD 155 954, DE 4 tl ~ 468.
WO 9 216 549. In this field of activity, NAPAP, derived from N-(naphthylsulfonyl) glycine of formula '' i se r ~ x-cx ~ -co-NH- ~ ~ -co N

N ~ AP y ~ 't ... ~
~ o NH
is described in Pharmazie, 1987, 42 (5), 346.
In addition, N-tosyl-alanine derivatives of the formula at ~. SOZ NH-CH2-CH2-CO-H-CONIb CHZ

20 c in which a and b together with the nitrogen atom to which they are bound constitute a such as piperidine, pyrrolidine or morpholine, are described in Pharmazie, 1984, 39 (5), 315-317.
Similarly, N- (arylsulfonyl) proline derivatives have been cited as inhibitors of thrombin in Pharmazie, 1986, 4i (4), 233-235 and Pharmazie, 1987, 42 (2), 114-116.
Furthermore, patent application EP 614 911 describes compounds of formula Rt Ru - ~ N-Q3 Ari SOZ-NC-CO NH-CH-CFI2 ~ ~ C 2 CHR'n Cp ~ _Zj_Q ~ _ Qz r1 ~ uRtv

3 in which particular ArI represents a naphthyl, a phenyl, a quinolyl, an isoquinolyl, optionally substituted;
Arli represents an optionally substituted phenyl or thienyl;
- RI, RII, R'II represent independently of one another H or (C1-C4) alkyl ;
- or RI represents nothing and N is linked to ArII and possibly RII and R 'II
form a double bond;
or R1 or R14 is linked to ArII and is (C1-C3) alkylene;
- RIII and RIV identical or different represent H, (C 1 -C 4) alkyl or form with the nitrogen atom to which they are bonded a (CS - C -) heterocycle;
Z1 represents a (C1-C12) alkylene;
Q1 represents methyl, amino, (C1-C6) alkoxycarbonylamino, (C1-C4) alkylamino, di (C1-C4) alkylamino, pyrrolidinyl, piperidino, morpholino, piperazinyl, (C1-C4) alkyl-4-piperazinyl, amidino, (C1-C4) alkylamidino, guanidino, (C1-C4) alkylguanidino, pyridyl, imidazolyl, pyrimidinyl, indolyl, hydroxy, (C1-C4) alkoxy, (C2-C8) alkoxycarbonyl, amino (C1-C4) alkyl-N- (Cl-) C4) alkylamino, carbamoyl or optionally substituted phenyl;
- Q2 represents H or (C1-C6) alkyl;
Q3 represents H or (C1-C4) alkyl or Q1 and Q3 are linked to form a heterocycle and together represent (C2-C8) alkylene while Z1 does not represent nothing, in the form of pure enantiomers or their mixtures in proportions any;
as well as their salts with acids.
These compounds have affinity for neuropeptide biological receptors Y.
According to the present invention, new compounds have now been found unexpectedly having an affinity for bradykinin.
The subject of the present invention is compounds of formula * *
Rt-SOZ ~ -CH-CH-CO ~ -ÇRyCONR4R5 RsRz R. ' RIC
I (I) VS

4 in which:
R 1 represents a phenyl, a naphthyl, a tetrahydronaphthyl, a quinolyl, or isoquinolyl, said rings being unsubstituted or substituted one or several times by R10;
R2 represents an unsubstituted or substituted phenyl one or more times by R11, unsubstituted or substituted phenyl (C1-C4) alkyl one or more phenyl with R11, an unsubstituted or substituted naphthyl or several times with R11, or unsubstituted or substituted cyclohexyl several times by R11;
- or R2 and R9 are bonded together and constitute a (C3-CS) non-alkylene substituted or substituted by R12 or a (C2-C4) alkylene interrupted by an oxygen atom or a sulfur atom and unsubstituted or substituted with R12;
- or RZ and R9 together with the carbon atom and the nitrogen atom to which they are bound constitute unsubstituted or substituted tetrahydroisoquinoline one or several times with a halogen, a hydroxy, a (C1-C4) alkyl, a (C1-Cç) alkoxy, or benzyloxy;
- R3 represents hydrogen or a hydroxy;
R4 and RS each independently represent hydrogen or a (C1-C4) alkyl;
- or R4 and R5 together with the nitrogen atom to which they are attached a heterocyclic radical chosen from pyrrolidin-1-yl, piperid-1-yl, perhydroazepin-1-yl, morpholin-4-yl, 4-oxopiperid-1-yl, dihydropyrro-1-yl and dihydroimidazol-2-yl, wherein said heterocycle radicals are unsubstituted or substituted one or more times with R13;
- Rg represents hydrogen or optionally represents a non-benzyl substituted or substituted on the phenyl one or more times by R13 or a ZR14 group when R7 is hydrogen;
- R7 represents hydrogen or a (C1-C6alkyl;
- Rg represents hydrogen; an unsubstituted or substituted benzyl on the phenyl one or more times with R13; or a group ZR14;

4a - or R7 and Rg together with the nitrogen atom to which they are attached a heterocyclic radical chosen from pyrrolidin-1-yl and piperid-1-yl perhydroazepin-1-yl, morpholin-4-yl, tetrahydropyrimidin-2-yl, piperazin-1 yle and piperazin-1-yl substituted in the 4-position by a (C1-C4) alkyl or a benzyl;
- or, when R7 is hydrogen, Rg and Rg are optionally linked together to form an unsubstituted or substituted (C2-C4) alkylene one or more once with a (C1-C4) alkyl;
R 9 represents hydrogen, a (C 1 -C 4) alkyl or a phenyl (C 1 -C 4) alkyl n substituted or substituted on the phenyl one or more times with R11;
R 1p represents a halogen, a (C 1 -C 4) alkyl, a (C 1 -C 4) alkoxy, a hydroxy, an amino, a (C1-C4) alkylamino or a di (C1-C4) alkylamino;

WO 97/25315

5 PCT / FR97100026 R11 -represents a halogen, a (C 1 -C 4) alkyl, a trifluoromethyl, a phenyl, hydroxy, a (C 1 -C 4) alkoxy or benzyloxy;
or R11 is in the ortho position of the phenyl representing R2 and forms with R3 a methylene group or an ethylene group;
or R11 is in the ortho position of the phenyl representing R2 and forms with R9 a methylene group or an ethylene group;
R12 represents a halogen, a (C1-C4) alkyl, a hydroxy, a (C1-C4) alkoxy, benzyloxy, oxo, phenyl, acetyloxy or trifluoroacetyloxy;
- R13 represents a (C1-C4) alkyl, halogen or hydroxy;
R14 represents a methyl, an amino, a (C1-C4) alkylamino, a di (C1-C4) alkylamino, tri (C1-C4) alkylammonium, amidino, (C1-C6) alkylamidino, a guanidino, a (C 1 -C 4) alkylguanidino, a hydroxy, a (C 1 -C 4) alkoxy, a (C1-C4) alkoxycarbonyl, an -AlkN (R15) Alk'N (R '15) 2 - group or a radical heterocyclic selected from pyrrolidin-1-yl, piperidin-1-yl, perhydroazepine yl, pyridyl, imidazolyl, dihydroimidazolyl, imidazolidinyl, pyrimidinyl, and indolyl;
- R 15 and R '15 represent independently of each other hydrogen or a (C 1-C4) alkyl;
R 16 represents hydrogen or methyl, or R 16 forms with R9 a group methylene;
- R 1 ~ represents hydrogen or methyl;
Alk and Alk 'independently of one another represent (C1-Crl) alkylene;
Z represents a (C2-C12) alkylene or a (C1-C6) alkylene interrupted or substituted by a (C 5 -C) cycloalkyl or phenyl;
- C * represents an asymmetric carbon atom;
as well as their salts with mineral or organic acids.
The salts are generally prepared with pharmaceutically acceptable acids acceptable but the salts of other acids useful for purification or isolation of compounds of formula (I) are also part of the invention. Salts of compounds of pharmaceutically acceptable formula (I) are, for example, hydrochloride, the hydrobromide, sulphate, methanesulphonate, benzenesulphonate, naphthalenesulphonate, maleate, fumarate, citrate, acetate, gluconate, the dobesilate, or sultosilate.
The compounds of formula (I) comprise 2 asymmetric carbon atoms (or possibly more) and the 4 (or possibly more) pure enantiomers so that their mixing in any proportions are objects of the invention.

WO 97/25315

6 PCT / FR97 / 00026 Halogen means chlorine, fluorine, bromine, iodine; chlorine and fluorine being preferred.
Alkyl, alkylene or alkoxy means an alkyl radical, a alkylene radical or a linear or branched alkoxy radical respectively.
Compounds of formula (I) in which in which RI represents a phenyl, a naphthyl, a tetrahydronaphthyl, a quinolyl, a isoquinolyl, said rings being unsubstituted or substituted one or several times P ~ RIO;
R2 represents an unsubstituted or substituted phenyl one or more times by RI1, a phenyl (C1-C4) alkyl unsubstituted or substituted one or more times sure phenyl by R 11 or unsubstituted or substituted naphthyl many times by RI l;
- or R2 and R9 are bonded together and constitute a (C3-C5) non-alkylene substituted or substituted by R I2 or a (C2-C4) alkylene interrupted by an oxygen atom or a sulfur atom and unsubstituted or substituted with R I2;
- or R2 and R9 together with the carbon atom and the nitrogen atom to which they are bound constitute unsubstituted or substituted tetrahydroisoquinoline one or several times with a halogen, a hydroxy, a (C 1 -C 4) alkyl, a (C 1 -C 4).
) alkoxy or benzyloxy;
- R3 represents hydrogen or hydroxy;
R4 and R5 each independently represent hydrogen or a (C1-C4) alkyl;
- or R4 and R5 together with the nitrogen atom to which they are attached constitute a heterocyclic radical chosen from pyrrolidin-1-yl, piperoyl-1-yl, perhydroazepin-1-yl, morpho-4-yl, 4-oxopiperid-1-yl, said radicals heterocyclics being unsubstituted or substituted with R 13;
- R6 represents hydrogen, R6 can also represent Rg when R ~ is hydrogen;
- R ~ represents hydrogen or a (C 1 -C 4) alkyl;
- Rg represents hydrogen; an unsubstituted or substituted benzyl on the phenyl one or more times by R13; or a group ZR14;
- or R ~ and Rg together with the nitrogen atom to which they are attached a heterocyclic radical chosen from: pyrrolidin-1-yl, piperid-1-yl, perhydroazepin-1-yl, morpholin-4-yl, piperazin-1-yl or piperazin-1-yl substituted at the 4-position by a (C 1 -C 4) alkyl or benzyl;

WO 97/25315

7 PCT / FR97 / 00026 or where R ~ is hydrogen, R6 and Rg are bonded together to form a (C2 C4) alkylene unsubstituted or substituted one or more times with a (C1-C4) alkyl;
R9 represents hydrogen, a (C1-C4) alkyl or a phenyl (C1-C4) alkyl non substituted or substituted on the phenyl one or more times with R11;
R10 represents a halogen, a (C1-C4) alkyl, a (C1-C4) alkoxy, a hydroxy, an amino, a (C1-C4) alkylamino or a di (C1-C4) alkylamino;
R11 represents a halogen, a (C1-C4) alkyl, a hydroxy, a (C1-C4) alkoxy or benzyloxy;
R12 represents a halogen, a (C1-C4) alkyl, a hydroxy, a (C1-C4) alkoxy, benzyloxy, oxo or phenyl;
R13 is (C1-C4) alkyl, halogen or hydroxy;
RLQ. represents a methyl, an amino, a (C1-C4) alkylamino, a di (Cl-C ~) alkylamino, tri (C1-C4) alkylammonium, amidino, (C1-C4) alkylamidino, a guanidino, a (C1-C4) alkylguanidino, a hydroxy, a (C1-C4) alkoxy, a (C1-C4) alkoxycarbonyl, a group -AIkN (R15) Alk'N (R '15) 2> or a radical heterocyclic selected from pyrrolidin-1-yl, piperidin-1-yl, perhydroazepine yl, pyridyl, imidazolyl, dihydroimidazolyl, imidazolidinyl, pyrimidinyl, and indolyl;
- R 15 and R '15 represent independently of each other hydrogen or a {C 1-C4) alkyl;
- R16 represents hydrogen;
- R 1 ~ represents hydrogen;
Alk and Alk 'independently of one another represent (C1-C4) alkylene;
Z represents a (C2-C12) alkylene or a (C1-C6) alkylene interrupted or substituted by a (CS-C) cycloalkyl or phenyl;
as well as their salts with mineral or organic acids.
Some substituent values are preferred. So we prefer compounds of formula (I) that meets at least one of the following conditions -R1 represents naphthyl, quinolyl or trichlorophenyl; RZ, R3, R4, R ~, R6, R6, RA, R6, R6 and R1 being as defined above for formula I;
b -R2 represents a phenyl which is unsubstituted or substituted by R11; R ,, R3, R4, R5, R ~ ,.
R ~, RR, R9, R6 and R ~~ being as defined above for formula I;
-NR4R5 represents a pyrrolidin-1-yl group; RE, R2, R3, R6, R6, R8, R9, Ris and R 1 ~ being as defined above for formula I;

oh d -C (NR6) NR ~ Rg represents a 4,5-dihydroimidazol-2-yl; R1, R2, R3, R4, Rs, R9, R6 and R17 being as defined above for formula I;
e-R3 = R9 = R16 = R1 = H; R1, R2, R4, RS. Rb, R ~ and Rg being such that defined above for formula I, as well as their salts with mineral or organic acids.
According to the invention, compounds of formula R, -sot-rrH-çH-cH2-corrl- ~ çH-coN ~~
"2a (Ia) C ~ ~
there in which R2a represents an unsubstituted or substituted phenyl in the meta or para by RII; a naphth-1-yl or a naphth-2-yl;
R1, R6, R6, R8 and R11 are as defined above for (I);
as well as their salts with mineral or organic acids.
In particular, compounds of formula SOZ-NH-CH-CON-CH-CON
.I ~
CHZ
(Ha) NOT
NOT
H
in Iaquehe Rla represents a naphth-I-yl, a naphth-2-yl, a 2,4,6-trichlorophenyl or one quinolin-2-yl;
R2a is as defined above for (Ia);
as well as their salts with mineral or organic acids.

More particularly, the compounds of formula (I 'a) in which R2a is phenyl which is unsubstituted or substituted in the meta or positional position para by R11.
In particular, the compounds of formula (I), (Ia) or (I'a) showing isomerism (R, R) on carbon atoms marked C *.
In the description and in the claims the abbreviations are used following:
Me: methyl And: ethyl iPr: isopropyl nBuOH: n-butanol iPrOH: isopropanol EtOH: ethanol MeOH: methanol Et20: ether: diethyl ether DMF: dimethylformamide DCM: dichloromethane THF: tetrahydrofuran AcOH: acetic acid 2 fl AcOEt: ethyl acetate DIPEA: Isopropylethylalmin DMAP: 4-dimethylaminopyridine DCC: 1,3-dicyclohexylcarbodimide DCU: dicyclohexylurea NSuOH: N-hydroxysuccinimide NSu: succinimido NBS: N-bromosuccinimide Fmoc: Fluorenylmethoxycarbonyl Boc: serves-butoxycarbonyl (Boc) 20: Ditertiobutyl bicarbonate NEt3: triethylamine Bn: benzyl Pd / C: palladium on charcoal Sephadex ~ LH 20: marketed by PHARMACIA
Sephadex ~ G 25: marketed by PHARMACIA
Alcalase: subtilisin Carlsberg, marketed by NOVO (Denmark) Penicillin Amidase: Penicillin amidohydrolase, marketed by Sigma BOP: benzotriazol-1-yloxytris hexafluorophosphate (dimethylamino) phosphonium K2C03: potassium carbonate K2S04: potassium sulphate KHS04: potassium hydrogen sulphate KHSO4 / K2SO4: solution of 16.66 g of KHSO4 and 32.32 g of K2SO4 in 1 liter water NaCl: sodium chloride Na2S04: sodium sulfate MgSO4: magnesium sulfate NaOH: soda NH40H: ammonia HCI. hydrochloric acid TFA: trifluoroacetic acid hydrochloric ether: saturated solution of hydrochloric gas in ether diethyl mPa. s: milli Pascal / second F: melting point TA: room temperature NMR: nuclear magnetic resonance DMSO: dimethyl sulfoxide

8: chemical shift s: singlet; it is: widened singlet; sd: split singlet; d: doublet;
dd: double doublet; t: triplet; te: expanded triplet; qd: quadruplet;
qt: quintuplet; mt: multiplet; m: massive The subject of the present invention is also the process for the preparation of compounds of formula (I) and their salts. This process, called method 1, is characterized in that a compound of formula R 1-SOZ-N-CH-CH-CON-CRI ~ -CONR4R5 i ~ Rz ~ R16 ~ (II) _ ï
CN
wherein R1, R2, R3, R4, R5, R9, R16, R17 and C * have the definitions data above for (I), in the form of a pure enantiomer or a mixture of isomers in any proportions, with an alcohol of formula R-OH in which R
represents a (C 1 -C 4) alkyl, in acidic medium, to form an imidate intermediate on which an amine of formula HNR7Rg (III) or a diamine of H2NR6R8NH2 formula (IV) in which R6, R7, Rg have the given definitions above for (I);
b1) the compound of formula (I) thus obtained is isolated in the form of a base or salt, cl) where appropriate, another salt of the compound of formula (I) is prepared.
Numerous methods for the synthesis of amidines are described in the book "The chemistry of anesthetics and imidates", DG Neilson, Ed. Saul Pat ~ i, Wiley years Sounds, 1975, 389-394. The preparation of certain amidines is described precisely in the patent application EP 614 911 A.
The formation of the imidate is preferably carried out in a strong acid medium, while imidoester in the form of a free base or in the form of salt, is react with amine (III) or diamine (IV) in an inert polar solvent, for example a alcohol, at a temperature between 0 ° C and the temperature of reflux of the solvent.
The amine intermediate is reacted with an amine whose formula depends on of that of the compound (I) that we want to obtain. To prepare a compound of formula (I) wherein R6 = H, an amine HNR-RB is reacted; to prepare a compound of formula (I) in which R6 = Rg and R = H, two moles of a amine of formula H ~ NRs per mole of imidate; to prepare a compound of formula (I) in which R; is hydrogen and R6 and Rg are bonded together to form a (C ~ -C4) alkylene unsubstituted or substituted one or more times with alkyl, made act a diamine of formula H, NR ~ RANH ~.
Most amines (III) and diamines (IV) are known and the products can be prepared by applying principles and methods known of the skilled person. For example, for derivatives in which R14 is a imidazolyl, reference is made to US Pat. No. 3,881,016 and to Synth.
Communion. 1987, 17 (21), 223-227.
The compounds of formula (I) in which R14 represents NH2 or alkylamino can be prepared by hydrolysis of the compounds of formula (I) in which contains a t-butoxycarbonylamino group, itself obtained according to Synth.
Common. 1990, 20 (16), 2559-2564.
The compounds of formula (I) in which R14 represents a guanidino group, substituted or not, by action on the compound of formula (I) in which R14 = NH2, of a compound of formula HZN-CY
NT
wherein T is H or (C 1 -C 4) alkyl and Y is a nucleofuge, such as S03H, for example, aminoiminomethanesulfonic acid (under the conditions described in Tetrahedron Letters, 1988, 3183-3186) or N-methylaminoiminomethanesulfonic acid (obtained according to the method described in J.
Org.
Chem. 1986, 51 (10), 1882).
The action of an amine (III) of formula H2NRg in excess on the resulting imidate of the reaction of ROH on a compound of formula (II) leads to the formation a mixture of 2 compounds of formula (I): for one R6 = R7 = H and for the other = R8 and R7 = H.
Compounds of formula (I) in which R6 and Rg together form a C2-C4) alkylene unsubstituted or substituted one or more times with a (C1-C4) alkyl can be prepared in a manner known per se, by the action of a diamine H2N-R6Rg-NH2 on the imidoester or possibly by action of the same diamine one of whose functions is protected by a labile group (such as Boc or Fmoc for example) which will be eliminated before cyclization.
The compounds of formula (I) in which R 14 represents a dihydroimidazole by the action of an alcohol in an acid medium on a compound of formula:

R 1-SOZ-N-CH-CH-CON-CR1 ~ -CONR4R5 C ~ i ~ Rz ~ R16 Hz (II ') C ~ ~~
NH NH
Z
CN
to form an intermediate imidate, which is reacted on an amine appropriate by the usual methods.
The nitriles of formula (II) are prepared using the methods classics of peptide chemistry, for example those described in The Peptides Ed. E.
Gross and J. Meienhofer, Academic Press, 1979, 1, 65-104. Known methods allow to perform peptide couplings without racemization of atoms of carbon of each constituent amino acid; in addition, the (3-alanines ~ i-substituted for which the chiral carbon is not adjacent to the carboxyl group are deemed not to not to be racemized {Ann. Rev. Biochem., 1986, 55, 855-878). By elsewhere, the Patent Application EP 236,163 describes methods for preserving the chirality of each amino acid.
In general, the coupling reactions between the 2 amino acids take place at temperatures between 0 ° C and 40 ° C in an inert solvent such as dichloromethane, acetonitrile, tetrahydrofuran or dimethylformamide, in presence of a coupling agent and at least one equivalent of an amine tertiary such as triethylamine, N-ethylmorpholine or diisopropylethylamine.
Thus, the preparation of a nitrile of formula (II) can be carried out according to one of synthetic routes below.

