CA2039706C - Method for preparing amino acid derivatives and therapeutical applications of same - Google Patents

Method for preparing amino acid derivatives and therapeutical applications of same Download PDF

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CA2039706C
CA2039706C CA002039706A CA2039706A CA2039706C CA 2039706 C CA2039706 C CA 2039706C CA 002039706 A CA002039706 A CA 002039706A CA 2039706 A CA2039706 A CA 2039706A CA 2039706 C CA2039706 C CA 2039706C
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oxo
group
propyl
phenyl
acetylthiomethyl
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CA2039706A1 (en
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Jean-Christophe Plaquevent
Denis Danvy
Thierry Monteil
Helene Greciet
Lucette Duhamel
Pierre Duhamel
Claude Gros
Jean-Charles Schwartz
Jeanne-Marie Lecomte
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Bioprojet SC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
    • C07F9/3882—Arylalkanephosphonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
    • C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems

Abstract

Amino acid drivatives, enkephalinase and ACE inhibitors, of the formula (1a) and (1b), wherein Rl represents a biphenyl group or one of the groups (a), wherein Z, Y and n have the meanings (b) or (c), wherein R'1, represents a hydrogen atom, a lower alkyl group; a phenyl group; a lower phenylalkylene group. R2 represents a hydrogen atom; a lower alkyl group; a lower hydroxyalkylene group; a lower phenylalkylene group; a lower hydroxyphenylalkylene group; a lower aminoalkylene group; a lower guanidinoalkylene group; a lower mercaptoalkylene group; a lower thioalkylene lower alkyl group; a lower imidazolylkylene group; a lower indolylalkylene group; a lower carbarnylalkylene group; a lower carboxyalkylene group or one of the groupings (d), where Z, Y and n have the meanings (e), X indicates a grouping responsible for chelating the zinc atom of enzymes, enkephalinase and ACE, and may be selected from the group which comprises a mercaptornethyl; hy-droxamic acid; an N-carboxyalkyl of the formula (f), wherein R3 represents a benzyl lower alkyl radical, or a benzyl lower alkoxy radical; phosphorus-containing derivatives of the formula (g) or (h).

Description

AMII~TO ACID DER1:YATIPES. THE PROCE~ FOR THEIR PREpaRaTTnu A$I> THEIR ~PPLICATIOAS TO THERAPY
The present invention relates to amino acid derivatives, mixed inhibitors of the enkephalinase enzyme (EC 3.4.24.11) and angiotensin-convertase enzyme <EC 3.4.15.1, ACE>.
It also relates to the process for preparing these amino acid derivatives.
It further relates to the application of these amino acid derivatives to the preparation of drugs.
European patent EP-A-0.038.758 CRoques et al.> discloses amino acid derivatives having enkephalinase-inhibiting properties, a peptidase which degrades enkephalins in particular. Enkephalin methionine and leucin~=_ are peptides discovered in the brain which are endogenous ligands c~f the morphine receptor. Moreover, auricular natriuretic factor ;A1~1F) :Ls an endogenous peptide which exerts vasorelaxing, diuretic; and natriuretic effects, potentially beneficial in the treatment of cardiovascular and renal diseases. ANF is a substrate for enkephal.inase and inhibitors of this peptidase slow down its degradation, increase its plasma levels and induce antihypertensive, diuretic and natriuretic effects.
It is also known, for example in French patent n' 2.623.498 filed in the applicant's name, that certain amino acid derivatives exert an inhibiting effect on the enzyme converting angiotensin I to angiotensin II <ACE), angiatensin II being an active vasomotor substance considered to be the agent responsible for various forms of hypertension. These compounds are thus useful in the treatment of hypertension and cardiac insufficiency.

2o~s~~~
Amino acid derivatives of the kind described in European patent EP-A-0.038.758 or in French patent n' 2.623.498 are thus known to exert an inhibiting effect on either one or the other of the two enzymes, enkephalinase and ACE, or on both these enzymes at the same time. However, in the latter case, their enkephalinase- and ACE-inhibiting properties are exerted to different degrees. Research up until the present has mainly concentrated on developing amino acid derivatives which have as wide a field of specificity as possible on one or the other of the two enzyme activities described above.
Aonetheless, the advantage of having amino acid derivatives at one's disposal which could inhibit enkephalinase and ACE enzymes with the same degree of efficacy is evident. These agents would prevent the formation of angiotensin II and promote the beneficial effects of endogenous ANF at the same time. Furthermore, inactivation of another peptide, bradykinin, seems to depend on both ACE and enkephalinase .
the simultaneous inhibition of these two peptidases is likely to promote the known vasorelaxing effects of bradykinin.
The applicant thus found it would be interesting, within the context of extending his previous research, to develop amino acid derivatives likely to inhibit the two enzymes, enkephalinase and ACE, to an equal degree, in particular through the careful selection of _ certain substituents.
One aim of the invention is thus to provide amino acid derivatives which are mixed inhibitors of enkephalinase and ACE
enzymes.
Another aim of the invention is to propose a process for preparing these mixed Inhibitors.
Yet another aim of the invention is to provide pharmaceutical compositions which contain these amino acid derivatives as the active principle.
The amino acid derivatives, mixed inhibitors of enkephalinase and ACE enzymes in accordance with the invention, have the following general formulae X - CH C - NH - CH - COOH
CH2 0 R2 (Ia) or X - C - C - NH - CH - COOH
il CH 0 R2 (Ib) wherein R1 represents for the formula Ia a phenyl group mono- or polysubstituted by a halogen atom, particularly fluorine, a biphenyl group or one of the following groups:
Z
(CH2)n Y~
wherein Z, Y and n have the following meanings:
Z Y n 2p ~970~
or OR's wherein R'1 represents a hydrogen atom, a lower alkyl group, a phenyl group, a lower phenylalkylene group, for the formula (Ib), R1 has the meaning defined hereinabove and can also be a phenyl group.
R2 represents a hydrogen atom, a lower alkyl group, a lower hydroxyalkylene group, a phenyl group, a lower phenylalkylene group, a lower hydroxyphenylalkylene group, a lower aminoalkylene group, a lower guanidinoalkylene group, a lower mercaptoalkylene group, a lower thioalkylene lower alkyl group, a lower imidazolylalkylene group, a lower indolylalkylene group, a lower carbamylalkylene group, a lower carboxyalkylene group or one of the following groups:
Z
(CH2)n wherein Z, Y and n have the following meanings:
Z Y n f$

X designates the group responsible for chelating the zinc atom of the enzymes (enkephalinase and ACE) and can be chosen from the group consisting of a mercaptomethyl, hydroxamic acid, an N-carboxyalkyl of formula R3 represents a lower alkyl radical, a benzyl lower alkyl radical or a benzyl lower alkoxy radical, phosphorated derivatives of formula to HO 0 jP-(CHZ) m -NH-P (OH) z HO or O m = 0 or 1.
In particular, the present invention provides amino acid derivatives wherein they correspond to the general formula:

CHZ 0 Rz (Ia) or (Ib) wherein R1 represents one of the following groups:
Z
j(CHZ)n ~Y

5a wherein Z and Y are O and n is 1 or 2, R2 represents a hydrogen atom, a lower alkyl group, a lower hydroxyalkylene group, a phenyl group, a lower phenylalkylene group, a lower hydroxyphenylalkylene group, a lower aminoalkylene group, a lower guanidinoalkylene group, a lower mercaptoalkylene group, a lower alkylthio lower alkylene group, a lower imidazolylalkylene group, a lower indolylalkylene group, a lower carbamylalkylene group, a lower carboxyalkylene group or one of the following groups:
j(CH2)n z ~Y
wherein Z, Y and n have the meanings defined below:
Z Y n X designates a mercaptomethyl group.
The present invention also particularly provides amino acid derivatives wherein they correspond to the general formula:

CHZ 0 Rz (Ia) or 5b (Ib) wherein R1 represents one of the following groups:
Z
j(CHZ)n ~Y
wherein Z and Y are O and n is 1 or 2, R2 represents a hydrogen atom, a lower alkyl group, a lower hydroxyalkylene group, a phenyl group, a lower phenylalkylene group, a lower hydroxyphenylalkylene group, a lower aminoalkylene group, a lower guanidinoalkylene group, a lower mercaptoalkylene group, a lower alkylthio lower alkylene group, a lower imidazolylalkylene group, a lower indolylalkylene group, a lower carbamylalkylene group, a lower carboxyalkylene group or one of the following groups:
Z
j(CHZ)n ~Y
wherein Z, Y and n have the meanings defined below:
Z Y n CH2 CHz 2 X designates a mercaptomethyl group, wherein the mercaptomethyl and carbonyl functions are protected.

5c The term "lower alkyl groups" refers to linear or branched chain alkyl groups having 1 to 6 carbon atoms and, preferably, 1 to 4 carbon atoms.
The term "lower alkylene groups" refers to alkylene groups having 1 to 6 carbon atoms and, preferably, 1 to 4 carbon atoms.
The amino acid derivatives in accordance with the invention include in their structure natural amino acids and, more particularly, glycine, alanine, valine, leucine, serine, threonine, cysteine, methionine, aspartic acid, aspargine, glutamic acid, glutamine, lysine, arginine, phenylalanine, tyrosine, tryptophan, histidine, with the exception of proline, as well as non-natural amino acids such as norvaline, norleucine, 3-(3,4-methylenedioxy phenyl) alanine, methionine sulfoxide.
The amino acid derivatives of formula (Ia) or (Ib) in accordance with the invention are new compounds, with the exception of compounds wherein R1 represents a phenyl group mono- or polysubstituted by a halogen atom, already described in European Patent EP-A-0.038.758.
The preferred amino acid derivatives in accordance with the invention are derivatives of formula (Ia) or (Ib) wherein the X group which chelates the zinc atom is a mercaptomethyl group.
These amino acid derivatives can also be in the form of a "prodrug" where the mercaptomethyl and carboxyl groups are protected as follows I

and H- f-R1 R2 O
R~-S-CH2-C-C-N-CH-C-O-R4 O H
wherein Ra represents, in particular, a linear or branched alkyl goup, a phenyl or phenylalkyl group, the latter two groups possibly being mono- or polysubstituted on the phenyl ring, or linear or branched susbtituents including one or more oxygen atoms, and wherein R..
represents a linear or branched aliphatic acyl radical, an aromatic acyl radical possibly mono- or polysubstituted, or a linear or branched acyl radical including one or more oxygen atoms.
The following can be cited as particularly preferred compounds of formula (Ia) or (Ib) .
- N-(RS>-f1-oxo- 2-<mercaptomethyl>- 3-C3,4-methylenedioxy phenyl) propyll glycine and its optically pure forms, - N-CRS>-tl-oxo- 2-(mercaptomethyl>- 3-<3,4-methylenedioxy phenyl) propylJ-<S)-alanine and its optically pure forms, - N-(RS>-(1-oxo- 2-(mercaptomethyl>- 3-(3,4-methylenediaxy phenyl) propyil-(S>-2-aminobutyric acid, - N-(RS>-L1-oxo- 2-(mercaptomethyl>- 3-(3,4-methylenedioxy phenyl) propyl)-(S>-norvaline, - N-<RS)-I1-oxo- 2-<mercaptomethyl>- 3-(3,4-methylenedioxy phenyl) propyll-(S>-norleucine, - N-CRS>-f1-oxo- 2-(mercaptomethyl)- 3-<3,4-methylenedioxy phenyl) propyll - (S)-leucine, - N-(RS)-tl-oxo- 2-<mercaptomethyl>- 3-(3,4-methylenedioxy phenyl) propyll-tS>-tryptophan, - N-CRS>-(1-oxo- 2-(mercaptomethyl)- 3-C3,4-methylenedioxy phenyl) propyll-(S>-phenylalanine, - N-CRS>-(1-oxo- 2-(mercaptomethyl>- 3-(3,4-methylenedioxy phenyl) propyl7-(S>-tyrosine, - N-(S>-(1-oxo- 2-(mercaptomethyl>- 3-(3,4-methylenedioxy phenyl) propyl7-CS>-serine - N-<S)-L1-oxo- 2-(mercaptomethyl>- 3-(3,4-methylenedioxy phenyl) propyll-CS>-methionine, - N-(S>-L1-oxo- 2-(mercaptomethyl>- 3-(3,4-methylenedioxy phenyl) propylJ-CRS>-methionine sulfoxide, - N-(S>-(1-oxo- 2-(mercaptomethyl>- 3-(3,4-methylenedioxy phenyl) propylJ-<RS)-3-(3,4-methylenedioxy phenyl)-alanine, - N-(RS>-fl-oxo- 2-Cmercaptomethyl)- 3-(3,4-ethylenedioxy phenyl) propyl7-glycine, - N-(RS>-f1-oxo- 2-(mercaptomethyl>- 3-<3,4-ethylenedioxy phenyl) propyll-(S>-alanine, - N-CRS)-L1-oxo- 2-(mercaptomethyl>- 3-(2,3-methylenedioxy phenyl) propylJ-glycine, - N-<RS)-(1-oxo- 2-(mercaptomethyl>- 3-(4-phenoxy phenyl) propylJ-glycine, - N-(RS>-L1-oxo-2-<mercaptomethyl)-3-(4-phenoxy phenyl) propylJ-(S>-alanine, - N-<RS>-L1-oxo-2-Cmercaptomethyl>-3-C4-phenyl phenyl) prapyl7-glycine and its optically pure farms, - N-t1-oxo-2-(mercaptomethyl)-3-(4-phenyl phenyl) propylJ-<S>-alanine and its optically pure forms, - N-(1-oxo-2-(mercaptomethyl)-3-(4-phenyl phenyl) propylJ-<S>-leucine, - N-CRS>-L1-oxo- 2-(mercaptomethyl>- 3-(3-fluoro phenyl) propylJ-glycine, ;~ 8 - N-(RS)-f1-oxo-2-(mercaptomethyl)-3-(3-fluoro phenyl) propylJ-(S)-alanine, - N-(RS)-f1-oxo-2-(mercaptomethyl)-3-(3,4-difluoro phenyl) propylJ-glycine, - N-(RS>-fl-oxo-2-Cmercaptomethyl>-3-(3,4-difluoro phenyl) propylJ-(S>-alanine, - N-CRS)-f1-oxo-2-(mercaptomethyl>-3-(3,5-difluoro phenyl) propyl7-glycine and its optically pure forms, - N-(RS>-f1-oxo-2-(mercaptomethyl>-3-(3,5-difluoro phenyl) propylJ-(S>-alanine, - N-(RS)-fl-oxo-2-(mercaptomethyl>-3-(5'-indanyl> propylJ-glycine, - N-<RS)-f1-oxo-2-(mercaptomethyl>-3-(5'-indanyl> propylJ-(S>-alanine, - N-tRS)-fl-oxo-2-(mercaptomethyl)-3-(2',3'-dihydro-5'-benzofuranyl>
propyl)-glycine, - N-(RS)-f1-oxo-2-(mercaptomethyl)-3-(2',3'-dihydro-5'-benzofuranyl) propyl7-CS)-alanine, - N-CRS>-f1-oxo- 2-(mercaptomethyl)- 3-(4-methoxy phenyl) propyll-glycine, - N-CRS)-f1-oxo- 2-(mercaptomethyl>- 3-(4-methoxy phenyl) propyll-(S)-alanine, - N-(S)-fl-oxo- 2-(mercaptomethyl>- 3-t4-methoxy phenyl) propyl7-glycine, - N-CS>-f1-oxo-2-<mercaptomethyl>- 3-(4-methoxy phenyl) propylJ-(S)-alanine, - N-(RS>-f1-oxo- 2-(mercaptomethyl>- 3-(4-ethoxy phenyl) propyll-glycine, - N-. (RS>-f 1-oxo- 2- <mercaptomethyl )- 3- (4-ethoxy phenyl > propyl J - CS)-alanine, - N-CE>-f1-oxo-2-(mercaptomethyl)-2-ene-3-phenyl propyl)-(S>-alanine, - N-(E>-f1-oxo- 2-(mercaptomethyl>-2-ene- 3-phenyl propyll-(S)-norvaline, - N-(E>-f1-oxo- 2-(mercaptomethyl>-2-ene- 3-phenyl propylJ-(S>-norleucine, ~:.~.~, 9 ~o ~~~os ~~
- N-<E>-tl-oxo-2-<mercaptomethyl>-2-ene-3-phenyl propyll-(RS)-3-(3,4-methylenedioxy phenyl>-alanine, - N-(Z>-t1-oxo-2-<mercaptomethyl>-2-ene-3-<3,4-methylenedioxy phenyl) propyll-glycine, - N-tN-<RS>-(1-carboxy pentyl)-(RS>-3-(3,4-methylenedioxy phenyl) alanyll-glycine hydrochloride, - N-(N-<RS>-(1-carboxy-2-phenyl ethyl) -<S>- phenylalanyll-glycine hydrochloride, - N-IN-(RS)-(1-carboxy-2-phenyl ethyl) -<RS>- 3-(3,4-methylenedioxy phenyl) alanyll-glycine hydrochloride, - N- (l~ts>-[ 2- (dihydroxyphosphinyl ) methyl-1-oxo-3- ( 3, 4-methylenedioxy phenyl) propyll-(S)-alanine and its calcium monosalt.
- N-<RS>-[2-(dihydroxyphosphinyl)methyl-1-oxo-3-(3,4-methylenedioxy phenyl) propyll-glycine and its calcium monosalt, - N-(RS>-[2-(dihydroxyphosphinyl)methyl-1-oxo-3-(4-phenyl phenyl) propyll-(S)-alanine and its calcium monosalt, - N-<RS>-[2-(dihydroxyphosphinyl)methyl-1-oxo-3-(4-phenyl phenyl) propyll-glycine and its calcium monosalt.
The amino acid derivatives of formula (Ia) or (Ib) in accordance with the invention have one, two or three asymmetric carbon atoms and can thus occur in the form of a racemic mizture or in the form of diastereomers. These compounds can be used in racemic or optically active form. The process for preparing these derivatives, described hereafter, uses the racemic mixture or one of the enantiomers as the starting product. When a racemic product is used to start with, the stereomers obtained can be separated in the product by conventional chromatographic or fractional crystallization processes.
The present invention also relates to the process for preparing compounds of formula <Ia> or (Ib) wherein X particularly designates the mercaptomethyl group.
The process in accordance with the invention is characterized in that it successively consists in a> reacting an ester of malonic acid such as ethyl malonate of formula D

2~ X9706 Et0 C - CH2 - C - OEt O O
wherein Et designates the ethyl radical with a halogenated compound of formula R,-CHI-Y, R, having the meaning defined hereinabove, in the presence of an alkaline metal alcoholic solution, in order to form a diester for formula (II>

.- I I
Et0 - C - CH - C OEt ( ) b> monosaponifying the diester of formula (II) to obtain a monoacid of formula (III>
Rl Et0 - C - CH - C - OH (III) O O
c> preparing, by a Mannich reaction, the acrylic ester of formula (IV), a reaction which consists in treating the monaacid <III) with an organic base such as diethylamine, then with formaldehyde, 2a ~~aa~
Rl H2C - C - COOEt (IV) d) saponifying the acrylic ester tIY> and following the saponification with a Michael addition with thioacetic acid CH3COSH in order to form thioacetyl acid of formula (Y>

CH3~ - C - S - CH2 - CH - COOK (V) il O
e> possibly splitting thioacetyl acid <V), f> coupling thioacetyl acid of formula <V>, in racemic or optically pure form, with the desired aminoester, such as a benzyl aminoester of formula (VI) H2N - ~H - i - O - R4 (VI) O
wherein R~ and Ra have the meanings defined hereinabove in order to form a compound of formula (VII) CH3 - C - S-CH2 - CH - C - NH - CH - COO R4 (VII) O O

zo ~~~o~
in the presence of a coupling agent such as dicyclohexylcarbodiimide, g> then sub,)ecting compound (VII) to alkaline deprotection in order to form the mixed inhibitors of formula <Ia>.
R2solutiori of thioacetyl acid <V> can be carried out by a process such as that described in French patent n' 2.698.463 mentioned hereinabove, according to which the acid is reacted with (+) or (-) ephedrine, depending on the case, the salt of the (+) or <-) enantiomorph obtained is recovered and enantiomorphic acid is released. Re Solution of the acid of formula (V) can also be carried out with a chiral amine such as a-methylbenzylamine.
The present invention also relates to the process for preparing compounds of formula (Ib> in which X particularly designates the mercaptomethyl group.
The process in accordance with the invention is characterized in that it successively consists in a> carrying out allylic bromination of an ethylenic acid <E> of formula (VIII) H3C - C - i - OH (VIII) (E) o wherein R, has the meaning defined hereinabove, with a bromination agent such as N-bromo-succinimide, in the presence of a catalytic amount of benzoyl peroxide, in order to form an acid of formula (IX) \ /
C
Br - CH2 - ~ - i - OIi (IX) (Z) O
b> substituting the bromine in ethylenic acid of formula <IX) with thioacetic acid in order to form thioacetylated <Z> ethylenic acid of formula <X) y _ 13 \C
It H3C - C - S - CH2 - C - C - OH (X) (Z) O
c> isomerizing the acid of formula <X>, for example by using an ultraviolet (U. Y.) lamp, then separating the isomer mixture <E/Z>
obtained with an amine, such as cyclohe~lamine, in order to obtain thioacetylated <E> ethylenic acid of formula <XI>
H\ / 1 C
I I
H3C - C - S - CH2 - C - i - OH (XI) d (E) ~ .
d) coupling thioacetylated (E) ethylenic acid of formula (XI> with the desired aminoester of formula (VI> in the presence of a coupling agent such as dicyclohexylcarbodiimide, in order to obtain the compound of formula (XII>
\ R1 C O
H3C II S - CH2 - IC - i - N - i H - C - O - R4 (XII) O (E) ~ H R2 e) then sub,~ecting the compound of formula (XII> to alkaline deprotection in order to form the mixed inhibitors of formula (Ib) (X = mercaptomethyl) \ C/ O
HS - CH2 .- C - C - N - CH - C - OH (Ib) Il t i (E) O H R2 The present invention also relates to the process for preparing compounds of formula <Ia) in which X particularly designates the A-carboxylalkyl group.
The process in accordance with the invention is characterized in that it successively consists in a> carrying out diazotization then hydrolysis of an amino acid of formula <XIII>

H2N - CH - C - OH (XIII) O
wherein R~ has the meaning defined hereinabove, in order to form a hydroxyacid of formula (XIV) HO - CH - C - OH (XIV) a b> carrying out protection of the hydroxy group of the compound of formula tXIV) with acetyl chloride in order to form the compound of formula (XV>
O
H3 C - C - O - CH - C - .OH ( XV ) c) esterifying the compound of formula <XV>, more particularly with tertiary butanol in the presence of phosphorous chloride in order to form the ester of formula <XYI>

H3 C - C - O - CH - C - O - C - CH3 ( XVI ) ll I t d> releasing the acetyl group of compound (XIV> by alkaline deprotection in order to form the hydroxye.ster of formula <XYII>

HO - CH - C - 0 - C - CH3 ( XVII ) t 2Q ~'~~a~

e) activating the alcohol group of the compound of formula (XVII), for example with trifluoromethane sulfonic anhydride, in the presence of pyridine in order to form the compound of formula (XVIII) iH3 F C - S - 0 - CH - C - 0 - C - CH ( XVIII ) f) substituting the trifluoromethane sulfonic group of the compound of formula (XVIII) with an aminoester of formula (XIX) H2N - CH - C - 0 - CH3 (XIX) wherein R1 has the meaning defined hereinabove, in the presence of bis-1,8-(dimethylamino)-naphthalene in order to form the compound of formula (XX) R3 - CH - NH - iH - COOCH3 (XX) iH2 g) subjecting the compound of formula (XX) to selective alkaline degrotection in order to form the compound of formula (XXI) C00 - C -~ CH3 R3 - CH - NH - CH - COOH (XXI) fit ~o ~~~o~

h) coupling the acid of formula (XXI) with the desired aminoester of formula (VI), wherein R4 is a benzyl group, in the presence of a coupling agent such as dicyclohexylcarbodiimide in order to form the compound of formula (XXII) R3 - CH - NH - CH - CONH - CH - C00 - CH2 - Ph (XRII) f i) hydrogenating the compound of formula (XXII) in the presence of a hydrogenation catalyst, such as Pd/C at a concentration of 10 ~
in ethanol, in order to form the compound of formula (XXIII) R3 - CH - NH - CH - CO - NH - CH - COOH (XXIII) j) then hydrolyzing the compound the tertiary butyl ester function of the compound of formula (XXIII), for example with a solution of hydrochloric acid in ethyl acetate, in order to form the diacid of formula (Ia) (X = N-carboxy-alkyl) COOH CH R

R3 - CH - NH - CH - CONH - CH - COOH (Ia) s ~~ ~~~A~ =~
- 16a - 26361-71 The present invention also relates to the process for preparing compounds of formula (Ia) wherein X particularly designates the phosphonate group.
The process in accordance with the invention is characterized in that it successively consists in:
a) saponifying the acrylic ester of formula {IV), .:~~' - 1? 203~'~~b H2C = C - ~ - O - Et (IV) O
wherein R, has the meaning defined hereinabove and following saponification with the addition of thionyl chloride in order to form acrylic acid chloride of formula <XXIV) XXIV) H2C = C - C - C1 ( b> coupling the acid chloride of formula (XXIV) with the desired aminoester of formula CVI>, in the presence of triethylamine for example, in order to form the compound of formula (XXV) I

H2C = C - C - N - CH - ~ - O - .R4 (XXV) c> carrying out a Michael addition with a dialkylphosphite, for example with diethylphosphite, in the presence of sodium hydride in order to form the compound of formula (XXVI) Et - O \ O CHZ R2 P - CH2 - CH - i - N - CH - ~C - O - R4 (XXVI) Et - O~ ~ H O
d> then hydrolyzing the protective functions of compound (XXVI) in order to form the inhibitors of formula (Ia) - _ 1$ 2Q~~"~~:~

( X = (HO) 2P - CH2 - ) I

HO~ P - CH2 - CH - C - N - CH - C - OH (Ia) this last step being advantageously carried out with bromotrimethylsilane followed by treatment with a 6N hydrochloric acid aqueous solution.
The compounds in accordance with the invention are characterized in that they have enkephalinase-inhibiting and ACE-inhibiting activities, expressed as 50 °,b inhibiting concentrations (ICsc>>, lower than 10 nM.
According to another important feature of the invention and which especially applies to compounds of formula (Ia> or (Ib), whose inhibiting concentrations IC~o range from 1 to 10 nli, these two concentrations are preferably in a ratio lower than 3-4 for the compound to be equipotent.
Nonetheless, it should be noted that in the case of very active compounds, that is to say those having enkephalinase- and ACE-inhibiting concentrations ICso lower than 1 nM, these compounds no longer have to be equipotent. In this case and at the usual doses, only a fraction of the amino acid derivative is used to inhibit ane or the other of the two enzyme activities and there always remains a sufficient amount of free compound to inhibit the other activity.
Thus, the present invention also relates to pharmaceutical compositions which contain compounds of formula (Ia> or (Ib> as the active principle in accordance with the invention.
These pharmaceutical compositions can be administered to humans by oral, parenteral or rectal route.

z9 2~~~~
These pharmaceutical compounds can be in solid or liquid form and presented in pharmaceutical forms commonly used in human medicine, far example simple or coated tablets, capsules, suppositories, preparations for injection.
The pharmaceutical compositions in accordance with the invention are administered in unit doses, preferably ranging from 1 to 200 mg of active principle and at a daily posology ranging from 2 to 400 mg of active principle.
Several non limiting examples for implementing the invention are given below to better illustrate the invention.
Examn~e 1 Prepps~ra_tion o N- (RS)-( 1-oxo-2- (mercaptomethyl )-3-~, 4-methylenedioxy phen~T1 > prop~rl l -gl~ cr ine ~tP.~ a : Malonic synthesis P~~aration of 3- (3, 4-met ,ylenedioxy phen5rl )-2-e,~, o~vcarbonyl eth~ v~a~~anaate 34.9 g (204.69 mmol> of piperonyl chloride and 137.5 g (130.3 ml>
(859.4 mmol) of diethyl malonate are placed in a 1-liter three-necked flask equipped with a cooling system, a dropping funnel and a calcium chloride guard. The mixture is stirred and a solution containing 12.2 g (530.4 mmol) of sodium in 312 ml of anhydrous ethanol <1.7 M
solution) is then added. This mixture is refluxed (oil bath temperature = 80'C) for 5 hours.
The ethanol is evaporated in a rotary evaporator and the residue is then taken up with water (150 ml> and ethyl ether (100 ml>. The ethereal phase is separated and the aqueous phase is extracted a second time with ethyl ether (2 times 100 ml ) . The combined ethereal phases are washed with water (1 time 100 ml), dried on ~igSOa, filtered and concentrated. An oily residue is obtained which is distilled in a vane pump in order to eliminate excess ethyl malonate (60-70'C under 0.2 mm Hg). The distillaton residue contains diethyl piperonyl malonate <II).
Weight = 54.7 g Yield = 91 °/.
' H NMR (CDC1:_ ) . 6. 9 to 6. 55 Cm, 3H) , 5. 95 <s, 2H) , 4. 1 (q, 4H, J =
6.8 Hz), 3.~5 (t, 1H, J - 8 Hz), 3.1 (d, 2H, J = 8 Hz>, 1.2 (t, 6H, J = 6.8 Hz>.
IR ; 1710 cm-' ~ :!
20 2a3~'~~~
~ b ~ Preparation of 3-<3,4-methetlenedioxy phenyl>-2-ethoxY
.ac rbog"~Dropanoic acid A solution of 54.7 g (186.05 mmol) of the product obtained in the previous step in 24 ml of absolute ethanol is placed in a flask equipped with a dropping funnel and calcium chloride guard. It is cooled down to about 0°C in an ice bath and a solution of 10.? g (190.69 mmol) of potash in 186 ml of absolute ethanol is added with continuous stirring over a period of 30 minutes. The solution is then stirred between 0°C and 10'C for 24 hours.
The solution is evaporated to dryness (rotary evaporator) and the residue is taken up with water <150 ml>. It is washed with ethyl ether <3 times 50 ml). The aqueous phase is cooled down and acidified to pH 2 with 3N hydrochloric acid aqueous solution. It is extracted with ethyl ether (4 times 50 ml>. The ethereal phases are combined, washed with water (1 time 50 ml>, with a saturated AaCl solution <1 time 50 ml), dried on MgS04, filtered and concentrated. An oil is obtained:
Weight = 43.75 g Yield = 87 ' H NMR <CDC1:~ ) . 10. 1 <s, 1H> , 6. 9 to 6. 3 (m, 3H) , 5. 85 (s, 2H> , 4.

(q, 2H, J = ?. 5 Hz> , 3. ? <t, 1H, J = ?. 9 Hz> , 3. 1 <d, 2H, J = ?. 9 Hz) , 1. 15 <t, 3H, J = ?. 5 Hz> .
IR : 1?05 cm-' ~~p c Preparation of 3-(3.4-methylenediox~phen' >-ethyl propenoata 41.71 g C156.8 mmol) of the manoester obtained in the previous step are placed in a flask cooled to 0-5'C in an ice bath.
16.25 ml (15? mmol) of diethylamine are added drop by drop at 0-5°C with continuous stirring,.followed by 15.8 ml (210.8 mmol) of 3?
formol in water. The temperature is left to return to room temperature and the solution is stirred for 24 hours.
The reaction mixture is taken up with water <50 ml) then extracted with ether (1 time 200 ml). The organic phase is cooled down in an ice bath and acidified with continuous stirring to pH 2 using a 1N hydrochloric acid aqueous solution. The ethereal phase is then separated, washed with water (2 times 50 ml>, washed with a ~~ ~~70~

saturated NaCl aqueous solution (1 time 50 ml), dried on MgS04, filtered and concentrated. An oil is obtained Weight = 31.6 g Yield = 84 9.
' H NI~LR (CDC1:~) . 6. 9 to 6. 5 (m, 3H) , 6. 15 (s, 1H> , 5. 8 (s, 2H) , 5.4 <s, 1H>, 4.1 (q, 2H, J = 6.8 Hz>, 3.5 <s, 2H>, 1.2 <t, 3H, J =
6.8 Hz>.
IR : 1?00, 1620 cm-' 5ten ti Yrenaration of (RS)- -~r-A~~xlthio~~~.'~ 4 methdtlene dio~hen,~~panoic a~
31.? g (135 mmol) of the acrylic ester obtained in the previous step in solution in 190 ml of an acetone/water mixture (?5/25) are placed in a flask equipped with a dropping funnel. The solution is cooled down to 5'C in an ice bath and 2?0 ml (270 mmol> of a lA AaOH
aqueous solution are added over a period of 10 minutes with continuous stirring. The temperature is left to return to room temperature and the solution is stirred for 20 hours.
Acetone is eliminated on a rotary evaporator and the aqueous phase is washed with ethyl ether (3 times 60 ml>. The aqueous phase is then cooled down in an ice bath and acidified to pH 2 with a lA HC1 aqueous solution. The acidic aqueous phase is then extracted with ethyl ether C4 times 60 ml>. The ethereal phases are combined, washed with water (1 time 60 ml), washed with a saturated AaCl aqueous solution (1 time 60 ml>, dried on MgS04, filtered and concentrated.
2-t (3, 4-methylenedioxy phenyl )methyl ] propenoic acid is obtained in the form of a solid white mass :
Weight = 26.9 g Yield = 96 x ?LP = 121'C
1H AMR (CDC13> . 9.9 <s, 1H>, 6.75 (m, 3H>, 6,4 <s, 1H>, 5.95 (s, 2H>, 5. 6 (s, 1H) , 3. 5 <s, 2H> .
IR <Au,~ of > . 1685, 1620 cm ' - Preparation of (RS>-2-acetylthiomethyl-3-03,4-methylenedioxy phenyl) propanoic acid 26.9 g 0130.5 mmol) of the acid obtained in the previous step and 15.9 g 1209.2 mmol) of thioacetic acid are placed in a flask equipped with a condenser and a calcium chloride guard. The mixture is heated at 70'0 for 24 hours with continuous stirring.
The excess thioacetic acid is evaporated under vacuum (vane pump 1 mm Hg, 60'0>. The pasty yellow residue obtained is taken up three times with 100 ml of ethyl ether. Each time, the ethyl ether is eliminated in a rotary evaporator, then the residue is dried under vacuum. A viscous yellow oil is obtained Weight = 36.7 g Yield = 100 ' H AMR tCDCl;,> . 9. 9 (s, 1H> , 6. 85 to 6. 5 (m, 3H> , 5. 85 <s, 2H) , 3.

to 2. 6 (m, 5H> , 2. 3 (s, 3H> .
IR : 1700 cm-' St~,p a in this ste~,~~litting of the acid obtained in the irPVi_oLS step can be carried oLt accord~n~ to example 2 Slap f Preparati_nn of N-<RS)-( 1-oxo-2-<a ~~lthiomethlt~ )-3-S3. 4-methylenediox~phen~~~rl l -benzy~v~i n~tP
1.37 g (4.85 mmol> of CRS) 2-(acetylthiomethyl>-3-03,4-methylene dioxy phenyl) propanoic acid in solution in 8 ml of anhydrous THF are placed in a flask equipped with a calcium chloride guard. The flask is cooled down to about 0-5'C in an ice bath and are 1.63 g (4.85 mmol>
of benzyl glycinate paratoluenesulfonate salt and 0.49 g (4.85 mmol) of triethylamine in 10 ml of chloroform, a solution of 0.74 g (4.85 mmol> of monohydrated hydroxybenzotriazole in 8 ml of THF and a solution of 1.0 g (4.85 mmol> of dicyclohexylcarbodiimide in 7 ml of chloroform successively added with continuous stirring. The mixture is left to return to room temperature then stirred for 6 hours.
The dicyclohexylurea (DCU> precipitate is filtered and evaporated to dryness. The pasty residue is taken up with ethyl acetate 112 ml).
DCU which precipitates again is filtered. The organic phase is successively washed with water (1 time 10 ml>, with a saturated sodium hydrogenoearbonate aqueous solution (3 times 10 ml>, water (1 time 2(~~'~=
ml> and with a saturated AaCl aqueous solution C1 time 10 ml > . It is dried on MgSOd, filtered and concentrated.
A solid white residue is obtained which is dissolved in a minimum amount of chloroform. Petroleum ether (25 ml> is added with continuous stirring and left for 15 hours. The solid is filtered, washed with petroleum ether, centrifuged and dried under vacuum.
Weight = 1.83 g Yield = 88 x (recrystallized in a chloroform/petroleum ether mixture) MP = 74'C
IR (Au~ol) : 3310, 1730, 1695, 1640 cm ' ' H AI4R (CDC13/TMS) . 7. 5 to 7. 3 (m, 5H) , 6. 7 (s, 3H> , 6. 6 Cs, broad, 1H), 5.9 (s, 2H>, 5.25 <s, 2H>, 4.0 <d, 2H, J - 5.3 Hz), 3.2 to 2. 4 (m, 5H> , 2. 3 <s, 3H> .
'3C NMR <CDC1~) . 195.4 <s>, 172.9 <s>, 169.1 <s>, 147.'3 (s), 145.8 <s>, 134.9 <s>, 131.9 <s), 128.2 (d>, 127.9 (d>, 121.6 (d>, 108.9 (d>, 107.9 <d), 100.5 (t>, 66.6 (t), 48.7 (d), 41.0 <t>, 37.7 <t>, 30.6 (t>, 30.2 <q>.
Microanalysis : C<<H<30~AS
Calc % C = 61.54 N = 3.26 H = 5.36 Found % C = 61.45 N = 3.36 H = 5.41 ~~gp g Pre,~aration of A- (RS)-L i-oxo-2- (mercaptomethgl >-3- <3. 4-mP~h~~ Pnorji f7XrotThPn~[,~~r~.~o~~~-a C.t ine 0. 43 g <1. 0 mmol ) of the compound obtained in the previous step in solution in 3 ml of methanol is placed in a flask. It is purged with argon and the solution is cooled down in an ice bath. 2.1 ml of a lA soda aqueous solution are added at a temperature of about 5'C. The solution is stirred for 2 hours at 20°C.
The methanol is evaporated under vacuum at a temperature below 35°C. The basic aqueous phase is washed with ether (2 times 10 ml). It is then acidified to pH 1 with a lA HC1 aqueous solution. It is extracted with ether (2 times 10 ml). The extraction phases are washed once with water, dried on MgS04, filtered and concentrated under vacuum. The residue is dried in a dessicator on phosphorous pentoxide in order to eliminate acetic acid. If necessary, purification by silica chromatography is carried out. A-<RS>-f1-oxo-2-(mercaptomethyl>-3-(3,4-methylenedioxy phenyl) propyll-glycine is obtained.

Weight = 0.29 g Yield = ?2 x (chromatos~raph ied) ?IP = 94'C (microscope) IR <Au~ol> , 3390, 1740, 1620 cm-' ' H AMR (CDCl~/TI~IS> . 10. 4 (s, iH) , 6. 8 to 6. 4 <m, 4H> , 5. 8 (s, 2H) , 3.95 <d, 2H, J = 5.3 Hz>, 3.1 to 2.2 (m, 5H>, 1.6 (t, 1H, J = ?.9 Hz>
'3C AMR (CDC13) . 174.4 (s), 173.1 (s>, 147.5 (s>, 146.1 <s), 131.9 (s>, 121.8 (d), 109.0 (d>, 108.2 (d), 100.7 <t>, 53.0 (d>, 41.2 (t>, 3?.6 (t>, 26.8 (t>, xicroanalysis : C,:~H,sO6AS
Calc 'G C = 52.52 A = 4.?1 H = 5.05 Found x C = 52.44 A = 4,62 H = 5.00 ~,xamp~le 2 Pre.yaration of (S)-2-(acet~ilthiomPthvl )-3-t3.4-",~+h~lenedioxv phenXl > p.L~panoic acid Sole tt~ ns~ with mstho~lbenzy amj n 32.2 g (114.2 mmol> of racemic 2-(acetylthiomethyl>-3-(3,4-methylenedioxy phenyl) propanoic acid in solution in 200 ml of ethyl ether are placed in a flask. 13.85 g (114.2 mmol> of <R)-a-methylbenzylamine are added drop by drop with continuous stirring.
Precipitation then takes place. The mixture is left for 1? hours.
The salt is filtered, washed with ether (50 ml> and dried under vacuum. The salt of the acid is thus obtained ;
Weight = 37.45 g Yield = 81 ' HP = 118'C
( a) D~6 = + 2. 2' <c = 1. 1 in methanol ) g~~rstalliz~ . on 37.45 g of the previous salt and l00 m1 of dichloromethane are placed in a -flask equipped with a condenser. The mixture is stirred and heated until the salt is completely dissolved. 100 ml of petroleum ether are then added <40-60'C). After the mixture has returned to room temperature, it is left f or 24 hours.
The salt is filtered, washed with petroleum ether (50 ml>, centrifuged and dried under vacuum :
Weight = 18,45 g D

~03~'~~
Yield = 50 'G
LaloS - -?.89' <c = 1.3 in methanol) This process is repeated 4 times.
The overall yield of these 5 recrystallizations is 20 x. The melting point of the optically pure salt is 122'C.
L a105 - -23' <c = 1. 2, I~LeOH) kelease of the onticalwpure (S> acid ?.4 g (18.36 mmol) of the optically pure salt are placed in a flask. Water (50 ml), dichloromethane C50 ml> and a 1A HC1 aqueous solution are added until a pH value of 2 is obtained, The mixture is stirred until the salt is completely dissolved. The organic phase is separated and the aqueous phase is extracted with dichloromethane (2 times 25 ml). The organic phases are combined, washed with water (2 times 25 ml>, dried on MgS04, fitered and concentrated. An oily residue which crystallizes is obtained Weight = 4.97 g Yield = 96 y°
MP = 60'C
LaloS - -23.0' (c = 1.3 in methanol) ' H >1MR (CDCl:,/T?LS> . 10. 4 (s, 1H> , 6. ?5 (s, 3H) , 5. 95 (s, 2H) , 3. 3 to 2. ? <m, 5H) , 2. 3 (s, 3H> , 35.46 mmoles of racemic acid in solution in 50 ml of ether are placed in a flask. 17.73 mmols of (+) ephedrine in solution in 60 ml of ether are added with continuous stirring. It is left to crystallize at room temperature without stirring. The salt is filtered, washed with ether and dried under vacuum.
The salt of the acid is obtained at a yield of 84 MP = 102-116'C
LaloS - +7.?' <c = 2.2, MeOH>.

.. ~ 26 Bec~ystallfzations g of the previous salt are placed in a flask. The salt is dissolved in 50 ml of chloroform then 100 ml of ethyl ether are added.
It is left for 24 hours.
The salt is filtered, washed with petroleum ether, centrifuged and dried under vacuum.
Weight = 7.8 g Yield = 78 ( a7 05 - +4. 3' <c = 1. 3, MeOH) This process is repeated 9 times.
Overall yield of recrystallizations = 40 MP = 122'C
( al 05 - -5. 3' (c = 1. 2, MeOH>
Proceed as for splitting with a-methylbenzylamine.
Yield = 95 °/.
( al 0 5 - -25. 7 ° (c = 1. 3, MeOH) Exag~le 3 Preparat i n" of N- (S)-L 1-oxo-2- <acetvlth_ ~~t ,y1 ~
(3. 4-methvlenediox3r p~yl ) p~pJi1 1-benzyl g~vcs natP
<S)-2-(acetylthiomethyl>-3-(3,4-methylenedioxy phenyl) propanoic acid is coupled with benzyl glycinate following the procedure described in example 1 (step f).
?iP = 92°C (Microscope) Yield = 76 ~ <chromatographied) falo5 - - 15.8° (c = 1.2 in methanol) IR (Au,jol> . 3280, 1725, 1690, 1640 cm-' 'H NMR tCDCl~/TMS) . 7.3 <s, 5H>, 6.65 (s, 3H>, 6.1 (s, broad, 1H>, 5.85 <s, 2H), 5.15 (s, 2H), 3.95 (d, 2H, J - 5.3 Hz), 3.15 to 2. 5 (m, 5H> , 2. 3 <s, 3H1.
The '~C NMR spectrum is identical to that of the racemic product (example 1>.