FIGURE 1: Path 1 RISOzN-ÇH-ÇH-COzH + HNRIS- 'R ~~ -CONR4R5 ~ Rz ~ ~ z (VI) CN
coupling ' FIGURE 2: Path 2 *
BOC-N-CHH-COzH + HNRts ~ RI ~ CONRaRs (~ ~ '~ (~) . ~
'-'-' Boc- ~ - i, H- ~ H-CONR16- 'RyCONR4R5 _ g ~~ ~ C ~ (~) CN
TFA
- =, H- ~ - i H-ÇH-CONR ~ s-ÇR ~~ -CONR4Rs g ~ Rz ~ ~ z (I7 ~
2) R1S ~ 1 {~~ CIV

To prepare a compound of formula (V), useful in route 1, the radical R, SO
is introduced in a conventional manner by the action of a sulfonyl halide of formula R ~ SOZHaI wherein R, is as defined above for (I) and Hal represents a halogen, preferably chlorine, on a compound of formula HN-CH-CH-COOR ' i ~ RZ
in which R2, R ~, R9 have the meanings given above for (/ j and R ' represents hydrogen or a (C 1 -C 4) alkyl It is also possible to prepare a compound of formula (V) in which R3 is hydrogen in 2 steps: firstly a compound of formula YN- ~ H-COOR '(Va) ~ R2 where Y represents R1SO2 or a protecting group such as Boc or Fmoc, then we extend the carbon chain of an atom using methods known then if necessary we eliminate the protecting group and react a halide of sulfonyl of formula R1 S02Ha1 and finally the group R 'is eliminated if it is different from H.
This procedure is suitable for example when R2 and R9 are linked together and constitute a (C3-C5) alkylene unsubstituted or substituted by R12 or a C2-Cq alkylene interrupted by an oxygen atom or a non-sulfur atom substituted or substituted one or more times with R 12.
The sulfonyl halides are known or prepared by methods known.
The compounds of formula (VI) are prepared by the action of an amine HNR4R5 on an amino acid of formula NHR ~ 6-ÇR 1 oCOOH

i CN
in which the amine is protected, for example by a Boc or Fmoc group, followed by removal of the protecting group.

In the reaction sequence of lane 2, the amine is deprotected in medium acid (TFA) and the radical R ~ SOz is conventionally introduced by a sulfonyl halide of formula: R, S02Ha1 wherein R1 is such that defined above above for (I) and Hal represents halogen, preferably chlorine.
In both lane 1 and lane 2, the introduction of the RiSOZ group is performed in the presence of a base, possibly in biphasic medium, in presence a phase transfer catalyst.
A substituent Rg can be introduced on a compound of formula (II) in which Rg = H by. known methods, for example by the action of a halide of formula R9Hal, in which Hal represents a halogen atom example the chlorine.
The compounds of formula (II) wherein Rg and R16 together form a methylene group are prepared by the action of paraformaldehyde on compounds of formula (II) wherein Rg = R16 = H.
The compounds of formula (II) are new and constitute a further aspect of the present invention.
Certain compounds of formula (V), derived from toluenesulfonamide or from phenylsulfonamide have been described in the following publications Tetrahedron, 1993, 49 (48), 11329-11340;
Centralblatt, 1929, II, 1398;
J. Org. Chem., 1978, 43 (23), 4.4.38-4441;
J. Org. Chem., 1966, 31 (7), 2385-2386.
Some other compounds of formula:

RgR2 R3 wherein R 1 represents a phenyl, a naphthyl, a tetrahydronaphthyl, a quinolyl or isoquinolyl, said rings being unsubstituted or substituted one or more times by R10 as defined for (I), provided that R1 does not does not represent p-toylyle; and R2, Rg, Rg and C * are as defined for (I), Being heard that 16a when R1 represents phenyl and R3 represents hydrogen, then R2 and Rg together with the carbon and nitrogen atoms to which they are linked, do not represent neither pyrrolidinyl nor 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolyl, are new and part of the invention.
According to a preferred embodiment of the invention, in this formula V, R1 represents naphthyl, quinolyl or trichlorophenyl and R3 represents a hydrogen atom.

WO 97/25315 l 7 PCTIFR97 / 00026 To prepare a compound of formula (I) wherein Rg and R11 together form a methylene or ethylene group, a beta is first prepared amino acid of formula (XIII) H- i ~ H ~ H-COOH
(XIII) wherein R 8 and R 11 form a methylene or ethylene group using known methods, for example that described in J. Org. Chem., 1987, 52, 616-622.
To prepare a beta-amino acid of formula (XIII) in which R3 and RI1 together form a methylene or ethylene group, methods are used known. Thus, the methyl ester of 1-aminoindan-2-carboxylic acid in 3 steps from indan-1-one: according to J. Med. Chem.

650, the action of methyl carbonate in the presence of sodium hydride to obtain the methyl ester of (1-oxo) indan-2-carboxylic acid, then, according to J.
Heterocycl. Chem. 1974, 11, 982, the methyl ester of the acid is prepared hydroxyiminoindan-2-carboxylic acid, finally the hydroxylamine is reduced to amine in presence of a catalyst.
1-Amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid can be prepared following the method described in J. Chromatogr. , 1994, 676, 297-302.
Alternatively according to another method, when the amidine group C (= NR6) NR7Rg does not include a function that can react in a step under the conditions of the peptide coupling, it is possible to prepare a derivative of amino acid having the amidine group from the corresponding derivative with a cyano group, and then perform the necessary couplings for obtain a compound according to the invention.
Thus, according to a later aspect, the subject of the present invention is another process for the preparation of a compound of formula (I), referred to as the process characterized in that a2) a compound of formula WO 97125315 I g PCT / FR97 / 00026 ~~ ~ XNR -CR1 -CONR4R5 (VIa) iy ,, CN
wherein X is hydrogen or a group Boc and R4, RS and C * are like as defined for (I), in the form of a pure enantiomer or a mixture isomers in any proportions, with an alcohol of formula R-OH in which R
represents a (C 1 -C 4) alkyl, in acidic medium, to form an imidate intermediate on which an amine of formula HNR ~ Rg (III) or a diamine of H2NR6RgNH2 formula (IV) in which R6, R ~, Rg have the given definitions above for (I) b2) the coupling of the compound thus obtained of formula HNR ~ 6-CRl ~ -CONR4R5 ò ~ NR6 VS' RRA ~
- with a compound of formula Pr-N-CH-CH-C02H
(XII) ~ R2 wherein R2, R3 and R9 are as defined for (I) and Pr represents a protective group, for example Boc or Fmoc and, after deprotecaion of the amine in an acidic medium, a sulphonyl halide of formula R1 SO2Ha1 wherein R 1 is as defined for (I) and Hal represents a halogen, for example chlorine;
- with a compound of formula Rt SOz-N-Ch-Ch-C02H
!, R9 ~ ~ (V) wherein R1, R2, R3 and R9 are as defined for (I) c2) the compound of formula (I) thus obtained is isolated in the form of a base or salt;
d2) if necessary, another salt of the compound of formula (I) is prepared.
The compounds of formula (VI) and (XI) in optically pure form can be obtained from an ester, for example, the ethyl ester of the 4-Racemic cyanophenylalanine according to the reaction scheme described herein HCI, HzN-CH-COi And CH2 ~ ~ CN
(Boc) 20INEt3 BocNH-G ~ i-C02Et VS
~ Alcaiase ~
CD) 'Boc-NH-CH-C02Et (D) S CH2 ~ ~ CN
NaOH
(I) BocNH-CH COzH ~ D) BocNH-CH-C02H
CHz CN
~ -CN

NSuOHlDCC NSuOH / DCG
(L) (D) BocNH-CH-C02NSu BocNH-CH-COzNSu CHz ~ ~ CN (D) ~ CHZ ~ I CN
bars bars CL) CD) BocNH-CH-CO NRaRs BocNH-CH-CO-NR4Rs CN
(L) g C ~ ~ ~ CN (D} 8 ~ ~ I
TFA TFA
Cl-.) CD) TFA, H2N-CH-CONRaRs TF ~ ~ N-CH-CONR4Rs C ~ ~ ~ CN
(L) (~ ~ ~ CD) (~
1} HCI, ROH 1} HCI, ROH
2) (~) 2} HI '(~) or or ~ z ~ sRs ~ Hz ~ 6ReNHz (L) (D) 2HC1, HzN-CH-CONRaRs 2HC1, HZN-CH-CONRaRs % NR6% NR6 The ethyl ester of racemic 4-cyanophenylalanine is described in patent application EP 614 911 A. The protection of the amine function of this compound is carried out conventionally, by the action of (Boc) 20 in the presence of triethylamine. The action of an enzyme, Alcalase ~, on compound 4 and got allows to selectively hydrolyze the ester function of the amino acid of configuration (L) and thereby isolate each of the compounds 5 and 6 in optically pure form (Synthesis, 1983, 1041-1043).
The compound of configuration (L) is isolated in acid form: (L) 6. The compound of configuration (D) is isolated in the form of an ethyl ester: (D) 5; this last is hydrolyzed by soda to obtain the acid form: (D) 6. Each of the 2 compounds of formula 6 is then treated with N-hydroxysuccinimide in a solvent inert such as DMF or dioxane, in the presence of a coupling agent such as DCC
to obtain a compound of formula 7. The action of an amine HNR4R5, followed by the action of trifluoroacetic acid makes it possible to prepare the compounds of formulas (L) (VI) and (D) (VI); the conventional reactions described below are then carried out on for obtain the desired amidines of formula (L) (XI) and (D) (XI).
Beta-amino acids of formula XIII
H-COOH (XIII) or the corresponding aliphatic esters are known or can be prepared by different methods for example according to J. Am. Chem. , 1936, 58, 299. A
fashion of particular preparation of beta-amino acids consists in carrying out a elongation of chain from an alpha-amino acid according to Tetrahedron, 1994, 50, 9457-or according to J. Chem. Soc. , Perkin Transact. II, 1977, 370.
More specifically, the preparation of certain beta-amino acids of formula (XIV) HAN-CH (R 2) -CH 2 -COOH is described in the publications or patents cited above.
after.

R2 Reference (R, S): commercial (R): Ber. 1910, 43, 2020 (S) J. Org. Chem., 1991, 56, 5883 J. Chem. Soc. Chem. Commun., 1993, 1153 Ct Ct Heterocycles, 1989, 28, 1015 Bull. Soc. Chim. Fr., 1987, 1079 Heterocycles, 1978, 1277-1285 OMe / C ~~ - Tetrahedron, 1987, 43, 3509-3517 Tetrahedron Lett. , 1988, 29, 6465 Heterocycles, 1989, 28, 1015 We J. Agric. Food Chem., 19? 7, 25, 965 OH
Tetrehedron, 1994, 50 (31), 9457-9470 Tetrahedron Lett. , 1990, 3 I, 5153-5156 Compounds (I) in which R2 and R9 are linked together and constitute a C3-CS alkylene unsubstituted or substituted with R 12 are prepared from compounds of formula (XIII) known or prepared by known methods.

To obtain optically pure compounds of formula (XIII) or (XIV), may for example use a menthol ester according to the technique described in Tetrahedron Lett., 1988, 29, 6465-6466; it is also possible to use a salt of quinine or quinidine according to Chem. Ber., 1910, 43, 2020, or the derivative phenylacetamido of the compound of formula (XIV) in racemic form may be used for enzymatic resolution with a penicillin amylase (Synlett, 339). It is also possible to implement enantioselective syntheses Tetrahedron, 1994, 50, 9517; Aldrichimica, Acta, 1994, 27 (1), 3.
To prepare an alpha-hydroxy-beta-amino acid, the method can be used described in Bull. Soc. Chim., France, 1940, 7, 593-603.
The affinity of the compounds according to the invention for the B 1 receptors of the bradykinin was measured on suspensions of MRCS cell membranes in using a technique similar to that described by KH Schneck et al., in Eur. J.
Pharmacol. , 1994, 266, 227-282. In this test, the affinity of [des-Arg9]
bradykinin is between 10-6M and 10-7M, that of [des-Arg 10] kallidine is 2.10-9M;
and the compounds of the invention have an affinity of up to 10-1.
OM.
The affinity of the compounds according to the invention for the B2 receptors of the bradykinin was measured on suspensions of MRCS cell membranes according to a technique similar to that described by DG Sawutz et al., in Eur.
J.
Pharmacol. , 1992, 227, 309-315. In this test, the affinity of bradykinin is close to 10-9M and that of the compounds of the invention varies around 10-6M
or 10-7M.
The toxicity of the compounds according to the invention is compatible with their use therapeutic.
The compounds according to the invention may be useful for the treatment or prevention of many pathologies, in particular pathologies of inflammation, persistent or chronic inflammatory diseases (Drug News and Perspectives, 1994, 10 (7), 603-611). By way of example, mention may be made neurogenic inflammation, pain (Brit J. Pharmacol., 1993, 110, / 93 198}, septic shock, asthma, rheumatoid arthritis, diseases inflammatory joints, burns (Pain, 1993, 53, 191-197), wounds, diseases of respiratory tract, for example rhinitis of viral or allergic origin, the systematic inflammatory response syndrome, edema (Brit J. Pharmacol., 1995, 114, 1005- / 013), angiogenesis (Brit J. Pharmacol., 1993, 109, 14-17), the Infectious Diabetes Type I (Abst.44th International Symp on Kinins, C49, Denver Colorado, Sept. 10-15, 1995) ventricular hypertrophy associated with diabetes, the pulmonary fibrosis and systemic progressive sclerosis, enterocolitis, and more generally all the bradykinin-dependent pathologies.
The compounds according to the invention are generally administered in units of dosage.
The invention also relates to pharmaceutical compositions comprising as the active ingredient one of the enantiomers of the compounds of formula (I), one of their mixture or the salts thereof with a pharmaceutically acid acceptable, as well as an excipient suitable for oral administration, injectable, topical or transdermal. Daily doses are based on the pathology to to treat and the patient.
The present invention also relates to pharmaceutical compositions containing an effective dose of a compound according to the invention or a salt pharmaceutically acceptable and suitable excipients.
Said excipients are chosen according to the pharmaceutical form and the mode desired administration.
In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular intravenous, topical, intratracheal, intranasal, transdermal or rectal, the principles assets of formula (I) above, or their optional salts, may be administered under forms units of administration, in admixture with pharmaceutical carriers animal and human beings for prophylaxis or treatment disorders or diseases above. Unit forms of administration appropriate include oral forms such as tablets, the capsules, powders, granules or oral solutions or suspensions, forms sublingual, oral, intratracheal, intranasal, forms subcutaneous, intramuscular or intravenous administration and of rectal administrations. For topical application, it is possible to use compounds according to the invention in creams, ointments, gels or lotions.
In order to obtain the desired prophylactic or therapeutic effect, the dose of active ingredient may vary between 0.01 and 50 mg per kg of body weight and day.
Each unit dose may contain from 0.5 to 1000 mg preferably from: a to 500 mg of active ingredients in combination with a pharmaceutical carrier. This dose can be administered 1 to 5 times daily to administer a dosage daily from 0.5 to 5000 mg, preferably from 1 to 2500 mg.
When preparing a solid composition in the form of tablets, mix the main active ingredient with a pharmaceutical vehicle such as the gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, a derivative cellulosic material, or other suitable materials or they can be treated of teile so that they have a prolonged or delayed activity and that they release a way continues a predetermined amount of active ingredient.
A preparation in capsules is obtained by mixing the active ingredient with a diluent such as glycol or glycol ester and pouring the resulting mixture in soft or hard capsules.
A preparation in the form of syrup or elixir or for administration under form of drops may contain the active ingredient together with a sweetener, preferably acaloric, methylparaben and propylparaben as antiseptic, as well as an agent giving a taste ~ t and a suitable dye.
Powders or granules dispersible in water may contain the ingredient active ingredient in admixture with dispersants, wetting agents or agents suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.
For rectal administration, suppositories are used which are prepared with binders melting at the rectal temperature, for example butter of cocoa or polyethylene glycols.
For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions that contain dispersing agents and / or pharmacologically wetting agents compatible, for example propylene glycol or butylene glycol.
For a local administration it is possible to use creams, ointments, lotions or gels for example.
For transdermal administration, patches can be used in the form of multilaminate or reservoir in which the active ingredient can be in solution.
The active ingredient can be formulated also in the form of microcapsules, optionally with one or more supports or additives.
The compositions of the present invention may contain, beside products of formula (I) above or one of the pharmaceutically acceptable salts, other active ingredients that may be useful in treating disorders or diseases indicated above.
The following Preparations and Examples illustrate the invention. Except indication contrary the compounds are obtained in the form of a mixture of diastereoisomers.

Nuclear Magnetic Resonance (NMR) spectra are recorded at 200 MHz in deuterated DMSO optionally containing TFA, using the tetramethylsilane as a reference. Chemical shifts are indicated in ppm.
Mass spectra indicate the MH + value PREPARATIONS
Preparation 1.1 1- [2-Amino-3- (4-cyanophenyl) propionyl] pyrrolidine, trifluoroacetate.
4.06 g of 2- [N- (Boc) amino] -3- (4-cyanophenyl) propionic acid is mixed with 1.15 ml of pyrrolidine and 7.5 g of BOP in 20 ml of DMF; we leave under stirring for 2 hours at RT keeping at pH = 7 by addition of NEt3. After Evaporation to dryness, chromatography on silica eluting with the mixture chloroform / methanol (9 / 0.5, v / v). After evaporation of the solvents, the solid obtained is treated with 20 ml of TFA in 20 ml of DCM for 30 minutes at RT.
The solvents are evaporated, taken up in ether and then dried to obtain 3.95 g of product expected.
Preparation 1.2 1- [2-Amino-3- (4- (3.4-dihydro-2-yl) phenyl) propionyl] pyrrolidine, dihydrochloride.
18 g of 1- [2 - ((N-Boe) amino) -3- (4-cyanophenyl) propionyl] pyrrolidine in 90 ml of DCM, added 90 ml of TFA and leave stirring for 40 minutes at RT. After evaporation to dryness, the residue is taken back by DCM then evaporated (2 times). Then taken up with 300 ml of anhydrous ethanol saturated with HCl at 0 ° C. and left for 18 hours at + 4 ° C. The middle is evaporated to dryness, taken up with ethanol, evaporated again, then taken up in DCM and evaporated (2 times). 23 g of intermediate imidate are obtained. The product obtained is dissolved in 1 1 liter of anhydrous ethanol and added in 30 minutes 4.41 g of ethylenediamine in 50 ml of anhydrous ethanol. After stirring for 48 hours at RT, the mixture is concentrated medium and then acidified to pH = 2 by addition of a saturated solution of HCl in methanol. We drain, evaporate to dryness, then take up with ether, drain and dried to obtain 17.4 g of the expected product.
NMR (DMSO + TFA): 1.50-1.80: m: 4H; 2.50-3.60: m: 6H; 4.00: s 4.35: is: 1H; 7.50: d: 2H; 8.15: d: 2H; 8.60: is: 3H; 11.10: s: 2H.
Preparation I.3 1- [2-Amino-3- (4- (N '- [3- (dimethylamino) propyl] amidino) phenyl) propionyl] pyrrolidine, tris-trifluoroacetate.
A) 1- [2-Amino-3- (4- (N ~ - [3- (dimethylamino) propyl] amidino}
phenyl) propionyl] pyrrolidine, trihydrochloride.
809 mg of 1- [2-amino-3- (4-cyanophenyl) propionyl] pyrrolidine are dissolved trifluoroacetate in 50 ml of methanol saturated with hydrochloric acid 0 ° C: and we leave one night in the refrigerator. After evaporation to dryness, the imidate formed is taken back with toluene, then the medium is evaporated and the residue is dried under vacuum on the potash. The product obtained is dissolved in 75 ml of anhydrous methanol and added 570 μl of N- (dimethyl) propane-1,3-diamine dissolved in 15 ml of anhydrous methanol. After stirring for 3 hours at RT, the mixture is evaporated to dryness and then The residue is dissolved in 30 ml of methanol by adding 5 ml of 4N HCl in dioxane and evaporate to dryness.
B) 1- [2- (N-Boc) amino-3- (4- (N1- [3- (dimethylamino) propyl] amidino) phenyl) propionyl] pyrrolidine, dihydrochloride.
The crude product obtained in the previous step is dissolved in 10 ml of dioxane and 10 ml of water. Triethylamine is added to reach pH = 8.3 and then 600 mg of (Boc) and allowed to stir at RT for 15 hours. The middle is diluted by water, washed twice with ether, acidified to pH = 1.5 by addition of 1N HCl then washed DCM. It is brought to pH = 7 by addition of 1N sodium hydroxide and evaporated to dryness. The The residue is taken up in DCM, the insoluble material is filtered and then purified by chromatography on silica eluting with chloroform / methanol (85/15 to 80120; v / v). We obtain 560 mg of the expected product.
C) 1- [2-Amino-3- (4- (N1- [3- (dimethylamino) propyl] amidino) phenyl) propionyl] pyrrolidine, tris-trifluoroacetate.
550 mg of the compound of step B are mixed with 15 ml of DCM and 15 ml of TFA and allowed to stir for 45 minutes at RT. After evaporation to dryness, the residue is dissolved in isopropanol, evaporated again to dryness, taken up twice of ether. It is decanted and then dried under vacuum in the presence of potassium hydroxide. We obtain , 80 mg of the expected compound.
Preparation 1.4 1- [2-Amino-3- (4-cyanophenyl) propionyl] -2,5-dimethyl-2,5-dihydropyrrole, trifluoroacetate.
A) 1- [2- (N-Boc) amino-3- (4-cyanophenyl) propionyl] -2,5-dimethyl-2,5-dihydro-pyrrole.