2?
liicroanalysis : C~~H2:,OsNS
Calc x C = 61,54 N = 3.26 Ii = 5,36 Found x C = 61.38 N = 3.19 H = 5.30 The product of example 3 is deprotected according to the method described in example 1 (step g>.
Yield = 60 x (chromatographied) (alo S - +54.4' <c = 1.0 in methanol) IR <CHC1:~> . 1730, 1670 cm-' ' H NMR <CDCla/TIdS> . 9. 6 (s, 1H> , 6. 8 to 6. 45 <m, 4H> , 5. 95 <s, 2H) , 4.05 (d, 2H, J = 4 Hz>, 3.3 to 2.3 (m, 5H>, 1.65 <t, 1H, J = ?.3 Hz).
?iicroanalysis : C~ ;~H, aOsHS
Calc '~G C = 52.52 H = 4,?1 H = 5.05 Found x C = 52. 35 N = 4.90 H = 5, 1?
(3. 4-methy~lenediox~~nhen;rl ) pro~;tll- ( S ) -benzyl alaninate 2-(acetylthiomethyl)-3-<3,4-methylenedioxy phenyl) propanoic acid in its racemic form (example 1, step d) is coupled with benzyl alaninate of configuration (S> according to the method described in example 1 (step f).
Yield - 82 '~ <chromatographied) (50/50 mixture of the two diastereomers) l~IP = 68'C (xicroscope>
IR (Au,~ol> . 3290, 1?30, 1690, 1640 cm-' 'H AMR <CDC13/TMS> . ?.25 <s, 5H>, 6.6 (s, 3H>, 6.4 <m, iH>, 5.8 (s, 2H>, 5.1 <s, 2H>, 4.6 (quintuplet, 1H, J = ?,3 Hz), 3.2 to 2,35 <m, 5H>, 2.2 (s, 3H>, 1.3 and 1.15 (2 doublets, 3H, J = 7.3 Hz).
'3C NMR (CDC13> :195.3 (s), 195.0 (s>, 1?1.9 (s>,14?.1 (s>, 145.? <s>, 135.0 (s), 131.9 Cs), 131.? (s>, 128.0 (d), 127.6 <d>, 121.5 Cd>, 108.9 <d>, 10?.? <d>, 100.3 (t), 66.4 (t>, 48,8 Cd>, 48.3 (d>, 47.6 (d), 37.? (t), 31.6 (t>, 30.5 <q>, 17.8 (q).
?ticroanalysis : C~:,H2s0eNS
Calc x C = 62.30 H = 3.16 H = 5.64 Found x C = 62.21 N = 3.11 H = 5.55 ~p,7 P f Prepara;~ i on of A- (RS>-C 1-oxo-2- (merca~,tomethvl )-3-(~, 4-meth~~ pnPdioxv phenwl ) pro~,~~l l - <S)-alanine Deprotection is carried out according to the operating procedure of example 1 (step g>.
Yield = ?2 y° (50/50 mixture of the two dfastereomers>
l~iP < 50' C
IR (Au~ol> . 3280, 1725, 1640 cm-' 'H bTMR (CDC1~/TMS) . 8.8 (s, 1H), 6.8 to 6.2 <m, 4H>, 5.8 (s, 2H), 4.5 (quintuplet, 1H, J = ? Hz>, 3.25 to 2.15 (m, 5H>, 1.65 (t, 1H, J =
6.5 Hz>, 1.4 and 1.25 (2 doublets, 3H, J = 7 Hz>.
'3C NMR <CDC1:~> 175.6 (s>, 1?3.5 (s>, 147.5 (s>, 146.0 Cs>, 132.0 <s>, 121.? (d>, 109.0 (d), 108.1 <d), 100.7 (t>, 53.4 (d), 52.9 <d), 48.0 <d>, 37.9 <t>, 3?.7 (t), 25.9 (t>, 25.7 Ct), 18.0 <q), 17.6 <q>.
~Licraanalysis : C,aH,~OSNS
Calc °/. C = 54.02 N = 4.50 H = 5.46 Found % C = 53.?3 A = 4.39 H = 5.40 FxaQl~?le 7 Preparation of N-<S)-C 1-oxo-2-(acetvlthiomethvl>3-~wlenedsox;~p~~propyll-(S)-benz,tl alaninate A Pr~,aratiot~ by coub],j~g onticall~pure (S)-2-Saeet~~lthiomethyl> 3 (3 4-methvlenedio~,~phen~~propanoic acid (example 2>
Yield = ?7 °!° <chromatographied>
1IIP = 104'(, one diastereomer only (Microscope) CaID = - 50.6° (c = 1.35 in methanol) IR (Au~ol) . 3280, 1?40, 1695, 1640 cm ' 'H NMR (CDCl:~/TMS) . ?.25 (s, 5H>, 6.6 (s, 3H), 6.0 (d, 1H, J = 7.5 Hz>, 5.85 <s, 2H>, 5.0 (s, 2H>, 4.5 (quintuplet, 1H, J = ?.5 Hz>, 3.05 (d, 2H, J = 6. 1 Hz> , 3. 0 to 2. 4 <m, 3H) , 2. 25 (s, 3H> , 1. 3 (d, 3H, J =
7.5 Hz).
liicroanalysis : C~,H~s06NS
Calc % C = 62.30 N = 3.16 H = 5.64 Faund % C = 62.20 N = 3.20 H = 5.30 B Preparation bit setarat~on of the diastereomers of examvle 5 5.7 g (12.86 mmol) of the compound obtained in example 5 in 20 ml of chloroform are placed in a flask. 80 ml of ethyl ether and 80 ml of petroleum ether are then added to this solution with continuous stirring. The mixture is left for 24 hours.
The solid is filtered, centrifuged and dried under vacuum Weight = 1.7 g Yield = 30 °,G
Product containing 80 °/ of the (S, S) isomer.
The previous process is repeated. 1. 7 g (3. 83 mmol ) of salt <80 °/.
rich in the CS, S) dfastereoisomer> are dissolved in a minimum amount of chloroform C7 ml). 25 ml of ethyl ether and 25 ml of petroleum ether are then added with continuous stirring. The mixture is left for 24 hours.
The white solid is filtered, centrifuged and dried under vacuum to obtain:
Weight = 1.2 g Recrystallization yield = 70 °k Product over 95 % rich in the (S,S> isomer.
The physical and spectral characteristics are identical to those obtained with the compound of example 7.A, Overall yield for these two recrystallizations is 21 %.
p,~ a 8 Preparation of N- (S)-f 1-oxo-2- Cmercaptomethyl )3-5,,3 4-methvlenediox~ phenyl) propelJ-<S)-alanine Deprotection is carried out according to the operating procedure of example 1 Cstep g).
Yield = 81 (alo ~ - +12.9° <c = 1.35, MeOH>
' H NMR (CDCl:~/T14S) . 9. 05 <s, 1H) , 6. 8 to 6. 6 (m, 3H> , 6. 45 <d, 1H, J
- 7 Hz ) > , 5. 85 (s, 2H> , 4. 55 (quintuplet, 1H, J = 7 Hz > , 3. 1 to 2. 25 Cm, 3H> , 1. 5 (t, 1H, J = 8. 5 Hz ) ) , 2. 4 Cd, 3H, J = 7 Hz ) ) .
Microanalysis : C,aH,O~NS
Calc °~ C = 54.08 H = 5.50 N = 4.50 Found % C = 53.65 H = 5.78 N = 4.38 30 ~Q~~~'~
g Preparation of A-(RS)-L1-oxo-2-(acetvlthiometh;rl>3-3-2-(acetylthiomethyl>-3-(3,4-methylenedioxy phenyl) propanoic acid in fts racemic form (example 1, step d> is coupled to 2-aminobenzyl butyrate of configuration CS> according to the operating procedure of example 1 (step f>.
Yield = 87 x MP = 61'C (Microscope) (50/50 mixture of the diastereomers>
'H AMR (CDCla/TMS) . 7.3 (s, 5H>, 6.65 <s, 3H>, 6.0 (m, 1H), 5.8 (s, 2H>, 5.15 ts, 2H), 4.55 (m, 1H), 3.2-2.4 (m, 5H>, 2.3 <s, 3H>, 1. 65 <m, 2H> , 0. 8 Ct, J = 7. 5 Hz, 3/2 H) , 0. 6 <t, J = 7. 5 Hz, 3/2 H> .
'3C HMR (CDC1:,> . 195.5, 172.3, 171.6, 147.6, 146.1, 135.3, 132.2, 128.3, 128.0, 121.7, 109.1, 108.1, 100.7, 66.7, 53.1, 52.9, 49.6, 49.35, 37.9, 31.1, 30.9, 30.3, 25.4, 25.2.
IR <Aujol> . 3300, 1730, 1690, 1640 cm ' Microanalysis : (C2aH~~05MS>
Calc % C = 63.00 H = 5.95 A = 3.06 Found % C = 62.89 H = 6.22 A = 3.33 ~,~me)P 10 Preparation of A-CRS)-(1-oxo-2-tmercantomethvl)-3-s;~, 4 meth~Llenediox~y phenX, ~rop~rll - (S)-2-aminobutvric acid Deprotection of the compound obtained in example 9 is carried out according to the operating procedure of example 1 (step g).
Yield = 69 °/.
MP = 118'C (Microscope) (50/50 mixture of the diastereomers>
'H AMR CCDC1:~/TMS) . 9.1 (s, 1H), 6.65 <s, 3H), 6.3 (m, 1H>, 5. 85 (s, 2H) , 4. 55 tm, 1H> , 3. 0-2. 2 (m, 5H> , 1. 6 (m, 5H) , 0. 9 Ct, J
=
7.5 Hz, 3/2H), 0.7 tt, J = 7.5 Hz, 3/2H).
"C NMR CCDC13) . 175.6, 173.5, 147.8, 146.4, 132.3, 121.9, 109.2, 108.4, 100.8, 53.8, 53.2, 37.9, 26.2, 25.8, 25.3, 24.8.
IR (Nu~ol) . 350, 1730, 1630 cm ' Microanalysis : C,sH,40sAS
Calc % C = 55.37 H = 5.89 A = 4.30 Found % C = 55.32 H = 5.64 A = 4.22 11 PreDars'~t~on of N-(RS)-f1-oxo-2-<acetylthiomethvl>3-(~4 methyl Pned~ ox~p en~l ) propvl l - (S)-benzy,L norval inate 2-acetylthiomethyl-3-(3,4-methylenedioxy phenyl) propanoic acid in its racemic form (example 1, step d> is coupled to benzyl norvalinate of configuration (S> according to the operating procedure of example 1 (step f).
Yield = 88 ?LP = 92'C (Microscope) (50/50 mixture of the diastereomers>
'H AMR (CDC13/TMS> . 7.3 <s, 5H>, 6.6 (s, 3H), 6.0 (m, 1H>, 5.85 (s, 2H), 5.1 (s, 2H>, 4.55 (m, 1H), 3.2-2.3 (m, 5H>, 2.1 <s, 3H), 1. 6-0. 9 (m, 4H> , 0. 6 <m, 3H) .
'~C NMR (CDC1:~> . 195.7, 195.5, 172.3, 171.8, 147.6, 146.1, 135.3, 132.4, 132.1, 128.3, 128.0, 121,8, 109.1, 108, 100.7, 66.7, 51.7, 49.6, 49.2, 37.9, 34.3, 31.1, 30.9, 18.2, 17.8, 13.3.
IR (Aujol) . 3300, 1730, 1690, 1635 cm ' Microanalysis : (C~sH~~O~NS) Calc °/ C = 63.68 H = 6.20 N = 2.97 Found % C = 63.47 H = 6.13 N = 3.19 rle 12~ Preparation of A-(RS)-f1-oxo-2-(mercaptomethvl)-3-( , ~' - v the diastereome~
Deprotection of the compound of example 11 is carried out according to the operating procedure of example 1 (step g>.
Yield = 75 °/.
Rf value = 0.35 (50/49/1 petroleum ether/ethyl acetate/acetic acid) 'H NMR <CDC1~/TMS> . 9.4 Cs, 1H), 6.6 <s, 3H>, 6.2 <m, 1H), 5. 85 (s, 2H> , 4. 5 (m, 1H) , 3. 0-2. 3 (m, 5H> , 1. 9-0. 8 <m, 8H) .
'~C NMR <CDC1:,> . 175.?, 173.5, 147.8, 146.4, 132.3, 121.9, 109.2, 108.4, 100,8, 54.0, 53.5, 51.9, 38.1, 34.0, 33.7, 26.3, 25.8, 18.5, 18.2, 13.4.
IR (Nujof> . 3350, 1740, 1630 cm-' Microanalysis : (C,rH~,NOsS) Calc %. C = 56.62 H = 6.23 N = 4.13 Found % C = 56.41 H = 6.08 N = 4.25 w 32 2-acetylthiomethyl-3-<3,4-methylenedioxy phenyl) propanoic acid in its racemic form (example 1, step d) is coupled to benzyl norleucinate of configuration (S> according to the operating procedure of example 1 Cstep f).
Yield = 85 °,G
MP = 104-126'( (Microscope) (50/50 mixture of the diastereomers>
'H NMR <CDC1:~/TMS) . ?.3 <s, 5H>, 6.6 <s, 3H>, 5.9 <s, 3H>, 5.1 (s, 2H>, 4.5 <m, 1H>, 3.2-2.4 (m, 5H>, 2.3 (s, 3H>, 1.6 Cm, 2H>, 1. 2 Cm, 4H) , 0. 8 (m, 3H) .
'=C NMR (CDC1:.> . 195.5, 1?2.3, 1?1.8, 14?.?, 146.6, 135.3, 132.4, 132.2, 128.3, 128.0, 121.8, 109.1, 108.1, 100.7, 66.?, 51.8, 49.6, 49.4, 3?.9, 31.9, 30.9, 30.2, 26.8, 22.1, 13.?.
IR (Nujol> . 3300, 1?40, 1680, 1640 cm ' Microanalysis : CC~bH~,NO~S) Calc % C = 64.31 H = 6.43 N = 2.88 Found % C = 64.50 H = 6.53 N = 3.06 _(7 4 methv~Pned~o~.,~ phenyl) pronylJ-W~-nor)PUCine Deprotection is carried out according to the operating procedure of example 1 (step g) .
Yield = ?5 °/.
Rf value = 0.35 (50/49/1 petroleum ether/ethyl acetate/acetic acid) (50/50 mixture of the diastereomers) 'H NMR (CDC1~/TMS> . 8.2 (s, 1H>, 6.6 <s, 3H), 6.4 (m, 1H>, 5. 8 (s, 2H> , 4. 5 <m, 1H> , 2. 9-2. 3 (m, 5H) , 1. 9-0. ? (m, lOH> .
'=C NMR (CDCl~> . 175.1, 1?3.5, 14?.8, 146.4, 132.3, 121.8, 109.2, 108.4, 100.8, 53.9, 53.6, 52.1, 3?.9, 31.6, 31.3, 2?.0, 26.3, 25.9, 22. 0, 13. 5.
IR (Nujol> . 3400, 1700, 1640 cm ' Microanalysis : (C,~H~:.NOSS) Calc % C = 5?.?? H = 6.56 N = 3.96 Found % C = 5?.56 H = 6.34 N = 3.69 ~ple 15 : Preparation of N-(RS)-(1-oxo-2-(acetyrlthiop~etho,rl>-3-~,.4-meth; lened Q;y en~c] ) prop~rll-(S)-benz'rl leucinate 2-acetylthiomethyl-3-t3,4-methylenedioxy phenyl) propanoic acid in its racemic form (example 1, step d) is coupled to benzyl leucinate of configuration CS> according to the operating procedure of example 1 (step f>.
Yield = 82 x MP = 74'C (Microscope) (50/50 mixture of the diastereomers>
' H NMR (CDC1~/TMS> . 7. 3 <s, 5H) , 6. 6 <s, 3H> , 5. 9 (m, 3H) , 5. 1 (d, J
- 3 Hz, 2H), 4.55 (m, 1H), 3.15-2.45 <m, 5H>, 2.3 <s, 3H), 1. 3 (m, 3H> , 0. 9 (d, J = 5 Hz, 3H) , 0. 75 (d, J = 5 Hz, 3H> .
''~C NMR (CDC1~) . 195.6, 195.4, 172.3, 172.1, 147.7, 146.1, 135.4, 132.4, 132.15, 128.4, 128.1, 121.8, 109.2, 108.0, 100.6, 66.7, 50.7, 50.4, 49.6, 49.2, 41.5, 37.8, 31.3, 30.9, 30.2, 24.6, 24.2, 22.4, 21.7, 21.4.
IR (Nu,~ol> . 330U, 1730, 1690, 1640 cm ' Microanalysis : CC~~H:~,N05S) Calc °/. C = 64.31 H = 6.43 N = 2.88 Found °/. C = 64.25 H = 6.38 N = 2.90 >_ Deprotection is carried out according to the operating procedure of example 1 (step g).
Yield = 69 x Rf value = 0.7 (ethyl acetate/acetic acid 98/2) ' H NMR (CDC1:~/TMS) . 10. 1 ts, 1H) , 6. 65 (s, 3H) , 6. 3 tt, J = 7 Fiz, 1H) , 5. 85 <s, 2H> , 4. 5 <m, 1H> , 3. 1-2. 2 (m, 5H> , 1. 65 (m, 4H) , 0. 9 (m, 6H) .
"C NMR (CDC13> . 176.2, 173.7, 147.8, 146.35, 132.4, 132.15, 121.95, 109.2, 108.2, 100.8, 53.95, 53.35, 50.8, 50.6, 41.2, 40.85, 37.95, 26.4, 25.8, 24.7, 24.45, 22.65, 21.?, 21.4.
IR <Nu,~ol) . 3340, 1?30, 1630 cm-' Microanalysis : CC,~H~:,NOsS) Calc '/. C = 57.77 H = 6.56 N = 3.96 Found x C = 57.48 H = 6.43 N = 3.62 D

2~~a .- 34 ~~~,1 P 1? PT'PDaT'a'f i nn of N- (RS)-( 1-oxo-2- <acet3rlthiometh;~1 >-3-S',~ 4 m2th~~ Pnedioxv v en~Tl ) propyl7-<S)-metha~,~l_trvutov~hanate 2-acetylthiomethyl-3-(3,4-methylenedioxy phenyl) propanoic acid in its racemic form (example 1, step d) is coupled to CS> methyl tryptophanate.
Yield = 81 %.
I~iP = 93-130°C CMicroscope> (50/50 mixture of the diastereomers>
' H NMR (CDC1:~/T14S> . 8. 3 Cm, 1H> , 7. 65-6. 85 (?i, 4H) , 6. 6 (m, 3H) , 6.0 Ct, J - 6.7 Hz, 1H), 5.85 <s, 2H>, 4.9 Cm, 1H>, 3.6 <s, 3H>, 3.25 (d, J = 6.7 Hz, 2H>, 3.2-2.3 (m, 5H), 2.25 (s, 3H).
'~'C AMR (CDC1;~> . 195.6, 172.5, 1?1.8, 147.55, 146.1, 136.15, 132.4, 132.0, 127.4, 122.9, 122.7, 121.9, 119.4, 118.4, 111.15, 109.3, 109.1, 108.1, 100.7, 52.5, 51.9, 49.35, 49.1, 37.8, 31.0, 30.65, 30.2, 27.7, 27.5.
IR (Nu~ol> . 3420, 3320, 1730, 1680, 1640 cm ' liicroanalysis : C_F,H26NzOES
Calc % C = 62.23 H = 5.43 N = 5.80 Found % C = 62.01 H = 5.74 N = 5.46 18 Preparation of N-<RS)-(1-oxo-2-<mercaptomPthYl>-3-~"~,,~4-methylenedioxv bhen.~],> pron~l7-(S)-tryptophan Deprotection is carried out according to the operating procedure of example 1 (step g).
Yield = 91 %
l~IP = 66°C CMicroscope> (50/50 mixture of the diastereomers) ' H NMR (CDC1~, DMSO d" TMS> . 8. 6 Cs, 1H) , 8. 35 (s, 1H) , 9. 6 <m, 1H) , 7.4-6.85 (m, 4H>, 6.75-6.2 (m, 4H), 5.75 (d, J - 6.7 Hz, 2H), 4. 35 Cm, 1H> , 3. 1 Cm, 2H> , 2. 9-2. 0 (m, 5H> , 1. 4 Ct, J = 8 Hz, 1H> .
'3C NMR <CDC1.> . 175.1, 173.8, 147.7, 146.1, 136.0, 132.3, 131.8, 127.4, 123.3, 123.0, 122.2, 121.9, 119.6, 118.4, 118.2, 111.2, 109.2, 108.2, 100.7, 53.5, 52.8, 52.6, 37.5, 27.1, 26.8, 26.0, 25.4.
IR tNu,~ol> . 3400, 3350, 1720, 1635 cm '' Microanalysis i CCLLH~'GNrO~,S) Calc % C = 61.96 H = 5.20 N = 6.57 Found % C = 60.59 H = 5.46 N = 6.82 2~3°~~~
'' 35 ~1 a ~ 9 Preparation of N- CRS)-( 1-oxo-2- (acetvlthiometh~L1 )-3-C3 4 methvl~nPd' ox~T y~pTStp~'-~~ - t~3-benz~~~L~ a! any na2e 2-acetylthiomethyl-3-(3,4-methylenedioxy phenyl) propanoic acid in its racemic farm texample 1, step d> is coupled to (S> benzyl phenylalaninate according to the operating procedure of example 1 (step f).
Yield = 73 7.
MP = 99-105'C (Microscope) (50/50 mixture of the diastereomers) 'H NMR CCDC1;~/TMS) . 7.3 (s, 5H>, 7.3-6.9 tm, 5H>, 6.6 <s, 3H>, 5. 9 <m, 1H> , 5. 85 (s, 2H) , 5. 1 (s, 2H) , 4. 8 (t, J = 7 Hz, 1H> , 3. 2-2.

(m, 5H), 2.3 ts, 1/2H>, 2.25 (s, 1/2H).
'~C NMR <CDC1~> . 195.4, 172.1, 170.8, 147.6, 146.1, 135.3, 134.8, 132.7, 131.9, 129.0, 128.3, 127.0, 121.5, 109.0, 108.0, 100.6, 66.8, 52.5, 49.5, 37.?, 31.15, 30.7, 30.2.
IR (Nujol> . 3300, 1725, 1685, 1640 cm ' Microanalysis : C:~.~Hr~,NO~S
Calc % C = 67.03 H = 5.63 A = 2.69 Found % C = 67.02 H = 5.51 A = 2.90 r:X~mniP 20 Prevar~tinn of N-(RS)-(1-oxo-2-tmercaptomethvl)-3-3-( -( of the diastereomers) Deprotection is carried out according to the operating procedure of example 1 (step g>.
Yield = 79 Rf value = 0.7 (ethyl acetate/acetic acid : 98/2) 'H NMR CCDC13/TMS) . 8.8 Cs, 1H>, 7.3-6.7 (m, 5H>, 6.6 <m, 3H>, 6. 1 <d, J = 7. 3 Hz, 1H) , 5. 85 <m, 2H> , 4, 85 <m, 1H) , 3. 3-2. 1 (m, 7H) , 1. 5 tt, J = 8. 5 Hz, 1H> .
'=C NMR <CDC1~:> . 174.5, 173.3, 14?.7, 146.2, 135.3, 132.1, 129.3, 129.1, 128.5, 127.1, 121.9, 109.2, 108.9, 108.2, 100.8, 53.6, 53.3, 52.9, 52.6, 37.7, 37.2, 26.0, 25.5.
IR (CDC1~> . 3420, 1720, 1660 cm ' Microanalysis : <C<c~H~, NO~.S>
Calc % C = 62.00 H = 5.46 N = 3.61 Found % C = 61.71 H = 5.19 N = 3.40 20~~'~a~

2-acetylthiomethyl 3-<3,4-methylenedioxy phenyl) propanoic acid in its racemic form (example 1, step d> is coupled to (S> benzyl tyrosinate according to the operating procedure of example 1 (step f).
Yield = 90 °/. (chromatographied) Rf value = 0.7 (50/50 petroleum ether/ethyl acetate) l~ < 45°C
'H NMR <CDClw/TMS> . 7.25 (s, 5H), 7.15-6.3 (m, 8H of which 1H
exchangeable by D<~0), 6.1 (d, J = 8 Hz, 1H>, 5.8 (s, 2H), 5.1 (s, 2H), 4. 8 <t, J = 6. 3 Hz, 1H> , 3. 2-2. 4 (m, 7H> , 2. 23 (s, 1, 5H> , 2. 19 (s, 1, 5H) .
'~C NMR (CDC1:,) . 196.0, 172.7, 171.0, 155.3, 14?.7, 146.2, 134.9, 131.9, 130.3, 128.5, 126.8, 126.6, 121.9, 115.4, 109.1, 108.2, 100.7, 67.0, 53.2, 53.0, 49.7, 49.4, 37.9, 37.0, 31.1, 30.6, 30.3.
IR (Nujol) . 3300, 1730, 1690, 1635 cm ' Microanalysis : (C::SH~~aNO~S) Calc % C = 65.03 H = 5.45 N = 2.61 Found % C = 65.19 H = 5.39 N = 2.73 ~~P 22 Preparation of N-(RS)-C1-oxo-2-(mercapto ° >-3-( , 5 diastereomers) Deprotection of the compound of example 21 is carried out according to the operating procedure of example 1 (step g>.
Yield = 85 °~ <chromatographied>
Rf value = 0.5 (50/49/1 petroleum ether/ethyl acetate/acetic acid) MP = 62-65°C (Microscope) ' H NMR (CDC1~~, DMSOdc, TMS) . 7. 3-6. 00 <m, 10H) , 5. 85 (s, broad, 2H> , 4.65 <m, 1H>, 3.15-2.00 (m, 7H), 1.65 (t, J = 8 Hz, 1H>.
IR (Nujol> . 3300, 1730, 1640 cm ' Microanalysis : C<«H~,NObS
Calc % C = 59.54 H = 5.24 N = 3.47 Found % C = 59.36 H = 5.30 N = 3.38 ~~~~d 3?
1 Pr ~ r ;on of N-<S)-C1-oxo-2-(acetvlth;omethvl>-3-<S>-2-acetylthiomethyl 3-(3,4-methylenedioxy phenyl) propanoic acid (example 2> is coupled to <S> methyl serinate accordingthe to operating procedure of example 1 (step f).

Yield = 89 /. (chromatographied>

?IP = 120C

LaloO - -15.5 <c = 1.1, CHCl:~) IR (Nu~ol> . 3460, 3260, 1725, 1690, 1630 cm-' 'H NMR (CDC1.~/TMS> . 6.85 (m, 3H), 6.4 (d, 1H, J - 6.6 Hz), 5.85 <s, 2H>, 4.? to 4.4 <m, 1H), 4.0 to 3.8 <m, 2H), 3.2 3.? (s, 3H>, to 2. 4 (m, 6H> , 2. 25 (s, 3H> .

Microanalysis : C,~H~,O~NS

Calc ~ C = 53.26 H = 5.48 N = 3.65 Found % C = 53.46 H = 5.59 N = 3.85 amnl P ~4 Pren~ r t; on of N- (S>-~ ~ -oxo-2- <mercantomPth~C.>>-3-R

x 4 methvlened; ox~~ph~ny.~T~ronvl J - (S)-serine Deprotection of the compound of example 23 is carried out according to the operating procedure of example 1 (step g).

Yield = 65 % (chromatographied) MP = 124C

L al o~ - +20. 3 <c = 1. 0, EtOH>

IR (Nu~ol> . 3340, 1?50, 1630 cm ' 'H NMR (CDC1.~/DMSO/TMS> . ?.0 Cd, 1H, J - 7.7 Hz), 6.? 3H>, (s, 5.85 (s, 2H>, 5.2 to 4.4 (m, 3H>, 3.9 <d, 2H, J - 3.5 Hz>, 3.0 to 2.4 <m, 5H), 1.6 Ct, 1H, J = 8.6 Hz).

Microanalysis : C,4Hl7O~NS

Calc ~ C = 51.3? H = 5.19 N = 4.28 Found /. C = 51.08 H = 5.24 N = 4.26 25 Preparation of N-(S)-L1-oxo-2-<acetylthior~thvl)-3-~~~~lened~ ox'r o_h_enx.~propyl l - CS)-methyl me+hi oninate CS)-2-acetylthiomethyl-3-(3,4-methylenedioxy phenyl) propanoic acid (example 2> is coupled to <S> methyl methioninate according to the operating procedure of example 1 (step f>.
Yield = 71 7. <chromatographied) MP = 85'C
LaloO - - 33.3' (c = 1.3, CHC1:~) IR (Nujol> . 3280, 2?30, 1690, 1640 cm ' ' H NMR (CDCl:~/TMS) . 6. 85 (m, 3H> , 6. 2 to 5. 9 <m, 1H) , 5. 85 <s, 2H> , 4.6 (quintuplet, 1H, J - 6.6 Hz), 3.65 <s, 3H), 3.1 <d, 2H, J -6.6 Hz>, 3.0 to 2.3 (m, 7H>, 2.25 <s, 3H), 2.0 <s, 3H>.
Microanalysis : C,9H~s05AS~
Calc °~ C = 53.38 H = 5.89 N = 3.28 Found % C = 53.?4 H = 5.6? N = 3.53 ~tamn ~ P 26 PrP~aration of N- (S)-f 1-oxo-2- (merca; +~~t ,x, ~-3-~,~,~~hyl enedioxy phenyl ) prop3rlJ - (S)-meths ovine Deprotection of the compound of example 25 is carried out according to the operating procedure of example 1 (step g>.
Yield = 56 % (chromatographied) Lalo~ - + 2.2° (c = 0.9, EtOH>
IR (Nujol> . 3300, 1?20, 1640 cm ' 'H NMR <CDC1~~/TM.S> . 9.5 (s, 1H>, 6.6 <m, 4H), 5.8 (s, 2H), 4.9 to 4. 4 (m, 1H) , 3. 4 to 1. 3 (m, 10H) , 2. 0 <s, 3H) .
Microanalysis : C,sH~,OsNS~
Calc °/. C = 51.?3 H = 5.?0 N = 3.??
Found °/. C = 51. 9? H = 5. ?9 N = 3. ?5 ~.x3.mple 2? Preparation of N-(S)-f 1-oxo-2-(acet3~lthiomethvl>-3 CS)-2-(acetylthiomethyl>-3-(3,4-methylenedioxy phenyl) propanoic acid (example 2) is coupled to CRS) methyl sulfoxide methioninate according to the operating procedure of example 1 (step f>.
Yield = 2?

'H NI(R (CDC1~/TMS> . 6.8 to 6.5 (m, 3H), 6.2 <d, 2H, J - 8 Hz), 5.85 (s, 2H>, 4.?5 to 4.4 (m, 1H), 3.65 and 3.6 (s, 3H>, 3.05 <d, 2H, J = 6. ? Iiz ) , 3. 0 to 1. 5 <m, 7H) , 2. 25 <s, 3H) , 2. 05 and 1. 95 (s, 3H
> .
IR (Nu,~ol> . 3300, 1?40, 1690, 1650 cm-' Microanalysis : C,~H~bO~NS~
Calc x C = 51.45 H = 5.68 N = 3.16 Found °~ C = 51.39 H = 5.52 N = 3.23 Example 28 Preparation of N-(S)-f1-oxo-2-(merra~.r"~+ ~ ~
(3,4-met y.hnedioxv ~hen3rl > ~,ro~w~ll- (RS)-methioni ne ~n1 (oxide Deprotection of the compound of example 27 is carried out according to the operating procedure of example 1 (step g>.
Yield = 71 °~
' H NMR (CDC1:,/TItS> . 8. 2 (s, 1H> , 6. 8 to 6. 2 (m, 4H> , 5. 9 and 5.85 <s, 2H), 4.8 to 4.5 (m, 1H), 3.2 to 1.3 (m, 9H), 2.05 and 1. 95 <s, 3H> , 1. 55 (t, 1H, J = 8 Hz > .
IR <Nu~ol) . 1?25, 1630 cm-' Microanalysis : C,sH~,OsNS~
Calc °/. C = 49.60 H = 5.46 N = 3.61 Found % C = 50.00 H = 5.39 N = 3.?2 Example 29 Preyaration of N- (S)-f -ox -2-(arty 1 thior~a~,~r1_ ~-3-_ ~.~-meznymeneaioxyr yhenl;~l) propyil-(RS>-3-(3,4-methylenPdiox~r phenyl) 1 eat girl alaninate (S)-2-(acetylthiomethyl>-3-<3,4-methylenedioxy phenyl) propanoic acid (example 2> is coupled to (RS> 3-<3,4-methylenedioxy phenyl) methyl alaninate according to the operating procedure of example 1 (step f).
Yield = 58 °/.
MP = 98°C
'H NMR (CDC13/TMS> . 6.8 to 6.0 (m, 6H), 5.85 (s, 4H>, 5.8 to 5. 6 <m, 1H> , 4. 95 to 4. 55 (m, 1H> , 3. 65 and 3. 6 (s, 3H) , 3. 15 to 2. 4 (m, ?H), 2.3 and 2.25 (s, 3H>.
IR <Nu,~ol> . 3300, 1730, 1?00 to 1680, 1650, 1645 cm'-' Microanalysis ; C~aH~«O~:yNS
Calc % C = 59.13 H = 5.1? N = 2.8?
Found °/. C = 59.50 H = 5.23 N = 2.90 40 203~7~~
30 Prepares+;on of N-(S)-f1-oxo-2-(mercaptomethvl>-3-C3y4 meth~tenedioxy ~henvl) propa,~lJ-<RS)-3-<3.4-methvlenedioxv ~h~n~l ) -a 1 ani ne Deprotection of the compound of example 29 is carried out according to the operating procedure of example 1 (step g>, Yield = ?4 %
?iP = 121 ' C
' H NMR <CDCl ./Tl~LS> . 9. 4 (s, 1H> , 7. 0 to 6. 0 (m, 6H> , 5. 8 (s, 4H) , 5. 0 to 4. 6 Cm, 1H> , 3. 9 to 3. 6 (m, 1H> , 3. 25 to 2. 2 <m, 7H> , 1. 5 and 1.4 (t, 1H, J = 8 Hz).
IR (Aujol> . 1705, 1640 cm'' 1'Licroanalysis : C<,.H~,O~NS
Calc % ~ = 58.46 H = 4.91 N = 3.25 Found °/. C = 58.76 H = 4.9? N = 3.39 ~;~~p1 P 31 ~ Preparation of N- CRS)-L 1-oxo-2- (acet~,~lthiometh~~l >3-(3 4-ethy,LE'nediox)tThenyl> ~rop~ClJ-benz~l gl~cina A PrP~aration of (RS>-2-acety],thiometh~T -1 3(3 4-ethvlenedioxv p]~n~, ) ~-opanoic aci d It is obtained in the same way as in example 1 (step d) by addition of thioacetic acid to 2-f(3,4-ethylenedioxy phenyl) methyl) propenoic acid.
Yield = 98 °~
IR (Nujol> . 1?20, 1690 cm ' 'H NMR (CDCl~:/Th.S> . 8.5 <s, 1H), 6.8 to 6.5 (m, 3H>, 4.2 (s, 4H>, 3.15 to 2.? (m, 5H), 2.3 (s, 3H>.
B Preparation of N-(RS)-f1-oxo-2-(acet~rlthiomethyl)-3-C3.4-~hy.1 enediox~ ~~ hen~,l3 propel J -benzXl glvcinate The acid obtained in step A is coupled to benzyl glycinate in the presence of HOBT and DCC, according to the operating procedure described in example 1.
Yield = 92 % (chromatographied) MP = 62°C (Microscope) IR (Nujol> . 3290, 1?45, 16?0, 1640 cm ' 'H NMR (CDC1;~/TMS> . 7.4 (s, 5H>, ?.0 to 6.55 (m, 3H), 5.9 (s, 1H>, 5. 2 (s, 2H) , 4. 2 (s, 4H> , 4. 0 <dd, 1H, J = 5. 3 Hz > , 3. 95 <dd, 1H, J =
5.3 Hz), 3.2 to 2.4 (m, 5H>, 2.3 (s, 3H).

~o ~~~os 'aC N14R (CDC1~) . 196.4 (s>, 173.1 <s), 169.3 <s>, 143.2 (s>, 142.1 (s), 135.3 (s), 131.5 (s>, 128.4 (d>, 128.0 Cd>, 121.6 (d>, 117.3 (d>, 116.9 (d), 66.9 (t>, 63.9 (t>, 48.6 <d>, 41.1 <t), 37.2 (t), 30.7 <t), 30. 2 (q) .
Microanalysis : C~:,H<=ObNS
Calc '/. C = 62.30 H = 5.64 A = 3.16 Found y. C = 62.15 H = 5.60 N = 3.02 Fxamnle 32 Pr~~~tion of A-(RSV- « -nxn-~' r~ pvl>-3-_(~~4 ethvlenedi oxv vhen~,~~p)'ll'gl;dine Deprotection of the compound of example 31 is carried out according to the operating procedure of example 1 (step g).
Yield = 66 '/.
I~tP = 138'( (Microscope) IR (Nu,jol) . 3480, 1745, 1630 c~ ' ' H NI~tR (CDC1.,-DMSO ds/TIhS) . 7. 6 (s, 1H) , 6. 75 <s, 3H) , 5. 8 (m, 1H) , 4.2 (s, 4H>, 3.9 (d, 2H, J - 5.3 Hz), 3.15 to 2.1 <m, 5H>, 1.7 (t, 1H, J = 6.6 Hz).
Microanalysis : C,aH,~OSNS
Calc °/. C = 54.02 H = 5.47 A = 4.50 Found °/. C = 53.76 Ii = 5.38 N = 4.26 S~ 4-a hv~ eng~X)' phenyl ) plon)C]~)- (S>-benzyl alaninate (50/50 mixture of the diastereomer~~
2-acetylthiomethyl-3-(3,4-ethylenedioxy phenyl) propanoic acid in its racemic form (example 1, step d) is coupled to <S) benzyl alaninate according to the operating procedure of example 1 (step f).
Yield = 78 '/.
Rf value = 0.2 (50/50 in ether/petroleum ether) 'H NMR (CDC1~/TId.S> . 7.3 (s, 5H), 6.8-6.5 (m, 3H>, 6.0 (m, 1H>, 5.1 <s, 2H>, 4.5 <m, 1H>, 4.2 (s, 4H), 3.2-2.4 <m, 5H), 2.3 (s, 3H), 1.35 (d, J = 7 Hz, 1.5H>, 1.15 (d, J = 7 Hz, 1.5H>.
'=~C NMR (CDC1:,) . 195.9, 172.3, 143.2, 142.2, 135.3, 131.8, 131.5, 128.5, 128.3, 128.0, 121.7, 117.5, 117.1, 66.8, 64.2, 49.4, 49.0, 48.0, 47.8, 37.7, 37.5, 30.9, 30.7, 30.3, 18.3, 18Ø

D

42 ~A X9706 IR (CC14> . 3400, 1735, 1675 cm ' Microanalysis : C2dH~:7ObNS
Calc y. C = 63.00 H = 5.95 N = 3.06 Found '/ C = 62.73 H = 5.93 A = 3.29 diastereomers) Deprotection of the compound of example 33 is carried out according to the operating procedure of example 1 (step g>.
Yield = 86 y°
Rf value = 0.3 (50/49/1 petroleum ether/ethyl acetate/acetic acid) 'H NMR (CDCl:y/T1IS) . 9.05 (s, 1H>, 6.9-6.4 (m, 3H>, 6.25 <m, 1H>, 4. 55 (m, 1H) , 4. 2 <s, 4H> , 3. 05-2. 3 (m, 5H> , 1. 6 (t, J = 8. 3 Hz, 1H) , 1. 4 (d, J = 6. ? Hz, 1. 5H) , 1. 25 (d, J = 6. 7 Hz, 1. 5 Hz > .
NMR (CDC13) . 175.9, 173.7 , 143.4, 142. 3, 131.8, 131.5, 121.8, 117.6, 117.3, 64.3, 53.6, 53.1, 48.0 ,37.6, 37.3, 26.0, 25.8, 18.0, 17.7.
IR (CDC1:,> . 3400, 1720, 1650 cm ' Microanalysis : C,~H,~.NOsS
Calc °/. C = 55.37 H = 5.88 N = 4.30 Found % C = 55.26 H = 5.65 N = 4.19 Example 35 : Pre ap ration of N SRS)-(1-oxo-2-<acet~rlthiomethvl)-3-~~ 3-methylenediox~vhenvl~~g)!]U~ be~vl~al~~
A. Preparation of <RS)-2-acet~ t~~~,hvl-3-~~ 3-methv n _dioxrv phenyl) nropanoic acid It is obtained in the same way as in example 1 (step d) by addition of thioacetic acid to 2-((3,4-methylenedioxy phenyl) methyll propenoic acid.
Yield = 85 IR (cm-'> . 1710, 1690 ' H NMR (CDCl:~ITMS> : 9 (s, lIi> , 6. 6 <s, 3H) , 5. 8 (s, 2H> , 3. 2 to 2. 4 (m, 5H) , 2. 2 <s, 3H) .

-2_ -3_ g~~hy~ ened~ ox~~phPn,°~pro~yl ) -benzy~g~ 3~cinate The compound obtained in step A is coupled to benzyl glycinate according to the operating procedure of example 1 (step f>.
Yield = 68 12P = 60'C
IR (Nujol> . 3320, 1740, 1690, 1650 cm ' 'H NMR CCDC1:~/TMS) . 7.2 (s, 5H), 6.8 (s, 3H), 6.3-6.0 <m, 1H), 5.8 (s, 2H>, 5.1 (s, 2H>, 3.95 (d, 2H, J - 5 Hz), 3.2-2.4 (m, 5H>, 2.2 (s, 3H).
'='C NMR (CDC1:~) . 195.5, 172.9, 169.3, 146.9, 145.4, 134.9, 128.4, 122.9, 121.3, 120, 107, 100.3, 66.8, 46.3, 41.1, 32.1, 30.5, 30.2.
Microanalysis : C«H~:a2v'O6S
Calc % C = 61.52 H = 5.39 N = 3.26 Found % C = 61.47 H = 5.36 N = 3.34 ~'-~---~, ~ '~5 prP.~aration of N- (RS)-( 1-oxo-2- (mercantomethy~-3-z-.~+ ~1PTP~ioxT~~~l,,V1) nropy~J-glycine Deprotection of the compound of example 35 is carried out according to the operating procedure of example 1 (step g>.
Yield = 71 IR (CDCl_~> . 3390, 1740, 1640 cm ' 'H NMR (CDC1~/TMS) . 9.4 (s, 1H), 6.8-6.4 (m, 4H), 5.8 (s, 2H), 4.0-3.8 (m, 2H>, 3.1-2.3 (m, 5H>, 1.65 (t, 1H, J = 7.9 Hz).
"C NI4R (CDCl~) . 173.2, 171.85, 147, 145.5, 122.9, 121.45, 120, 107, 100.4, 50.3, 41.1, 32, 25.9.
liicroanalysis : C, ~.H, sNDsS
Calc % C = 52.51 H = 5.08 N = 4.71 Found °/° C = 52.38 H = 4.87 N = 4.51 Example 37 ~ Preraration of N-(RS)-jJ -oxo-2-(ace~xlthiometh )-3-(4-phenox~p, en,~pro~vl l -benzxl gl~Tcinate A Brenaration of (RS)-2-acetyrlthiometh~tl_-3-(4- h~enoxv phen~
nropanoic acid It is obtained in the same way as in example 1 (step d> by addition of thioacetic acid to 2-f(4-phenoxy phenyl) methyll propenoic acid.

Yield = 98 %
IR (film) . 1740 cm-' 'H NMR (CDC1:,/TMS) . 9.5-9.1 (m, 1H>, 7.5-6.8 (m, 9H>, 3.2-2. 8 (m, 5H> , 2. 2 <s, 3H> .
Preparation of N- <RS>-( 1-oxo-2- (acet;~~lthiomethyl >-3- (4-phenoxy pheny ) vropyll-benzyl gay Ana The compound obtained in step A is coupled to benzyl glycinate according to the operating procedure of example 1 (step f).
Yield = 52 °~G
MP = 66°C (Microscope) 'H NMR CCDC13/TMS) . 7.2 (s, 5H>, 7.2-6.7 <m, 9H>, 5.8 Ct, J -6.7 Hz, 1H>, 5.0 <s, 2H), 4-3.8 (m, 2H), 3.1-2.4 <m, 5H), 2.2 (s, 3H).
IR (Nujol) . 3300, 1730, 1680, 1640 cm-' Microanalysis : (C<~H~~NOsS>
Calc % C = 67.90 H = 5.69 N = 2.93 Found °/. C = 67.59 H = 5.55 N = 3.03 r~xamplP 38 preparation of A- ('2S)-( 1-oxo-2- (merca.ptomAthvl )-3-(4-ahQnoxv ohenvl> nrop,~glycine Deprotection of the compound obtained in step B of example 37 is carried out according to the operating procedure of example 1 (step g) .
Yield = 60 °/.
1:P = 94°C Cl~icroscope) ' H N2~ <CDC1::,/TMS) . 7. 6-6. 2 (m, 11H> , 4. 2-3. 8 (m, 2H) , 3. 1-2.2 (m, 5H>, 1.8-1.4 (m, 1H>.
IR (Nujol> . 3300, 1740, 1630 cm ' Microanalysis : (C,~~H,4NOaS) Calc % C = 62.58 H = 5.54 N = 4.05 Found % C = 62.80 H = 5.67 N = 4.12 . -( (4 ~henox~~henvl ) Dropvl l - (S>-benzyl alaninate The compound obtained in step A is coupled to (S) benzyl alaninate according to the operating procedure of example 1 (step f>.
Yield = 73 % (50/50 mixture of the diastereomers>
IR (CDC1:~> . 3300, 1740, 1690, 1650 cm ' ' H AMR (CDC1:,/TMS> . ?. 2 <s, 5H> , 7. 2-6. 7 <m, 9H> , 6 (t, J = 6. 6 Hz, 1H), 5.1 ts, broad, 2H), 4.7-4.4 (m, 1H), 3.2-2.8 <m, 4H>, 2.8-2.4 (m, 1H), 2.25 (s, 3H>, 1.3 and 1.15 t2d, 3H, J = 6.6 Hz>.
'3C NMR (CDC1~> . 195.9, 195.6, 172.2, 157.4, 155.7, 135.2, 133.5, 130.2, 129.6, 128.5, 128, 122.9, 118.9, 118.5, 66.9, 49.5, 49.1, 47.7, 37.4, 30.9, 30.3, 18.3, 18.
Microanalysis : CaeH~SNOsS
Calc x C = 68.4 H = 5.94 N = 2.85 Found y. C = 68. 15 H = 6.06 N = 3. 15 F~p]e 40 Pre rat ,QIL of N- (RS)-( 1-oxo-2- (merca tnmPi-__ X11 -3-i4-phenox~.phe~~y''1) pL~.~Xll=(~S>-alanine Deprotection of the compound of example 39 is carried out according to the operating procedure of example 1 (step g).
Yield = 63 y. (50/50 mixture of the diastereomers) IR (CDC1:,) . 3420, 1720, 1650 cm-' ' H AMR (CDC1:,/TMS) . 9. 3 <s, 1H> , ?. 4-6. 7 (m, 9H) , 6. 3 <t, J = 8 Hz, 1H>, 4.8-4.4 (m, 1H), 3.1-2.2 (m, 5H>, 1.45 and 1.25 (2d, 3H, J -7.1 Hz>.
'3C NMR (CDC1:,> . 174.9, 173.1, 157.3, 155.7, 133.25, 130.1, 129.6, 123, 118.9, 118.5, 53.2, 52.75, 48.15, 47.9, 37.45, 37.1, 26, 25.8, 18.1, 17.8.
Microanalysis : C,~.H~,NOdS
Calc '~ C = 63.48 H = 5.88 N = 3.89 Found °/. C = 63.25 H = 6.1 N = 3.72 ~r1~41 Pre~~~tion of N-(RS)-( 1-oxo- ,=(ac ~~~lthiomet vl (4-phen~Cl phenyl ) ~_olZ;tll-benzyl glycinate P
rronanoic acid It is obtained in the same way as in example 1 (step d) by addition of thioacetic acid to 2-t(4-phenyl phenyl) methyll propenoic acid.
Yield = 97 °/.
IR (cm-'> . 1740, 1690 ' H NMR (CDC1:~/T14.S> . 9. 6 (s, 1H) , 7. 7 to 7. 1 (m, 9H) , 3. 2 to 2. 8 (m, 5H> , 2. 25 <s, 3H) .

D

_ 46 1_ The compound obtained in step A is coupled to benzyl glycinate according to the operating procedure of example 1 (step f).
Yield = 64 % (chromatographied) MP = 99-103'( (Microscope) IR (Aujol> = 3290, 1745, 1690, 1650 cm ' ' H NMR (CDC13/T?t.S> . 7. 7 to 7. 1 <m, 14H) , 5. 9 (m, 1H> , 5. 1 (s, 2H> , 3. 95 <m, 2H) , 3. 2 to 2. 8 (m, 5H> , 2. 3 (s, 3H> .
'=C NMR (CDC1:~) . 196.1 (s>, 173.3 (s), 169.6 (s), 140.9 <s), 139.6 (s>, 13?.8 (s>, 135.2 (s>, 129.4 Cd), 128.7 (d>, 128.3 (d), 127.3 (d), 127.0 (d>, 66.9 (t>, 48.9 (d>, 41.1 (t>, 37.7 (t>, 30. 9 (t ) , 30 . 3 (q> .
?ticroanalysis ; C~~H~~OdNS
Calc °/° C = ?0.28 H = 5.85 N = 3.03 Found % C = 70.10 H = 6.01 N = 3.03 Rxamp,~ 42 Preparation of N-(RS>-tl-oxo-2-(mercaptomethvl)-3-(4-vhenvl nyen,~p_rg~,r~lJ_-gl~Tcine Deprotection of the compound of example 41 is carried out according to the operating procedure of example 1 Cstep g).
Yield = 78 °/. (chromatographied>
liP = 70-73'C (Microscope) IR (Nujol> = 1?35, 1670 c m-' ' H N~ (CDC1:~-DMSO de/TMS) . ?. 9 to 7. 2 (m, 9H) , 6. 0 (s, broad, 2H) , 4. 0 (d, 2H, J = 6. 8 Hz> , 3. 4 to 2. 4 (m, 5H> , 1. 95 <s, broad, 1H) .
'aC NMR <CDC1.,-DMSO due) . 173.6 (s>, 170.5 (s), 139.7 (s>, 138.0 <s), 13?.4 (s>, 128.6 (d), 127.9 (d>, 126.0 <d), 125.9 (d>, 51.0 <d), 40.2 (t), 36.7 (t>, 25.3 (t).
Microanalysis ; C, e:H, ~yO~;NS
Calc % C = 65.65 N = 4.25 H = 5.77 Found %. C = 65.63 N = 4.13 H = 5.93 A solution of 0.79 g (4.78 mmol> of (+> ephedrine in 25 ml of ether is added to a solution of 3 g (9.55 mmol> of 2-acetylthiomethyl 3-(4-phenyl phenyl) propanoic acid. The mixture is left for 41 hours, filtered, the crystals washed with ether and centrifuged.

Weight = 2.15 g MP = 132-142'C
ta7o5 - +14.5' (c = 1.3, MeOH>
Recr~~al_1 ; ~a ? ons 2.10 g of the (+> salt are placed in a flask and 17 ml of chloroform plus 28 ml of petroleum ether are added. After 22 hours, filtration is carried out, the salt is washed with ether and centrifuged.
Weight = 1.38 g Yield = 66 MP = 138-142'C
t aJ o" - +11. 6' (c = 1. 4, MeOH>
This process is repeated 4 times.
Overall yield of 5 recrystallizations = 16 °/.
?iP = 148'C
( aJ os - +5. 9' (c = 1. 1, MeOH>
R~_)ieas~ of the optical b~pure (s) acid 0.33 g of optically pure C+) salt is dissolved in chloroform, water is added and the mixture acidified to pH = 1 with a 7 N HC1 aqueous soluticn. The organic phase is separated and extracted again with CHC13. The organic phases are combined, washed with water, dried on M,gSOa, filtered and concentrated.
Weight = 0.22 g Yield = 100 °/.
MP = 121'C
t a7 05 - -10. 1 ° (c = 1. 3 in methanol >
IR (Nu~ol> . 1710, 1690 cm ' 'H NJ~t <CDCls/TMS) . 10.95 <s, 1H>, 7.7 to 6.95 (m, 9H), 3.3 to 2. 6 Cm, 5H> , 2. 2 <s, 3H) .
'~'C NMR (CDC1_> . 195.1 (s), 179.5 (s>, 140.5 (s), 139.4 (s>, 136.4 (s), 129.2 (d), 128.5 (d), 127.0 (d>, 126.8 (d>, 47.7 (d), 36.9 (t>, 30.3 (t), 29.5 (q>.

Example 43 Preparation of N-(S>-f1-oxo-2-(acetvlthiomethvl>-3-(~-nhenvl_ nhen~~7ronvlJ-benz~l_~lvcinate 2-acetyithiomethyl-3-(4-phenyl phenyl) propanoic acid in its <S>
form is coupled to benzyl glycinate according to the operating procedure of example 1 (step f).
Yield = 62 % (recrystallized in ether) MP = 108-109'( (Microscope) ( al 05 - -6 . 7 ' (c = 1. 1 i n CHCl:~ >
IR (Nujol> . 3300, 1730, 1680, 1645 cm ' ' H NMR (CDC1.,/T~'.S> . 7. 7 to 7. 1 (m, 14H> , 5. 9 (t, 1H, J - 4 Hz> , 5. 05 (s, 2H) , 3. 95 (dd, 1H, J = 4 Hz ) , 3. 9 (dd, 1H, J = 4 Hz > , 3. 2 to 2.4 (m, 5H), 2.25 <s, 3H).
The '=C NMR spectrum is identical to that of the racemic product.
Iiicroanalysis : C.~H<-~OaNS
Calc % C = 70.28 N = 3.03 H = 5.85 Found °/. C = 69.96 N = 3.24 H = 5.93 Example 44 Fre~aration of N-(S)-(1-oxo-2-(acetylthi,Qmethvl>-3-(4-phenyl phen~Tl ) prop~rl l - (S>-benzvl alaninate 2-acetylthiomethyl-3-(4-phenyl phenyl) propanoic acid in its (S>
form is coupled to (S) benzyl alaninate according to the operating procedure of example 1 (step f).
Yield = 67 % (recrystallized in a CHC1:,/petroleum ether mixture) MP = 110'(, one diastereomer only (Microscope) (alos - -11.7' Cc = 1.1 in CHC1~) IR (Nujol> . 3320, 1725, 1680, 1640 cm-' ' H NriR (CDC1~/TMS) . 7. ? to 7. 0 (m, 14H) , 5. 95 (d, 1H, J = 6. 8 Hz> , 6.0 (s, 2H), 4.5 (quintuplet, 1H, J - 6.8 Hz), 3.2 to 2.4 (m, 5H>, 2. 25 Cs, 3H ) , 1. 3 (d, 3H, J = 6. 8 Hz ) .
"C NMR (CDC1_~> :195.7 (s), 172.3 (s>, 171.9 (s>, 140.5 (s>, 139.2 Cs>, 137.5 <s), 135.0 <s>, 129.2 (d>, 128.5 (d), 12.9.3 (d), 128.2 (d>, 127.8 (d), 126.9 <d>, 126.7 (d), 66.8 <t>, 49.2 (t>, 47.7 Cd>, 38.0 (t>, 31.1 (t), 30.3 (q>, 17.9 (q>.

Microanalysis : C~:.H«OaNS
Calc °/. C = ?0.73 N = 2.94 H = 6.10 Found 7. C = ?0.33 N = 2.97 H = 6.10 F~ple_ 45 : Preparati on of N- (S>-( 1-oxo-2- (mercaR om - yl ~-3- (Q
phen~], nhen~l ) pI-op~~l l - (S)-alanine Deprotection of the compound of example 44 is carried out according to the operating procedure of example 1 (step g).
Yield = 62 %. (chromatographied>
?iP = 131'(, one diastereomer only (Microscope) (alo5 - +36.4' (c = 1.0 in CHC1:~)IR (CHCl:~) . 1720, 1675 cm-' ' H NMR (CDC1 ~/TMS) . 8. 8 (s, 1H) , 7. 7 to 7. 0 (m, 9H> , 6. 15 (d, 1H, J =
8 Hz), 4.5 (quintuplet, 1H, J = 8 Hz>, 3.2 to 2.3 (m, 5H), 1.5 <t, 1H, J = 7.2 Hz>, 1.35 (d, 3H, J = 8 Hz>.
"C NMR (CDCl_~) :176.0 (s>, 173.1 (s>, 140.5 (s), 139.3 (s), 137.2 (s), 129.2 (d>, 128.6 (d>, 127.1 (d), 126.8 (d>, 52.8 <d), 48.2 (d), 37.6 (t>, 25.9 (t>, 18.0 (q>.
I'ticroanalysis : C, ~H~, O:,NS
Calc % C = 66.47 N = 4.08 H = 6.12 Found % C = 66.54 N = 3.98 H = 6.20 isle 46 Preparation of f-(S)-t1-oxo-2-(acet~~hiometh 1y_)3-(4-bhen~phen~l) nro~~l-(S>-benzyl leucinatg 2-acetylthiomethyl-3-(4-phenyl phenyl) propanoic acid in its (S>
form is coupled to (S> benzyl leucinate according to the operating procedure of example 1 (step f>.
Yield = 42 ~. (chromatographied) MP = 100°C, one diastereomer only (Microscope) falo5 - -20.7° Cc = 1.1 in CHC1=>
IR tNu,~ of > . 3320., 1720, 1700, 1640 cm-' 'H NMR (CDC1;./TMS> . 7.8 to 7.0 (m, 14H>, 5.9 (d, 1H, J - 8 Hz>, 4.95 (s, 2H), 4.75 to 4.35 <m, 1H>, 3.2 to 2.4 (m, 5H>, 2.2 (s, 3H>, 1. 75 to 1. 3 (m, 3H> , 0. 8 (d, 6H, J = 4 Hz ) .