WO 97125315 2g PCTIFR97 / 00026 2.1 g of 2 - [(N-Boc) amino] -3- (4-cyanophenyl) propionic acid are mixed with 0.715 g of 2,5-dimethyl-2,5-dihydropyrrole in 10 ml of DMF is added 3.9 g of BOP and adjusted to pH = 7 by addition of NEt3. After 18 hours under stirring at RT, evaporated to dryness, then taken up with AcOEt, washed with solution of NaHCO3, with KHSO4 / K2SO4, with saturated NaCl solution. We dry on Na2SO4 then evaporate. It is taken up in an etherhehexane mixture and then dried over Na2S04. 1.4 g of the expected compound are obtained.
NMR: (DMSO + TFA) 1.15-1.25: m: 6H; 1.30: s: 9H; 2.9-3.1: rr ~: 2H;
4.3-4.6: m: 1H; 4.6-4.75: m: 1H; 4.9-5.1: m: 1H; 5.75-5.9: m: 2H;
7.5 d: 2H, 7.9: d: 2H.
B) 1- [2-Amino-3- {4-cyanophenyl) propionyl] -2,5-dimethyl-2,5-dihydropyrrole, trifluoroacetate.
The compound of the preceding step is dissolved in 5 ml of DCM, 5 ml is added.
of TFA and then stirred for 40 minutes at RT. Evaporate to dryness, resumes by DCM and evaporated (3 times) and then taken up with an ether / hexane mixture. We drain and then dry over Na2SO4 to obtain 1.5 g of the expected product.
Proceeding as in Preparation 1.4, step A above, the compounds described in the table below BocHN-CH-CO-NR4R5 i CN

WO 97/25315 ~ 9 PCT / FR97 / 00026 Preparation -NR4R5 NMR (DMSO + TFA) 1.5 / ~ 1.20: s: 9H; 2.75-2.95:
mt: 2H;

-NO
~ 3.30-3.60: m: SH; 4.60:
mt: 1H;

7.40: d: 2H; 7.70: d:

1.6 Me 0.8-1.2: m: 6H; 1.3: s : 9H;

-N-iPr 2.7-3: m: SH; 4-4.8: m : 2H;

7 S: d: 2H, 7.8: d: 2H

1.7 Me 0.8-1.1: m: 6H; 1.15: s : 9H;

-N 1.5-2.1: m: 4H; 2.7-2.9 : m: 2H;

3.6-4: m: 2H; 4.1-4.4:
m: 1H;

Mw 7.4: d: 2H; 7.7: d: 2H;

IS Preparation 1. 8 1- [2-N-methylamino-3- {4-cyanophenyl) propionyl] pyrrolidine trifluoroacetate.
A) 2- (N-Boc-N-methyl) amino-3- (4-cyanophenyl) propionic acid.
1.16 g of 2- [N-Boc-amino] -3- (4-cyanophenyl) propionic acid are dissolved in ml of THF is added at 0 ° C. 2 ml of methyl iodide and then, in portions, 360 mg of 80% sodium hydride in the oil. It is left stirring one night YOUR. The reaction medium is diluted with AcOEt and then water is added and the mixture is at pH = 2.5 with 1N HCl. The organic phase is decanted and then washed with water, a saturated solution of NaCl, then dried over Na 2 SO 4 and evaporated. The residue is taken back by Et2O-hexane (1/1, v / v). The powder formed is filtered and dried for give 1 g of the expected compound.
NMR (DMSO + TFA): 1.20: sd: 9H; 2.55: sd: 3H; 2.90-3.25: m: 2H;
4.50-4.80: m: 1H; 7.30-7.70: m: 4H.
B) 1- [2- (N-Boc-N-methyl) amino-3- (4-cyanophenyl) propionyl] pyrrolidine.
10 g of the compound of the preceding step are mixed with stirring, 0.35 ml of pyrrolidine and 1.78 g of BOP in 15 ml of DMF, is adjusted to pH = 6 by addition of DIPEA. After stirring for 2.5 hours, the mixture is extracted with AcOEt and then the organic phase is washed with 0.25 N NaOH, 0.25 N HCl, H 2 O then a solution saturated with NaCl. The thick wax formed takes in mass after a few days to + 4 ° C. 1.25 g of the expected compound are obtained.
NMR (DMSO + TFA): 1.10: sd: 9H; 1.60-185: m: 4H; 2.60: sd: 3H;
2.75-3.40: m: 6H; 4.80-5.10: m: 1H; 7.25-7.7U: m: 4H.

C) 1- [2-N-methylamino-3- (4-cyanophenyl) propionyl] pyrrolidine, trifluoroacetate.
0.72 g of the compound of the preceding step are placed in 12 ml of TFA and 12 ml of DCM. After stirring for 40 minutes at RT, the reaction medium is concentrated in vacuo and then evaporated with DCM. 0.75 g of the compound is obtained.
waited in the form of a thick wax.
Preparation 1.9 N, N-diethyl- [2-amino-3- (4- {3,4-dihydro-2-yl)} phenyl] propionamide, dihydrochloride.
N, N-Diethyl- [2- (N-Boc) amino-3- (4-cyanophenyl)] propionamide is prepared by proceeding according to the procedure described in Preparation 1.4, step A. The expected product is then obtained by following the procedure described in Preparation 1.2.
Preparation 1.10 2- (N-Boc) amino-3- (4-cyanophenyl) propionic acid ethyl ester.
26 g of Boc20 in solution in 100 ml of DCM are gradually added to a solution of 25.5 g of ethyl ester hydrochloride of 2-amino-3-{4-cyanophenyl) propionic acid and 13.9 ml of NEt3 in 400 ml of DCM. After 6 hours stirring at RT the reaction medium is washed with a KHSO4 / K2SO4 solution, by a saturated solution of NaHCO3, with a saturated solution of NaCl. After drying on Na2SO4 and evaporation of the DCM, the residue is triturated in heptane to give 29 g of white powder.
Preparation 1.11 (R) 2- (N-Boc) amino-3- (4-cyanophenyl) propionic acid ethyl ester compound B and (S) 2- (N-Boc) amino-3- (4-cyanophenyl) propionic acid:
AT.
A mixture of 24 g of the product obtained above and 8.4 g of NaHCO 3 in 900 ml of AcOEt and 500 ml of H 2 O is treated with 2 ml of Alcalase ~ for 24 hours at TA.
Both phases are decanted; the AcOEt phase is rewashed with 100 ml of a solution to 10% of NaHCO 3 which is joined to the first aqueous phase and the aqueous phase is washed again by 100 ml of AcOEt joined to the first AcOEt phase. The AcOEt phase thus obtained is dried over Na 2 SO 4 and then evaporated to dryness; we get 12.45 g of compound B
aD = + 8.8 ° (c = 1; MeOH) The aqueous phase is taken up with AcOEt and brought to pH = 2.5 by HCl 6N. AcOEt is decanted, washed again by a solution KHS04 / K2S04, by a solution saturated with NaCl, dried over Na 2 SO 4 and evaporated to dryness, 10.1 g of the compound are obtained.
AT.
aD = + 8.8 ° (c = 1; MeOH) Preparation 1.12 I- [2-Amino-3- (4-cyanophenyl) propionyl] pyrrolidine, trifluoroacetate, isomer (S).
A) 2,5-dioxopyrrolidin-1-yl ester of 2- (N-Boc) amino-3- (4-cy ~ ophényl) propionic, isomer (S).
9.85 g of 2- (N-Boc) amino-3- (4-cyanophenyl) propionic acid, isomer (S) and 4.14 g of NSuOH and added slowly 8.5 g of DCC in solution in 30 ml of dioxane at RT and then left under agitation 8 hours at TA. The DCU is filtered and washed with acetone. After evaporation at dry of filtrate, the residue is dissolved in acetone and then left overnight at RT.
The Remaining DCU which has precipitated is removed then the filtrate is evaporated to dryness, crushed in Et20 then wrung, washed with Et2O and dried. 11.5 g of the compound are obtained expected, aD = -29.7 ° (c = 1, MeOH) B) 1- [2- (N-Boc) amino-3- (4-cyanophenyl) propionyl] pyrrolidine, isomer (S).
11 g of the compound of the preceding step are placed in 150 ml of acetonitrile and 20 ml of DMF and 2.5 ml of pyrrolidine in 30 ml are added in 10 minutes.
of acetonitrile. The mixture is stirred for 2 hours at RT and then left night in YOUR. It is evaporated to dryness, taken up again by Acu ~ t and then a buffer is added ~ 504 / K2S04. It is extracted with AcOEt and then washed with a saturated solution of NaHCO3 then a saturated solution of NaCl; we dry on Na2SO4 and then c: vapore dried up. The residue is triturated in Et 2 O, drained, washed with Et 2 O and dried. We gets 6.95 g of the expected compound, at. D = + 26 ° (c = I, MeOH) C) 1- [2-Amino-3- (4-cyanophenyl) propionyl] pyrrolidine, trifluoroacetate, isomer (S).
6.75 g of the compound of the preceding step are dissolved in 50 ml of DCM and filters the insoluble. 50 ml of TFA are added and the mixture is stirred for minutes. It is evaporated to dryness, redissolved in isopropanol, evaporated to dryness at new then triturated in Et 2 O, drained, washed with Et 2 O and dried over Na 2 SO 4. We gets 6, 13 g of the expected compound, mp 193-196 ° C.

aD = +51 ° {c = 1; MeOH) Preparation 1.13 1- [2-Amino-3- (4-cyanophenyl) propionyl] pyrrolidine, trifluoroacetate, isomer (R).
A) (R) 2- (N-Boc) amino-3- (4-cyanophenyl) propionic acid.
To 12.18 g of compound B of Preparation 1.11, dissolved in 180 ml of MeOH, 43 ml of 1N NaOH solution are added and the mixture is stirred for 1 hour at RT. Then we add 43 ml of 1N HCl solution and evaporate 150 ml of methanol then take up in AcOEt, and wash with water and saturated solution of NaCl. 11 g of expected compound are obtained. After crystallization by a mixture Et2Olheptane.
aD = -9.5 ° (c = 1; MeOH) B) 2,5-dioxopyrrolidin-1-yl ester of (R) 2- (N-Boc) amino-3- (4-) acid cyanophenyl) propionic acid.
To 10 g of the acid obtained above dissolved in 10 ml of dioxane is added 4.2 After 20 minutes, 8.62 g of DCC dissolved in 30 ml of dioxane. After stirring for 1 night at RT, the DCU formed is filtered, washed with ~ Oxane. The filtrate is evaporated to dryness and the residue triturated in ether to give give a solid which is filtered and dried. 12.09 g of the expected compound are obtained.
a, D = + 27.1 ° (c = 1; MeOH) C) 1- [2- (N-Boc) amino-3- (4-cyanophenyl) propionyl] pyrrolidine, isomer (R).
To 11.6 g of the compound obtained in the above step dissolved in 1 ml.
of acetonitrile plus 20 ml of DMF is added in 10 minutes 2.6 ml of pyrrolidine dissolved in 20 ml of acetonitrile. After 1 night of agitation at TA, eliminates a little of insoluble material and concentrates the filtrate in vacuo. The residue is taken up in AcOEt and washed with KHSO4 / K2SO4 solution, saturated NaHCO3 solution, saturated solution with NaCl; after drying over Na2SO4 the AcOEt is evaporated under vacuum and the triturated residue in ether, 9.3 g of the expected compound are obtained form of a white solid.
a25 - -29.2 ° (c = H; MeOH) D

D) 1- [2-Amino-3- (4-cyanophenyl) propionyl] pyrrolidine, trifluoroacetate, isomer (R).
8.7 g of product obtained in the preceding step are stirred for 35 minutes in a mixture of 50 ml of DCM and 50 ml of TFA. After evaporation to dryness, we resume the residue in isopropanol and reevaporated to dryness gives 8.67 g of compound expected in solid form.
aD = -46 ° (c = 1; MeOH) Preparation 1.14 1- [2-Amino-2-methyl-3- (4-cyanophenyl) propionyl] pyrrolidine, trifluoroacetate.
AT) A mixture of 7 g of (D, L) alanine methyl ester, 14 ml of NEt.3, 4.2 g of MgSO 4, 3 H 2 O and 5.1 ml of benzaldehyde in 100 ml of dichloromethane is stirred 18 hours at RT. The insoluble matter is filtered, the filtrate concentrated under vacuum and the residue taken up in an ether-water mixture; the ether is decanted, washed again with water and then by one saturated NaCl solution, dried over Na 2 SO 4 and evaporated. 8.3 g of expected compound in the form of oil.
B) 2.29 g of the product of the preceding step dissolved in 60 ml of THF are added at -70 ° C 13.2 ml of lithium bis (trimethylsilyl) amide (1M in the THF) in 20 minutes. After 30 minutes, 2.35 g of 4-bromomethylbenzonitrile dissolved in 15 ml of THF, and allowed to slowly the temperature. After 3.5 hours the reaction medium is taken back in AcOEt and washed with water, with saturated NaCl solution. After drying and evaporation of AcOEt, 3.6 g of the expected compound are obtained in the form oil.
VS) The compound of the above step is taken up in 60 ml of ether plus 60 ml of HCl 1N and stirred 18 hours at RT. The aqueous phase is decanted, brought into contact AcOEt and brought to pH = 10 with 1N NaOH; AcOEt is decanted, washed again by H2O, a saturated NaCl solution, dried, evaporated. 2.20 g of the compound are obtained expected in the form of oil.
D) 2.18 g of the compound of the above step dissolved in 10 ml of dioxane add at 2.degree. C. in 10 minutes 2.42 g of Boc20 dissolved in 10 ml of dioxane; then it is stirred overnight at RT and then at 40 ° C. for 3 hours. The reaction medium is taken up in AcOEt that is washed with water, then with a saturated solution of NaCl, which is dried then evaporate to give an oil used directly in the next step.
E) The product of the previous step is dissolved in 10 ml of methanol and added 2.4 ml of 8.36 N KOH solution and stirred overnight; we add 2.4 ml of the solution KOH and refluxed 1 hour. The reaction medium is cooled, taken up by a water-ether mixture; the aqueous phase is decanted, taken up with AcOEt and we bring to pH = 2 with 1N HCl. AcOEt is decanted, rewashed by H20, by a solution Saturated NaCl, dried with Na 2 SO 4 and then evaporated. 0.99 g of the compound is obtained after chromatography on silica eluting with chloroform / MeOH / AcOH
(94/6 / 0.2, v / v / v).
F) To 0.98 g of the compound of the preceding step in 10 ml of DMF is added 0.30 ml of pyrrolidine, 1.55 g of BOP and DIPEA to obtain a pH of 6-7.
After 2.5 hours of stirring the reaction medium is taken up by AcOEt and wash by H2O, 0.2N NaOH, 0.2N HCl, H2O, saturated NaCl solution. After drying and evaporation, 1.13 g of the expected compound is obtained, mp 84 ° -87 ° C.
NMR (DMSO + TFA): 1.20: s: 3H; 1.45: s: 9H; 1.60-1.90: m: 4H;
3.00-3.50: m: 6H; 7.30: d: 2H; 7.80: d: 2H;
BOY WUT) 1.12 g of the compound of the preceding step are stirred for 1 hour in a mixture of 10 ml of DCM and 12 ml of TFA. After evaporation and drying, 1.15 g are obtained of expected compound in solid form.
Preparation 2.1 3-amino-3- (naphth-2-yl) propionic acid, hydrochloride.
The method described in J. Am. Chem. Soc., 1936, 58, 299. On mixture 15.5 g of 2-formylnaphthalene, 10.4 g of malonic acid and 15.4 g acetate of ammonium in 150 ml of ethanol and heated at reflux for 6 hours.
After cooling to RT, filtered, washed with EtOH and dried. The product obtained is dissolved in a sufficient quantity of 2N HCl and the insoluble material is filtered off. The solution The acid is concentrated by evaporation in vacuo and the solid thus formed is recrystallized from 20 ml of AcOH / H 2 O (1/1 vv). 3.8 g of expected product.
According to the procedure described above, the compounds of the TABLE 2 below.

H2N-CH-CH2-COOH, HCl RZ
R2 Preparations 2.2 THIS
2.3 10 OBn 2.4 OHn \ /
2.5 C1 THIS
Preparation 2.6 3- (N-Boc) amino-3- (3,4-dichlorophenyl) propionic acid.
From the compound of Preparation 2.5, the beta-amino acid N-protected as follows.
I0 g of 3-amino-3- (3,4-dichlorophenyl) propionic acid is dissolved in 100 ml of water and 9 ml of triethylamine are added, then, progressively, 9.3 g of (Boc) in 100 ml of dioxane. After a night at TA under agitation, we concentrated the medium and then taken up with water adjusting to pH = 9 by addition of soda 1 N. Wash twice with ether, take up the aqueous phase and acidify to pH = 3 with addition of 1N HCl, extraction with AcOEt and concentration to obtain 3.9 g of expected compound, mp = 128 ° C.
NMR (DMSO) 1.25 ppm: s: 9H; 2.50-2.65 ppm: mt: 2H; 4.75 ppm: q: 1H;
7.25 ppm: d: 1H; 7.20-7.40 ppm: m: 3H
Preparation 2.7 3-amino-3- (3-isopropyloxyphenyl) propionic acid hydrochloride.
A) (3-isopropyloxyl) benzaldehyde.
To 12.2 g of 3-hydroxybenzaldehyde in 100 ml of DMSO is added 3.4 g of K 2 CO 3 and 1.5 g of benzyltriethylammonium chloride are then added 10 ml of isopropyl iodide dissolved in 20 ml of DMSO and leash one night with agitation at TA. Poured onto 400 ml of water and then extracted with AcOEt washed with a saturated solution of NaCl and then dried over Na 2 SO 4 and evaporated to dryness.
The oil obtained (14.4 g) is used as it is in the next step.
B) 3-Amino-3- (3-isopropyloxyphenyl) propionic acid hydrochloride.
A mixture containing 14 g of the oil is heated overnight at 80 ° C.
obtained at the previous step, 150 ml of methoxyethanol, 8.95 g of malonic acid and 13.2 boy Wut ammonium acetate. After cooling, evaporate to dryness and dissolve the oil formed in ethanol and 50 ml of 2N HCl. We proceed by evaporation fractionated to obtain the expected compound which is drained and then washed with AcOEt. We gets 4.56 g.
NMR (DMSO): 1.25: d: 6H; 4.65: heptuplet: 1H; 7.20-7.55: mt: 4H;

9.95: s: 1H.
Following the procedure described in the Preparation above, is prepared the compounds described in the table below.