50 ~a~~~~s '='C NMR <CDC1=) :195.6 (s), 172.3 (s), 172.0 (s), 140.6 <s), 139.2 (s>, 137.3 (s), 135.1 <s), 129.1 (d), 128.5 (d>, 128.1 (d>, 12?.8 <d>, 127.0 (d), 126.8 (d), 66.6 Ct>, 50.6 <d), 49.0 (d), 41.4 (t>, 37.8 (t), 31.0 Ct), 30.3 (q>, 24.5 (d>, 22.6 (q>, 21.7 (q).
Microanalysis : C~,H~~OQAS
Calc '/° C = 71.95 N = 2.70 H = 6.76 Found °/. C = 72.07 N = 2.70 H = 6.80 Fvamnlp 4? Preparation of N-t1-oxo-2-<mercaytomethYl)-3-(4-nh~n hphen.~].~.~rop;rll-(S~-leucine Deprotection of the compound of example 46 is carried out according to the operating procedure of example 1 (step g).
Yield =?1 °~G
MP < 50'C, one diastereomer only talo5 - +33.5° (c = 1.1 in CHC1:.>
IR (Nu~ol> . 3290, 1?20, 1630 cm-' ' H NMR (CDC1:./TI4S> . 10. 2 (s, 1H) , ?. 7 to 7. 0 <m, 9H> , 6. 0 <d, 1H, J
=
8. 8 Hz> , 4. 75 to 4. 35 (m, 1H> , 3. 2 to 2. 3 (m, 5H> , 1. 9 to 1. 3 (m, 3Ii) , 1.55 <t, 1H, J = 7.9 Hz), 0.8 <d, 6II, J = 4 Hz>.
"C NMR (CDC1:~> . 176.8 <s), 173.4 <s>, 140.? (s>, 139.3 <s>, 137.8 (s>, 129.2 <d), 128.6 (d), 12?.3 (d), 12?.1 <d), 126,9 (d>, 53.0 (d), 50.6 (d>, 40.9 (t>, 37.6 (t>, 26.0 (t>, 24.6 (d), 22.7 <q>, 21.5 (q).
Microanalysis : C~~Hyc,O:.~NS
Calc °/. C = 68.75 N = 3.64 H = 6.?7 Found ~. C = 67.9 N = 3.46 H = ?.22 (3-f luoro nhen~.Lpr~Dxt -l benz.fl gl; c nate >_ ~nropanoic acid It is obtained in the same way as in example 1 (step d> by the addition of thioacetic acid to 2-t(3-fluoro phenyl) methyll propenoic acid.
Yield = 98 %
IR (film) . 1700, 1610, 1590 cm ' D

'H NMR <CDC1~/TMS> . 11.25 (s, 1H), 7.45-6.75 <m, 4H>, 3.3-2. 6 (m, 5H) , 2. 3 (s, 3H> .
B. Preparation of h[_(R,~)-( i-oxo-2-(acetylthiometh,girl)-3-(3-flu,Qro p]ienyl> prop.~rll-benzy~l g],~t~inate The compound obtained in step A is coupled to benzyl glycinate according to the operating procedure of example 1 (step f>.
Yield = 83 y.
MP = 60'C (Microscope) 'H NMR (CDC13/TMS> . 7.35 (s, 5H), 7.3-6.7 (m, 4H>, 6.05 (m, 1H), 5.10 (s, 2H>, 3.95 (m, 2H>, 3.25-2.55 (m, 5H>, 2.3 (s, 3H>.
'3C NMR <CDC1~> . 195.8, 172.8, 169.3, 162.8 (d, J - 246.6 Hz>, 141.1 (d, J - 7.3 Hz>, 135.1, 129.8 (d, J - ?.3 Hz), 128.5, 124.5, 115.0 Cd, J - 46.5 Hz>, 114.0 (d, J - 46.5 Hz>, 66.9, 48.7, 41.2, 37.7, 31.0, 30.3.
IR (Nu~ol) . 3300, 1730, 1680, 1640 cm-' Microanalysis : (C:., H~~.~FN04S) Calc '~ C = 62.51 H = 5.49 N = 3.47 Found °/. C = 62.70 H = 5.35 N = 3.64 r"a~g.le 49 Preparation of N-(RS)-( 1-oxo-2-(merca~mPth~l)-3-(3-fluoro phenyl) prop~rl)-glv.~ine Deprotection of the compound obtained in step B of example 48 is carried out according to the operating procedure of example 1 (step g>.
Yield = ?9 '/.
MP = 125'( (Microscope) 'H AMR (CDC13-DMSOde/TMS) . 7.65 (m, 1H), 7.45-6.65 <m, 4H), 6.3 (m, 1H), 3.90 (m, 2H>, 3.2-2.3 (m, 5H>, 1.75 <t, J = 8.5 Hz, 1H).
'=~C NMR (CDCly-DMSOde., 400 MHz) . 172.9, 171.1, 162.5 (d, J' - 244 Hz), 141.2 (d,Jw = ?.3 Hz>, 129.5 (d,J~ _ ?.3 Hz>, 124.4, 115.5 (d, J
- 22 Hz), 113.0 (d, J~ = 22 Hz), 51.8, 40.9, 37.3, 25.8 IR (Nu,~ol> . 3380, 1745, 1620 cni-' Microanalysis : <C,zH,aO:,NFS) Calc °.4 C = 53.13 H = 5.20 N = 5.16 Found y. C = 53.26 H = 5.11 N = 5.01 D

_ 52 + ' .,f u- lRR)-f 1 -OXO-2- ~ a'"~+i''~ +h i nmPth_vl ) -d -rYamDlP 50 Prey ZT 1 » Or0 vh n~v~~n~~~ ~ - (S)-benzvl alaninate 2-acetylthiomethyl-3-(3-fluoro phenyl) propanoic acid in its racemic farm is coupled to (S> benzyl alaninate according to the operating procedure of example 1 (step f>.
Yield 90 MP = 52-55°C <Microscape> (50/50 mixture of the diastereomers) ' H NMR <CDCl~ /Tl~i,S> . 7. 3 (s, 5H) , 7. 3-6. 65 (m, 4H) , 6. 0 <m, 1H> , 5. 1 (s, 2H> , 4. 5 (quintuplet, J = ? Hz, 1H) , 3. 2-2. 4 (m, 5H> , 2. 3 (s, 3H) , 1. 35 (t, J = 7 Hz, 1, 5H) , 1. 15 (t, J = ? Hz, 1, 5H) .
'=C NMR (CDC1:~) . 195.5, 1?2.3, 171.8, 162.6 (d, J - 244 Hz), 141.0, 135.0, 129.? (d, J = 9.7 Hz), 128.4, 128.1, 127.9, 124.5, 115.6 (d, J = 21 Hz>, 113.2 <d, J = 21 Hz>, 66.8, 50.5, 48.5, 4?.9, 47.6, 37.8, 30.8, 30.2, 18.0, 17.8.
IR (Nujol> . 3290, 1?40, 1720, 1680, 1645 cm ' Microanalysis : (C~~.<H~aFAOdS>
Calc % C = 63.29 H = 5.79 A = 3.35 Faund % C = 63.52 H = 5.90 A = 3.40 -( >_ _( t~ fluoro m en~L oroav W -(S)-alanine Deprotection of the compound of example 50 is carried out according to the operating procedure of example 1 (step g>.
Yield = ?1 %.
MP = 120-122°C (Microscape> (50150 mixture of the diastereomers) 'H NMR <CDC1;~, DMSOd6/TMS> . 7.55-6.4 (m, 6H), 4.4 (m, 1H), 3.15-2. 3 <m, 5H> , 1. 65 (m, 1H> , 1. 4 (d, J = 8 Hz, 1. 5H) , 1. 2 (d, J = 8 Hz, 1.5H).
IR (Nujol> . 3300, 2580, 1715, 1640 cm ' Microanalysis : (C,.-_<H,.,FAO.S) Calf % C = 54.?2 H = 5.65 N = 4.91 Faund % C = 54.57 H = 5.44 A = 4.82 ~~4 difluor~ahenvl> mronW -benzyl ff7v~inate _( p~.ano~ c acid It is obtained in the same way as in example 1 (step d) by the addition of thioacetic acid to 2-((3,4-difluoro phenyl) methyll propenoic acid.
Yield = 98 '/.
IR (film) . 1700, 1610 cm-' 'H NI~tR (CDC1:,/T?tS> . 10.6 <s, 1H), 7.35-6.7 <m, 3H>, 3.3-2.6 (m, 5H>, 2. 3 (s, 3H) .
B. Preparation of N-(kS)-t 1-oxo-2-(acet~rlthiomethyl)-~(3~~
difluoro phenyrhropyll-benz.~rh~-l~tcinate The compound obtained in step A is coupled to benzyl glycinate according to the operating procedure of example 1 (step f).
Yield = 87 '/.
XP = 78'C (Microscope) ' H NMR (CDC1;~/T14S) . ?. 3 <s, 5H) , ?. 25-6. ?5 (m, 3H) , 6. 0 <m, 1H) , 5.15 (s, 2H>, 4.0 (m, 2H>, 3.2-2.55 <m, 5H>, 2.3 <s, 3H>.
"C NMR <CDC1~) :195.6, 172.6, 169.2, 149.6 (dd, J' - 247 HZ, Jw -12 Hz), 148.5 (dd, J' - 247 Hz, Jj - 12 Hz>, 135.4, 134.9, 128.4, 124.7, 117.5 <d, J2 = 17 Hz>, 116.9 (d, J~ = 17 Hz>, 66.8, 48.5, 40.9, 36.8, 30.9, 30.2.
IR (Au,~ol> . 3300, 1740, 1680, 1640 cm ' Microanalysis : (C21H21F2N04S>
Calc °/. C = 59.85 H = 5.02 N = 3.32 Found °/. C = 59.53 H = 5.17 A = 3.50 Examp_1~~,53 : Preparation of N- <kS>-f 1-oxo-2- (,~~tv ~hi..QmQ,.~h~tl,~-3-(3, 4-difluoro ~henyrl) pro~rll-glhcine Deprotection of the compound obtained in step B of example 52 is carried out according to the operating procedure of example 1 (step g>.
Yield = 82 '/.
l~IP = 139'C (Microscope) ' H NMR (CDC1~-DMSOds>/TIZS> . 9. 0 (s, lli> , 7. 2-6. 6 <m, 3H) , 3. 9 (d, J
=
6 Hz, 2H), 3.1-2.2 <m, 5H>, 1.75 <t, J = 8.5 Hz, 1H>.
'~'C NMR <CDC1~./DMSOd~, 400 HZ> . 172.6, 171.0, 149.6 (dd, J' - 247 Hz, Jz = 12 Hz) , 148. 5 (dd, J' - 247 Hz, J~~ = 12 Hz ) , 135. 5, 124. 6, 117. 3 (d, J~' = 16 Hz>, 116.6 (d, J~ _. 16 Hz>, 51.7, 40.7, 36.6, 25.8.

t IR (Nujol> . 3300, 1?20, 1640 cm ' ?iicroanalysis : <C,~H,:~F~NO:yS) Calc °~ C = 49.82 H = 4.53 N = 4.84 Found ~. C = 49.?0 H = 4.34 N = 4.63 ~ple 54 ~ Pre..garation of N- CRS)-L i-oxo-2- (aceterlthi omethgl >3-(~'~,~~difluoro phenyl ) pro~vll- (S>-benz~t~alani nate 2-acetylthiomethyl-3-C3,4-difluoro phenyl) propanoic acid in its racemic form is coupled to <S) benzyl alaninate according to the operating procedure of example 1 (step f>.
Yield = 93 MP = 76-79°C (Microscope) (50/50 mixture of the diastereomers) 'H NMR (CDCl:j/TMS) . 7.3 (s, 5H>, 7.2-6.? Cm, 3H>, 6.1 (d, J = ? Hz, 1H>, 5.1 (s, 2H>, 4.5 (quintuplet, J = ? Hz, 1H>, 3.1-2.4 (m, 5H>, 2.3 (s, 3H) , 1. 3 (d, J = 7 Hz, 1, 5H) , 1. 15 <d, J = ? Hz, 1, 5H> .
'=C h'MR (CDC1~:) . 195.8, 172.3, 171.8, 149.8 (dd, J' - 247 Hz, J~ _ 17 Hz), 148.6 (dd, J' - 24? Hz, J'~ - 1? Hz), 135.6, 135.2, 128.5, 128.0, 124.9, 11?.5 (d, J~ = 17 Hz>, 116.9 (d, J~ - 1? Hz>, 66.9, 49.1, 48.7, 4?.9, 3?.1, 31.0, 30.3, 18.1.
IR CNujol> . 3295, 1?40, 1680, 1640 cm ' Microanalysis : (C«H~~F:~NOnS) Calc % C = 60.68 H = 5.32 N = 3.22 Found % C = 61.02 H = 5.23 N = 3.27 Example ,.5y5 Preparation of N-(RS)-Li-oxo-2-(mercaptomethYl>-3-i~i~ 4-dif luoro i~henyl ) propgl l - CS)-alanine Deprotection of the compound of example 54 is carried out according to the operating procedure of example 1 (step g>.
Yield = ?2 MP = 103-10?°C (Microscope) (50/50 mixture of the diastereomers>
'H NMR (CDC1~,, DMSOdr,/TMS) . ?.8 (s, 1H>, 7.5-6.65 (m, 3H), 4.45 (quintuplet, J = 8 Hz, 1H) , 3. 1-2. 2 (m, 5H) , 1. 65 (m, 1H> , 1. 35 (d, J
- 8 Hz, 1, 5H) , 1. 2 (d, J = 8 Hz, 1, 5H> .
IR (Nu j of > . 3300, 2560, 1?20, 1645 cm ' Microanalysis : (C, ~H, ~-,F~NO::jS>
Calc % C = 51.47 H = 4.98 N = 4.62 Found % C = 51.33 H : 4.87 N = 4.46 _ 55 ~Ya~P 56 Preparation of N-<RS)-(1-oxo-2-(acetXlthiomPthyl~-3-(~~-difluoro ~hen~LL~trop~rll-benzyl g~.vcinate A Preparation of CRS>-2-acetythiomethoo -3-<3 5-difluoro phenvl) ps-opanoic acid It is obtained in the same way as in example 1 (step d) by the addition of thioacetic acid to 2-((3,5-difluoro phenyl) methyl) propenoic acid.
Yield = 98 °/.
IR (film) . 1700, 1620, 1590 cm ' 'H NMR (CCld> . 11.1 (s, 1H>, 6.9-6.35 Cm, 3H>, 3.2-2.7 <m, 5H>, 2. 3 (s, 3H> .
B Pre~r_ation of N-(RS>-(1-oxo-2-(acet~lthiomethyl>-3-(3.5-dy f 1 uoro ~2,h~)L> > r~opYl J -benz,~? glycina The compound obtained in step A is coupled to benzyl glycinate according to the operating procedure of example 1 Cstep f).
Yield = 89 MP = 67°C (Microscope) 'H NMR <CC14) . 7.25 Cs, 5H), 6.85-6.40 (m, 3H> , 6.2 <m, 1H>, 5.05 <s, 2H>, 3.85 (m, 2H), 3.2-2.4 (m, 5H>, 2.15 (s, 3H).
' ~C NMR (CDC1~~> . 195. 7, 1~2. 4, 169.3, 162. 6 (dd, J' - 249 Hz, J~' _ 12 Hz>, 142.5, 135.1, 128.5, 128.3, 111.1 <d, J~ = 24 Hz>, 102.0 Ct, 3~ = 24 Hz), 67.1, 48.5, 41.1, 37.5, 31.1, 30.3.
IR (Nujol) . 3300, 1750, 1690, 1650, 1620, 1595 cm-' Microanalysis : (C:~,H~,F~N04S>
Calc % C = 59.85 H = 5.02 N = 3.32 Found % C = 60.0 H = 5.14 N = 3.33 ~xam~ P 57 Pre~-ation of A- (RS)-( 1-oxo-2- (mercaptometh;tl )-3-7aoro phenyl) propyl)-g~)r-cinene Deprotection of the compound obtained in step B of example 56 is carried out according to the operating procedure of example 1 (step g>.
Yield = 69 MP = 85°C (Microscope) 'H NMR (CDC1:;, DMSOdr/TMS) . ?.3 (s, 1H), 6.9-6.35 (m, 3H), 3.9 (d, J = 5 Hz, 2H), 3.15-2.2 (m, 5H>, 1.75 <t, J = 8.5 Hz, 1H).

56 ~~~~~e~~i~
' 3C NMR (CDC1.~, DMS0d5, 400 Hz > . 172. 5, 1?1. 0, 162. 4 (dd, J' = 248. 3 Hz, J=~ - 12.5 Hz), 142.6, 111.4 (d, J~ - 24 Hz>, 101.4 (t, J~ -24 Hz), 51.4, 40.?, 3?.2, 26Ø
IR (Nujol) . 3290, 1720, 1640, 1620, 1595 cm ' ?iicroanalysis : (C, aH, :~F~NO;~S) Calc % C = 49.82 H = 4.53 N = 4.84 Found °/. C = 50.00 H = 4.54 N = 4.71 ~~~le 58 ~ Preparation of N-tRS)-f 1-oxo-2-<acetylthiometh~rl>-3-c~ 5-difluoro p~~~propyll-(S)-benzyl alaninate 2-acetylthiomethyl-3-(3,5-difluoro phenyl) propanoic acid in its racemic form is coupled to (S> benzyl alaninate according to the operating procedure of example 1 (step f).
Yield = 96 MP = 64-?3°C (Microscope) (50/50 mixture of the diastereomers>
'H NMR (CDC1:~/TMS> . 9.25 (s, 5H), 6.95-6.30 (m, 4H), 5.1 (s, 2H>, 4. 45 (quintuplet, J = 7 Hz, 1H> , 3. 2-2. 4 (m, 5H) , 2. 3 <s, 3H> , 1. 3 <d, J = 7 Hz, 1. 5H) , 1. 1 <d, J = ? Hz, 1. 5H> .
'-'C NMR <CDCl:~) . 195.8, 172.3, 171.5, 162.? (dd, J' - 247 Hz, J' _ 12 Hz) , 142. 8, 135, 128. 4, 127. 9, 111. 6 (d, J1 = 24 Hz > , 101. 8 (t, J
= 24 Hz>, 66.8, 48.6, 47.7, 37.5, 31.0, 30.3, 18.
IR (Nujol> . 3300, 1740, 16?0, 1640, 1620, 1590 cm ' Microanalysis : (Ca<Hz:~F~NO4S>
Calc % C = 60.68 H = 5.32 N = 3.22 Found °/. C = 60.93 H = 5.26 N = 3.29 ~ple 59 Pr~,~aration of N-(RS)-t 1-oxo-2-(mercantomethaY~)-3-'~ 5-difluoro ~h_enyl) prop5~ll-CS)-alanine Deprotection of the compound of example 58 is carried out according to the operating procedure of example 1 (step g).
Yield = 62 MP = 115-118°C (Microscope) (50/50 mixture of the diastereomers>
' H NMR (CDC1:~, DM~SOd~ /TMS> . 8. 15 (s, 1H> , 7. 15-6. 4 <m, 3H) , 4. 45 (quintuplet, J = 7 Hz, 1H) , 3. 1-2. 25 (m, 5H) , 1. 65 (m, 1H> , 1. 4 <d, J
= 7 Hz, 1. 5H) , 1. 25 (d, J = ? Hz, 1. 5H> .
'=C NMR (CDClc,/DMSOd~:> . 174.5, 171.9, 163.2 <dd, J' = 249 Hz, J~=' = 12 Hz>, 142.6, 111.6 (d, J~ - 24.4 Hz, 101.9 (t, Jw - 24.4 Hz>, 52.6, 52.1, 47.8, 37.4, 26.3, 26.1, 18.15, 17.8.

IR (Nujol> . 3300, 1715, 1640, 1620, 1595 cm ' Microanalysis : CC13H75F~NO:;S) Calc ~. C = 51.47 H = 4.98 N = 4.62 Found ~. C = 50.98 H = 4.8? N = 4.43 g~~,,1 a 60 Prenarat~ on of N- (S>-f 1-oxo-2- <acet~~lthiomethvl)-3-S,,'iy5 difluoro nhenx,~pro~;tll-<S>-benzyl alaninate (<-> isomer) It is obtained by fractional recrystallization of the diastereomer mixture of example 58 in an ether/petroleum ether mixture.
falo5 - -58.3 ° Cc = 1.2, MeOH) MP = 113°C (Microscope) ' H NMR (CDC1;~/T14S) . 7. 25 (s, 5H) , 6. 95-6. 4 <m, 3H> , 6. 2 <m, 1H) , 5.1 (s, 2H),.4.45 (quintuplet, J = 7 Hz, 1H>, 3.2-2.4 (m, 5H), 2.3 <s, 3H> , 1. 35 <d, J = 7 Hz, 3H> .
IR <Nujol> . 3300, 1735, 1670, 1640, 1590 cm ' 1P 61 ~ Preparation o~ N-(RS>-fl-oxo-2-(acetvlthiomethy (5'-indan~Cl> ~LQpvll-benzxl glvcinate A Preparation of <RS)-2-acet ~lthiomethvl-3-(5'-indanvl>
nr~enoic acid It is obtained in the same way as in example 1 (step d) by the addition of thioacetic acid to 2-((5'-indanyl) methyll propenoic acid.
Yield = 96 IR (cm ' ) . 1700 'H NMR <CC14/TMS> . 11.2 Cs, 1H>, ?.2-6.8 (m, 3H>, 3.2-2.4 <m, 9H>, 2. 2 <s, 3H) , 2. 2-1. 8 <m, 2H> .
Preparation of N-<RS>-fl-oxo-2-(acetylthiometh,tl>-3-(5'-~ndan~.)) gropvll-benz~glycinate The compound obtained in step A is coupled to benzyl glycinate according to the operating procedure of example 1 (step f).
Yield = 6?
MP = 71-72°C
IR (Nujol> . 3300, 1740, 1690, 1650 cm ' 'H NMR (CCla/TM~.S) . 7.2 (s, 5H), 7.1-6.8 (m, 4H), 5 (s, 2H), 3.9-3. 7 <m, 2H) , 3. 1-2. 5 <m, 9H) , 2. 1 (s, 3H) , 2. 1-1. 8 (m, 2H) .

?ticroanalysis : C~aH~<7NOdS
Calc % C = 67.73 H = 6.39 N = 3.79 Found % C = 68.02 H = 6.44 N = 3.50 C5'-indanvl) pro~t,~ll-~l~cine Deprotection of the compound obtained in step B of example 61 is carried out according to the operating procedure of example 1 (step g>.
Yield = 68 MP = 90 ° C
IR (Nujol) . 3380, 1740, 1620 cm-' ' H NMR <CDCl_ /TMS) . 8 <s, 1H) , 7. 2-6. 8 (m, 3H> , 6. 4-6. 2 (m, 1H) , 4.

3.8 (m, 2H), 3,0-2.4 (m, 9H>, 2.25-1.8 <m, 1H), 1.6 <t, 1H, J -7.8 Hz>.
'1C NMR (CDC1:~> , 174.6, 172.6, 144.6, 142.5, 135.9, 126.5, 124.7, 124.2, 53.1, 41.2, 37.8, 32.6, 32.2, 25.8, 25.2.
Microanalysis : C,sH,.~NO:,S
Calc % C = 61,4 H = 6.52 N = 4.77 Found % C = 61.35 H = 6.50 N = 4.82 Rx~mY ~ P 63 ~ Preparation of N- CRS>-f 1-oxo-2- (acet~rlthiometh~l )-3-C5'-indanyl) pro~vl7-(S)-benzvl alaninate The compound obtained in step A of example 61 is coupled to <S>
benzyl alaninate according to the operating procedure of example 1 (step f).
Yield = 67 °/.
IR : 3300, 1740, 1680, 1650 cm ' 'H NMR tCDCl:,/TMS) . 7.2 Cs, 5H>, 7.1-6.8 <m,3H>, 6.5 and 6.2 C2d, 1H, J = 6. 6 Hz > , 5 (s, 2H) , 4. 7-4. 3 (m, 1H ) , 3. 2-2. 5 (m, 9H) , 2. 2 <s, 3H) , 2. 1-1. 8 (m, 2H) , 1. 3 and 1. 1 <2d, 3H, J = 6. 7 Hz > .
'=C NMR (CDC1~> . 195.8, 172.2, 144.3, 142.2, 136.1, 135.2, 128.4, 128.1, 127.8, 126,4, 124.7, 124, 66,7, 49.3, 48.7, 47.9, 47,5, 38.2, 37.8, 32.3, 32.1, 30.9, 30,6, 30.2, 25.2, 18, 17.8.
liicroanalysis : C<<,H~_~NOaS
Calc % C = 68.3 H = 6.65 N = 3.18 Found % C = 68. 1 H = 6.60 N = 3.05 v .._ 59 64 Preparation of N-(RS)-fl-oxo-2-(mercantomethvl)~3-(5' -i ndanvl > pTop~'1 ) - <S)-al anine Deprotection of the compound of example 63 is carried out according to the operating procedure of example 1 (step g).
Yield = 86 °/.
?LP = 40-45°C
IR (Nujol) . 3440, 1720, 1660 cm ' 'H NMR <CDC13/TMS> . 8.4 (s, 1H), 7.2-6.8 (m, 3H>, 6.3-5.8 <m, 1H>, 4.6-4.4 (m, 1H), 3.0-2.3 (m, 9H>, 2.2-1.8 <m, 2H>, 1.6 (t, 1H, J =
9 Hz > , 1. 45 and 1. 2 (2d, 3H, J = 7. 3 Hz ) .
'3C NMR <CDC1:,> . 175.6, 173.8, 144.5, 142.5, 135.9, 126.55, 124.9, 124.25, 53.5, 52.9, 48.1, 47.9, 38.1, 3?.9, 32.5, 32.2, 25.9, 25.3, 17.9, 17.55.
Microanalysis : C,cH~,NO:_S
Calc °~ C = 62.51 H = 6.88 N = 4.55 Found °/. C = 62.30 H = 6.81 N = 4.38 ~,~,ama~ a 65 Preparation ~f N- (RS>-f 1-oxo-2- (acetvlthiomethvl )~3-c~' 3' dih3Tdro-5'-benzofuranyl) I2ropyl)-benzy~glvcinate ~', Prepc'~ratio~ of <RS> 2- (acety~hiometh~l )-'~- (2' 3' -dihvdro-5' -~Pnzofuran~,~~roranoic acid It is obtained in the same way as in example 1 (step d> by the addition of thioacetic acid to '2-C(2',3'-dihydro-5'-benzofuranyl>
methyl) propenoic acid.
Yield = 98 %.
IR (cm '> . 1700 'H NMR <CDC1:,/TMS> . 10.2 (s, 1H>, 7.1-6.8 (m, 2H>, 6.65 (d, 1H, J =
8.1 Hz), 4.5 (t, 2H, J = 8 Hz), 3.3-2.4 (m, 7H), 2.2 <s, 3H>.
B Preparation of N-(RS)-C1-oxo-2-(acet~rlthiomethyl)-3-(2'.3'-~i hydro-5' -benzofuran~l ) Dropvll -benz~l gl~tcinate The compound obtained in step A is coupled to benzyl $lycinate according to the operating procedure of example 1 (step f).
Yield = 85 ?iP = 85 ° C
IR (Nujol> . 3300, 1720, 1680, 1635 cm-' 'H NMR (CDC13/TMS) . ?.2 (s, 5H), ?-6.?5 (m, 2H), fi.65 Cd, 1H, J =
8 Hz), 6-5.8 (m, 1H>, 5.1 (s, 2H>, 4,5 <t, 2H, J = 8.8 Hz>, 3.9 (t, 2H, J = 5 Hz>, 3.3-2.4 (m, 7H>, 2.2 (s, 3H).
Microanalysis : Ca:~H~sNOsS
Calc °~ C = 64.61 H = 5.89 N = 3.2?
Found % C = 64.60 H = 5.87 N = 3.36 ~,x~~le 66 Preparation of A- (RS)-L 1-oxo-2- (mercantometh~rl >-3-S,2' 3' -dih~~dro-5' -benzofuranyi ) pro~,y~ l -gl~ ct ine Deprotection of the compound obtained in step B of example 65 is carried out according to the operating procedure of example 1 (step g).
Yield = ?0 °/
MP = 121°C
IR (Nu~ol> . 3380, 1740, 1610 cm-' ' H NMR (CBC1.,/TMS> . 9. 4 (s, 1H> , ?. 05-6. 8 <m, 2H> , 6. 65 <d, 1H, J =
8 Hz > , 6. 65-6. 4 (m, 1H) , 4. 5 (t, 2H, J = 8 Hz ) , 3. 9 (t, 2H, J = 5 Hz > , 3. 3-2. 4 (m, ?H> , 1. 6 (t, 1H, J = 8 Hz ) .
Microanalysis : C,4H,~N04S
Calc % C = 56.92 H = 5.80 N = 4.?4 Found % C = 56.84 H = 5.'70 N = 4.51 ~~le 6? ~ Pre~ar~ion of N- CRS)-( 1-oxo-2- (acetylthiometh,rl >3-(2' 3'-dih~dro-5'-benzofuran~rl) propyll-(S)-benzyl alaninate The compound obtained in step A of example 65 is coupled to (S>
benzyl alaninate according to the operating procedure of example 1 (step f>.
Yield = 66 °/.
MP = 63-67°C
IR (Nu,jol) . 3280, 1?20, 1680, 1640 cm ' 'H NMR (CDC1~/TMS) . 7.2 (s, 5H), ? to 6.? (m, 2H), 6.6 (d, 1H, J =
8 Hz), 6.2-5.? <m, 1H>, 5 (s, 2H>, 4.6-4.3 (m, 3H), 3.3-2.4 <m, ?H), 2. 2 (s, 3H) , 1. 3 and 1. 1 (2d, 3H, J = 8 Hz ) .
Microanalysis : C~aH<rNOr,S
Calc % C -- 65.28 H = 6.16 N = 3.17 Found % C = 64.9? H = 6.2? A = 3.19 "'_ 61 ' 3 a 68 Pr~,,aration of N- CRS)-( 1-oxo-2- (mercaptomethyl )-3-~' ~3' -dih~dro-5' -benzof uran'rl > prop~rl ) - (S)-alanine Deprotection of the compound of example 67 is carried out according to the operating procedure of example 1 (step g).
Yield = 81 °/.
I~LP = 40-45°C
IR (CDC1~> . 3420, 1720, 1640 cm-' 'H AMR (CDC1:~/TMS) . 8.8 (s, 1H>, 7-6.?5 (m, 1H>, 6.65 (d, 1H, J =
8 Hz>, 6.3 (t, 1H, J = 8 Hz), 4.7-4.3 (m, 1H), 4.5 (t, 2H, J = 8 Hz>, 3.3-2.4 (m, 7H), 1.6 <t, 1H, J - 9 Hz), 1.4 and 1.2 (2d, 3H, J -6.7 Hz>.
'=C Nl~iR (CDCl_:) . 175.6, 173.65, 158.9, 130.3, 128.3, 127.2, 125.35, 109.1, 70.95, 53.7, 53.2, 47.9, 3?.6, 37.3, 29.4, 25.9, 25.7, I7.9, 17.5.
?iicroanalysis : C,sH,gNOdS
Galc ~ C = 58.23 H = 6.19 N = 4.52 Found % C = 58.08 H = 6.10 N = 4.44 RxamnlP 69 : Preparation of N-(RS>-(1-oxo-2-(acetvlthiomethvl>-3-A. PrPnaration of N-(RS>-2-acetvlthiomet~lvl-;i-t4-methoxv ~henvl) It is obtained in the same way as in example 1 (step d> by the addition of thioacetic acid to 2-((4-methoxy phenyl) methyll propenoic acid.
Yield = 84 °/.
IR : 1740-1685 cm ' ' H NMR <CDClc~/Tl~LS> . 11. 0 (s, 1H) , 7. 2 and 6. 9 (AB, 4H, J - 8 Hz ) , 3.8 (s, 3H>, 3.3 to 2.8 (m, 5H>, 2.-3S (s, 3H>.
R. PrPnaratinn of N-<RS>-(1-oxo-2-(acetvlthiomethvl)-3-(4-methoxv The compound obtained in step A is coupled to benzyl glycinate according to the operating procedure of example 1 (step f>.
Yield = 68 % (chromatographied) ~iP = 62-64 ° C
IR (Nujol> = 3300, 1735, 1690, 1650 cmw' 'H NMR (CDCl~y/TMS> . 7.4 (s, 5H>, 7.15 and 6.8 <AB, 4H, J - 9.3), 6.3 (t, broad, 1H>, 5.15 (s, 2H), 4.1 to 3.85 (m, 2H), 3.7 (s, 3H>, 3.2 to 2.45 <m, 5H), 2.25 <s, 3H>.
"C NMR <CDC1:~> . 195.4 (s>, 173.0 (s>, 169.0 (s>, 157.9 <s>, 134.7 (s), 130.1 (s), 129.5 (d>, 128.1 (d>, 113.5 (d), 66.6 (t>, 54.7 (q>, 48.6 <d), 40.9 <t), 37.0 (t), 30.6 (t), 30.2 (q).
Microanalysis : C~>~H~sOsNS
Calc % C : 63.61 N : 3.3? H : 6.02 Found °/. C : 63.80 N : 3.53 H : 6.12 ~p7 70 Preuaration of N-(RS)-(1-oxo-2-(mercaptomethvl>-3-(4-met oxy p~.n~~~~pY..l.~~gl~ ct ine.
Deprotection of the compound obtained in step B of example 69 is carried out according to the operating procedure of example 1 (step g) .
Yield = 85 °/.
MP = 122-123°C
IR (Nujol> . 3390, 1750, 1620 cm ' 'H NMR (DMSO D5> . 8.0 Cm, 1H), 6.8 and 6.6 CAB, 4H, J - 9.3>, 3.4 Cm, 5H>, 2.6 to 1.8 (m, 6H>.
' wC NMR (DM.SO D6> . 174. 3 (s) , 172. 4 (s> , 158. 8 <s> , 132. 1 (s) , 131.

(d), 114.8 (d>, 56.1 (q), 52.0 <d), 41.7 (t), 37.5 (t>, 26.6 (t).
Microanalysis : C, ::~H~mOaNS
Calc % C : 55.12 N : 4.94 H : 6.00 Found % C : 54.78 N : 4.85 H : 5.95 ~p~,e 71 Pre$ar~ ion f N-(RS>-f 1-oxo-2-(acetylthiomethy!1>-3-(4-methox~~ph~ly..LL~~Y1J-(S)-benzvl alaninate (RS>-2-(acetythiomethyl)-3-<4-methoxy phenyl) propanoic acid is coupled to <S> benzyl alaninate according to the operating procedure of example 1 (step f).
Yield = 50 % (chromatographied) MP = 50-51°C
IR (Nujol) . 3320, 1740, 1690 to 1645 cm ' 'H NMR (CDC1</TMS) . 7.25 (s, 5H), 7.1 to 6.75 CAB, 4H, J = 8 Hz), 6.3 and 6.15 (2 doublets, J = 7.2 Hz>, 5.05 (s, 2H>, 4.5 (quintuplet, 1H, J = 7. 2 Hz) , 3. 6 (s, 3H> , 3. 15 to 2. 4 (m, 5H> , 2. 2 (s, 3H> , 1. 3 and 1.1 <2 doublets, 3H, J = 7.2 Hz).

~a~~~

'~C NMR (CDCl:~) . 195.2 (s>, 172.0 Cs>, 15?.8 (s>, 135.0 (s), 130.2 (s), 129.5 (d>, 128.1 <d), 12?.9 (d), 127.6 <d>, 113.4 (d>, 66.5 (t), 54.? Cq), 48.9 (d), 48.4 <d>, 4?.? (d>, 47.4 (d>, 3?.3 Ct>, 30.6 (t), 30.1 <q>, 17.8 (q).
Microanalysis : C<~H«OsNS
Calc °~ C : 64.33 N : 3.26 H : 6.29 Found % C : 63.98 N : 3.30 H : 6.26 F'vamnl P ?2 Prepay +i ~~ of N <RS>-( 1-oxo-2- (merca-otometh~l >3-(4 methox~nzhenyl ) propvlJ-(S>-alan ne Deprotection of the compound of example ?1 is carried out according to the operating procedure of example 1 (step g>.
Yield = 83 % (chromatographied) IR : 3320, 1?30, 2630 cm ' ' H NMR (CDCl:~/TI~IS> . 9. ? (s, 1H> , 7. 05 and 6. ?5 CAB, 4H, J = 8 Hz> , 6.55 and 6.4 <2 doublets, 1H, 3 = ?.6 Hz), 4.5 C2 quintuplets, 1H, J =
7. 6 Hz ) , 3. ? (s, 3H) , 3. 1 to 2. 2 (m, 5H> , 1. 6 (t, 1H, J = 8 Hz ) , 1.

and 1.2 (2 doublets, 3H, J = ?.6 Hz).
'3C NMR (CDC1.~) . 173.6 (s>, 158.1 Cs), 155.5 Cs>, 130.3 Cs>, 129.7 Cd>, 113.8 <d>, 55.1 <q>, 53.5 (d>, 53.0 (d>, 48.1 (d>, 37.3 (t>, 3?.0 Ct), 26.0 (t>, 25.? (t>, 1?.9 <q), 1?.6 <q>. -Microanalysis : C,4H,~OaNS
Calc % C : 56.56 N : 4.71 H : 6.39 Found % C : 56.21 N : 4.57 H : 6.22 T
acid 3.05 g of <-) ephedrine in solution in 25 ml of ether are added to 10 g of 2-acetylthiomethyl 3-<4-methoxy phenyl) propanoic acid in solution in 60 ml of ether. The mixture is left for seven days then filtered.
Weight obtained = 6.1 g MP = 126°C
al os - -23 . 3 °

-.
Recr~rstal l izations 6 g of the (-) salt are placed in a flask and 25 ml of chloroform plus 35 ml of ether are added. The mixture is left for 15 hours then filtered. This process is repeated three times.
sleight obtained = 4.35 g Overall yield of the four recrystallizations = 73 °~
?iP = 122'C
(alos - -40.7' (C = 1.2, MeOH>
Release of the Qptieall~r nu~ re (S) aei d An experimental process similar to that described in example 2 (II) is employed.
Yield = 98 '/.
falo5 - -24.4' <C = 1.3, MeOH>
Rxamnl_a 93 Preparat~n of N-(S?-f 1-a~xo-2-(acetylthiomet~rl )-3-~4-methoxyr~henyl ~ ro~,rl l -be~n7ty1 gl~rcinate 2-acetylthiomethyl>-3-(4-methoxy phenyl) propanoic acid in its (S> form is coupled to benzyl glycinate according to the operating procedure of example 1 (step f).
Yield = 90 y. (chromatographied>
14P = 84'C
talc 5 - -14.7' (c = 1.3 in methanol) Microanalysis : C2:~HzbOSNS
Calc '~G C : 63.61 N : 3.3? H : 6.02 Found °/. C : 63.43 N ; 3.50 H ; 6.05 Exa a ?4 Pre~ration of N- (S>-( 1-oxy-2- (mersay .~~ .h,yrl )3-(4-methoxir nhen~~ ~rroyyll ~lvTci~
Deprotection of the compound obtained in example ?3 is carried out according to the operating procedure of example 1 (step g>.
Yield = 84 7. <chromatographied) f al 0 5 - +50. 5' (c = 1. 05 in methanol >

D

Microanalysis : C "H,~OdNS
Calc °~ C : 55.12 N : 4.94 H : 6.00 Found °~ C : 55.04 N : 4.76 H : 6.13 $~p,1 P 75 Preparation of N- <S>-( 1-oxo-2- (acetyl thiomethy~.>-3-(4-methox~phen~Lprczp~Lll-(S>-he:nzvl alaninate 2-acetylthiomethyl-3-<4-methoxy phenyl) propanoic acid in its (S>
form is coupled to (S> benzyl alaninate according to the operating procedure of example 1 (step f>.
Yield = 56 °,6 (recrystallized in a chloroform/petroleum ether mixture) MP = 74°C
t a) 05 - -47 . 1 ° <c = 1. 2 in methanol ) IR (Aujol> . 3310, 1730, 1680, 1640 cm-' 'H NMR (CDC1:~/TMS) . 7.3 (s, 5H), 7.05 and 6.75 <AB, 4H, J = 8 Hz>, 6.1 (d, 1H, J - 7.2 Hz>, 5.05 (s, 2H), 4.5 (quintuplet, 1H, J -7. 2 Hz> , 3. 7 <s, 3H> , 3. 2 to 2. 4 (m, 5H) , 2. 2 (s, 3H> , 1. 3 (d, 3H, J
=
7.2 Hz>.
'~'C NMR (CDCI;,) . 195.5 (s>, 172.1 (s>, 157.9 Cs), 135.0 <s>, 130.3 (s>, 129.6 <d>, 128.1 (d), 127.7 (d>, 113.5 (d>, 66.6 <t>, 54. 8 <q> , 49. 1 (d> , 47. 5 (d) , 37. 4 (t> , 30. 8 (t> , 30. 2 (q) , 17. 8 (q) .
Microanalysis : C~:,H<~OsNS
Calc % C : 64.33 N : 3.26 H : 6.29 Found °G C : 64.03 N : 3.18 H : 6.50 P ?6 Preparati on of N- (S)-C 1-oxo-2- (mercaptometh~Yl >3-(4-methoxy nhenvl) propYll-(S)-alanine Deprotection of the compound obtained in example 75 is carried out according to the operating procedure of example 1 (step g).
Yield = 83 % (chromatographied) f al 0 5 - -5. 8 ° (c = 1. 2 in methanol >
IR : 3290 to 3390, 1730, 1645 cm ' 'H NMR CCDCl.-=/TMS> . 9.85 <s, 1H), 9.05 and 6.8 <AB, 4H, J = 8 Hz), 6.3 (d, 1H, J - 7.3 Hz), 4.5 (quintuplet, 1H, J - 7.3 Hz), 3.7 Cs, 3H> , 3. 15 to 2. 25 (m, 5H) , 1. 7 to 1. 15 <m, 1H) , 1. 4 Cd, 3H, J -7.3 Hz>.

~0~~"~~

''C NMR (CDC1:~> . 176.1 (s>, 173.6 (s), 158.2 (s), 130.2 <s>, 129.7 (d>, 113.9 (d>, 55.1 Cq>, 53.0 (d), 48.2 (d>, 37.1 (t>, 25.7 (t), 18.0 (q>.
?ficroanalysis : C, dH, ~,04NS
Calc % C : 56,56 A : 4.71 H : 6.39 Found % C : 56.45 A : 4.70 H : 6.28 Example 77 : Preparation of N-(RS>-(1-oxo-2-(acetylthiomethy )-3-(4-ethox~~ phen~~l ) ~~pyl l -benz;~gl vc~ nat~
A. Preparation of (RS>-2-acetylthiomethy=1-3-(4-ethoxy~phen~~l) nronanoic acid It is obtained in the same way as in example 1 (step d) by the addition of thioacetic acid to 2-f(4-ethoxy phenyl)-methyll propenoic acid.
Yield = 95 %
' H NMR (CDC1:~/TMS) . 9. 6 (s, 1H> , 7. 15 and 6. 8 (AB, 4H, J = 9. 3 Hz) , 4. 0 (9, 2H, J = 6. 6 Hz> , 3. 25 to 2. 7 (m, 5H) , 2. 3 (s, 3H> , 1. 4 (t, 3H, J = 6.6 Hz>.
B. Preparation. of N-(RS)-( 1-oxo-2-(a -~~~lthiometh;rl)-3-(4-ethoxy.
phenyl ) rp onv.ll-benz~~,glycinate The compound obtained in step A is coupled to benzyl glycinate according to the operating procedure of example i (step f>.
Yield = 82 % (chromatographied>
l~'IP = 78 ° C
IR : 3300, 1730, 1690, 1640 cm ' ' H AMR (CDC1 ~/T?iS> . 7. 3 (s, 5H> , 7. 05 and 6. 75 (AB, 4H, J = ?. 5 Hz ) , 5.85 (m, 1H>, 5.1 (s, 2H>, 4.3 to 3.6 (m, 4H), 3.2 to 2.3 (m, 5H>, 2. 25 Cs, 3H> , 1. 3 <t, 3H, J = 6. 5 Hz ) .
Example 78 Preparation of A-(RS)-fl-oxo-2-(merca,ptom + y~)-3-(4-ethoxy phenyl) ropyl)-gl,cine Deprotection of the compound obtained in example 7I is carried out according to the operating procedure of example 1 (step g).
Yield = 82 MP = 124'C
IR : 3380, 2560, 1745, 1620 cm ' 2Q~3~7~

'H Nl~iR (DMSO/TMS> . 7.8 <d, 1H, J = 4.7 Hz), 7.1 and 6.75 (AB, 4H, J =
7. 5 Hz ) , 4. 2 to 3. 5 (m, 4H) , 3. 1 to 2. 2 (m, 5H) , 1. 8 (t, 1H, J -6.7 Hz>, 1.3 Ct, 3H, J = 6.7 Hz>.
Example 79 : Preparation of N-<RS)-f1-oxo-2-(acetylth~ometh~y~,)-3-(4-ethox~~h~e ,°y~~~~~L <S>-benz~rl alaninate 2-acetylthiomethyl-3-(4-ethoxy phenyl) propanoic acid is coupled to (S> benzyl alaninate according to the operating procedure of example 1 (step f>.
Yield = 75 % <chromatographied) MP = 52°C
IR : 3280, 1725, 1675, 1640 cm ' 'H NMR (CDC1~/TMS) . 7.15 <s, 5H>, 7.05 and 6.75 CAB, 4H, J = 7.5 Hz), 6. 2 to 5. 8 <m, 1H) , 5. 1 (s, 2H> , 4. 5 (quintuplet, 1H, J = 7 Hz ) , 3. 95 (q, 2H, J = 6 Hz) , 3. 2 to 2. 3 (m, 5H) , 2. 25 (s, 3H> , 1. 3 (t, 3H, J =
6Hz > , 1. 3 and 1. 1 <d, 3H, J = 7 Hz > .
Rxampl_e 80 Pre~sarati~n of N- CRS)-~J,-oxo-2- <mercaz tome+.hv> >-3-(4-ethoxv ahen~~propylJ-(S)-alaninp Deprotection of the compound obtained in example 79 is carried out according to the operating procedure of example 1 (step g>.
Yield = 52 IR : 3300, 1720, 1635 cm ' ' H NMR (CDC1:~/TMS> . 10. 4 (s, 1H) , 7. 05 and 6. 75 <AB, 4H, J = 8 Hz> , 6.6 to 6.15 <m, 1H), 4.55 (quintuplet, 1H, J = 6 Hz), 3,9 (q, 2H, J =
6.7 Hz>, 3.1 to 2.2 <m, 5H>, 1.6 (t, 1H, J - 7.5 Hz), 1.6 to 1. 0 <m, 6H> .
E~~iple 81 Preparation of N-(E>-f 1-oxo-2-(acety,lthiomethyl ø~G-3-ahenvl nrop~t~-(S>-benzyl alaninate A. Preparation of (Z>-2-bromometh~T1 cinnam~c acid A mixture of 2 g (12.34 mmol) of (E) 2-methyl cinnamic acid, 2.19 g (12.34 mmol) of N-bromosuccinimide (NBS> and a catalytic amount of benzoyl peroxide in 6 ml of CC14 are heated under reflux for 6 hours, The residue is filtered and washed with ether. The organic phase is successively washed with a 1N HC1 aqueous solution then with water. It is dried on MgSOd, filtered and evaporated to dryness.

Yield = 5'l °/ (recrystallized in ether) MP = 168'C
IR (Nu~ol> . 1665 cm-' 'H NMR <CDC13/TMS) . 10.0 (s, 1H>, 7.9 <s, 1H>, 7.8 to 7.2 <m, 5H), 4. 0 (s, 2H> .
B Preparation of (Z> 2-acet~Tlthiomethvl cinnamic acid 2.1 g of the acid obtained previously (8.70 mmol>, 0.93 g (8.70 mmol) of NaHCOs and 3 ml of water are mixed together. A solution of 0.69 g (8.8 mmol> of thioacetic acid and 1.44 g (10.43 mmol> of K~CO:< in 21 ml of water are then added at 0'C. The mixture is stirred for 15 hours at 20'C. It is then acidified with a 6A HC1 aqueous solution. It is extracted twice with ether. The combined ethereal phases are washed with water, dried on MgS04, filtered and concentrated.
Yield = 67 % (recrystallized in ether) MP = 114°C
IR (Nu~ol> . 1670 cm ' 'H NMR (CDC1;,/TMS> . 9.55 (s, 1H>, 8.0 (s, 1H>, 7.5 <s, 5H>, 4. 1 (s, 2H) , 2. 3 (s, 3H> .
C Preparation of CE> 2-acet~rlthiomethvl cinnamic acid 2 g of the previous (Z) acid in solution in 30 ml of ethanol are irradiated for 16 hours with a Hanovia TQ 150 lamp.. After evaporation, a Z/E 60/40 mixture of the acid is obtained. This mixture is taken up with 25 ml of ether and a solution of 0.39 g of cyclohexylamine (0.4 eq.) in 5 ml of ether are added to it. After 30 minutes of continuous stirring, the solution is filtered. The salt is recovered and treated with a 3N HC1 aqueous solution. It is extracted with ether. The organic phase is washed with a saturated NaCl aqueous solution, dried on MgSOn, filtered and concentrated.
Yield = 32 MP = 5?°C
' H NMR (CDC1~,/TI~LS> . 9. 6 (s, 1H> , 7. 3 (s, 5H> , 7. 2 (s, 1H) , 3. 85 (s, 2H> , 2. 25 (s, 3H) .

~., ~/'a ,rz .r, 69 ~~~ ~ Ur D. ps-~,paration of N- (E>-( 1-oxo-2- <acetylthiomethyl )-2-ene-3-_nhenyl prod l-(~.--benzyl alaninate (E) 2-acetylthiomethyl cinnamic acid obtained in step C is coupled to <S> benzyl alaninate according to the operating procedure of example 1 (step f>.
Yield = 83 °/. (chromatobraphied) MP= I03°C
t al o~ - -25 . 2 ° <c = 1. 8 , CHCl:, >
IR (Nu~ol> . 3280, 1?30, 1690, 1630 cm-' 'H NMR (CDC1~/TMS> . 7.3 Cs, 5H), ?.25 (s, 5H>, 6.9 (s, 1H>, 6.05 <d, 1H, J = 6.6 Hz), 4.6 <m, 1H>, 3.85 (s, 2H), 2.3 <s, 2H>, 1.2 (d, 3H, J = 6.6 Hz>.
Microanalysis : C«H~~OQNS
Calc °/ C = 66.47 H = 5.83 N = 3.52 Found °/. C = 66.36 H = 5.68 N = 3.53 Example 82 Preparation of N-(E)-f1-oxo-2-(mercaptowl>-2-Pne-3 ~ en~prolZVll-(S)-alanine 3.4 mmol of LiOH (4 eq.) are added, at 0°C and under an argon atmosphere, to a solution of 0.85 mmol of the diester obtained in step D of example 81 in solution in a THF-H~0 mixture (?5-25> and the mixture is stirred for 2 hours. The THF is evaporated, the aqueous phase is washed with ether and acidified with a 3N HCl aqueous solution. It is extracted with ether, washed with a saturated NaCl aqueous solution, dried on MgSOa, filtered and evaporated.
Yield = 60 % (chromatographied) MP = ?8°C
IR (Nu,~ol) . 3300, 1?20, 1650, 1610 cm ' 'H NMR CCDC13/TMS) . 9.15 (s, 1H>, 7.25 <s, 5H), 6.?0 (s, 1H>, 6.25 (d, 1H, J = 6.6 Hz>, 4.55 (m, 1H>, 3.5 (d, 2H, J = 8 Hz>, 1.8 (t,iH, J = 8 Hz > , 1. 25 Cd, 3H, J = 6. 6 Hz ) .
Microanalysis ; C, ~~H, ~.O:~NS
Calc % C = 58.84 H = 5.69 N = 5.28 Found °/ C = 58.86 H = 5.83 N = 5.14 ?0 ~p~ p 83 Prey aration of N- (E)-L 1-oxo-2- <~~P+_y.l~hi~~th~C1 >~2-~ne3-p]zen;tl nro~,Xl l - (S>-benzyl norval inate (E> 2-acetylthiomethyl cinnamic acid obtained in step C of example 81 is coupled to (S) benzyl norvalinate according to the operating procedure of example 1 (step f).
Yield = 83 x (chromatographied>
I~IP = 80' C
L a100 - -26. 4' (c = 1. 53, CHC1:~>
Ik <Nu~ol> . 3300, 1720, 1680, 1640, 1620 cm-' 'H NMR (CDCla/TMS) . 7.3 (s, 5H>, ?.25 (s, 5H), 6,85 (s, 1H>, 6 (d, 1H, J - 7.6 Hz), 5.1 (s, 2H), 4.8 to 4.4 <m, 1H), 3.85 <s, 2H), 2.3 (s, 3H>, 1.85 to 0.6 (m, ?H).
Microanalysis : C::4H~~~04AS
Calc °/. C = 67.73 H = 6.39 N = 3.29 Found °/ C = 67.71 H = 6.35 N = 3.38 E~pple 84 Preparation of N- (E>-L 1-oxo-2- (acetylthiomethyrl )- -~nP-_~~-ph~.n.~!~.prop~rll-<S)-benz~tl norleucinate (E> 2-acetylthiomethyl cinnamic acid (example 81 C) is coupled to (S) benzyl norleucinate according to the operating procedure of example 1 (step f).
Yield = 79 ~
14P = ?9'C
f aJ2n~ - 22. 1' (c = 1. 5, CHC1~ >
IR (Nu~ol) . 3280, 1720, 1670, 1640, 1620 cm-' ' H NlLR (CDC1:,/T?iS> . ?. 3 <s, 5H) , 7. 25 <s, 5H) , 6. 85 (s, 1H) , 6. 0 (d, ltf, J - 7. 4 Hz ) , 5. 1 <s, 2IL) , 4. 8 to 4. 45 (m, 11J > , 3. 85 (s, 2H> , 2. 3 (s, 3H> , 1. 8 to 0. 6 <m, 9H> .
?ticroanalysis : CasH2904NS
Calc °/ C = 68.30 H = 6.65 N = 3.18 Found ~ C = 67.67 H = 6.4? N = 3.43 R~ple 85 Preparation of N-<E>-L1-oxo-2-(acet~lthiomethyl>2-enediox hen l -methyl ~laninate 1~