H2N-CH-CH2-COOH, HC1 R2 NMR preparation 2.8 - (DMSO) 2.85-3.15: mt: 2H; 3.85 : s:: 3H;

OMe 4.60: t: 1H; 6.95-7.45:
mt: 4H

2.9 -(DMSO + TFA) OM

2.50-3.00: mt: 2H; 3.70 e: s:: 3H; ' 4.50: t: 1H; 6.90: d: 2H; 7.40: d:

2.10 - '(DMSO + TFA) 2.80-3.10: mt: 2H; 4.60 : t: 1H;

Cl, 7.30-7.60: m: 4H

2.11 - (DMSO + TFA) 2.90-3> 20: mt: 2H; 4.75 : t: 1H;

CF3 7.00-8.05: mt: 4H

2.12 (DMSO + TFA) 3.00-3.20: mt: 2H; 5.40 to 5.60 : mt 1H;

7.50-8.30: m: 7H

2.13 F (DMSO + TFA) 2.75-3.10: mt: 2H; 5.60 : t:: lH;

~ ~

7.00-7.45: m: 4H

2.14 (DMSO + TFA) 0.90-1.75: m: 11H; 2.40 to 2.70 ; mt 2H;

3.15-3.30: m: 1H

2.15 - (DMSO + TFA) 2.25: s: 3H; 2.80-3.05:
mt: ZH;

Me 4.55: t: 1H; 7.10-7.30:
m: 4H

Preparation 2.16 3- (N-Boc) amino-3-biphenyl-4-ylpropionic acid.
A) 3-Amino-3-biphenyl-4-yl-propionic acid hydrochloride.
18.2 g of 4-phenylbenzaldehyde, 10.4 g of malonic acid and 15.4 g are mixed together.
g of ammonium acetate in 150 ml of methoxyethanol. After a night of heating to 80 ° C, allowed to cool and the product formed is washed ethanol, ether, and then dried. After a new wash with water, the product is recrystallized in a methanol-water mixture with a little HCI. We obtain a mixture of the product and 3-amino-3-biphenyl acid methyl ester hydrochloride 4-yl-propionic, used as it is in the next step.
B) 3- (N-Boc) amino-3-biphenyl-4-ylpropionic acid.
The product of the previous step is placed in 200 ml of dioxane, and 55 2N NaOH and stirred at RT for 1 hour 40 minutes. We 13 g of Boc20 are added and the stirring is maintained overnight. Filter insoluble, diluted with 200 ml of water, the mixture is washed with Et 2 O and then acidified to pH = 2.5 by addition of 2N HCl in the presence of 100 ml of AcOEt. Extracted by AcOEt, lava by WO 97! 25315 38 PCTIFR97 / 00026 KHSO4 / K2SO4, with a saturated solution of NaCl and then dried over Na2SO4 and evaporated to dryness to obtain 11.03 g of the expected compound.
NMR (DMSO): 1; 40: s: 9H; 2.60-2.85: mt: 2H; 5.00: qd: 1H; 7,35-7.80: mt: OH; 12.30: se: 1H.
Preparation 2.17 3- (N-Boc) amino-3-biphenyl-4- acid-2,5-dioxopyrrolidin-1-yl ester ylpropionique.
3.41 g of the acid described in the Preparation above is placed in 50 ml of dioxane and treated with 1.26 g of hydroxysuccinimide in the presence of 2.5 g of DCC.
We leave overnight stirring at RT and then drained and washed with acetone. The filtrate is evaporated to dryness and then taken up in isopropanol. The solid is wrung out, washed the ether and dried to give 3.46 g of the expected compound, mp = 161 ° C.
NMR (DMSO): 1.35: s: 9H; 2.80: s: 4H; 3.00-3.20: mt: 2H; 5.00: qd 1H; 7.30-7.75: mt: OH.
Preparation 2.18 (1,2,3,4-Tetrahydroisoquinolin-1-yl) acetic acid.
This compound is prepared according to J. Org. Chem., 1987, 52, 616-622.
A) 3,4-dihydroisoquinoline.
9.4 ml of 1,2,3,4-tetrahydroisoquinoline are dissolved in 200 ml of DCM and 14.7 g of NBS are gradually added. It is left stirring at RT in cooling slightly to maintain a lower temperature than 40 ° C during minutes, then 50 ml of NaOH! ON are added and the mixture is stirred for 1 hour at YOUR. The organic phase is decanted and washed with 100 ml of water and then twice ml of HCI 4N. The aqueous phases are washed with DCM and then brought to pH = 9 by Addition of concentrated NH 4 OH. It is extracted with DCM, dried over Na 2 SO 4 and evaporates dried up. The oil obtained is distilled. 7.16 g of the expected compound is obtained.
=
50-54 ° C at 0.05 mbar.
B) (1,2,3,4-Tetrahydroisoquinolin-1-yl) acetic acid.
A mixture containing 6.62 g is triturated in an oil bath at 120 ° C.
3.4 Dihydroisoquinoline and 5.13 g of malonic acid. The mixture thickens and bECOMES
completely solid, it is reduced to powder with a spatula. The total duration of heater is about 40 minutes. The mixture is cooled to 60 ° C and treated by 120 ml MeOH and 20 ml of water, which dissolves the medium. A first roll is obtained at cold then a second by evaporating the filtrate and crystallizing the residue in the acetone.
NMR (DMSO + TFA): 2.90-3.15: mt: 4H; 3.30-3.60: mt: 2H; 4.90: t 1H; 7.20-7.40: m: 4H.

Preparation 2.19 3-amino-3-phenylpropionic acid, trifluoroacetate, isomer (R).
A) 3- (N-Boc) amino-3- (2-isopropyl-5-methyl) cyclohexyl ester phenyl propionic, isomer (R).
This reaction is carried out according to Tetrahedron Letters, 1988, 29, 6465-6466.
We prepare a solution containing 11.1 g of 3- (N-Boc) amino-3-phenylpropionic 7.5 g of L (-) menthol and 2.1 g of DMAP in 400 ml of DCM; after shaking, one gradually introduced 11.2 g of DCC in solution in 50 ml of DCM. After overnight under stirring at RT, filter, wash with acetone DCU and evaporate at room temperature.
dry. The the residue is taken up in 150 ml of heptane at 80-90 ° C .; the insoluble is filtered and the solution is dropped at RT for 4 hours. The solid is wrung out, washed heptane the and dried at 40 ° C until disappearance of the menthol odor. We obtain 4.25 g of expected compound.
a, D = -16.5 ° (c = 1; MeOH) B) 3- (N-Boc) amino-3-phenylpropionic acid, isomer (R).
A mixture containing 4.22 g of the title compound is refluxed for 4 hours.
the previous step, 15.7 ml of 1N NaOH in 100 ml of methanol. The environment The reaction mixture is cooled, treated with 15.7 ml of 1N HCl and then evaporated to dryness and taken back in heptane. After dropping a few hours at RT, the product crystallizes, it is drained, washed with heptane and then dried at 40 ° C. until no more the smell of menthol.
2.65 g of the expected compound are obtained, aD = + 42.1 ° (c = 1, MeOH) C) 3-amino-3-phenylpropionic acid, trifluoroacetate, isomer (R).
2.3 g of the compound obtained in the previous step are dissolved in 15 ml of DCM.
and 15 ml of TFA is added. After stirring for 35 minutes at RT, the mixture is evaporated dry.
The product is taken up in isopropanol, evaporated and then crystallized in And20. We drained, washed with Et 2 O and dried to obtain 2.16 g of the expected compound.
Preparation 2.20 3-amino-4-phenylbutyric acid, hydrochloride, isomer (S).
A) 2- (N-Boc) amino-3-phenylpropionic acid methyl ester, isomer (S}.
10.8 g of (L) 2-amino acid methyl ester hydrochloride are mixed together.

3-phenylpropionic in 150 ml of DCM and 7 ml of NEt3 and added Gradually 13 g of (Boc) in 50 ml of DCM. After 5 hours under stirring at RT, the reaction medium is washed with KHSO4IK2SO4 and then solution saturated with NaCl. Dry to remove (Boc) excess, then dissolve in DCM and 1.5 ml of N, N-dimethylpropanediamine are added. After 4 hours under stirring, washed with KHSO4 / K2SO4 then with a saturated solution of NaC'.1. We dried over Na 2 SO 4 and then evaporated to dryness to obtain 11.9 g of the expected compound.
B) 2- (N-Boc) amino-3-phenylpropanol isomer (S).
This step and the following 2 are performed according to Tetrahedron, 1994, Sa (31) 9457. 10 g of the compound of the previous step are dissolved in 120 ml of THF and we cool in an ice bath; 3.7 g of lithium chloride is added, followed by 2.8 g of sodium borohydride and gradually 170 ml of EtOH. After a night under stirring at RT, 70 ml of 1 M KHSO 4 are added slowly and concentrated at dry. It is diluted with chloroform and 1 M KHSO 4 and then extracted with chloroform.
It is washed with saturated NaCl solution, dried over Na 2 SO 4 and evaporated to dryness.
for obtain 8.65 g of the expected compound.
C) 2-amino-3-phenylpropyl ester of methanesulfonic acid isomer (S).
7.5 g of the compound of the preceding step are dissolved in 40 ml of pyridine and we cools in an ice bath; 3.3 ml of chloride of mesyl then stirred for 2 hours at RT. 15 ml is added in 5 minutes of water then the medium is diluted with ether and washed with 1 M KHSO 4 (twice), water and then with saturated solution of NaCl; dry over Na 2 SO 4 and then evaporate to dryness for get 9.2 g of the expected compound.
at D = -24.3 ° (c = 1, MeOH) D) 3- (N-Boc) amino-4-phenylbutyronitrile, isomer (S).
A solution containing 9.05 g of the compound from the previous step is prepared with 7.3 g of 18 crown crown ether and 120 ml of DMSO and 9 g of potassium cyanide are stirred in the ice bath. After 5 hours of heater at 50 ° C., the mixture is cooled and then 600 ml of Et 2 O are added. Washed with water (3 times) then by a saturated solution of NaCl; dry over Na 2 SO 4 and then evaporate to dryness for obtain b, 58 g of the expected compound.
E) 3-amino-4-phenylbutyric acid, hydrochloride, isomer (S).
This step is carried out according to Tetrahedron Letters, 1990, 31, 5153.
4.1 g of the compound of the preceding step in 50 ml of 6N HCl are suspended and refluxed for 5 hours. Concentrate to get a first roll of pure expected compound. By dry evaporation we obtain a second jet of compound 1.4 g soiled with NH4Cl. A sample is treated with (Boc) 20 and measured its rotary power, aD = -17 ° (c = 1, MeOH) Literature at D = -16 ° (c = 1, MeOH) Preparation 2.21 3-amino-3-phenylpropionic acid, trifluoroacetate, isomer (S).
The preparation is identical to that described in 2.19 but using the D (+) menthol.
Preparation 3.1 3-phenyl-3- (2,4,6-trichlorobenzenesulfonamido) propionic acid.
1.15 g of 3-amino-3-phenylpropionic acid are dissolved in 25 ml of dioxane and 7 ml of 1N sodium hydroxide and 1.95 g of sodium chloride are gradually added.
2,4,6-trichlorobenzenesulfonyl in 5 ml of dioxane while maintaining the pH at 1 (), 5-11 by adding 1N sodium hydroxide. After stirring for 2 hours at RT, the mixture is diluted 100 ml of water, extracted twice with AcOEt and acidified to pH = 2 by addition of 6N HCl. The solid formed is drained, washed with water and dried at 40 ° C. We obtain 2.09 g of the product expected, mp 218-219 ° C.
NMR (DMSO + TFA): 2.60-2.95: mt: 2H; 4.75: q: 1H; 7.10-7.30: m 5H; 7.60: s: 2H; 8.85: d: 1H.
Preparation 3.2 3- (naphth-2-yl-sulfonamido) -3-phenylpropionic acid.
4.13 g of 3-amino-3-phenylpropionic acid are dissolved in 100 ml of dioxane 25 ml of 1N sodium hydroxide solution and 5.6 g of sodium chloride naphthalene-2-sulphonyl maintaining at pH = 10.5-11 by addition of N sodium hydroxide.
After stirring for 2 hours at RT, dilute with 400 ml of water and add 2N HCl.
to obtain pH = 2. Extracted with AcOEt, Iave with a KHSO4 / K2SO4 buffer, dries on Na2SO4 and evaporates to dryness. The residue is triturated in heptane, decanted then dried under vacuum. 7.33 g of the expected product is obtained, mp = 126-129 ° C.
NMR (DMSO + TFA): 2.55-2.70: mt: 2H; 4.70: t: 1H; 6.85-8.15: m 12H.
Preparation 3.3 2-hydroxy-3- (naphth-2-yl-sulfonamido) -3-phenylpropionic acid.
This compound is prepared according to Bull. Soc. Chim., France, 1940, 593-603.
By operating according to the procedures described in Preparations 3.1 and 3.2 from the compounds obtained in Preparations 2 and naphthalene 2-sulphonyl, the acids described in TABLE 4 below are obtained.

SOI - NH- H-CHz-COOH
w PreparationsR2 RMN FC

3.4 (DMSO) 145-150 2.80: d: 2H; 4.90: q: 1H;

7.15-8.20: m: I4H
;

8.60: d: 1H

3.5 (DMSO + TFA) 223-228 VS! 2.00-2.20: mt: 2H
;

4.45: t: 1H;

7, LO-8.25: m: 11H

3.6 (DMSO) 253-255 OBn 2.50-2.75: mt: 2H

4.60-4.80: mt: 3H

6.65-8.15: m: 16H

8.40: se: 1H

3.7 NMR (DMSO) 2.40-2.65: mt: 2H

4.65: s: 2H; 4.75 : qd: 1H;

6.40-8.05: m: 16H

8.40: se: 1H

The acids described above are transformed by the action of N-hydroxysuccinimide in the presence of DCC in DMF. The compounds obtained are described in TABLE 5 below.

~ SOz NH-i H-CH. ~ -COONSu ww Preparations R2 NMR (DMSO) FC

3.8 2.75: s: 4H; 3.20: mt 165 : 2H;

4.90: qd: 1H; 7.20 to 8.10 : m: I4H;

8.70: d: 1H

3.9 - '192 3.10 187 OBn 3.11 OBn 2.80: s: 4H; 3.15: mt 110 : 2H;

4.65: s: 2H; 4.75: qd : 1H;

6.45-7.95: mt: 4H;

7.25-8.20: mt: 12H; 8.60 : d: 1H

Preparation 3.I2 3- (2-hydroxyphenyl) -3- (naphth-2-yl-sulfonamido) propionic acid.
1.1 g of 3-amino-3- (2-hydroxyphenyl) propionic acid are dissolved, hydrochloride, prepared according to J. Agric. Food Chem., 1977, 25, 965, in 25 ml of dioxane and 10 ml of NaOH N is added; 1.12 g of naphthalene-2-sulphonyl chloride maintaining at pH = 11.5-12 by addition of 1 N NaOH. After stirring for 2 hours at RT, the reaction medium is diluted.
in water; washed with AcOEt (2 times) then acidified to pH = 1.5-2 by addition 6N HCl. The white precipitate formed is drained, washed with water and dried to get 0.82 g of the expected product, mp = 190-200 ° C.
NMR (DMSO) 2.50-3.20: mt: 2H; 4.80: mt: 1H; 6.95-8.30: m: 11H; 8.75: s: 1H.
Preparation 3.13 3-phenyl-3- (quinol-2-ylsulfonamido) propionic acid.

WO 97/25315 q.4 PCT / FR97 / 00026 A) Quinoline-2-sulphonyl chloride.
3.2 g of 2-mercaptoquinoline are suspended in 40 ml of water containing 0.156 g of iron trichloride. Let cool in a bath of ice cream then bubbled for 1 hour of chlorine at 4 ° C. We evaporate then we take back in a minimum of water, drain and dry to obtain 2.30 g of the expected compound in dry form.
B) 3-Phenyl-3- (quinol-2-ylsulfonamido) propionic acid.
1.65 g of the compound prepared in the previous step are dissolved in 40 ml of dioxane, 20 ml of 1N NaOH and, little by little, 2.27 g of 3-alkenino-3 phenyl propionic, maintaining at pH = 10.
stirring at TA then evaporate to dryness. The residue is taken up in a DCM-H20 mixture, decant then extracted with water. It is acidified to pH = 1 by addition of HCl then we filtered and dried over MgSO4 to obtain 1.9 g of the expected compound.
NMR (DMSO + TFA): 2.4-2.9: m: 2H; 4.9: mt: 1H; 6.9-7.1: mt: 3H;
7.2: d: 2H; 7.7-8.1: m: SH; 8.4: d: 1H; 8.8: d: 1H.
Preparation 3.14 3-phenyl-3- (quinol-8-ylsulfonamido) propionic acid.
This compound is prepared according to the procedure described above from quinoline-8-sulfonyl chloride.
Preparation 3.15 3- (3-Isopropyloxyphenyl) -3- (naphth-2-ylsulfonamido) propionic acid.
1.3 g of the compound of Preparation 2.7 are suspended in 20 ml of dioxane and treated with 2N NaOH then 1N NaOH to bring to pH = 12.
in small portions 1.13 g of naphth-2-ylsulfonyl chloride while now the pH at pH = 10.5-11.5 by addition of 1N NaOH. Leave stirring for 2 hours at TA then diluted with water, washed with AcOEt then brought to pH = 2 by addition HCl 2N. It is extracted with AcOEt and then washed with a KHSO4 / K2SO4 buffer and with a saturated solution of NaCl. Dry over Na2SO4 and concentrate to obtain 900 mg of the expected compound, mp = 126 ° C.
NMR (DMSO): 0.95: d: 6H; 2.40-2.55: mt: 2H; 4.10: qt: 1H;
4.60: qd: 1H; 6.20 - 8.05: mt: 11H; 8.30: d: 1H; 12.20: se: 1H.
Following the procedure described in Preparation above, and in using as the starting material the compounds of Preparations 2.8 to 2.15 are prepared the compounds described in Table 6 below.

SO, NH-CH-CHI-COOH
Preparation R2 NMR Fw C

3.16 "" (DMSO) 154 2.35-2.55: mt: 2H; 3.35 : s: 3H;

OMe 4.60: qd: 1H; 6.20 to 6.85 : mt: 4H;

7.40-8.0: mt: 7H; 8.30:
d: 1H;

12,20: se: IH

3.17 - (DMSO) 2.35-2.60: mt: 2H 139 ;

OMe 3.35: s: 3H; 4,55: qd:
IH;

6.35: d: 2H; 6.90: d:
2H;

7.40-7.95: mt: 7H;

8.25: d: 1H; 12,20:
: IH

3.18 - (DMSO) 2> 40-2.70: mt: 2H 133 ;

4.60: mt: 1H; 6.70 to 7.10 m: 4H;

CI 7.40-8.20: m: 7H; ; 8.45 from: 1H;

12.30: se: 1H

3.19 - (DMSO) 2.40-2.70: mt: 2H 164 ;

4.70: qd: 1H;

CF3 7.00-8.00: m: 11H; 8.45 : d: 1H;

I2, 20: se: 1H

3.20 (DMSO) 2.80: from: 2H; 5.60 189 ii: mt: IH

7.10 to 8.10: m: 14H; 8.65: d: 1H;

12.30: se: 1H

3.21 - F (DMSO) 2.45-2.65: mt: 2H167 ; 4.70: qd a 6.60-7.05; m: 4H; 7.50 to 8.15 : m: 7H

8.50: d: 1H: 12.30: se : 1H

3.22 (DMSO + TFA) 0, 80-1.60: m I 98 : 11H;

1.85-2.30: mt: 2H; 3.40 : qd: 1H;

7.50-8.30: m: 7H

3.23 - (DMSO) 1.85: s: 3H; 102 2.45-2.65: mt: 2H; 4.65 : qd: 1H;

Mp 6.60-6.90: m: 4H;

7.50-8, 15: m: 7H; 8.40:
of: 1H;

12,20: se: 1H

The acids described above (Preparations 3.I5 to 3.23) are transformed by action of N-hydroxysuccinimide in the presence of DCC in dioxane. The Compounds obtained are described in Table 7 below.