... 71 2~~~~~
(E> 2-acetylthiomethyl cinnamic acid (example 81 C) is coupled to CRS>-3-(3,4-methylenedioxy phenyl) methyl alaninate according to the operating procedure of example 1 (step f).
Yield = 48 MP = 75'C
IR (Aujol> . 3250, 1?40, 1690, 1640 cm-' Microanalysis : C~:~H<s06NS
Calc °~ C = 62.5? H = 5.25 N = 3.1?
Found °/. C = 62.28 H = 5.07 N = 3.44 'H AMR <CDC1~/TMS> . 7.25 (s, 5H>, 6.8 (s, 1H>, 6.?5 to 6.15 <m, 3H>, 6.15 to 5.8 (m, 1H>, 5.85 (s, 2H>, 5.0 to 4.6 (m, 1H>, 3.85 (s, 2H>, 3.6 (s, 3H>, 2.9 (d, 2H, J = 7.6 Hz), 2.3 (s, 3H>.
F_xamy P 86 Preparation of N-(E>-fl-oxa-2-(mercaptomethvl>-2-~ne-3-phen~~l ~_opvll-(R,S)-3-<3.4-meth~rlenediox~~phenyl)-alanine It is obtained by deprotection of the compound of example 85 according to the operating procedure of example 82.
Yield = ?5 °/.
MP = 50°C
IR (Nujol> . 3400, 1720, 1620 to 1600 cm-' ' H NMR (CDC1 ,/TMS> . 8. 3 (m, 1H) , 7. 25 (s, 5H> , 6. ? (s, 1H> , 6. 55 to 6.0 (m, 4H), 5.85 (s, 2H), 5.0 to 4.65 (m, 1H), 3.45 (d, 2H, J -8.2 Hz>, 2.9 (d, 2H, J = 5.1 Hz>, 1.?5 (t, 1H, J = 8.2 Hz).
Microanalysis : C~c~H,40sAS
Calc °,6 C = 62. 32 H = 4.96 N = 3.63 Found °,G C = 62.18 H = 5.06 N = 3.39 Example 87 Preparation of N-(7,,1-f1-oxo-2-(acet~lthiomethvl)-2-ene-3-(3~-methylenediox~ hen,~propylJ-benzyl glycinate A Preparation of (Z) 2-bromomethvl-3-(~, 4-methvlenediox~,Lp~n~~
pr~~ enoic acid (E) 2-methyl-3-<3,4-methylenedioxy phenyl) propenoic acid (prepared by a PERKIN reaction using piperonal> is substituted with N-bromosuccinimide in chloroform according to the operating procedure described in example 81 A.
Yield = 75 MP = 158°C

2~397~~
' H NMR (CDC1:./TMS) . 8. 6 (s, 1H) , ?. 7 (s, 1H> , ?. 3 to 6. ? (m, 3H> , 6. 0 (s, 2H> , 4. 35 (s, 2H) .
nhen,yl ) ~ropenoic acid A solution of 1.26 g of thioacetic acid (1. 05 eq. > and 2. 12 g of diisopropylethylamine <1.05 eq.) in 80 ml of THF are added at 0'C to a solution of 4.4? g of the acid prepared in step A in solution in 80 ml of THF. The mixture is stirred at 0'C for 30 minutes. The THF is evaporated and the residue taken up with 100 ml of ether. It is washed with a 1N HC1 aqueous solution. The organic phase is dried on MgSOd, filtered and concentrated.
Weight obtained = 4 g Yield = 86 MP = 142'C
'H NMR (CDC1~;/TMS) . 8.6 <s, 1H>, ?.8 (s, 1H>, 7.1 to 6.? <m, 3H), 6. 0 <s, 2H> , 4. 05 (s, 2H> , 2. 3 (s, 3H> .
- prPparat~nn of N-(Z)-L1-oxo-2-(acetylthiomethvl>-2-ene-3-(3.4-meth~rlenPdioxy phenvl ) propXl~-benzy,l-glyci nate (Z) 2-acetylthiomethyl-3-(3,4-methylenedioxy phenyl) propenoic acid obtained in step F3 is coupled to benzyl glycinate according to the operating procedure described in example 1 (step f>.
Yield = 55 °/.
MP = 102°C
'H NMR <CDC1:,/TMS> . 7.5 (s, 1H), ?.3 (s, 5H>, ?.0 to 6.? (m, 3H), 5.95 (s, 2H), 5.15 <s, 2H), 4.15 (d, 2H, J - 5.2 Hz), 4.0 (s, 2H>, 2. 3 (s, 3H> .
P 88 Pra~aration of N-(Z>-f 1-oxo-2-(mercantometh~l>2-ene-3- (3,, 4-me~th~ enediox2~hen~~propyl J -glycine Deprotection of the compound obtained in example 8? is carried out according to the operating procedure described in example 82.
Yield = ?5 MP = 91°C
'H NMR (DMSO/TMS) . 7.20 Cs, 1H>, ?.0 to 6.? (m, 3H), 6.0 <s, 2H), 4.10 <d, 2H, J - 4.5 Hz), 3.65 (d, 2H, J - 7 Hz>, 2.0 <t, 1H, J =
," Hz).

__ F.x~mple 8g Pre~~aration of N-(F)-( 1-oxo-2-(acetylthiomethvl)-2-~ne-3-(3,4-metrwlenediox~ ~2h..Pn~T1> propel)-benzetl gl~rcinate A~ PrP,~aration of (E> 2-~c~c~t,~rlthiomethy~l-3-(3.4-methorlenedioxv ph~n~rl ) pro~noic acid <Z) 2-acetylthiomethyl-3-(3,4-methylenedioxy phenyl) propenoic acid prepared in example 8? (step B) is irradiated according to the operating procedure described in example 81 (step C>.
Yield = 25 °/°
' H NMR (CDCl:~/TM.S> . 10. 6 (s, 1H> , 7. 2 to 6. 6 <m, 4H> , 5. 9 (s, 2H) , 3. 8 (s, 2H> , 2. 3 (s, 3H> .
~, Preparation of N- (E)-f 1-oxo-2- (acet~rlthiometh~rl >-2-ene-3- (3. 4-mP+ y7 PnPr~; nx~phenyl ) _»ropylJ -benzyl glycinate (E) 2-acetylthiomethyl-3-(3,4-methylenedioxy phenyl) propenoic acid obtained in step A is coupled to benzyl glycinate according to the operating procedure described in example 1 (step f).
Yield = 58 h~P = 113°C
' H 2dMR (CDC1~</TMS) . 7. 3 (s, 5H) , 7. 0 to 6. 65 (m, 4H) , 6. 15 (m, 1H) , 5.9 (s, 2H), 5.15 <s, 2H>, 4.05 (d, 2H, J - 5 Hz), 3.8 <s, 2H>, 2. 3 (s, 3H) .
Examrle 90 . Preparation ~ N-(N-CRS)-L1-tert.-butoxvcarbonvl-2-A Preparation of (RS)-2-h° d~~T-3-nhen~~propanoic acid A solution of 22.55 g (326.80 mmol) of sodium nitrite in solution in 90 ml of water is added, over a period of one hour at -5°C, to a solution of 15 g (90.80 mmol> of (S> phenylalanine in 230 ml of a 10 sulfuric acid aqueous solution. The solution is left to return to room temperature then the reaction medium is heated at 50°C for 3. hours.
After returning to room temperature, the solution is extracted by 3 times 10U ml of ethyl acetate. The combined organic phases are washed with 50 ml of water and with 50 ml of a saturated sodium chloride aqueous solution. After drying on magnesium sulfate, filtration and evaporation, 9.25 g of a solid yellow residue are obtained. This solid is recrystallized in an ether/petroleum ether solvent system. 6.44 g of a white solid are obtained.

~~~~ l ~
Yield = 43 °
Rf value : 0.55 (eluent : ?0/30 benzene/acetic acid) 'H NMR (acetone De./TMS1 . ?.2 (s, 5H>, 7.2 to 5.4 (m, 1H>, 4.55 to 4.3 Cm, 1H>, 3.35 to 2.? (m, 3H>.
B Preparation of (RS)-2-acet,~rloxy-3-phenyl propanoic acid 4.83 g (61.53 mmol> of acetyl chloride are added to 8.88 g (53.49 mmol) of <RS1-2-hydroxy-3-phenyl propanoic acid. The mixture is refluxed for 30 minutes. The excess acetyl chloride is evaporated.
11.18 g of (RS)-2-acetyloxy-3-phenyl propanoic acid are obtained.
Yield = 98 ' H NMR (CDC1:~/TMS> . 11. 0 (s, 1H) , 7. 2 (s, 5H> , 5. 25 (m, 1H> , 3. 4 to 2. 8 (m, 2H> , 2. 0 <s, 3H> .
C Pre~yaration of (RS)-2-acetalox_~phenyl-tert.-butvl_ pr~~anoate ' A solution of 8.4 g (54.80 mmol> of phosphorous oxychloride in 12 ml of dichloromethane is added, at a temperature lower than 40'C, to a solution of 11.4 g (54.80 mmol) of the acid obtained in step B
and 4.06 g (54.80 mmol) of tertiary butanol in solution in 27 ml of pyridine.
The mixture is cooled down to a temperature of 5°C, filtered and the precipitate washed with dichloromethane, The filtrate is successively washed with water, 2 times with a saturated NaHCO~, aqueous solution, 2 times with a 1N HC1 aqueous solution and 1 time with water. The organic phase is dried on MgSOd, filtered and concentrated. 10.5 g of (RS)-2-acetyloxy-3-phenyl-tert.-butyl propanoate are obtained.
Yield = ?3 ' H NMR <CDCl:,/T14.S> . ?. 2 (s, 5H) , 5. 1 (t, 1H, J = 5. 3 Hz ) , 3. 05 <d, 2H, J = 5.3 Hz>, 2.0 (s, 3H>, 1.3 (s, 9H).
PreiQaration of (RS)-2-hydroxv-3-phenvl-tert.-butyl nropanoate 9.25 g (35.03 mmol> of the product obtained in step C in solution in 60 ml of a methanol/H~0 mixture (?0/30) are placed in a flask. The mixture is cooled down to 0'C and 17.5 ml of a 1N NaOH aqueous solution are added. The solution is stirred for 1 hour.

2Q~~' ''~ 7 5 The methanol is evaporated under vacuum and the aqueous phase is extracted 2 times with ether. The organic phases are combined, washed once with water, dried on MgS04, filtered and concentrated. 6.52 g of an oil are obtained, which is then chromatographied on silica <eluent : 10/90 ether/petroleum ether>.
Weight obtained = 5.98 g Yield = ?? %.
Rf value : 0.36 <25/?5 ether/petroleum ether) 'H NMR <CDC13/TMS> . 7.2 (s, 5H), 4.3 Cm, 1H), 3.1 to 2.75 (m, 3H>, 1. 35 (s, 9H> .
F Preparation of (RS)-2-hydroxv-3-phenyl-tert -hutvl propiona ~riflate 0.5 g (2.25 mmol> of <RS>-2-hydroxy-3-phenyl-tert.-butyl propanoate and 0.18 g <2.25 mmol) of pyridine in solution in 1 ml of CH~C1~ are added, at a temperature of -20°C, to a solution of 0.?3 g (2.61 mmol> of trifluoromethane sulfonyl anhydride in 3 ml of CH~C1:~.
The solution is stirred for 30 minutes.
The reaction medium is taken up with water and CH~C1~, the organic phase is washed with a 0.1IT HC1 aqueous solution then with a saturated NaHCO~. aqueous solution and, finally, with water. The organic phase is dried on MgSOd, filtered and concentrated. 0.? g of (RS)-2-hydroxy-3-phenyl-tert.-butyl propionate triflate are obtained.
Yield = 89 °/.
'H NMR (CDC1:,/TMS> . 7.25 <s, 5H>, 5.1 (m, 1H>, 3.2 <m, 2H>, i. 4 <s, 9H> , F. Preparat~~T of ~-(RS>-(1-tert -butoxvcarbonyl-2-phenyl eth~~l>-(S>-meths, nhen~t].alaninate A solution of 0.4 g (1.86 mmol> of (S)-methyl phenylalaninate in 6.5 ml of CH~C1< is added, at 0°C over a period of 5 minutes, to a solution of 0.66 g (1.86 mmol> of (RS>-2-hydroxy-3-phenyl-tert.-butyl propionate triflate and of 1.86 mmol of bis-1,8-(dimethylamino>-naphthalene in 6.5 ml of CH~Cl~. The solution is stirred at room temperature for 24 hours. It is filtered, the filtrate is washed with water and dried on MgS04. Filtration and concentration are then carried out. 1 g of the product is obtained, which is then chromatographied on silica.

.2a ~~~ ~~
Yield = 82 '/.
Weight = 0,58 g IR : 3320, 1?35 cm-' 'H HMR tCDCl~/T?IS) . 7.1 <m, 10 H), 3.55 and 3.5 <s, 3H>, 3.5 to 3.15 <m, 2H), 3.0 to 2.7 (m, 4H), 2.05 (m, 1H), 1.25 and 1.2 (s, 9H>.
G. P~Q",I,,aration of N-(RS>-I1-tert.-butoxycarbonyl-2-pheny ethlrll-S,,S>-~hen;rlalanin~
One equivalent of 1N NaOH is added at 0'C to a solution of 1.5 mmol of the compound obtained in step F in solution in 5 ml of methanol. The solution is stirred for 24 hours at room temperature.
The MeOH is evaporated and the aqueous phase is washed with ether. It is acidified with a 1N HC1 solution and extracted with CHC1~. The combined organic phases are dried on MgS04, filtered and concentrated.
Yield = 87 °/.
' H NMR <CDC1;;/TMS> . ?. 3 to 6. ? tm, lOH) , 6. 3 (m, 2H> , 3. 5 to 3. 2 <m, 2H> , 3. 15 to 2. 6 (m, 4H> , 1. 35 and 1. 3 <s, 9H) .
H. Preparation of N-t N-<RS)-( 1-tert -butox~rsarb~~
~~,rll-(S)-phenyrlalan.yr )-benz~;rl~l~rcinate The compound obtained in step G is coupled to benzyl glycinate according to the operating procedure of example 1 (step f).
Yield = 74 °/. (chromatographied) IR : 3300, 1730, 16?0 cm-' 'H NMR (CDC13/TMS> . ?.5 to 6.8 (m, 16H>, 5.1 <s, 2H), 4.1 to 3. 9 (m, 2H> , 3. ? to 2. 4 (m, 6H> , 1. 8 (m, 1Ii> , 1. 25 and 1. 2 (s, 9H> .
Microanalysis : C:" H:,sOsN~
Calc "/. C = ?2.0? H = ?.02 N = 5.42 Found °/. C = ?1.85 H = 6.91 N = 5.38 Fxamnl a 91 : Preparation of N-L N- (RS)-( 1-carboxy~~~henv~ 1 eth~tl l-~~h~n~lalan.~rl1-st.lycine, hydrochloride A solution of 0.9 mmol of the compound of example 90 H in 7 ml of ethanol is hydrogenated for 15 hours at room temperature in the presence of 50 mg of 10 °/. palladium carbon. It is filtered, evaporated to dryness and the residue is taken up with 5 ml of a solution of 4H
HC1 in ethyl acetate. After 15 hours of continuous stirring, the solution is evaporated to dryness, the solid obtained is triturated in ether and dried on P.~Oe~; in a dessicator.

D

77 , e, Yield = 90 '/.
1~IP = 80' C
'H NMR (CDC1:~/TMS> . 9.0 to 7.8 (m, 4H>, ?.1 (s, 11H), 4.6 to 2. 8 (m, 8H> .
?ticroanalysis : C~oH~:~OsN~Cl Calc '.G C = 59.14 H = 5.70 N = 6.89 Found '/. C = 59.40 H = 6. 10 N = 6.50 F.xam~.1 P 92 Preparation of N-f N- (RS)-( 1-tent -butoxv carbo~r_] -2~nhenvl et )Cl l - <RS)-3- <~, 4-methvlenedioxy .p],'~yrl >algnylL
benzvl glvcinate A Pretiaration of N-(RS)-( 1-tert -butoxyrcarbon~l-2-phenyrl eth3rll-(RS)-3-('i,+4-met]i~tlenediox~~henyrl)-metharl alaninate (RS)-2-hydroxy-3-phenyl-tert.-butyl propionate triflate prepared in example 90 E is substituted by (RS>-3-<3,4-methylenedioxy phenyl)-methyl alaninate according to the operating procedure of example 90 F, Yield = 53 °/. (chromatographied) 'H NMR (CDC1:~/TMS) . ?.15 (s, 1H), 6.? to 6.4 (m, 3H), 5.8 (s, 2H>, 3.6 and 3.55 (s, 1H), 3.6 to 3.2 <m, 2H>, 2.9 to 2.6 (m, 4H>, 2. 1 (m, 1H) , 1. 3 and 1. 25 <s, 9H) .
B Preparation of N-(RS)-L 1-tert -butox;rcarbon)r.l-2-phen~Tl eth~rll-SRS)-'i.- (3~4-methyLPn ioxy pheg~rl )-alanine The compound obtained in step A is deprotected according to the operating procedure of example 90 G.
Yield = 87 °/.
1~IP = 128' C
' H NMR (CDC1:,/TIiS) . 7. 2 <s, 5H) , 6. 7 (m; 3H) , 5, 9 (s, 2H> , 5. 8 to 5.0 (m, 2H>, 3.? to 2.4 (m, 6H), 1.35 and 1.3 <s, 9H).
C PreF,aration of N-(N-(RS)-(1-tert -butoxyrcarbonyl-~phenwl_ ~t_h~rll-<RS)-~ (3 4-methylenedioxy heny.m-aian~rm-oe~tz~~gyrcm~
The product obtained in step B is coupled to benzyl glycinate according to the operating procedure of example 1 (step f).
Yield = ?3 y.
IR : 3340, 1?40 to 1710, 1660 cm-' ,8 2Q~'~
'H NMR <CDC1~/TMS) . 7.3 Cs, 5H), 7.1 (s, 5H), 6.8 to 6.3 (m, 4H>, 5.8 <s, 2H), 5.1 (s, 2H), 4.1 to 3.9 (m, 2H>, 3.7 to 2.3 (m, 6H>, 1. 8 <m, 1H> , 1. 25 (s, 9H1.
Microanalysis : C~~H;,sO~N~
Calc % C = 68.56 H = 6.47 N = 5.00 Found °/. C = 68.90 H = 6.62 N = 5.09 Example 93 : Preparation of N-(N-(RS>-f 1-car~ogy-2-pheny et ~~17-CRS>-3-(3.4-meth~rlenediax~phen~rl>-alan~~ll-glycine ,~drochloride The compound of example 92 C is deprotected according to the operating procedure of example 91.
Yield = 93 MP = 127'C
'H NMR (CDC1:~/TMS> . 9.2 to 7.7 (m, 4H>, 7.2 (s, 5H>, 7.1 to 6. 4 (m, 4H) , 5. 8 (s, 2H) , 4. 6 to 2. 8 (m, 8H> .
Microanalysis : C~,H~;,O~N~C1 Calc % C = 55.94 H = 5.14 N = 6.21 Found % C = 56. 30 H = 5.29 N = 6, 15 Exa~le 94 preparation of N-f N- CRS)-f 1-tert -butoxycarbony~
A. Preparation of (RS)-2-hydroxv-hexanoic acid It is prepared using (RS> norleucine, according to the operating procedure of example 90 A.
Yield = 53 Rf value = 0.48 (eluent : 70/30 benzene/acetic acid) 'H NMR (CDC1:,/TMS> . 7.3 <s, 5H>, 4.3 <m, 3H), 2.2 to 0.65 Cm, 9H).
B. Preparation of <RS)-2-acetylox;r-hexanoic acid The compound obtained in step A is treated with acetyl chloride according to.the process described is example 90 B.
Yield = 98 'H NMR <CDC1~/TMS> . 11.8 <s, 1H), 4.9 (t, 1H, J - 6.4 Hz>, 2. 0 (s, 3H> , 2, 0 to 0. 6 (m, 9H> .
C. Preparation of (RS)-2-ace~Tlox~r-tert -butv,Lhexanoate The compound obtained in step B is esterified in the same way as in example 90 C.
Yield = 82 %

_ ~-- 7 9 'H NMR (CDC1~/TIiS) . 4.8 (t, 1H, J = 6.4 Hz), 2.1 ts, 3H), 2.0 to 1.6 tm, 2H) , 1. 4 (s, 9H) , 1. 6 to 0. 6 <7H) .
D Pr~aration of <RS)-2-h~rdrox;t-tert. -butyl hexanoate The compound obtained in step C is treated with 1A NaOH in the same way as in example 90 D.
Yield = 6? %
'H NMR <CDCI:~/TMS) . 4.0 (m, 1H), 2.8 (d, 1H, J - 5.4 Hz), 1.9 to 0. 6 (m, 18H) .
E. CRS)-2-h,~rdroxv-tert.-but~rl hexanoate triflate The compound obtained in step D is treated with trifluoromethane sulfonyl anhydride in the same way as in example 90 E.
Yield = 46 'H NMR (CDC1:~/TMS) . 5.1 (m, 1H), 1.9 to 0.? <m, 18H>.
F. Pre an ratir~ of N-(RS>-(1-tert.-butoxycarbon,~pentvl)-CRS>-3-(3.4-meth~enedioxy phenyl)-methyl alaninate CRS>-2-hydroxy-tert.-butyl hexanoate triflate is substituted by 3-<3,4-methylenedioxy phenyl)-methyl alaninate according to the operating procedure of example 90 F.
Yield = 59 % (chromatographied>
IR : 3340, 1735 cm'-' 'H NMR (CDC1~/TMS) . 6.6 tm, 3H), 5.9 (s, 2H>, 3.6 (s, 3H), 3.6 to 3.2 (m, 2H), 3.2 to 2.7 <m, 4H>, 1.9 (m, 1H), 1.3 (s, 9H), 1.? to 0. 6 (m, ?H> .
G. Preparation of N- <RS)-f 1-tert. -butox~carbonyl~ ent~l J - (RS>-3-(3,4-methvlenedioxJ~phenvl)-alanine The compound obtained in step F is saponified according to the operating procedure of example 90 G.
Yield = 82 'H NltLR tCDCla/TMS> . 6.7 tm, 3H>, 5.9 (s, 2H>, 5.8 to 5.3 (m, 2H>, 3.6 to 2. 8 (m, 6H) , 1. 4 Cs, 9H> , 2. 1 to 0. 5 (m, ?H) .
H. Preparation of N-f N- (RS)-f 1-tert. -butoxycarbon'Y1 ~rent,tl J - CRS>-3- (3, 4-meth~rlenedio~y phen~rl )-alan~, l -ben .~~1 glycinate The compound obtained in step G is coupled to benzyl glycinate according to the operating procedure of example 1 (step f).
Yield = 80 ~A ~~~Afi -~
IR : 3360, 1720, 1660 cm-' 'H NMR (CDC1~/T?tS) . ?.3 <s, 5H), 6.? <m, 4H>, 5.85 <s, 2H>, 5. 2 (s, 2H) , 4. 1 to 3. 9 (m, 2H> , 3. 6 to 2. 4 (m, 6H> , 1. 4 <s, 9H> , 2.

to 0. 6 <m, 8H) .
Microanalysis : C«H~60~?N2 Calc '% C = 66.14 H = ?.2? N = 5.32 Found % C = 65.88 H = ?.03 N = 5.44 Example 95 Preparation of N-( N- (RS>-( 1-carboxyr pent~rl)- (RS)-3-(3.4-methylenedio~;~,! h~nyl)-alanglh-plycine,~b,ydrochloride The compound of example 94 H is deprotected according to the operating procedure of example 91.
Yield = 94 y°
MP = 85°C
'H NMR (CDC13/TMS) . 9.2 to ?.8 <m, 4H), ?.2 to 6.4 (m, 4H), 5.8 <s, 2H), 4.8 to 3 (m, 8H>, 2.3 to 0.6 <m, ?H>.
Microanalysis : C~,~H~~O~N~C1 Calc °~ C = 51. 86 H = 6. 04 N = 6. ?2 Found % C = 51.68 H = 6.21 N = 6.53 Rxample 96 Preuaration of N- L$.,S)-L 2- <diethoxy~ mhi T~~) alaninate A Preparation of 2- «3, 4-meth~Clehpdioxv .~hen~rl ) methyl >
propenoic acid chloride 1.3 ml of thionyl chloride (1?.? mmol, 1.5 eq.) are added, at 0°C
and with continuous stirring, to 2.43 g C11.8 mmol> of. the product obtained in example 1 (step d). The temperature is left to return to 20°C and, after 14 hours, the residual thionyl chloride is evaporated.
2.65 g of a yellow oil are obtained.
Yield = 100 °~
'H NMR . 3.50 (s, 2H>, 5.60 (broad s, 1H>, 5.95 (s, 2H), 6.45 (broad s, 1H>, 6.75 <m, 3H>.
13. Preparation of N-( 1-oxo-2- ( ('~, 4-methyl nP ~xa~phen~tl > methyl nropenyll-(S>-benzyl a],~ ninatP
1 g of triethylamine (10 mmol, 2 eq.> in solution in 20 ml of tetrahydrofuran are added, at 0'C and with continuous stirring, to s ~Q 3~70~
1. 12 g of the product obtained in step A <5 mmol, 1 eq. ) in solution in 50 ml of a 50/50 mixture of chloroform and tetrahydrofuran. 1.8 g of benzyl alaninate paratoluene sulfonate <5 mmol, 1 eq.) in solution in 50 ml of a 50/50 mixture of chloroform and tetrahydrofuran. The temperature is left to return to 20'C and, after 14 hours, the solvents are evaporated. After taking up the residue with 50 ml of ethyl acetate and 50 ml of water, two washings are carried out with 100 ml of a 1N hydrochloric acid solution and 100 ml of a saturated sodium hydrogen carbonate aqueous solution. The organic phase is recovered, dried on magnesium sulfate, filtered and concentrated.
Purification by chromatography (eluent : chloroform 97.5/methanol 2.5) Yield = 90 '/.
1.50 g of a beige solid are obtained.
MP < 50'C
' H NMR : 1. 10 <d, 3H, J = 6 Hz ) , 3. 60 <s, 2H> , 4. 60 to 4. 65 <m, 1H> , 5.05 (s, 2H>, 5.10 (broad s, 1H>, 5.65 (broad s, 1H), 6.00 <s, 2H>, 6.20 to 6.40 (broad s, 1H), 6.70 to 6.80 <m, 3H), 7.25 (broad s, 5H).
C. Preparation of A- (R, S>-L 2- (d' thox~hos~i ~~r~~methyl-1-oxo-3-~a 4-methylenedioxy nhen~rlLprnn~tll- (S)-benzyl alaninate 630 mg of diethylphosphite (4.6 mmol, 1 eq.> in solution in 50 ml of tetrahydrofuran are added, under an inert atmosphere and at 0'C, to 220 mg of sodium hydride (5.5 mmol, 1.2 eq.) (at a concentration of 60 '/. in mineral oil, previously washed with 2 X 10 ml of petroleum ether). After hydrogen emission has ceased, 1.50 g of the product obtained in step B (1 eq.) in solution in 25 ml of tetrahydrofuran are added. The temperature is left to return to 20'C and, after 14 hours, 2 ml of ethanol are added. The solvents are evaporated. After taking up the residue with 50 ml of ethyl acetate and 50 ml of water, two washings are carried out with 50 ml of a 1N hydrochloric acid solution and 50 ml of a saturated sodium hydrogen carbonate aqueous solution.
The organic phase is recovered, dried on magnesium sulfate, filtered and concentrated. 1.50 g of an oil are recovered by chromatography <eluent : chloroform 96/methanol 4>.
Yield = 72°/.

D

~a ~~aas ' H N~IR . 1. 10 to 1. 40 <m, 9H) , 1. 70 to 2. 65 (m, 2H> , 2. ?0 to 3.25 (m, 3H>, 3.40 to 4.20 (m, 4H), 4.55 to 4.65 (m, 1H>, 5.10 (broad s, 2H>, 6.00 (s, 2H), 6,20 to 6.80 (m, 4H>, 7.20 (broad s, 5H>, IR : 3280, 1740, 1675, 1550, 1255, 1065, 1030 cm-' ?ficroanalysis : C~EH~.~NO~P
Calc °G C = 59.41 N = 2.92 H = 6.31 Found °/ C = 59.58 N = 2.79 H = 6.25 1LS : 505; 496, 468, 420, 401, 380, 353, 311, 2?3, 234.
Example 9? Preparation of N-<R S1-(2-(dihydrox~~~hosphinyl) methyrl-1-oxo-3- (3, 4-methylenesiiox~c. ph~----enyTl.~pr~l ) - (S)alb 3.33 ml of bromotrimethylsilane <24 mmol, 5.5 eq.> are added at room temperature, under an argon atmosphere and with continuous stirring, to a solution of 1.50 g of the product of example 96 C
(3.31 mmol, 1 eq. > in 7 ml of methylene chloride. After 4 hours, the mixture is concentrated. 15 ml of 6N hydrochloric acid are then added.
After 14 hours, the water of the aqueous phase and the volatile products are evaporated and 657 mg of a hygroscopic orange solid are recovered.
Yield = 99 °/.
'H NHR : (CD30D) 1.20 (d, 3H, J = 5 Hz>, 1.?0 to 2.55 (m, 2H), 2.65 to 3. 35 (m, 3H> , 4. 50 to 4. 60 (m, 1H) , 4. 80 (broad s, 4H ) , 5. 00 (s, 2H >
, 6.20 to 6.80 <m, 3H>.
?ticroanalysis : C,QH,6NO.yP.2H~0 Calc % C = 42.53 N = 3.54 H = 5.5?
Found % C = 43.2? N = 3.68 H = 5.43 l~tS : 359, 302, 287, 251, 196.
Example 98 Preparation of the calcium monosalt of N-(R S)-(2-~d~i ~ rox~ph~~F~hinvl t methyl-1-oxo-3- ( 3 . 4-methylenedioxy phenyl ) propel ) - (S>-,alanine A mixture of 325 mg of the product obtained in example 97 (1.19 mmol), 33.6 mg of calcium monoxide (0.60 mmol) and 5 ml of water are sub,)ected to ultrasonic waves until the solid is totally dissolved. The water is evaporated and 350 mg of an off'-white salt are recovered.
Yield = 100 °l.
y 20497-649 83 .
Microanalysis : C,dH,~N06P,Ca,~2 Calc y. C = 44.35 N = 3.86 H = 4.72 Found °G C = 44.24 N = 3.?4 H = 4.65 F,xamnle 99 Pr~garati ~T of N- (R ~)_f 2_ (di p+hoxx~,~phinv ~ ;
methyl-1-oxo-3- (3 4-methylenediOXo,L.-~ h~n~ll ) ~,lro~~l 1 han~~l glycinate A. Preparation of N- (1-oxo- - ('i. 4-m h~rlenedioxs~phenatl ) methd,~
nropen~rl )-benzv~gl ~, .fit na-tP
The operating procedure is identical to that described in example 96 B, except that benzyl glycinate paratoluene sulfonate is used instead of benzyl alaninate paratoluene sulfonate. Purification by chromatography (eluent : chloroform 9?.5/methanol 2.5).
Yield = 88 ~.
A beige solid is obtained.
'fi N?iR : 3.60 (s, 2H>, 4.05 (broad s, 2H>, 5.05 <s, 2H>, 5.10 (s, 1H>, 5. 65 (broad s, 1H> , 6. 00 (s, 2H) , 6. 20 to 6. 40 (broad s, 1H> , 6. ?0 to 6.80 <m, 3H), ?.25 (broad s, 5H>.
B. Preparati nn of N- (R, )-f 2- (diethoxyrp~~,~ methyl 1 oxo 3 i~ 4-methyl PTIPfI~ nxv bhenvl ) propyl l -~~n .n I~rcinatg The operating procedure is identical to that described in example 96 C, except that benzyl glycinate is used instead of benzyl alaninate. A beige powder is obtained. Purification by chromatography (eluent : chloroform 96 / methanol 4). .
Yield = 69 '/°
1~'IP < 50 ° C
'H NMR : 1.10 to 1.35 (t, 6H, J = ? Hz), 1.70 to 2.65 (m, 2H>, 2.?0 to 3. 25 (m, 3H) , 3. 40 to 4. 20 (m, 6H) , 5. 10 <s, 2H) , 6. 00 (s, 2H ) , 6.

to 6.80 <m, 4H), ?.20 (broad s, 5H).
Microanalysis : C24H~u0~P
Calc °/ C = 58.66 N = 2.85 H = 6.31 Found °/. C = 58. 77 N = 2. ?9 H = 6. 25 MS : 491, 400, 372, 344, 312, 286.
Example 100 Preparati nn of N- (R ~~-r ~ (dih,; droxX~,hosn methyl-1-oxo-3- (3, 4-met ~1 ana~i nYY-phenyl ) ~rrQ~,~r~glycine D

~~ ~~aa~
The operating procedure is identical to that described in example 97, except that the product obtained in example 99 B is used instead of the product obtained in example 96 C. A hygroscopic orange solid is obtained.
Yield = 99 y.
'H NMR . (CD30D) 1.70 to 2.55 (m, 2H), 2.65 to 3.30 (m, 3H>, 4.05 (broad s, 2H>, 4.80 (broad s, 4H>, 6,00 (s, 2H>, 6.20 to 6.80 <m, 4H>.
Microanalysis : C,:,H,sN06P.2H~0 Calc °G C = 40.94 N = 3.67 H = 5.25 Found °/ C = 41,19 N = 3.68 H = 5.03 ?t.S = 345, 300, 271, 243, 211, 1?5, 121.
Example 101 Preyaration of the calcium monosalt of N-~~,~-I2-(dih.ydroxy~nhosnhinvl ) methyl-1-oxo-3- ( 3~, 4-methylenedioxy phenyl ) nrop.'i~l ) -gh ct i ne The operating procedure is identical to that described in example 98, except that the product obtained in example 100 is used instead of the product obtained in example 97. A white powder is obtained.
Yield = 100 °/.
Microanalysis : Cm~H,ENO,~P,Ca,~2 Calc °~ C = 42.86 N = 3.85 Ii = 4.6?
Found % C = 43.14 N = 3.?4 H = 4.75 Example 102 Preparation of N- (R _S)-( 2- (diethox~hQ~hin~t.]~2 meth;tl-~-oxo-3- (4-.phen~rl phenyl )~ ropyl l - (S)-benz~C,~ alaninat,e ~pr~naration of 2- ( (4-pheu~~l ~iln~1 >-methyl > prQg~uoic acid chloride The acid chloride is prepared by reacting (2-(4-phenyl) benzyl) acrylic acid with thionyl chloride according to the operating procedure of example 96 A. A yellow oil is obtained.
Yield = 100 °~6 'H Nt~IR . 3.50 (s, 2H>, 5.64 (s, 1H), 6.48 (s, 1H>, ?.20 to 7.70 <m, 9H>.
B. Preparation of_N-L 2- (4-ph~ny.l~zhs.n~,1 ) methyl-1-oxo propenyl l -~.S)-benzyl alaninate The product obtained in step A is coupled according to the operating procedure of example 96 B.

Chromatography <eluent : chloroform 97.5/methanol 2.5) Yield = 91 %
1.50 g of a beige solid are obtained.
?IP < 50°C
' H AMR : 1. 10 (d, 3H, J = 6 Hz > , 3. 60 (s, 2H> , 4 . 50 to 4. 60 <m, 1H) , 5. 00 (s, 2H) , 5. 10 (s, iH) , 5. 60 (.broad s, 1H) , 6. 20 to 6. 40 (broad s, 1H), ?.20 to 7.70 <m, 14A).
C. Preparation of A- (R ~S)-( 2- (dieth xyphosphin~l )methyl-1-oxo-3-(4-p: enyl ~henoyrl ) prod 1) -SS)-benzyl alaninate It is prepared from the compound obtained in step B, according to the operating procedure of example 96 C.
Chromatography (eluent : chloroform 96/methanol 4).
An oil is obtained.
Yield = 69 '~
'H N?tR . 1.10 to 1.40 (m, 9H), 1.70 to 2.65 <m, 2H>, 2.70 to 3. 30 (m, 3H> , 3. 40 to 3. 80 (q, 4H, 3 = 6 Hz > , 4 . 50 to 4. 60 <m, 11i) , 5.10 (s, 2H>, 6.20 to 6.50 (broad s, 1H>, ?.20 to 7.80 (m, 14H).
IR : 3280, 1740, 1675, 1550, 1255, 1065, 1030 cm'-' ?ticroanalysis : C:,<,H~~~NOr.P
Calc '~ C = 67.03 N = 2.61 H = 6.75 Found °~G C = 67.58 N = 2.?4 H = 6.75 liS : 537, 446, 418, 390, 341, 318, 285, 247.
E~ple_103 P~P~ar~~it'tn of N- (R~S>-L 2- <dih~iz~xvphosphinwl ) methyl=LQxS~'~(4-p]1~,~~~phen)C1 ) pro~rll- (S>-alanine The product of example 102 C is deprotected according to the operating procedure of example 97.
An oil is isolated by chromatography (eluent . chloroform 96I
methanol 4>.
Yield = 73 7°
'H NIdR (CD30D) . 1.25 <d, 3H, J = 5 Hz), 1.70 to 2.65 (m, 2H), 2.70 to 3.20 Cbroad s, 3H), 4.55 to 4.60 <m, 1H>, 4.80 (broad s, 4H), 7.20 to 7.80 Cm, 9H>.
Microanalysis : C,~H::~NOcP.2H~0 Calc °~G C = 53.40 N = 3.28 H = 6.13 Found °~ C = 54.2? N = 3.39 H = 6.02 MS : 391, 342, 319, 256, 194, 1?6.
Example 104 Preparation of the calcium monosalt of N-(R
~di d~ rox;tnhosphinvl )methyl-1-oxo-3- (4-phenyl phe~y7.) propyll - (S) -The product of example 103 is treated according to the process described in example 98.
A white powder is obtained.
Yield = 100 Microanalysis : C,~H~,NO~P,Ca,~2 Calc °~ C = 55.61 A = 3.41 H = 5.16 Found °/. C = 55.49 N = 3.54 H = 5.26 Example 105 Preparation of N- (R-S ) - f 2- (diethox~t~hosphinyl ) methyl-1-oxo-3-(4-~euy.Lphenyl) D~O~~benzyl alyeinate A, Preparation of A-f 2- (4-p 1 -en y], alvcinate The compound of example 102 A is coupled to benzyl glycinate according to the operating procedure of example 96 B. A white powder is obtained. Purification by chromatography (eluent . chloroform 97.5/
methanol 2.5).
Yield = 92 '/.
' H NMR : 3. 60 (s, 2H> , 4. 05 (broad s, 2H> , 5. 05 (s, 2H) , 5. 10 (s, 1H>
, 5.60 (broad s, 1H>, 6.20 to 6.40 (broad s,~ 1H>, ?.20 to ?.?5 (m, 14H).
H. Preparation of N- (R S>-f 2- (diethox~~phin~ethyl-1-oxo-3 .S4-phenyrl phenyl~~l1-benz~tl gl~lcinate It is prepared in the same way as in~example 96 C. A beige powder is obtained which is purified by chromatography (eluent . chloroform 96/ methanol 4) Yield = ?0 Y.
MP < 50'C
'H NMR : 1.10 to 1.35 (t, 6H, J = 7 Hz), 1.?0 to 2.65 (m, 2H>, 2.?0 to 3. 25 <m, 3H> , 3. 40 to 4. 20 <m, 6H> , 5. 10 w (broad s, 2H> , 6. 30 to 6.
?0 (broad s, 1H>, ?.20 to ?.80 (m, 14H).
Microanalysis : C~~:H_~QNO~.P
Calc °G C = 66.53 N = 2.68 H = 6.55 Found °,G C = 66.58 N = 2.73 H = 6,45 MS : 523, 432, 404, 376, 31?, 281.

Rx~mple 106 Preparation of N- (R S)-( 2- <dih~,rdroxXphosnhi mgi;~~rl-1-oxo-3-(4-phene~l nhendrl? pro~C],l-gl~tS~i~~.
The compound of example 105 B is treated according to the process described in example 97. A hygroscopic orange solid is obtained.
Yield = 98 x ' H NI~tR . (CD30D> 1. 95 to 2. 55 <m, 2H> , 2. 65 to 3. 30 <m, 3H> , 4.05 (broad s, 2H>, 4.80 (broad s, 4H>, 6.20 to 6.50 (broad s, 1H>.
?ticroanalysis : C,~H~oNO~P.2H20 Calc '/° C = 52.30 N = 3.39 H = 5.85 Found 'G C = 53.13 N = 3.48 H = 5.73 I4S : 333, 254, 188, 164 P 109 Preparation of the calcium mono=alt of A- (R S) - [ 2-(~i ~~~Methyl-1-oxo-3-(4-phenyl phenyl) propel]-glycine The product of example 106 is treated according to the process described in example 98. A white powder is obtained.
Yield = 100 Microanalysis : C,~.,H,~NOsP,Ca,~~
Calc °/. C = 54.55 N = 3.53 H = 4.83 Found °/. C = 54.69 N = 3.44 H = 4.92 BIOLOGj~AL STUDY
Quantitative determinations of the enkephalinase (Enkase> and ACE
inhibiting activities (Giros et al., J. Pharmac. Egp. Ther., 198?, 243, 666) of the above-mentioned I compounds are carried out.
Table I gives the results obtained from I compounds in racemic form and table II gives the results obtained from a number of I
compounds in optically pure form.

R~i n MIXED INHIBITORS HS _ J_ f/ NH \ OH (RsS ) ~S
~b IC 50 ( nm) EDC ACE

EX 12 nPr 10 6 EX 14 nBu 4 10 0~

~~O -CI-IZw ~

EX 18 CN ~ 4 4 ~

-Z

n EX 20 -CH2-Ph 10 8 EX 22 _~y~z~~p,~ 6 1,5 EX 3 2 j~ H 5 10 , -CWi~

EX 49 ~ H 3 10 -CND

EX 57 r H 4 8 EX 59 r CH3 2,5 10 EX 64 -CN1-"~~ CH3 8 10 CH ~ 5 9 EX 68 ~ C~lz~~o 3 TABLE II
OPTICALLY PURE MIXED INHIBITORS
R' O
HS N (s~
(s~ OH

(nm) EX 4 ~ 0 H 5 5 CH

z EX 2 4 0 CHZ-OH 3 11, EX 26 CHz- ~ CHZ-CHZ-SCH3 0,75 4,8 EX 45 CH3 0,2 10 CHz O

EX 60 CH3 1, 5 9 F

CHZ O

The stereochemical assignment of the carbon atom attached to the R2 group is not applicable when RZ=H.

2~~~'~

It can be seen that the compounds listed in these tables have IC50 inhibiting concentrations which range from 0.1 to 1 nM and a ratio of inhibiting activities on the two enzymes of less than 3-4.
These compounds are excellent mixed inhibitors of enkephalinase and ACE enzymes.
It can also be seen that the use of compounds Ia or Ib in optically pure form further improves their enkephalinase- and ACE-inhibiting properties (see example 4).
In conformity with their in vitro twofold inhibiting activity, it was observed that the compounds listed in tables I and II, or their esterified or thioesterified derivatives, administered by oral route at a dose of 3 mg/kg lead to : a slowing down in the degradation of '~~~I ANF in the mouse, an increase in natriuresis and diuresis in the normally or spontaneously hypertensive rat, a significant decrease in average blood pressure.

Claims (20)

CLAIMS:
1 - Amino acid derivatives wherein they correspond to the general formula:

wherein - R1 represents one of the following groups:

wherein Z and Y are 0 and n is 1 or 2, - R2 represents a hydrogen atom, a lower alkyl group, a lower hydroxyalkylene group, a phenyl group, a lower phenyldlkylene group, a lower hydroxyphenylalkylene group, a lower aminoalkylene group, a lower guanidinoalkylene group, a lower mercaptoalkylene group, a lower alkylthio lower alkylene group, a lower imidazolylalkylene group, a lower indolylalkylene group, a lower carbamylalkylene group, a lower carboxyalkylene group or one of the following groups:

wherein Z, Y and n have the meanings defined below:

Z~ Y~ n O~ CH2~ 1 - X designates a mercaptomethyl group.
2. Amino acid derivatives according to claim 1, wherein they correspond to the general formula (Ia).
3. Amino acid derivatives according to any one of claims 1 and 2, wherein n = 1.
4. Amino acid derivatives according to any one of claims 1 to 3, wherein R2 is a lower alkyl.
5. Amino acid derivatives according to any one of claims 1 to 4, wherein R2 is a methyl group.
6. Amino acid derivatives according to claim 1, wherein they are chosen from:

- N- (RS) -[1-oxo- 2-(mercaptomethyl)- 3-(3,4-methylenedioxy phenyl) propyl] glycine and its optically pure forms, - N- (RS) -[1-oxo- 2-(mercaptomethyl)- 3-(3,4-methylenedioxy phenyl) propyl]-(S)-alanine and its optically pure forms, - N- (RS) -[1-oxo- 2-(mercaptomethyl)- 3-(3,4-methylenedioxy phenyl) propyl]-(S)-2-aminobutyric acid, - N- (RS) -[1-oxo- 2-(mercaptomethyl)- 3-(3,4-methylenedioxy phenyl) propyl]-(S)-norvaline, - N- (RS) -[1-oxo- 2-(mercaptomethyl)- 3-(3,4-methylenedioxy phenyl) propyl]-(S)-norleucine, - N- (RS) -[1-oxo- 2-(mercaptomethyl)- 3-(3,4-methylenedioxy phenyl) propyl]-(S)-leucine, - N- (RS) -[1-oxo- 2-(mercaptomethyl)- 3-(3,4-methylenedioxy phenyl) propyl]-(S)-tryptophan, - N- (RS) -[1-oxo- 2-(mercaptomethyl)- 3-(3,4-methylenedioxy phenyl) propyl]-(S)-phenylalanine, - N- (RS) -[1-oxo- 2-(mercaptomethyl)- 3-(3,4-methylenedioxy phenyl) propyl]-(S)-tyrosine, - N- (S) -[1-oxo- 2-(mercaptomethyl)- 3-(3,4-methylenedioxy phenyl) propyl]-(S)-serine, - N- (S) -[1-oxo- 2-(mercaptomethyl)- 3-(3,4-methylenedioxy phenyl) propyl]-(S)-methionine, - N- (S) -[1-oxo- 2-(mercaptomethyl)- 3-(3,4-methylenedioxy phenyl) propyl]-(RS)-3-(3,4-methylenedioxy phenyl)-alanine, - N- (RS) -[1-oxo- 2-(mercaptomethyl)- 3-(3,4-ethylenedioxy phenyl) propyl]-glycine, - N- (RS) -[1-oxo- 2-(mercaptomethyl)- 3-(3,4-ethylenedioxy phenyl) propyl]-(S)-alanine, - N- (RS) -[1-oxo- 2-(mercaptomethyl)- 3-(2,3-methylenedioxy phenyl) propyl]-glycine, -N- (Z) -[1-oxo- 2-(mercaptomethyl)- 2-ene-3-(3,4-methylenedioxy phenyl) propyl]-glycine.
7. Amino acid derivatives according to any one of claims 1 to 6, which are selected from N- (RS) -[1-oxo- 2-(mercaptomethyl)- 3-(3,4-methylenedioxy phenyl) propyl]-(S)-alanine and its optically pure forms.
8. Amino acid derivatives according to claim 7, which is the N-(S)-[1-oxo-2- (mercaptomethyl) -3- (3,4-methylenedioxy, phenyl) propyl] -(S)-alanine.
9. Amino acid derivatives wherein they correspond to the general formula:
wherein - R1 represents one of the following groups:
wherein Z and Y are 0 and n Is 1 or 2, - R2 represents a hydrogen atom, a lower alkyl group, a lower hydroxyalkylene group, a phenyl group, a lower phenylalkylene group, a lower hydroxyphenylalkylene group, a lower aminoalkylene group, a lower guanidinoalkylene group, a lower mercaptoalkylene group, a lower alkylthio lower alkylene group, a lower imidazolylalkylene group, a lower indolylalkylene group, a lower carbamylalkylene group, a lower carboxyalkylene group or one of the following groups:

wherein Z, Y and n have the meanings defined below:

Z Y n -X designates a mercaptomethyl group, wherein the mercaptomethyl and carbonyl functions are protected.
10. Amino acids derivatives according to claim 9 wherein they correspond to the general formulae:

wherein -R1 and R2 have the meaning given in claim 9, -R4 represents a linear or branched alkyl group, a phenyl group or a phenylalkyl group, optionally mono- or polysubstituted on the phenyl ring, or linear or branched substituents comprising one or more oxygen atoms in their structure.

- R6 represents a linear or branched aliphatic acyl radical, an aromatic acyl radical, optionally mono- or polysubstituted, or a linear or branched acyl radical comprising one or more oxygen atoms in its structure.
11. Amino acid derivatives according to any one of claims 9 and 10, wherein they correspond to the general formula
12. Amino acid derivatives according to any one of claims 9 to 11, wherein n = 1.
13. Amino acid derivatives according to any one of claims 9 to 12, wherein Rz is a lower alkyl.
14. Amino acid derivatives according to any one of claims 9 to 13, wherein R2 is a methyl group.
15. Amino acid derivatives according to any one of claims 9 to 14, wherein R4 is a benzyl group.
16. Amino acid derivatives according to any one of claims 9 to 15, wherein R5 is an acetyl group.
17. Amino acid derivatives according to claim 9, wherein they are chosen from:

- N-(S)-[1-oxo-2-(acetylthiomethyl)-3-(3,4 methylenedioxy phenyl) propyl]-benzyl glycinate, - N-(RS)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-methylenedioxy phenyl) propyl]-S-benzyl alaninate, - N-(S)-[1-oxo-2-(acetylthiomethyl) 3-(3,4-methylenedioxy phenyl) propyl]-(S)-benzyl alaninate, - N-(RS)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-methylenedioxy phenyl) propyl]-(S)-2-aminobenzyl butyrate, - N-(RS)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-methylenedioxy phenyl) propyl]-(S)-benzyl norvalinete, - N-(RS)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-methylenedioxy phenyl) propyl]-(S)-benzyl noricucinate, - N-(RS)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-methylenedioxy phenyl) propyl]-(S)-benzyl leucinate, - N-(RS)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-methylenedioxy phenyl) propyl]-(S)-benzyl phenylalaninate, - N-(S)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-methylenedioxy phenyl) propyl]-(S)-methyl serinate, - N-(RS)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-ethylenedioxy phenyl)propyl]-benzyl glycinate, - N-(RS)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-ethylenedioxy phenyl) propyl]

(S)-benzyl alaninate, - N-(RS)-(1-oxo-2-(acetylthiomethyl)-3-(2,3-methylenedioxy phenyl) propyl]-benzyl glycinate, -N-(Z)-(1-oxo-2-(acetylthiomethyl)-2-ene-3-(3,4-methylenedioxy phenyl) propyl]-benzyl glycinate, - N-(E)-[1-oxo-2-(acetylthiomethyl)-2-ene-3-(3,4-methylenedioxy phenyl) propyl]-benzyl glycinate.
18. Amino acid derivatives according to claim 9, wherein they are chosen from:
- N-(S)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-methylenedioxy phenyl)-propyl]-benzyl glycinate, N-(RS)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-methylenedioxy phenyl) propyl]-S-benzyl alaninate, - N-(S)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-methylenedioxy propyl]-(S)-benzyl alaninate, - N-(RS)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-methylenedioxy phenyl) propyl]-(S)-2-aminobenzyl butyrate, - N-(RS)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-methylenedioxy phenyl) propyl]-(S)-benzyl norvalinate, - N-(RS)-[1-oxo-2-(acetylthiomethyl)-:3-(3,4-methylenedioxy phenyl) propyl]-(S)-benzyl norleucinate, - N-(RS)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-methylenedioxy phenyl) propyl]-(S)-benzyl leucinate, - N-(RS)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-methylenedloxy phenyl) propyl]-(s)-methyl tryptophanate, - N-(RS)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-methylenedioxy phenyl) propyl]-(S)-benzyl phenylalaninate, - N-(RS)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-methylenedioxy phenyl) propyl]-(S)-benzyl tyrosinate, - N-(S)-[1-oxo-2-(acetylthiomethyl)-3-(3.4-methylenedioxy phenyl) propyl]-(S)-methyl serinate, - N-(S)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-methylenedloxy phenyl) propyl]-(S)-methyl methioninate, - N-(S)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-methylenedioxy phenyl) propyl]-(RS)-3-(3,4-methylenedioxy phenyl) methyl alaninate, - N-(RS)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-ethylenedioxy phenyl) propyl]-benzyl glycinate, - N-(RS)-[1-oxo-2-(acetylthiomethyl)-3-(3,4-ethylenedioxy phenyl) propyl]-(S)-benzyl alaninate, - N-(RS)-[1-oxo-2-(acetylthiomethyl)-3-(2,3-methylenedioxy phenyl) propyl]-benzyl glycinate,
19. Amino acid derivatives according to any one of claims 9 to 18, wherein they are chosen from N-(RS)-[1-oxo-2-acetylthiomethyl)-3-(3,4-methylenedioxy phenyl) propyl]-(S) benzyl alaninate.
20. Amino staid derivatives according to any one of claims 9 to 19, which is the N-(S)-[1-oxo-2-acetylthiomethyl)-3-(3,4-methylenedioxy phenyl) propyl]-(S) benzyl alaninate.
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