SOZNH-CH-CH2-COONSu Preparations R2 NMR F ° C
3.24 - - 97 \ /
OiPr 3.25 - "- 142 OMe 3.26 - - 135 \ / OMe 3.27 '- - 163 THIS

3.28 - - 14 2 \ /

3.29 (DMSO + TFA) ii ~ 2.70: s: 4H; 3.25: d: 2H;
5.60: t: 1H; 7.05-7.95: m: 14H
3.30 F (DMSO) 174 2.70: s: 4H; 2.95-3.10: mt: 2H;
4.75: qd: 1H; 6.50-6.90: m: 4H;
7.45-8.10: m: 7H; 8.60: d: 1H
3.31 (DMSO + TFA) 0.60-1.60: m: 11H 135 IS 2.40-2.80: mt: 2H; 2.70: s: 4H;
3.35: mt: 1H; 7.50-8.30: m: 7H
3.32 - 142 \ /
Me Preparation 3.33 3- (3,4-dichlorobenzenesulfonamido) -3-phenylpropionic acid.
A) 3,4-Dichlorophenylbenzenesulfonyl chloride.
5.4 g of (3,4-dichloro) thiophenol are suspended in 60 ml of water; we 0.234 g FeCl 3 is added and the chlorine is bubbled for one hour at a temperature below 10 ° C. We evaporate, drain, wash with water then dry by azeotropic entrainment to obtain 6.7 g of the expected compound.
B) 3- (3,4-dichlorobenzenesulfonamido) -3-phenylpropionic acid.
The procedure is then followed according to the procedure of Preparation 3.1 to obtain the expected compound.
NMR (DMSO): 2.5-2.9: m: 2H; 4.6-4.8: q: 1H; 7.1: s: SH; 7.5-7.7 mt: 3H; 8.7: d: 1H; 12.4: s: 1H.
Preparation 3.34 3- (5,6,7,8-tetrahydronaphth-2-ylsulfonamido) -3-phenylpropionic acid.
A) 5,6,7,8-tetrahydronaphthalene-2-sodium sulfonate.

WO 97/25315 4 $ PCTIFR97 / 00026 3.9 g of 1,2,3,4-tetrahydronaphthalene are dissolved in 10 ml of anhydrous CCl 4 to 0 ° C; 4.3 g of dioxane in 10 ml of CCl4 and then 6.1 ml are added anhydride sulfuric. The mixture is left stirring for 18 hours at RT and then for 3 hours at 80 ° C. We add a water / ice mixture and then extracted with ether. The aqueous phase is adjusted to pH =
6.5 by addition of NaOH SN. It is drained, dried over Na 2 SO 4 and then training azeotropic. 10.6 g are obtained.
B) 5,6,7,8-tetrahydronaphthalene-2-sulfonyl chloride.
2 g of the sulphonate obtained in the preceding step and S g of pentaclllorure phosphorus and heated at reflux for 6 hours. We evaporate, throw on a ice-water mixture, then extracted with DCM, dried over Na 2 SO 4 and evaporated for obtain 1.5 g of the expected compound.
C) 3- (5,6,7,8-tetrahydronaphth-2-ylsulfonamido) -3-phenylpropionic acid.
Then proceed according to the procedure of Preparation 3.1 to obtain the expected product.
NMR (DMSO): 1.6-1.8: m: 4H; 2.5-2.8: m: 6H; 4.5-4.7: dd: 1H;
7.7.2: m: 7H; 7.3: d: 1H; 8.1: d: 1H; 12.3 s: 1H.
Preparation 3.35 1- (naphth-2-ylsulfonamido) -indane-2-carboxylic acid.
A) Methyl ester of (1-oxo) indan-2-carboxylic acid.
The reaction is carried out according to J. Med. Chem., 1970, 650. A mixture of suspension of 6.75 g of 80% sodium hydride in the oil and 45 g of carbonate of methyl in 120 ml of benzene. At 60 ° C, added in 1 hour and half 11.9 g of indan-1-one dissolved in 100 ml of benzene and then brought to reflux. After I
hour, distil benzene. We add xylene and we bring it back to reflux.
After 1 hour, the mixture is cooled, 30 ml of AcOH are added and the mixture is poured into 200 ml of mixed water / ice containing 30 ml of 1N HCl. Insoluble is removed by filtration then the filtrate is extracted with Et2O. Washed with water, with a saturated solution of NaHC03, at water, with a saturated solution of NaCl, and then dried over Na 2 SO 4. We chromatography on silica, eluting with AcOEt / hexane (1/3, v / v) to obtain 3.05 g of the expected compound.
NMR (DMSO): 3.25-3.50: mt: 2H; 3.70: sd: 3H; 4.85-4.90: mt: 1H;
7.40-7.80: m: 4H. Multiple signals because the product is partly in form enol.
Note: using THF as a solvent instead of benzene and xylene, we get a better return: 67% instead of 30%.

B) Methyl ester of 1-hydroxyiminoindan-2-carboxylic acid.
The reaction is carried out according to J. Heterocycl. Chem., 1974, 11, 982. 3, C14 g of compound from the previous step in 9 ml of MeOH are added in 10 minutes to a mixture of 2.11 g of sodium acetate and 3.1 g of hydroxylamine hydrochloride in 3 ml of water. Then we heat to reflux for 1 hour 30 minutes then cools and extracted by AcOEt. Washed with water, with saturated NaHCO3 3/4 solution, at water, with a saturated solution of NaCl. After evaporation of AcOEt gets 3, 28 g of the expected compound in solid form.
C) Methyl ester of 1-aminoindan-2-carboxylic acid, hydrochloride.
3.27 g of the compound of the preceding step are dissolved in 80 ml of EtOH, add 1.2 g of 10% Pd / C and then 20 ml of 1M hydrochloric ethanol and leave under stirring under hydrogen pressure (5 bar) at RT overnight. The The catalyst is filtered, the filtrate is concentrated under vacuum and then taken up by AcOEt and the water. The water is decanted and then brought to pH = 8.5 by addition of 2N NaOH. We extracted with AcOEt, washed with water, with saturated NaCl solution, dried over Na2S04 and evaporate. The residue is taken up in 20 ml of MeOH and 6 ml of 2.5N HCl. We concentrated in vacuo and the residue is triturated in Et2O. 2.71 g of the expected compound in powder form.
D) Methyl ester of 1- (naphth-2-ylsulfonamido) -indan-2-acid carboxylic acid.
0.91 g of the above compound is placed in 10 ml of chloroform and then add in small portions 0.95 g of naphthalene-2-sulphonyl chloride and 0.68 ml of DIPEA in small portions to maintain at pH = 7-8. After 3 hours, the middle The reaction mixture is extracted with AcOEt and then washed with NaOH, OSN, 0.25N HCl, water and a saturated solution of NaCl. 0.99 g of the expected compound is obtained under form of a pinkish white solid.
NMR (DMSO + TFA): 2.80-3.30: mt: 2H; 3.40: s: 3H; 3.50: q: 1H;
5.10: d: 1H; 6.40-8.50: mt: 11H.
E) 1- (naphth-2-ylsulfonamido) -indane-2-carboxylic acid.
0.98 g of the compound of the preceding step are placed in 10 ml of MeOH, add 1 ml of 8.36 N KOH and heat for 3 hours at 50 ° C and then add C), 25 ml of 8.36N KOH. After 2 hours, the medium is diluted by the addition of water and AcOEt and brought to pH = 2.5 by addition of 1N HCl. The organic phase is decanted, washed with H2O, saturated NaCl solution and then dried over Na2SO4 and evaporates.
0.80 g of the expected compound is obtained in the form of a foam.
Preparation 3.36 [2- (naphthalen-2-sulfonyl) -1,2,3,4-tetrahydroisoquinolin-1-yl] acetic acid.

WO 97/25315 $ 0 PCT / FR97 / 00026 1.9 g of (1,2,3,4-tetrahydroisoquinolin-1-yl) acetic acid (Preparation 2.18) is suspended in 2 $ ml of dioxane, 10 ml of NaOH, 1N, then, in small portions, 2.3 g of naphthalene-2-sulphonyl chloride and keeps in pH = 10.5-12 by addition of 1N NaOH. It is stirred with pH
constant for 2 hours at RT. The reaction medium is diluted with 100 ml of water and washed 2 once with AcOEt and brought to pH = 1.2 by addition of 6N HCl in the presence of AcOEt.
Extracted with AcOEt, washed with a saturated solution of NaCl, dried over Na 2 SO 4 and evaporate to dryness. The expected product crystallizes in heptane, it is drained, washed to heptane and then dried to give 3.14 g, mp = 32 ° C.
NMR (DMSO + TFA): 2.40-2.80: m: 4H, 3.40-3.90: m: 2H, 5.45: t 1H;
6.90-7.20: m: 4H; 7.50-8.40: m: 7H.
Preparation 3.37 The 2,6-dioxopyrrolidin-1-yl ester of the above acid is prepared by action 1% NSuOH in the presence of DCC in dioxane.
NMR (DMSO + TFA): 2.50-2.70: m: 2H; 2.75: s: 4H; 3,10-3,3 ~: mt 2H;
3.50-3.80: mt: 2H; $, 50: t: 1H; 6.80-8.40: m: 11H.
Preparation 3.38 3- (naphth-2-ylsulfonamido) -3-phenylpropionic acid, isomer (R).
2 g of the compound of step 2.I9 are placed in 30 ml of dioxane in the presence of 7.2 ml 2N NaOH; 1.6 g of sodium chloride are added in small portions naphth-2-ylsulfonyl while maintaining pH = 10.5-11.5 by addition of 1N NaOH. After 2 hours stirring at RT is diluted by adding 100 ml of water and then wash by AcOEt (several times). The aqueous phase is diluted with AcOEt and then treated with 2N to pH = 2.2. Extracted with AcOEt, washed with a saturated solution of NaCl dries on Na2SO4 and evaporates to dryness. The expected compound crystallizes in heptane he is drained, washed with heptane and dried. 2.2 g, F = 123-126 ° C.
aD = +67.9 (c = 1; MeOH) Preparation 3.39 Ester of 2, $ - dioxopyrrolidin-1-yl of 3- (naphth-2-ylsulfonamido) -3-phenylpropionic, isomer (R).
A solution of 2 g of the above compound and 657 mg of N
hydroxysuccinimide in 35 ml of dioxane and gradually add 1.24 g of DCCI in 10 ml of dioxane. After stirring for 5 hours at RT, the DCU is WO 97/25315 51 PCT / FR97 / 0002b drained, washed with acetone and the filtrate is evaporated to dryness. The residue is taken up in isopropanol. The product which crystallizes is drained, washed with Et20 then dried. We 2.18 g of the expected compound is obtained.
Preparations 3.40 and 3.41 We proceed as in the 2 Preparations described above from the compound of Preparation 2.21 to obtain 3- (naphth-2-ylsulfonamido) -phenylpropionic acid, isomer (S) and its 2,5-dioxopyrrolidin-1-yl ester.
Preparation 3.42 3- (4-Chlorophenyl) -3- (naphth-2-ylsulfonamido) propionic acid, isomer (R).
A) 3- {4-Chlorophenyl) -3- (phenylacetamido) propionic acid.
9.6 g of 3-amino-3- (4-chlorophenyl) propionic acid are dissolved in 500 ml.
of dioxane and about 50 ml of 1N NaOH to pH = 10.5-11> 5. The The medium is cooled to + 5 ° C. and then 6.34 ml of chloride of phenylacetic acid while maintaining at pH = 10.5-11.5 and at a temperature enter + 5 ° C and + 10 ° C. Stirring is maintained for 1 hour and half then concentrate the medium in half before diluting with 500 ml of water. We wash 2 times by AcOEt then acidified to pH = 1-2 by addition of 6N HCl. The solid is drained, washed with water and dried to give 14 g of the expected compound.
B} 3-Amino-3- (4-chlorophenyl) propionic acid, isomer (R).
This step is performed according to Syn. Letters, 1993, 339. Suspended 16.8 g of the compound of the preceding step in 300 ml of water and NH 4 OH is added IN until pH = 7.5. 0.6 ml of penicillamidase ~ Sigma and stirred for 72 hours at 40 ° C. The expected compound precipitates.
It is drained, washed with water and with acetone, then dried at 40 ° C. 2.85 g are obtained.
~, D - _5 ° (c - 1, 1N HCl) C) 3- (4-Chlorophenyl) -3- (naphth-2-ylsulfonamido) propionic acid, isomer (R).
I g of the compound obtained in the preceding step is dissolved in 15 ml of dioxane and 5 ml of 1N NaOH to reach pH = 10.5-1.5. We add gradually 1.15 g of (naphth-2-yl) sulfonyl chloride while keeping the pH constant.
After 2 hours with stirring at RT, the medium is diluted by addition of an equal volume water then washed twice with AcOEt. The medium is acidified to pH = 1.3 by addition 6N. Extracted with AcOEt, washed with a saturated solution of NaCl (several times).
It is dried over Na 2 SO 4, evaporated to dryness and the expected product crystallizes from heptane. 1.31 g are obtained.
at D = + 92 ° (c = 1, MeOH) Preparation 3.43 The 2,5-dioxopyrrolidin-1-yl ester of the above acid is prepared according to usual technique.
Preparation 3.44 4-phenyl-3- (naphth-2-ylsulfonamido) butanoic acid, isomer (S).
1.08 g of the compound of Preparation 2.20 are dissolved in 30 ml of dioxane and ml of water. 1N NaOH is added to reach pH = 14 and then added by small fractions 1.13 g of naphth-2-ylsulfonyl chloride while maintaining the pH =

10, 5-11, 5. Stirring is maintained for 2 hours and then diluted with water and lava by 10 AcOEt. It is diluted again with AcOEt and acidified to pH = 2 by addition of HCl 2N
and extracted by AcOEt; washed with a saturated solution of NaCl (several times} then dry and evaporate to dryness. By addition of heptane the expected product crystallizes. We gets 1.25 g.
a25 - -26.8 (c = 1; MeOH) D
Preparation 3.45 The 2,5-dioxopyrrolidin-1-yl ester of the above acid is prepared by using the usual techniques.
Preparation 3.46 (2S, 4R) (4- (Benzyloxy) -1- (naphth-2-ylsulfonyl) pyrrolidin-2-yl} acetic acid.
A) 4- (hydroxy) -1- (naphth-2-ylsulfonyl) pyrrolidin-2-carboxylic acid.
2.62 g of (2S, 4R) 4-hydroxyproline are dissolved in 15 ml of water containing 5.9 g.
of Na 2 CO 3 and 5.21 g of naphth-2-ylsulfonyl chloride are added. After 18 stirring vigorously at RT, the mixture is filtered and the filtrate is acidified to pH
=: 1. On squeeze again, washed with water and dried to obtain 4.1 g of the expected compound.
B) 4- (Benzyloxy) -1- (naphth-2-ylsulfonyl) pyrrolidin-2-yl acetic acid.
1 g of the compound of the preceding step is dissolved in 20 ml of DMF at 0 ° C
under nitrogen; 0.204 g of 80% sodium hydride in the oil is added and then let stir 1 hour at 0 ° C and 30 minutes at RT. We cool to 0 ° C then add 10 mg Crown 16 crown ether 6 and 0.921 ml benzyl bromide. We let stirring for 1 hour at 0 ° C and 18 hours at 50 ° C and add 10 ml of NaOH N. After 18 hours stirring at RT, dilute with water and then extract with ether and acidified to pH = 2 by addition of 1N HCl. We extract by AcOEt, dry over Na 2 SO 4 and evaporated to obtain 0.8 g of the expected compound.
C (2S, 4R) 4-Benzyloxy-2-hydroxymethyl-1- (naphth-2-ylsulfonyl) pyrrolidine.

Om dissolves 2.8 g of the compound of the previous step in 20 ml of THF:
add 1.12 ml of NEt3 then 0.968 ml of ethyl chloroformate in 30 minutes at TA, finally 0.762 g of sodium borohydride in 5 ml of water are added. After 20 stirring at RT, evaporated and then taken up with 20 ml of water and acidified to pH = 3 by addition of 1N HCl. We drain, wash with water, dry then we precipitated in the AcOEt / hexane mixture to obtain 1.9 g of the expected compound.
D) (2S, 4R) 4-Benzyloxy-2-mesyloxymethyl-1- (naphth-2-ylsulfonyl) pyrrolidine.
3 g of the compound of the preceding step are dissolved in 100 ml of DCM at 0 ° C
1.28 ml of NEt3 and then 0.72 ml of mesyl chloride are added. After 30 minutes with stirring at 0 ° C., 1.28 ml of NEt3 and then 0.72 ml of chloride of mesyl and then stirred for 30 minutes at RT. Cold wash by KHSO4 / K2SO4 then the insoluble material is filtered off, the filtrate is dried and evaporated. The residue taken back by Et20 is used as is in the next step.
E) (2S, 4R) 4-Benzyloxy-2-cyanomethyl-2- (naphth-2-ylsulfonyl) pyrrolidine.
The product of the previous step is dissolved in 50 ml of DMSO, 2 g are added.
Crown 10 crown ether 6 and cooled in an ice bath. We add then 5 g of potassium cyanide and heated for 4 hours at 50 ° C. The middle is diluted with 250 ml of AcOEt then washed with water, dried and evaporated. We resume at ether. The The expected compound crystallizes and 1.7 g are obtained.
F) (2S, 4R) -An (4- (benzyloxy) -1- (naphth-2-ylsulfonyl) ethyl ester pyrrolidin-2-yl) acetic acid.
1.6 g of the compound of the previous step are dissolved in 50 ml of saturated ethanol in HCl at 0 ° C. The mixture is left stirring for 48 hours at + 4 ° C. and then evaporates. The the residue is taken up in EtOH and evaporated (twice) and then taken up in Et20 and evaporated (2 times). 20 ml of boiling water are added and then a few ml of the mixture are added.
dioxane / EtOH to homogenize. The solution is heated for 15 minutes at 100 ° C.
evaporated, taken up with dioxane and then neutralized to pH = 6 by addition of NaOH
1N. The solution is used as is in the next step.
G) (2S, 4R) (4- (Benzyloxy) -1- (naphth-2-ylsulfonyl) pyrrolidine-2- acid yl) acetic acid.
To the solution of the previous step, 2.4 ml of NaOH SN are added and the mixture is heated.
at 50 ° C for 30 minutes. The solvent is evaporated and then acidified to pH
= 3 by addition of concentrated HCl. Sore, wash with water, dry to obtain 1.44 g of expected compound.
Preparation 4.1 A) N- (2- {4- {3,4-dihydroimidazol-2-yl) phenyl) -1 - ((pyrrolidin-1) yl) carbonyl) fl: hyl} -3- (3,4-dichlorophenyl) -3- (N-Boc) aminopropionamide.

1.09 g of 1- [2-amino-3- (4- (3,4-dihydroimidazol-2-yl) phenyl) is dissolved propionyl] pyrrolidine, dihydrochloride in 15 ml of DMF, 350 μl of NEt3 and stir for a few minutes before adding 835 mg of 3 - ((N
Boc) amino} -3- (3,4-dichlorophenyl) propionic (obtained in Preparation 2.61 and S mg of DCC.
After stirring for 3 hours, the mixture is evaporated to dryness and the residue is taken up of methanol. The DCU is drained, concentrated by half and diluted with acetone. We filter then evaporate to dryness. The residue is chromatographed eluting with a mixture chloroform / methanol (100 / 2.5 to 100/20, v / v).
B) N- (2- (4- (3,4-dihydroimidazol-2-yl) phenyl) -1 - ((pyrrolidin-1) yl) carbonyl) ethyl) -3- (3,4-dichlorophenyl) -3-aminopropionamide.
The crude product obtained in the previous step is placed in 20 ml of a solution of 4N HCl in dioxane and enough MeOH to allow dissolution complete. After 1 hour at RT, evaporate to dryness, triturate the residue twice in ether then drained, washed with ether and dried under vacuum in the presence of KOH. We obtain mg of the expected compound.
Preparation 4.2 N- [2- (4-cyanophenyl) -1 - ((pyrrolidin-1-yl) carbonyl) ethyl] -3-phenyl-3-aminopropionamide, trifluoroacetate, isomer (R, R).
A) N- [2- (4-cyanophenyl) -1 - ((pyrrolidin-1-yl) carbonyl) ethyl] -3-phenyl-3- (N-Boc) aminopropionamide, isomer (R, R).
The 2,5-dioxopyrrolidin-1-yl ester of the acid obtained is prepared by Preparation 2.19, Step B. 800 mg of this compound is added to a mixture containing 790 mg of the compound of Preparation 1.13 in 15 ml of acetonitrile and 380 μl of DIPEA. It is left stirring for a few hours then we leave one night to YOUR.
The medium is evaporated to dryness, taken up in KHSO4 / K2SO4 and then extracted with AcOEt. The The organic phase is washed with a saturated solution of NaCl and then dried over Na2S04 and evaporated to dryness. 1.1 g of the expected compound which crystallizes in heptane.
B) N- [2- (4-Cyanophenyl) -1 - ((pyrrolidin-1-yl) carbonyl) ethyl] -3-phenyl-3 aminopropionamide, trifluoroacetate, isomer (R, R).
1 g of the compound of the preceding step is dissolved in 6 ml of DCM and then add 6m1 of TFA and leave stirring for 35 minutes at RT. The environment reaction is evaporated to dryness, redissolved in isopropanol, then evaporated, triturated in Et20, wring and dry to obtain 0.88 g of the expected compound.

THIS
I, HCl: R1 = ~ ~ ~, R2 = Cl girl, -N _C / NRs N
R ~ 6 = R17 = R9 = g3 = ~ NRaRj ° ~~ '' N
H
In 10 ml of dioxane and 5 ml of water, 210 mg of the compound of the Preparation 4.1 and 1N sodium hydroxide is added to reach pH = 9.5. We added 3 times 84 mg of naphthalene-2-sulphonyl chloride while maintaining pH = 9-9.5 by addition of sodium hydroxide O, SN. After one night at RT, the medium is diluted with water and acidified to pH = 2.5 by addition of 1N HCl. The solid formed is chromatographed on Sephadex ~ LH20 eluting with methanol. The fraction containing the product expected is concentrated, treated with a solution of 4N HCl in dioxane then evaporated to dryness; the residue is taken up in ether, drained and dried. We gets 41 mg of the expected compound.
MH +: 692: dichlorinated isotopic profile NMR (DMSO + TFA) 1.40-1.70: m: 4H; 2.50-3.40: m: SH; 4.00: sd: 4H; 4.45-4.70: m: 2H
6.60-8.00: m: I4 H

I, HCl: RI = ~ ~ ~, R ~
Laugh . R1-g9-g3 = PI, NR4Rs = -N. ', _C w _ ~. ~ JN ~ N
H
AT) ,.
II: R1 = ~, Rz =
. ~ ~ /
Ris = Rt7 = Rs = gs = ~ NRaRs = -N
715 mg of the compound of Preparation 1. 1.15 ml of CH3CN, 250 p.1 triethylamine, 710 mg of the compound of Preparation 3.2 and 450 mg of DCC
and The mixture is stirred for 5 hours at RT. Evaporate to dryness, take up the residue in acetone, squeeze the DCU and then evaporate again to dryness. The residue is crushed in the ether then decanted several times. Dry under vacuum in the presence of P205 for obtain 6I0 mg of the expected compound, mp 195-200 ° C.
NMR (DMSO + TFA) 1.40-1.70: m: 4H; 2.30-3.40: m: 8H; 4.40-4.60: m: and 4, b0-4.70: m 2H; 6.75-8.15: m: 16H
B) 600 mg of the product obtained in the previous step are dissolved in 20 ml of Ethanol solution saturated with hydrochloric acid at 0 ° C. After one night at refrigerator, evaporated to dryness and dried under vacuum in the presence of KOH. The product The product obtained is diluted with 25 ml of anhydrous ethanol and several times 134 p.1 of ethylenediamine in 2 ml of anhydrous EtOH. After a night at TA, we evaporated dry then chromatograph the residue on silica eluting with a mixture chloroform / methanol (85/15, v / v). Fractions containing the expected compound are combined, evaporated and then taken up in dilute hydrochloric ether. After spinning and drying under vacuum in the presence of KOH, 180 mg of the product is obtained expected.
MH ~ ': 624 NMR (DMSO + TFA) 1.40-1.80: m: 4H; 2.55-3.45: m: 8H; 4.00: s: 4H; 4.55: .te: and 4.70 : you 2H; 6.70-8.20: m: 16H
20 ~ '' I, 3TFA: R1 ° ~ ~ ~ '. Rz - /

Ris = Rm ~ Rs ~~ = H ~ NR4Rs ___ _N
30 ~ ~ NC ~ ~ / C
- C ~ - -C
\ /

56a AT) 800 mg of the compound obtained in EXAMPLE 2, step A, are dissolved at 0 ° C.
in 20 ml of a saturated solution of HCl in anhydrous EtOH. After a night at refrigerator, evaporate to dryness and then dry the residue under vacuum in the presence of KOH.
The residue is dissolved in 30 ml of anhydrous EtOH and 175 μl of NEt 3 are added.
then 350 mg of N-Boc- (4-aminomethyl) benzylamine. After 48 hours at RT, evaporate to dryness and then the residue is chromatographed on Sephadexd LH20 eluting with MeOH.
2 fractions containing two different compounds are obtained. For one (fraction 570 mg), the amidine is monosubstituted by a group Rg-4 ((N-Boc) aminomethyl) benzyl and R6 and R7 = H; for the other (fraction 2, 150 mg), the amidine is disubstituted by R6 = Rg = -4 (N- (Boc) aminomethyl) benzyl and R7 =
H.
B) 125 mg of the compound of fraction 2 are suspended in 1 ml of DCM.
obtained in the previous step, 1 ml of TFA is added and the mixture is left stirring minutes to TA. After evaporation to dryness of the medium, the residue is dissolved in isopropanol and then evaporated to dryness again; the residue is triturated in and20, drained, washed with Et20 and dried. We obtain 110 mg of the expected compound.
MH +: 836 NMR (DMSO + TFA) 1.40-1.80: m: 4H; 2.40-3.30: m: 8H; 3.90-4.80: m: OH;
6.80-8.45: m: 24H
I; 3TFA: R1 = ~ ~ R = _ NH
R16 = R "- ~ - g3 = H ~ ~ 4RS = -N ~, C ~~ 6 - -C
/ C ~ H:
DCM 535 mg of the compound of Fraction 1 is suspended in 8 ml of DCM.
obtained in EXAMPLE 3, step A, 8 ml of TFA are added and then 40 minutes with stirring at RT. After evaporation to dryness of the medium, the residue is triturated in the ether and then dried under vacuum in the presence of potassium hydroxide. We obtain 520 mg of compound expected.
MH +: 717 NMR (DMSO + TFA); 1.30-1.70: m: 4H; 2.20-3.30: m: 8H; 3.90: s 2H; 4.40-4.70: m: 4H; 6.80-8.00: m: 20H

' I, HCl: R =
~ -'=' ~ i Rls = Ri ~ = ~ _ ~ = H ~ ~ 4Rs- _N ~ ~ C \
H
960 mg of the compound of Preparation 3.8 are mixed in 20 ml of DMF with 852 mg of the compound of Preparation 1.2 and 280 μl of NEt3 are adjusted to pH = 7.

7.5 by addition of NEt3. After one night with stirring, evaporate to dryness then the The residue is taken up in methanol and chromatographed on Sephadex ~ LH 20 in eluting with methanol. The fractions containing the product are combined, evaporated then taken up in 20 ml of butanol, 10 ml of HCl, 1N and 10 ml of water. After stirring and decantation, the organic phase is evaporated. The residue is chromatographed on Sephadex ~ LH 20 eluting with methanol and fractions collected undergo the same treatment as before. 180 mg is obtained of expected compound.
MH ~ ': 674 NMR (DMSO + TFA) 1.00-1.70: m: 4H; 2.30-3.20: m: 8H; 4.05: sd: 4H; 4.50: rnt and 4.80 mt: 2H; 7.05-8.10: m: 18H

i I, HCl: Rl = ~ ~ ~, ~ _ ~ / Cl, NOT
Ris-Rv? -Rg-R3 = H, NR4R5 = -N ~ ~ C \ _ s N
H
This compound is obtained by operating as in EXAMPLE 5 from Preparations 3.9 and 1.2.
MH +: 658: monochlorine isotopic profile NMR (DMSO + TFA) 1.40-1.70: m: 4H; 2.40-3.30: m: 8H; 3.90: sd 4H;
4.40-4.65: m: 2H; 6.70-8.00: m: 15H

~ \ /, I, HCI: RI = ~ ~ ~, Rz = ~ / ~ Bn, NOT
R16 - Rt7 = Rg = g3 = ~ ~ 4R5 = - ~ ~ C ~
NOT
H
880 mg of the compound of Preparation 1.2 are dissolved in 15 ml of DMF and 300 N, 1 of NEt3 is added 1.12 g of the compound of Preparation 3.10 and leaves under stirring for 5 hours at RT. After evaporation to dryness of the medium, the residue is taken back by a mixture of 1N HCl and butanol and then decanted and evaporated to dryness the phase higher. The residue is chromatographed on Sephadex ~ LH20 eluting with MeOH. The product thus obtained is taken up in a solution of HCl, 1 N in the butanol, then evaporate to dryness, triturate the residue in ether, drain, wash the ether and dry to obtain 330 mg of the expected product.
MH +: 730 NMR (DMSO + TFA); 1.45-2.25: m: 4H; 2.30-3.30: m: 8H; '3.85: s and 3.95: s: 4H; 4.50-4.70: m: 4H; 6.35-8.00: m: 20H.

ii I, HCl: R1 = ~, ~ _ '~, ~ OFi r ~ -; NOT
R16 = Rt = R9 = R3 = H, NR4R5 = - i ~ Cys N
The debenzylation reaction is carried out according to J. Chem. Educ., 1987, 64, 1062.
425 mg of the compound of EXAMPLE 7 are mixed in 20 ml of methanol.
with 120 mg of ammonium formate in the presence of 500 mg of 10% Pd / C, 50% wet. After heating for 24 hours under reflux, the palladium is filtered off, the washed with methanol and the filtrate evaporated to dryness; the residue is dissolved in methanol then chromatographed on Sephadex LH 20 eluting with methanol. The product obtained is taken up by a mixture of a solution of 2N HCl in water and butanol;
after stirring, the aqueous fraction is extracted with butanol and the fractions organic combined are evaporated to dryness. The residue is taken up in ether, drained, washed with the ether and dried. 171 mg of the expected product are obtained.
~ +; 640 NMR (DMSO + TFA) 1.50-1.85: m: 4H; 2.40-3.30: m: 8H; 4.05: sd: 4H; 4.50-4.70: m:
2H; 6.40-8.20: m: 15H
The compounds described in TABLE 8 are prepared as the EXAMPLES 7 and 8 above.

10 ~ ~, SOz ~ - i H-CH ~ z-CONH- ~ CH-CON
w ~ Rz CHz HCl eyelashes ~ +
PZ
Exem the R -C ~ g ~ ~ MSO + TFA) MH +; 730 N, 1.45-1.5: m: 4H;
2.40-3.40: m: 8H;
3.95: s: et4,00: s: 4H;
H, 4.50-4.70: m: 4H;
6.40-8.10: m: 20H
MH +: 640 10 ~ NI, 45-1.80: m: 4H
2.25-3.30: m. 8H
~ OH H 3.95: s: 4H
4.45-4.70: m: 2H
6.30-8.20: m: 15H

MH +: 683

11 1.45-1.80: m:

1.95-2.10: m:

2.75: sd: 6H

2.50-3.60: m:

4,55: mt: and 4.70: mt:

2H 6.80-8.10: m : 16H

, I, HC1: R1 = ~ ~ Cl, R ,, _ \

NRs N
Ris _ R17 _ g9 = R3 - H, NR4Rs = _N ~ ~ C \ _ t --- NR ~ Rg N
H
900 mg of the compound of Preparation 1.2 are mixed in 10 ml of DMF and 550 μl of NEt3 with 1.04 g of the compound of Preparation 3.1 and 1.3 is added.
boy Wut of BOP and a sufficient amount of NEt3 to reach pH = 6-7. After 5 hours while stirring, maintain the medium at pH = 6-7 by addition of NEt3, dilute medium to ether then triturate and decant (2 times). We chromatography oil Sephadex ~ LH 20 eluting with methanol and the product obtained is again chromatographed on silica using an um "i ~~
chloroform / methanol (90/10, v / v). The product obtained is washed with AcOEt in of water, by AcOEt then dried; the solid is taken up in ether, drained, then Iavé to ether and dried. 313 mg of the expected product is obtained.
MH-E ': 676: trichlorinated isotopic profile NMR (DMSO + TFA) 1.50-1.85: m: 4H; 2.70-3.20: m: 8H; 3.95: se: 4H; 4.50-4.75: m 2H; 6.90-8.00: m: 11H
Operating as in EXAMPLE 12, the compounds described in table below.

i: ~ y SOZNH- ~ H- i H-CONH- ~ -CO
ww Rz R3 ~ x HCl C ~~~
ws Examples R2 R3, CG ~ MH +
N (DMSO + TFA) MH "~: 640 13. HN 1.60-1.80: m: 4H
~ 2.60-3.50: m: 8H.
HO H 3.80: s: and 4.00: s: 4H
4.60-4.90: m: 2H
6.90-8.70: m: 15H
MH +: 640 14 OH N 1.40-1.70: m: 4H
2.50-3.20: m: 8H
H 3.85: sd: 4H
4.00: dd: 1H
4.30-4.70: m: 2H
6.55-8.10: m: 16H
EXAMPLE IS
ii I, HC1: R, = I, R2 =
NOT
i Ris 'Rte - ~' ~ - H ~ bars - -N ~ ~ C. ~ _ HC ~
This compound is prepared from the compound prepared in EXAMPLE 2 Step A
and operating as in EXAMPLE 2 step B using 2-methylpropane-1,2-diamine.

MH +: 652 NMR (DMSO + TFA) 1.30: s: 6H; 1.30-I, 70: m: 4H; 2.25-3.20: m: 8H; 3.65: s: 2H;
4.40-4.70: m: 2H; 6.70-8.05: m: 16H

I, 2HC1: R1 = \ ~ ~, R2 =
NOT
NOT
Rt6 = R17 = R9 = R3 = ~ bar = ._ N, C ~
NR ~ Rg N
0.812 g of the compound of Preparation 3.13 and 0.810 g of the compound are dissolved of Preparation 1.2 in 10 ml of DMF and 1.22 g of BOP are added and then added at pH = 7 by addition of NEt3. After 18 hours under stirring at RT, evaporate at dry. The residue is taken up in AcOEt and a saturated solution of NaHCO3 and then wash with AcOEt, with KHSO4 / K2SO4 buffer, with saturated NaCl solution. We dries on Na2SO4 and evaporates. The residue is chromatographed on silica eluting by the mixture CHCl3 / MeOH / concentrated ammonia (10 / 0.5 / 0.1; v / v / v ~.
0.390 g of the expected compound.
MH '~: 625 NMR (DMSO): 1.5-1.8: mt: 4H; 2.5-3.7: m: 8H; 4: s: 4H;
4.4-4.6: mt: 1H; 4.7-4.9: mt: 1H; 6.8-7: mt: 3H; 7-7.1: mt: 2H; 7.4 : d 2H; 7.7-8.1: m: 5H; 8.3-8.4: m: 2H; 8.7: d: 1H; 10.7: s: 1H.

i I, 2HCl: Rt = \, RZ =
NOT
-NC / ~ N
NR, Rg N
H
This compound is prepared following the procedure of the EXAMPLE
preceding from the compound of Preparation 3.14 and that of Preparation 1.2.
MH +: 625 NMR (DMSO): 1.4-1.7: mt: 4H; 2.4-3.3: m: 4H; 4: mt: 4H; 4.5-4.7 mt: 2H; 6.7-6.9: mt: 2H; 7.2-8.4: m: 16H; 9: mt: 1H; 10.7: s: 1H.

I, HC1: R =
'~~ ~ I' R1 = \
EXAMPLE 18 OiPr / ~ ~ NRs N
R11 - R17 ° R9 = R ~ - H, NRaRs _ -N ~,. C \ _ - ~ /
NOT
H
740 mg of the compound of Preparation 1.2 are placed in 10 ml of DMF.
240 μl of DIPEA and then 740 mg of the compound of Preparation 3.24 are added. After a overnight stirring at RT, add ether, decanted, diluted again with of ether then triturate and decant. The organic phase is chromatography on Sephadex ~ LH 20 eluting with MeOH. Useful fractions are included in a mixture containing 5 ml of butanol, 5 ml of 1N HCl and 5 ml of AcOEt. The sentence The organic material is washed with 5 ml 1N HCl and evaporated to dryness. The residue is dissolved in the methanol and precipitated with ether. 470 mg of the expected compound are obtained.
MH +: 682 NMR (DMSO): 1.00: d: 6H; 1.45-1.80: m: 4H; 2.30-3.20: m: 8H;
3.95: sd: 4H; 4.05-4.20: m: 1H; 4.50-4.70: m: 2H; 6.30-8.40: m: 17H
(15H aromatics + 2H amides); 10.70: se: 1H.
By proceeding according to the procedure described above, the compounds according to the invention of the table below from the compounds of Preparations 3.25 to 3.32.

S02NH-CH-CH2-CONH-CH-CO-N, ~ J
i ~, HC1 N 'NH
u Example R2 NMR MH +

19 - (DMSO + TFA) 1.50-1.80: 654 m: 4H;

2.25-3.25: m: 8H; 3.40 : s: 3H;

4.00: sd: 4H; 4.45 to 4.75 : m: 2H;

OMe 6.35-6.90: mt: 4H; 7.30 to 8.15 : m 20 - (DMSO + TFA) 1, 50-1, 80,654 m: 4H;

OM 2,30-3,25: m: 8H; 3.40 : s: 3H;

4.00: sd: 4H; 4.60: qt : 1H: 6.40 d: 2H; 6.90: d: 2H;
7.25-8.05: m 21 - (DMSO + TFA) 1.50-1.80: 658-660 m: 4H; ~

2.35-3.40: m: 8H; 4.00 : sd: 4H;

4.50-4.70: m: 2H; 6.75 to 7.00 : m 4H; 7.25-8.10: m: 11H

22 - (DMSO + TFA) 1.40-1, 80: 692 m: 4H;

2.40-3.40: m: 8H; 3.95 : sd: 4H;

4.50-4.65: mt: 1H; 4.75 : qd: 1H;

6.90-8.00: m: 15H

23 - (DMSO + TFA) 1.20-i, 60,674 m: 4H;

2.40-3.20: m: 8H; 3.95 : se: 4H;

4.25 - 4.50: mt: 1H; 5.45 : t: 1H;

7.00-7.90: m: 18H

24 - (DMSO + TFA) 1.50-1.75: 64-7.
m: 4H;

2.60-3.40: m: SH; 4.00 : se: 4H;

4.50-4.75: m: 2H; 6.55 to 8.10 : m F

(DMSO + TFA) 0.60-1, 70.630 : m: 15 H; 1.80-2.20: m: 2H .2.60-3.40 m: 7H; 3.90: s: 4H;
4.30-4.60: m 1H;

7.25-8.25: m: 11H

~ (DMSO + TFA) 1.50-1.80: 638.
m: 4H;

1/90: s: 3H; 2.20 to 3.30 : m: 8H;
M.sub.45: sd: 4H; 4.55 to 4.75 : m: 2H;
6.60-8.10: m: 15H

I, HCl: Rl = \ \ I, ~ _ \ ~ \ /, R = R __ _ _ ~ ~ _N C% '~ _ 17 ~ ~ ~ 4 ' NOT
H
A) N- (2- (4-cyanophenyl) -1- (pyrrolidin-1-ylcarbonyl) ethyl) -3- (biphenyl-4-yl) -3-(NOT-Boc) aminopropionamide.
1.19 g of the compound of Preparation 1.1 are placed in 30 ml of acetonitrile and 0.46 ml of NEt3 and 1.46 g of the compound of Preparation 2.17 are added. We left overnight at RT and then evaporated to dry, taken up by KHS04 / K2S04 and extracted by AcOEt. Washed with a saturated solution of NaCl, dried over Na 2 SO 4 then evaporate to dryness. The expected compound crystallizes in heptane, is filtered off, wash at heptane and then dry to obtain 1.86 g.
B) N- (2- (4-Cyanophenyl) -1- (pyrrolidin-1-ylcarbonyl) ethyl trifluoroacetate) (Biphenyl-4-yl) -3-aminopropionamide.
A mixture containing 1.82 g is stirred at RT for 35 minutes.
of the compound of the previous step in 15 ml of DCM and 15 ml of TFA. We evaporates to dryness, dissolves the residue in isopropanol and evaporates to dryness at new. The expected product crystallizes in Et20, it is drained, washed with Et20 and dried for give I, 37 g VS) i ~ - _ u: R =
1 ww ('~ - \ / \ /
Ris - Rc ~ R9 - R3 = H, NRaRs = N

1.34 g of the compound of the previous step are placed in 25 ml of DCM and 850 ml.
1 of DIPEA, and 522 g of 2-naphthyl chloride are added gradually.
ylsulfonyl in 5 ml of DCM. After stirring for 2 hours at RT, dilute with 60 ml of DCM and then washed with KHSO4 / K2SO4, with saturated NaCl solution. Dry on Na 2 SO 4, evaporated to dryness and then chromatographed on fine silica eluting by chloroform containing 1% MeOH. 0.802 g of the expected compound is obtained.
NMR (DMSO + TFA): 1.45-1.85: m: 4H; 2.40-3.35: m: 8H; 4.50 to 4.90 mt: 2H; 7.05-8.20: m: 20H.
D) 0.778 g of the compound of the preceding step are placed in 50 ml of anhydrous EtOH.
saturated with HCl at 0 ° C; it is left stirring in the refrigerator until dissolution then we leave 48 hours in the refrigerator. Evaporate dry and dry dryer under vacuum in the presence of potash for 2 hours. Dissolve in 80 ml EtOH
anhydrous, adds 206 μl of DIPEA and 93 μl of ethylenediamine. After 24 hours at TA, evaporated to dryness and then chromatographed on Sephadex ~ LH 20 eluting with methanol. The fractions containing the product are taken up by a mixture of 6 inl butanol and 6 ml of 1N HCl. After stirring and decantation, the organic is washed with 3 ml of 1N HCl and evaporated under vacuum. We take again by Et20, the solid formed is filtered off, washed with Et2O and dried to give 0.495 g of the compound expected.
MH +: 700 NMR: 1.40-1.80: m: 4H; 2.40-3.30: m: 8H; 3.80: s: 2H; 3.95: s: 2H;
4.50-4.80: mt: 2H; 7.00-8.05: m: 20H.

I, HCl: R 1, R 2 -ww /
_N C
- Rg - R3 - H '~' c ~ s - '~ N

~ s H
0.790 g of the compound obtained in EXAMPLE 2, step A is dissolved in 10 ml of EtOH saturated with HCl at 0 ° C. and is left stirring for 48 hours at 0 ° C. We evaporated to dryness and then taken up in EtOH and evaporated (twice). We take over by DCM
and evaporate (2 times). It is taken up in 20 ml of EtOH and then neutralized by addition of NEt3. 0.109 ml of diaminopropane is added and the mixture is left for 24 hours at RT. We evaporated to dryness, taken up by DCM, washed with KHSO4 / K2SO4. We then perform a chromatography on silica eluting with a mixture chloroform / methanol / concentrated ammonia (10/1/1, v / v / v). 0.12 g is obtained of expected compound.
MH '~: 638 ii I, HC1: Rt = \ \ I, g ~. ~ ~, ~ NR 6 R16 = RIS - g9 = g3 = g ~ ~ 4 ~ ~ _.N ~, C ~ _ H
AT) ~ i _ II: R1 = \ \ (, Ri6 RI7 ~ - ~ - ~ ~ 4 ~
VS
0.888 g of the compound of Preparation 3.2 and 0.957.g of the compound of Preparation 1.4 in 5 ml of DMF; add 1.22 g of BOP and then adjust to pH
= 7 by addition of NEt3. After stirring for 18 hours at RT, the mixture is evaporated dry then we take again by AcOEt. Washed with NaHCO 3 solution, KHSO4 / K2SO4, with a saturated solution of NaCl and then dried over Na2SO4 and evaporates. It is taken up with ether and a few drops of hexane and then squeeze and dried over Na 2 SO 4 to give 1.1 g of the expected compound.
B) 1 g of the compound of the preceding step is dissolved in 20 ml of saturated EtOH in HCl at 0 ° C. After 48 hours at + 4 ° C, evaporate and then resume by EtOH (3 times) then evaporate and resume by DCM (2 times). The residue is taken up in 20 ml of EtOH, then adjusted to pH = 7 by addition of NEt3 and 0.12 ml added ethylene diamine. After stirring for 18 hours at RT, the mixture is evaporated to dryness and then we taken up with DCM and washed with 10 ml of KHSO4 / K2SO4. Chromatography on silica eluting with a chloroform / methanol / ammonia mixture (10/1 / 0.1;
v / v / v) to obtain 0.640 g of the expected compound.

MH +: 650 NMR (DMSO + TFA): 0.8-1.2: m: 4H; 2.3-3.1: m: 4H; 4: s: 4H;
4.3-4.7: m: 4H; 5.4-5.7: mt: 2H; 6.8-7.9: m: 15H; 8.2: d: 1H.
By operating as in EXAMPLE 12, the compounds described in Table 11 below.

, HCl N ~ .C ~ NH
u Example R 1 R2 MH +

THIS \
\ /
31 ~ - 628 By operating according to the procedure of EXAMPLE 2, steps A and B, The compounds according to the invention are prepared according to the table below.

S02NH-CH-CH'-CONH- i H-CONR4R5 ii ~ ~ I ~ I CHZ
wi HCl w N ~ NH

Example -NR4R5 FC / NMR (DMSO + TFA) MH +

- 2.40-3.45: m: 12H; 4.00 : se: 4H;

4.60-4.90: m: 2H;

6.80-8.15: m: 16H

Me 0.6-0.9: mt: 6H; 2,2-3,626 m: 7H;

-N iPr 3.9: s: 4H; 4.3-4.9:
m: 3H;

6.7-7.8: m: 15H; 8 ,: d : 1H

Me 0.6-1.6 m: 8H; 1.6-1.9 652 : mt: 2H;

N 2.4-3.1: m: 4H; 3.2 to 4 : m; 6H;

4.2-4.8: m: 2H; 6.8 to 7.9 m: 15H;

Me. 8: s: 1H

I, HCI: R1 = \, ~ ~, NOT
~ -Rn-SRS + Rts-'CH2 '~ ~ 4R5 - N ~' C \ s -NOT
AT) i ~ -r1: R1 = 1 ~, ww '~ - \ /
~ = R17 = ~ ~ '~ ~ - Ris _' C ~ '~ .NR4R5 = _N
580 mg of the compound obtained in EXAMPLE 2, step A is mixed with 250 mg of paraformaldehyde and 60 mg of para-toluenesulphonic acid monohydrate in ml of benzene. Refluxed in a Dean Stark apparatus for 1 hour.
The The reaction medium is then washed with a saturated solution of NaHCO 3, a saturated solution of NaCl then dried over Na 2 SO 4 and evaporated to dryness. The residue is chromatographed on fine silica eluting with chloroform to obtain 165 mg'du expected compound.
NMR (DMSO + TFA): 1.55-1.85: m: 4H; 2.40-3.40: m: 8H; 4.60 to 5.50 m: 4H; 6.90-8.30: m: 16H.
B) The procedure is as in EXAMPLE 2, step B to obtain the expected compound which is purified by chromatography on Sephadex ~ LH 20 eluting with MeOH.
MH +: 636 NMR (DMSO + TFA): 1.50-1.80: m: 4H; 2.40-3.30: rn: 8H; 3.95: s 4H;
4.90-5.45: rn: 4H; 6.90-8.10: m: 16H.

I, HCl: Rt = \ ~ i, ~~ s g3 = Rts = RpH, Rs = Me, -NRaRs = _N ~ 'C ~ _ RRA ~
AT) i -II: R1 = '\ I, g ~ = ~~ = Rts = Rm_ me ~ _ ~ = ~ hT sRs 1.05 g of the compound of EXAMPLE 2, step A is mixed with 0.262 g of potassium carbonate in 12 ml of DMF and 423 μl of iodide of métl2yle. The next day, evaporate to dryness, then resume with water and AcOEt.
Wash with water, with saturated NaCl solution and then dry over Na 2 SO 4. We 0.6 g of the expected compound is obtained.
MH +. 595 NMR (DMSO + TFA): 1.50-1.80: m: 4H; 2.20-3.30: m. 8H; 2.55:

4.35-4.65: mt: 1H; 5.45-5.60: mt: 1H; 7.10-8.45: m: 16H.
B) The procedure is as in EXAMPLE 2, step B, to obtain the expected compound which is purified by chromatography on silica DCM / MeOH (93/7; v / v) then by a second chromatography on Sephadex ~ LH 20 eluting with methanol, F =
154 ° C.
MH +: 638 NMR (DMSO + TFA): 1.20-1.80: m: 4H; 2.10-2.40: mt: 2H; 2.50:
3H; 2.40-3.20: m: 6H; 4.00: s: 4H; 4.40-4.70: mt: 1H; 5,35-5,55: mt IH;
7.05-8.40: m: 16H.

I, HC1: R =
i Ri i ~ + Rl t - -CHz '~ ~ - Rts - Rte - H ~' ~ Rs - ~ C ~ ~ 6 _ ~ N
~ NRzRg '''~ N
H
AT) i II: R = yw g ~ + Ri ~ - -CHZ-, Rg - Ri6 = Rm - H ~ ~ 4 ~ _ -N
A mixture containing 0.79 g of the compound of Preparation 3.35 is prepared.
0.79 g of the compound of Preparation 1.1 and 1.06 g of BOP in 10 ml of DMF, adds DIPEA to obtain pH = 7 and is left stirring for 2 hours at RT.
We extracted with AcOEt, washed with H2O, a solution of NaOH, 0.25 N, a solution of 0.25 N HCl, water and then a saturated solution of NaCl. Dry on Na ~ SO4 then evaporated and the residue is chromatographed on silica eluting with mixed chloroform / MeOH (9515; v / v).
B) The expected product is obtained by proceeding as in EXAMPLE 2, step B. II
is purified by chromatography on Sephadex ~ LH 20 eluting with DCM / MeOH
(3/2; v / v) MH +: 636 NMR (DMSO + TFA): 1.40-1.80: m: 4H; 2.60-3.60: m: 9H; 3.95: s:
4H; 4.60-5.20: m: 2H; 6.20- 8.50: m: 15H.

i ~
I, HCl: R ~ \ \ I, g ~ _ /
RII
NOT
_N C ~~ 6 /
Ra = Ris = Ris - ~ RS + Ri ~ _ -CI ~ -CHz-, -NR4R3 = \
NOT
H
533 mg of the compound of Preparation 3.37 are ice-cold in 10 ml of DMF and 205 p.1 of DIPEA, 573 mg of the compound of Preparation I.2 are added, followed by leave one night at TA. It is diluted with 100 ml of Et 2 O and then the residue is chromatographed.
gum formed on Sephadex ~ LH 20 eluting with MeOH. The good fractions are combined, drained and the residue is taken up in 6 ml of butanol and 6 ml of HCI. The The organic phase is decanted and then washed with 3 ml of 1N HCl and evaporated to dryness.
The crystallized in Et2O, it is drained, dried to give 430 mg of compound expected.
MH +: 650 NMR (DMSO + TFA): 1.50-1.90: m: 4H; 2.50-3.80: m: 12H; 4.00: sd 4H;
4.45-4.80: m: 1H; 5.40: qd: 1H; 6.75-8.35: m: 15H.

~~, i -i, HCl: Rl = '~, g ~ -_, \ /
NRs N
~ '~ ° RI ~ ° ~ Ris = CH3 ~ NR4R5 = -N ~, C ~ -NRrRg N
H
AT) / i II: R, ° ww, ~ '~ \ /' ~ - Rs = Ri7 = ~ Ris = CH3, -NR4Rs = -N
A reaction medium containing 710 mg of the compound of the preparation is stirred.
3.2, 750 mg of the compound of Preparation I.8 and 0.98 g of BOP in 12 ml of DMF, DIPEA is added to bring to pH = 6. After 2 hours stirring at TA, extracted with AcOEt. The crude product obtained is chromatographed on silica in eluting with AcOEt / toluene (3/2, v / v). 0.52 g of the expected compound is obtained under form of a white solid.
B) The expected compound is obtained in the same manner as in EXAMPLE 2, step B.
It is purified on Sephadex ~ LH 20 eluting with DCM / MeOH (3/2; vlv).
MH +: 638 IuVIN (DMSO + TFA): 1.40-, 175: m: 4H; 2.30-3.20: m: 11H; 4.00: s 4H; 4.60-5.40: mt: 2H; 6, 80-7.15: m: 16H.

i I, HC1: R ~ _ \ /
~ NR6 NH
R3 = Rs = R16 = R17 = H, .NR4R5 = -N ~~ C, _ /
AT) 0.42 g of the compound of Example 2, Step A is treated with 10 ml of ethanol.
saturated hydrogen at -10 ° C. After 72 hours at + 4 ° C, evaporate dry then we Vacuum dry in the presence of potash. We obtain 0.51 g of non product purified in the form of hydrochloride.
B) 0.5 g of the ethyl imidate obtained in the preceding step are cooled to 0 ° C and 10 ml of saturated ammoniacal ethanol are poured at 0 ° C. Let's go back to YOUR. The the next day, evaporated to dryness and then chromatographed on silica gel.
eluting with a DCM-MeOH mixture (90/10; v / v) and then another chromatography on Sephadex ~ LH 20 eluting with MeOH. 0.15 g of the expected compound, Fc = 180 ° C.
MH- ~ ': 598 NMR (DMSO): 1.40-1.70: m: 4H; 2.25-3.10: m: 8H; 4.40-4.70: m 2H; 6.80-8.30: m: 18H.

i ~ -I, HC1: R1 = (R2 =
w ~ ° g9-Ri6 = Rice = H, NR4R3 = -N, , made '-C ~ NH _ ~~ N
C ~~ Z_ ~ ~~ 'NH_ ~ CHz) 3 ~~

NOT
A) 4-Aminobutyronitrile.
This compound is prepared according to J. Am. Soc., 1952, 74, 1836. In a bomb, 6.7 ml of 4-bromobutyronitrile and 35 ml of liquid ammonia are SO ° C.
After closing, the. bomb is left at RT for 48 hours. The residue is taken back with a solution of 50% NaOH and then extracted with ether; the organic phase is dried over Na 2 SO 4, evaporated to dryness and chromatographed on silica, eluting ,by DCM / MeOH / NH 4 OH (90/10 / 0.3, v / v / v) to give 1.07 g of the expected compound.
B) 0.62 g of the compound is treated in EXAMPLE 2, step A with 10 ml of ethanol saturated hydrochloric acid at -10 ° C. After 24 hours at + 4 ° C, evaporate dry, then dry under vacuum. 0.8 g of unpurified product in the form of hydrochloride.
VS) 20,,, _ II ', HCl: Rt = ww ~' Rz ~ = ~ -R16 = R ~~ = ~. ~ 4R5 = -N
~ NH r% NH
_ _VS
C ~ ldH-Z-CN r ~ ~ ~ ~ 3 ~
0.8 g of the compound which has been prepared in the above step are dissolved in 10 ml of EtOH and 108 mg of 4-aminobutyronitrile diluted in 10 ml are added dropwise.
EtOH.
The next day, evaporate dry, take again MeOH then add some drops hydrochloric ether. After evaporation to dryness, chromatography on silica in Eluting with DCM / MeOH (90/10, v / v) to obtain 0.38 g of the expected compound, F
=
I4 ~ C.
MH +: 665 D) At 0 ° C., 10 ml of saturated hydrochloric ethanol are poured at -10 ° C.
about 0.35 g of compound obtained in the previous step. We leave in the refrigerator one night. The next day evaporated to dryness and dried under vacuum in the presence of KOH. The product 6btenu (0.35 g) is dissolved in 80 ml of ethanol; we add drop by drop 43 ~ 1 of ethylene diamine in 10 ml of ethanol. After a night of agitation, evaporates dry and then chromatography on silica eluting with a mixture DCM / MeOH (50:50 v / v). 0.075 g of the expected compound is obtained, F =
I95 ° C.
MH +: 708 NMR (DMSO + TFA): 1.35-1.50: m: 4H; 1.80-2.00: mt: 2H; 2.40 to 3.20 : m: OH; 3.40: mt: 2H; 3.70: s: 4H; 4.40-4.70: mt: 2H; 6.70-8.05:
m 16H.

. f .._ -I, HCl: R, - ww '' Rz \! ' NOT
- RS - Ris -_ Ris ~ ~ - ~ 4Rs = _N ~ t) 2 ~ -C =
\ 'NR ~ Rg N
H
This compound is prepared by following the method described in EXAMPLE 12 from compounds of Preparations 1.9 and 3.2.
MH +: 626 i I, HCl: R, w. ~ '~ - \ /' ', ~ sNRs l ~ - ~ ~ Ris - RW H ~ -bars - - 'N''~ -C ~
NRTRg N
H
isomer (R, R).
AT) II: R i = ~, g ~. \ /, ~ - ~ - Rts - Ry H ~ _NR4Rs - - N
isomer (R, R).

1.44 g of the compound of Preparation 1.13 are mixed in 40 ml of acetonitrile with 700 μl of DIPEA and 1.81 g of the compound of Preparation 3.39.
The precipitated formed is dissolved in DCM and washed with KHSO4 / K2SO4, a saturated solution NaHCO3, a saturated solution of NaCl. Dry and evaporate to dryness, the product obtained (1.57 g) is used as it is in the next step.
NMR (DMSO): 1.40-1.60; m; 4H; 2.20-3.10: m: 8H; 4.40: qd: 1H;
4.60: qd: 1H; 6.80-8.35: m: 18H.
B) 1 g of the product of the preceding step are suspended in 30 ml of ethanol anhydrous saturated with HCl at 0 ° C. and allowed to stir for 24 hours at fridge.
It is evaporated to dryness, dried in a desiccator in the presence of potash. We place the product in 100 ml of anhydrous ethanol and 273 μl of DIPEA and 136 μl are added.
of ethylenediamine. After stirring for 24 hours at RT, evaporate to dryness, resumes in butanol / chloroform / HCl / 1 N (1/1/1, v / v / v). We decant then we the organic phase is washed with 1N HCl and evaporated to dryness. The residue is chromatographed on Sephadex ~ LH 20 eluting with MeOH. The product obtained is treated by a butanol / chloroform / 1N HCl (1/1/1, v / v / v) and then concentrated. After crystallization with Et20, the crystals are drained, washed with Et20 then dried. We obtains 198 mg of the expected compound.
a, D = + 38.1 ° (c = 1, DMF) MH +: 624 NMR (DMSO): 1.50-1.75: m: 4H; 2.40-2.70: mt: 2H; 2.75-3.25: m 6H; 4.05: s: 4H; 4.55: qd: 1H; 4.75: qd: 1H; 6.95-8.20: m: 16H;
8.50: t : 2H; 10.80: se: 2H.
Using the procedure described in EXAMPLE 43 and in the Preparations the different isomers described in Table after.

O
* * ii ~ ~ SO2-NH-CH-CH2-CO-NH-CH-C-N
ww I 'ICHZ
~ J
HN ~ N HC1 U

Example Isomer D5 - (c = 1, DMF) MH +

FC

44 (S, S) -41.9624 45 (R, S) +42.2624 46 (S, R) mp 195-201C 624 g ~ N (DMSO) of the EXAMPLE
44:
1.50 to 1.75 : m : 4H
; 2.40 to 2.70 : mt : 2H
;

2.75 to 3.25 : m : 6H
; 4.05 : s : 4H
; 4.55 : qd : 1H
; 4.75 : qd : 1H
; 6.95 to 8.20 m: 16H
; 8.50 : t : 2H
; 10.80 :
: 2H.

NMR (DMSO) of the EXAMPLE
45:
1.65 to 1.90 : m : 4H
; 2.40 to 3.45 : m : 8H
;

4.05 : s : 4H
; 4.55 to 4.85 : mt : 2H
; 6.95 to 8.25 : m : 16H
; 8.45 : t : 2H
; 10.80 is 2H.

NMR (DMSO
+ TFA) of the EXAMPLE
46:
1.50-1.80 : m : 4H
; 2.25 to 2.95 m: 4H
; 3.00 to 3.40 : m : 4H
; 4.00 : s : 4H
; 4.30 to 4.75 : mt : 2H
; 6.80 to 8.15 : m 16H.

EXAMPLE

I, HCl: R1 = Cl ~, Rz =, ~ ' Cl __ __ __ __ __ _ Ris Ri 'R9 ~ ~ bars N ~ C ~ _ ~ rRa N-H
isomer (R, R).
VS!
II: R1 =, ~ ~ Cl, R2 =
Cl Ris - R "= Rg -R3 = H, NR4Rs = -N
isomer (R, R).

These 2 compounds are prepared in 2 successive stages following the mode procedure described in EXAMPLE 27, steps C and D from the compound obtained at the Preparation 4.2 and (2,4,6-trichlorophenyl) sulfonyl chloride.
at -24 ° (c = 0.5: MeOH) MH +: 676 with trichlorinated isotopic profile.
NMR (DMSO): 1.50-1.65: m: 4H; 2.45-3.20: m: 8H; 3.95: s: 4H;
4.40-4.70: mt: 2H; 7.05: s: 5H; 7.45: d: 2H; 7.50: s: 2H; 7.90: d : 2H;
8.45: d: 1H; 8.80: d: 1H; 10.70: se: 1H.
u: NMR (DMSO): 1.50-1.60: m: 4H; 2.45-3.15: m: 8H; 4.40-4.55: qd 1H; 4.60-4., 75: qd: 1H; 7.05: s: SH; 7.40: d: 2H; 7.50: s: 2H;
7.70: d 10, 2H; 8.40. d. 1H; 8.70. d. 1H.
i I, HCl: Ri = ~ ~ ~, Ri = ~ Cl, R16 = R17 = R3 = R3 ° ~ ~ 4R5 = - ~, C ~ ~ rRs N
H
isomer (R, R) i II: Rl = ~ ~ ~, Ri ° Ci R16 = R1 = R9 = R3 = H, NR4R5 = -N
isomer (R, R) This compound is prepared in 2 stages by following the procedure described in bXEMPLB 43, from the compounds of Preparations 3.43 and 1.13.
I: aD = + 57 ° (c = 1; DMF) MH +: 658 and 660 NMR (DMSO + TFA): 1.40-1.60: m: 4H; 2.25-3.10: m: 8H; 3.95: s 4H; 4.45-4.65: mt: 2H; 6.80-8.05: m: 15H.
II: D = +6 t ° (c = I, DMF) ~ N (DMSO): I, 40-1.60: m: 4H; 2.25-3.10: m: 8H; 4.35-4.60: mt 2H; 6.85-8.05; m: 15H; 8.25: t: 2H.

EXEM ~ 'LE 49 ii I, HC1: R1 =. ~. ~. ~ '~ =' C ~ \ / ' _ i. ~ s Ris Ris Rs ~ ~ ~ NC
H
isomer (S), (R, S).
800 mg of the compound of Preparation 1.2 in 20 ml of DMF are mixed with 250 μl of DIPEA and 933 mg of the compound of Preparation 3.45. After one night with stirring at RT, the mixture is diluted with ether and then decanted. The formed gum is 10 triturated in ether and then chromatographed on Sephadex ~ LH 20 eluting by MeOH. The good fractions are evaporated and the residue is taken up in a mixed butanol / AcOEt / 1N HCl (1/1/1; v / v / v). The organic phase is decanted and evaporated to dryness, the residue is taken up in Et20, drained and dried to give 770 mg of expected compound.
MH +: 638 NMR (DMSO + TFA): 1.55-1.85: m: 4H; 2.05-3.50: m: 11H; 3.75: s 2H; 4.00: s: 2H; 4.45-4.95: mt: 1H; 6.70-8.20: m: 16H.

ii I, HCI: Ri = ~ ~ ', R3 = R16 = R ~ 9 ° H, 20 -i-fH- ~ N
O'C ~ \ / '~ = H ~ NR4Rs' _N ~. - ~ \
NRiRg N
H
This compound is prepared from the compound of Preparation 3.46 and compound of Preparation 1.2 following the procedure of EXAMPLE 5.
NMR (DMSO + TFA): 1.5-1.8: mt: 6H; 2.7-3.6: m: 6H; 3.6: mt: 3H;
3.6-3.9: mt 8H; 4.6-4.8: mt: 2H; 6.5: d: 2H; 6.8-7: m: 4H; 7.4 to 8.1 : m 8H;
8.4: d: 2H.

i I, HCl: R ~ ~ ~ ~ ~, ~ = Ris = Ri9 - H
NOT
N ~ 6 -C.
-N_ i H_ _ _ N, ~ = H ~ ~ 4Rs = _N ~, _ ~ \ _ N
~ Rz O

0.4 g of the compound obtained in the preceding example is dissolved in 8 ml of TFA and 0.2 ml of thioanisol. After stirring for 24 hours at RT, the mixture is evaporated residue is taken up by Et20 and drained. Wash several times with ether and then dry sure Na2SO4 to obtain 0.385 g of the expected compound.
MH '~': 700 NMR (DMSO + TFA): 1.7-2.1: mt: 6H; 2.5: d: 2H; 2.9-3.7: m: 13H;
3.7 to 4: m: I3H; 4.8: mt: 1H; 5.3: mt: 1H; 7.2 to 8.3: m: HOl; 8.5: s: IH.

i .-I, HCl: R 1 = R 1, R 3 = R 6 = R 19 = H, _N_CH_ - _ N ~ ~ = H ~ 4Rs = _N, _ ~, NR6 _ N
OH
The compound obtained in the preceding example is dissolved in 50 ml of MeOH containing 0.106 g of KOH. After stirring for 18 hours at RT, acidifies at pH = 2 by addition of a saturated solution of HCl gas in dioxane. We evaporate, take up with 5 ml of water and triturate. We drain, wash with water then dried to obtain 0.160 g of the expected compound.
MH + = 604 i I, HCI: R1 = ~ ~ ~, Rz -NRs N
_ /
R16 = R1 = Rg-R3-H, NR4Rs = -N, Cy ~ Rs isomer (R, R) This compound is prepared according to the procedure described in EXAMPLE 43 but using naphth-1-ylsulfonyl chloride in Preparation 3.38.
a25 - -18 ° (c = 1; DMF) D
MH +: 624 NMR (DMSO): I, 50-1.75: m: 4H; 2.25-3.20: m: 8H; 4.05: s: 4H;
4.50-4.75: mt: 2H; 6.85-8.70: m: 18H (16H aromatics + 2H).

i I, 2HC1: Rt = ~ ~ ~, R2 = ~ ~, Ris - ~ _ ~ - ~ Rm. = _CH3 ~ NR4R5 = I, C r ~ -~ s NH
This product is prepared in 2 steps according to the procedure described for EXAMPLE 2 using the compounds from Preparations 3.2 and 1.14.
MH +: 638 NMR (DMSO + TFA): 0.95: sd: 3H; 1.30-1.60: m: 4H; 2.40-3.40: m 8H; 4.00: sd: 4H; 4.75: mt: 1H; 6.65-8.15: m: 16H.

ii I, 2HC1: R ~ _ ~ ~ ~, Ra. _, NR i Ris - Rv = ~ - Ru -H ~ bars = -NJ ~ C ~ 6 - -C ~~ - (C ~) 2_ ~ z isomer (R, R) I, 30 g of the product obtained according to the procedure of EXAMPLE 43, step A
are stirred for 18 hours at 4 ° C. in 45 ml of methanol containing 22 HC1 g gas. The reaction medium is concentrated under vacuum, reevaporated twice with MeOH
and the residue dried under vacuum in the presence of KOH. To this product dissolved in 250 ml of methanol is added in 90 minutes 0.18 ml of ethylenediamine diluted in 15 ml of methanol and stirred for another 18 hours. The reaction medium is concentrated under vacuum to 10 ml, an Et 2 O / HCl solution is added to bring to pH = 3 and concentrated dried up. The residue is purified by partition chromatography on Sephadex ~ G
25 in using the solvent system nBuOH / iPrOH / H20 (4 / 0.2 / 5, v / v / v). We isolate first the product with cyclized amidine (410 mg) as described in The example 43 then the product with the expected open amidine (410 mg).

WO 97/25315 8. ~ PCT / FR97 / 00026 aD = + 37.6 ° (c = O, S, DMF) NMR (DMSO + TFA): 1.50-1.70: m: 4H; 2.30-3.15: m: OH; 3.70: t 2H; 4, SS: t: 1H; 4.70: t: 1H; 6.90-8.10: m: 16H.
S
EXAMPLE S6 Glide dose 10 mg Composite of EXAMPLE 43 (weight expressed in equivalent in non salified form) 10.0 mg Lactose monohydrate 200 mesh QS

Methylhydroxypropylcellulose 6 mPa.s 3.0 mg Sodium carboxymethylcellulose reticulate 4, S mg Magnesium starate 1, S mg Water purifies for wet granulation For a "white-opaque" gel size n 3 filled 1 mg mg 1S EXAMPLE 57 Compressed tablet back SO mg Composite of EXAMPLE 43 (weight expressed in equivalent in non-salified form) 50.0 mg Lactose monohydrate 200 mesh QS

Microcrystalline cellulose SO ~ m 27.0 mg Methylhydroxypropylcellulose 6 mPa.s 3.6 mg Sodium carboxymethylcellulose S, 4 mg Magnesium starate 1.8 mg Water purifies for wet granulation For a tablet end mill 180 mg 2S E ~ MPLE S8 Glucose Dose Img Composite of EXAMPLE 43 (weight expressed in equivalent in non salified form) 1.0 m ~;

Lactose monohydrate 200 mesh Methylhydroxypropylcellulose 6 mPa. s 3, 0 m ~;

Sodium carboxymethylcellulose 4, S m ~;

Magnesium starate 1, S m ~;

Water purifies for wet granulation For a "white-opaque" gel size n 3 filled 100 mg.

Claims (11)

1. A compound of the formula:

in which:
- R1 represents a phenyl, a naphthyl, a tetrahydronaphthyl, a quinolyl or isoquinolyl, said rings being unsubstituted or substituted one or several times by R10;
- R2 represents an unsubstituted or substituted phenyl one or more times by R11, unsubstituted or substituted phenyl(C1-C4)alkyl one or more times by R11, naphthyl unsubstituted or substituted one or more times by R11, or a cyclohexyl unsubstituted or substituted one or more times by R11;
- or R2 and R9 are bonded together and constitute a non-(C3-C5)alkylene substituted or substituted by R12 or a (C2-C4)alkylene interrupted by an atom oxygen or a sulfur atom and unsubstituted or substituted by R12;
- or R2 and R9 together with the carbon atom and the nitrogen atom to which they are linked constitute the unsubstituted or substituted tetrahydroisoquinoline a or more times with a halogen, a hydroxy, a (C1-C4)alkyl, a (C1-C4)alkoxy, or a benzyloxy;
- R3 represents hydrogen or hydroxy;
- R4 and R5 each independently represent hydrogen or a (C1-C4)alkyl;
- or R4 and R5 together with the nitrogen atom to which they are attached constitute a heterocyclic radical chosen from pyrrolidin-1-yl, piperid-1-yl, perhydroazepin-1-6le, morpholin-4-ytle, 4-oxopiperid-1-yl, dihydropyrrol-1-yle and dihydroimidazol-2-yl, said heterocyclic radicals being non substituted or substituted one or more times with R13;
- R6 represents hydrogen or optionally represents benzyl not substituted or substituted on phenyl one or more times by R13 or a band ZR14 when R7 is hydrogen;
- R7 represents hydrogen or a (C1-C4)alkyl;
- R8 represents hydrogen; unsubstituted or substituted benzyl on the phenyl one or more times by R13; or a ZR14 group;
- or R7 and R8 together with the nitrogen atom to which they are attached constitute a heterocyclic radical chosen from pyrrolidin-1-yl, piperid-1-yl, perhydroazepin-1-yl, morpholin-4-yl, tetrahydropyrimidin-2-yl, piperazin-1-yl and piperazin-1-yl substituted in position 4 by a (C1-C4)alkyl or a benzyl;
- or, when R7 is hydrogen, R6 and R8 are optionally bonded together to form an unsubstituted or substituted (C2-C4)alkylene one or several times with a (C1-C4)alkyl;
- R9 represents hydrogen, a (C1-C4) alkyl or a phenyl (C1-C4) alkyl not substituted or substituted on phenyl one or more times by R11;
- R10 represents a halogen, a (C1-C4)alkyl, a (C1-C4)alkoxy, a hydroxy, an amino, a (C1-C4)alkylamino or a di(C1-C4)alkylamino;
- R11 represents a halogen, a (C1-C4)alkyl, a trifluoromethyl, a phenyl, a hydroxy, a (C1-C4) alkoxy or a benzyloxy;
- or R11 is in the ortho position of the phenyl representing R2 and forms with R3 a methylene group or an ethylene group;
- or R11 is in the ortho position of the phenyl representing R2 and forms with R9 a methylene group or an ethylene group;
- R12 represents a halogen, a (C1-C4)alkyl, a hydroxy, a (C1-C4)alkoxy, benzyloxy, oxo, phenyl, acetyloxy or trifluoroacetyloxy;
- R13 represents a (C1-C4)alkyl, a halogen or a hydroxy;
- R14 represents a methyl, an amino, a (C1-C4)alkylamino, a di(C1-C4) alkylamino, a tri(C1-C4)alkylammonium, an amidino, a (C1-C4)alkylamidino, a guanidino, a (C1-C4)alkylguanidino, a hydroxy, a (C1-C4)alkoxy, a (C1-C4)alkoxycarbonyl, a group -AlkN(R15)Alk'N(R'15)2, or a heterocyclic radical chosen from pyrrolidin-1-yl, piperidin-1-yl, perhydroazepin-1-yl, pyridyl, imidazolyl, dihydroimidazolyl, imidazolidinyl, pyrimidinyl and indolyl;
- R15 and R'15 independently represent hydrogen or a (C1-C4)alkyl;
- R16 represents hydrogen or a methyl, or R16 forms with R9 a group methylene;
- R17 represents hydrogen or methyl;
- Alk and Alk' independently represent a (C1-C4)alkylene;
- Z represents a (C2-C12)alkylene or an interrupted (C1-C6)alkylene or substituted by a (C5-C7)cycloalkyl or by a phenyl;
- C* represents an asymmetric carbon atom;
as well as its pharmaceutically acceptable salts with mineral acids or organic. 2. A compound of formula (I) according to claim 1, in which:
- R1 represents a phenyl, a naphthyl, a tetrahydronaphthyl, a quinolyl or isoquinolyl, said rings being unsubstituted or substituted one or several times by R10;
- R2 represents an unsubstituted or substituted phenyl one or more times by R11, unsubstituted or substituted phenyl(C1-C4)alkyl one or more times on phenyl by R11 or unsubstituted or substituted naphthyl one or several times by R11;
- or R2 and R9 are bonded together and constitute a non-(C3-C5)alkylene substituted or substituted by R12 or a (C2-C4)alkylene interrupted by an atom oxygen or a sulfur atom and unsubstituted or substituted by R12;
- or R2 and R9 together with the carbon atom and the nitrogen atom to which they are linked constitute the unsubstituted or substituted tetrahydroisoquinoline a or more times with a halogen, a hydroxy, a (C1-C4)alkyl, a (C1-C4)alkoxy, or benzyloxy;
- R3 represents hydrogen or hydroxy;
- R4 and R5 each independently represent hydrogen or a (C1-C4)alkyl;

- or R4 and R5 together with the nitrogen atom to which they are attached constitute a heterocyclic radical chosen from pyrrolidin-1-yl, piperid-1-yl, perhydroazepin-1-yl, morpholin-4-yl and 4-oxopiperid-1-yl, said radicals heterocyclic being unsubstituted or substituted by R13;

- R6 represents hydrogen or optionally represents a benzyl not substituted or substituted on phenyl one or more times by R13 or a band ZR14 when R7 is hydrogen;

- R7 represents hydrogen or a (C1-C4)alkyl;

- R8 represents hydrogen; unsubstituted or substituted benzyl on the phenyl one or more times through R13; or a ZR14 group;

- where R7 and R8 together with the nitrogen atom to which they are attached constitute a heterocyclic radical chosen from pyrrolidin-1-yl, piperid-1-yl, perhydroazepin-1-yl, morpholin-4-yl, piperazin-1-yl and piperazin-1-yl substituted in position 4 by a (C1-C4)alkyl or a benzyl;

- or, when R7 is hydrogen, R6 and R8 are optionally bonded together to form an unsubstituted or substituted (C2-C4)alkylene one or several times with a (C1-C4)alkyl;

- R9 represents hydrogen, a (C1-C4) alkyl or a phenyl (C1-C4) alkyl not substituted or substituted on phenyl one or more times by R11;

- R10 represents a halogen, a (C1-C4)alkyl, a (C1-C4)alkoxy, a hydroxy, amino, (C1-C4)alkylamino or di(C1-C4)alkylamino;

- R11 represents a halogen, a (C1-C4)alkyl, a hydroxy, a (C1-C4) alkoxy or benzyloxy;

- R12 represents a halogen, a (C1-C4)alkyl, a hydroxy, a (C1-C4) alkoxy, benzyloxy, oxo or phenyl;

- R13 represents a (C1-C4)alkyl, a halogen or a hydroxy;

- R14 represents a methyl, an amino, a (C1-C4)alkylamino, a di(C1-C4) alkylamino, a tri(C1-C4)alkylammonium, an amidino, a (C1-C4)alkylamidino, a guanidino, a (C1-C4)alkylguanidino, a hydroxy, a (C1-C4)alkoxy, a (C1-C4)alkoxycarbonyl, a group AlkN(R15)Alk'N(R'15)2, or a heterocyclic radical chosen from pyrrolidin-1-yl, piperidin-1-yl, perhydroazepin-1-yl, pyridyl, imidazolyl, dihydroimidazolyl, imidazolidinyl, pyrimidinyl, and indolyl;
- R15 and R'15 represent independently of one another hydrogen or a (C1-C4)alkyl;
.
- R16 represents hydrogen;

- R17 represents hydrogen;
- Alk and Alk' represent independently of one another a (C1-C4)alkylene;
- Z represents a (C2-C12)alkylene or an interrupted (C1-C6)alkylene or substituted by a (C5-C7)cycloalkyl or by a phenyl;
as well as its pharmaceutically acceptable salts with mineral acids or organic. 3. A compound of formula (I) according to claim 1, corresponding to at least one of the following conditions:
a - R1 represents a naphthyl, a quinolyl or a trichlorophenyl; R2. R3, R4, R5, R6, R7, R8, R9, R16 and R17 being as defined in claim 1;
b - R2 represents a phenyl unsubstituted or substituted by R11; R1, R3, R4, R5, R6, R7, R8, R9, R16 and R17 being as defined in claim 1;
c - NR4R5 represents a pyrrolidin-1-yl group, R1, R2, R3, R6, R7, R8, R9, R16 and R17 being as defined in claim 1;
d - C(NR6)NR7R8 represents 4,5-dihydroimidazol-2-yl; R1, R2, R3, R4, R5, R9, R16 and R17 being as defined in claim 1;
e - R3 = R9 = R16 = R17 = H, R1, R2, R4, R5, R6, R7, and R8, being such that defined in claim 1;
as well as its pharmaceutically acceptable salts with mineral acids or organic. 4. A compound according to claim 1, of formula:

in which :
- R2a represents an unsubstituted or substituted phenyl in the meta position or para by R11; naphth-1-yl or naphth-2-yl;
- R1, R6, R7, R8 and R11 are as defined in claim 1;
as well as its pharmaceutically acceptable salts with mineral acids or organic. 5. A compound according to any one of claims 1, 2, 3 or 4, of formula:

in which:
- R1a represents a naphth-1-yl, a naphth-2-yl, a 2, 3, 6-trichlorophenyl or quinol-2-yl;
- R2a is as defined in claim 4;
as well as its pharmaceutically acceptable salts with mineral acids or organic. 6. A compound of formula (Ia) according to claim 5, wherein R2a is unsubstituted or substituted in the meta position or in the para position by R11. 7. A compound according to any one of claims 1, 2, 3, 4, 5 or 6, exhibiting an (R,R) isomerism on the carbon atoms marked C*. 8. A process for the preparation of a compound of formula (I) according to the claim 1, characterized in that:

a1) a compound of formula is treated:

where R1, R2, R3, R4, R5, R9, R16, R17 and C* have the definitions given in claim 1, in the form of a pure enantiomer or of a mixture of isomers in any proportions, with an alcohol of formula R-OH in which R represents a (C1-C4)alkyl, in an acid medium, to form an intermediate imidate on which an amine of formula HNR7R8 is reacted (III) or a diamine of formula H2NR6R8NH2 (IV) in which R6, R7, R8 have the definitions given in claim 1;
b1) the compound of formula (I) thus obtained is isolated as it is or in the form of salt, c1) if necessary, another salt of the compound of formula (I) is prepared. 9. A process for the preparation of a compound of formula (I), according to the claim 1, characterized in that:
a2) a compound of formula is treated:

in which X represents hydrogen or a Boc group, and R4, R5, R16, R17 and C* are as defined in claim 1, in the form of a enantiomer pure or of a mixture of isomers in any proportions, qwith an alcohol of formula R-OH in which R represents a (C1-C4)alkyl, in acid medium, to form an intermediate imidate on which is reacted an amine of formula HNR7R8 (III) or a diamine of formula H2NR6R8NH2 (IV) in which R6, R7, R8 have the definitions given in claim 1:
b2) the compound thus obtained of formula is coupled:
- either with a compound of formula:
wherein R2, R3 and R9 are as defined in claim 1, and Pr represents a protective group, then, after deprotection of the amine in acid medium, a sulfonyl halide of formula R1S02Hal is reacted in wherein R1 is as defined in claim 1 and Hal represents a halogen;

- either with a compound of formula:

in which R1, R2, R3 and R9 are as defined for (I) in the reference specification 1:

c2) the compound of formula (I) thus obtained is isolated as such or as form of salt;

d2) if necessary, another salt of the compound of formula (1) is prepared. 10. A compound of the formula:

where R1, R2, R3, R4, R5, R9, R16, R17 and C* have the definitions given in claim 1. 11. Pharmaceutical composition comprising as active ingredient a compound according to any one of claims 1 to 7 in association with a pharmaceutically acceptable excipient.