WO1994011390A1 - Novel pseudodipeptide derivatives, preparation thereof and use thereof as gastrin antagonists - Google Patents

Abstract

Novel pseudodipeptide derivatives of general formula (I), the preparation thereof and drugs containing same.

Description

 New pseudo-dipeptide derivatives, their preparation and their use as agonistagonists

Cholecystokinin (CCK) belongs to a group of peptides found in the central nervous system as well as in the gastrointestinal system; this is the case for gastrin, which is a polypeptide hormone related to CCK (both have a carboxy-terminal pentapeptide sequence) which has multiple biological activities, the main one being gastric stimulation (Konturek, Gastrointestinal Hormones , c. 23, p. 529-564, 1980, ed. GBJ Glass, Raven Press, NY). It is known that the rearrangement of certain amino acids in the sequence of gastrin or of its fragments leads to peptide derivatives which sometimes antagonize at a high level the action of gastrin on gastric secretion. However, the therapeutic use of such derivatives is considerably limited by the brevity of their activity due to the very rapid destruction of peptic compounds in the body.

The discovery of CCK antagonists of non-polypeptide structure such as proglumide or benzotript has stimulated the search for new CCK antagonists (J.F. Kerwin Jr., Drugs of the Future, 16, 1111-1119, 1991).

The present invention relates to new pseudo-dipeptide derivatives, which have a strong antagonistic activity of gastric secretion and which are capable of limiting the progression of ulcers, in vivo.

The prior art in this field is illustrated in particular by:

 - French patent 8608458

 - the publication of CDs. Horwell (Neuropeptides. 19, 57-64, 1991) and patents W09204038-A1, W09204045-A1, WO9204320-A and W09204322-A1 relate to dipeptoid compounds derived from trypophane

- American patent US 5128346-A. The present invention relates to compounds of formula:

and their physiologically acceptable salts, their preparation and the drugs containing them.

In formula (I):

 Z represents a phenyl, benzyl, indanyl, cycloalkyl, polycycloalkyl, indolylalkyl, naphthyl, naphthylmethyl, phenoxy methyl, naphtoxymethyl radical, optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio radicals,

R ₁ represents (CH ₂ ) _n CO ₂ H in which n is between 1 and 5, R ₂ represents an alkyl radical, branched or linear,

X represents -NH- or -CO-,

Y represents -NH- or -CO-, it being understood that X and Y are different from each other,

Z 'represents a hydrogen atom or a methyl radical,

Z "represents a hydrogen atom or CO ₂ R ₃ or NHCO ₂ R ₃ , it being understood that if Y = NH, Z" cannot be NHCOR, and that if Y = CO, Z "cannot be COR ₃ ,

R ₃ represents an alkyl, cycloalkyl, polycycloalkyl, phenyl radical, optionally substituted with one or more substituents chosen from halogen atoms and alkyl, alkoxy, alkylthio and nitro radicals, and their physiologically acceptable salts.

 In the above definitions and those which will be cited below, unless otherwise stated, the alkyl and alkoxy radicals contain 1 to 4 carbon atoms and the polycycloalkyl portions contain 7 to 12 carbon atoms.

 In formula (I), the halogen atoms are preferably chlorine, bromine or fluorine atoms.

 Advantageously, Z represents a 3,4-dichlorophenyl radical.

For its part, R ₁ preferably represents (CH ₂ ) ₂ CO ₂ H, and R ₂ represents a linear or branched butyl radical.

 The compounds of formula (I) containing 1 or more asymmetric centers have isomeric forms. The racemates and pure enantiomers of these compounds are also part of this invention.

Preferably, derivatives corresponding to formula (I) will be chosen in which the asymmetric centers of the carbons linked to the substituents R ₁ and R ₂ are of D configuration.

 The pseudopeptide derivatives according to the invention can be prepared from an esterified derivative of formula (Y)

in which R ' ₁ is (CH ₂ ) _n CO ₂ R where R is an alkyl, phenyl or benzyl radical, by hydrogen reaction of the ester function using the appropriate method depending on the nature of the ester. Thus a tert-butyl ester will preferably be treated in an acid medium (HCl) -MeOH; CF ₃ CO ₂ H) while a benzyl ester will preferably be treated by catalytic hydrogenation using hydrogen at atmospheric pressure in the presence of paladium on carbon, in a solvent such as THF, ethanol or isopropanol. The compounds of formula (I ') can be prepared by the action of an amino derivative of formula (II)

dans laquelle R₂, X, Y, Z' et Z" ont les mêmes significations que dans la formule (I) mais dans laquelle R'₁ est un dérivé estérifié du radical carboxyalkyle R₁ défini dans la formule (I), sur un dérivé d'acide carboxylique de formule (III)

in which R ₂ , X, Y, Z 'and Z "have the same meanings as in formula (I) but in which R' ₁ is an esterified derivative of the carboxyalkyl radical R ₁ defined in formula (I), on a carboxylic acid derivative of formula (III)

(III)

dans laquelle Z a la même signification que dans la formule (I). Cette réaction nécessite l'activation préalable de la fonction acide du composé III par des méthodes et techniques de la condensation peptidique. Lorsque l'on met en oeuvre l'acide, on opère en présence d'agent de condensation tel qu'un carbodiimide (par exemple le dicyclohexylcarbodiimide) ou le N,N'-diimidazole carbonyle, dans un solvant inerte tel qu'un éther (par exemple THF, dioxane), un amide (par exemple le DMF) ou un solvant chloré (par exemple le chlorure de méthylène, dichloroéthane, chloroforme) à une température comprise entre 0ºC et 60°C. Lorsque l'on met en oeuvre un dérivé réactif de l'acide, il est possible de faire réagir l'anhydride, un anhydride mixte, un halogénure d'acide ou un ester (qui peut être choisi parmi les esters activés ou non de l'acide). On opère alors soit en milieu organique, éventuellement en présence d'un accepteur d'acide tel qu'une base organique azotée (par exemple une trialkylamine, une pyridine, le diaza-1,8 bicyclo[5.4.0]undécène-7 ou le diaza-1,5 bicyclo[4.3.0] nonène-5). dans un solvant tel que cité ci-dessus, ou un mélange de ces solvants, à une température comprise entre 0ºC et la température de reflux du mélange réactionnel, soit en milieu hydro-organique biphasique en présence d'une base alcaline ou alcalino-terreuse (soude, potasse) ou d'un carbonate ou bicarbonate d'un métal alcalin ou alcalino-terreux à une température comprise entre 0 et 40ºC.

in which Z has the same meaning as in formula (I). This reaction requires the prior activation of the acid function of compound III by methods and techniques of peptide condensation. When the acid is used, it is carried out in the presence of a condensing agent such as a carbodiimide (for example dicyclohexylcarbodiimide) or N, N'-diimidazole carbonyl, in an inert solvent such as an ether (eg THF, dioxane), an amide (eg DMF) or a chlorinated solvent (eg methylene chloride, dichloroethane, chloroform) at a temperature between 0ºC and 60 ° C. When a reactive acid derivative is used, it is possible to react the anhydride, a mixed anhydride, an acid halide or an ester (which can be chosen from activated or non-activated esters of l 'acid). The operation is then carried out either in an organic medium, optionally in the presence of an acid acceptor such as a nitrogenous organic base (for example a trialkylamine, a pyridine, the diaza-1,8 bicyclo [5.4.0] undecene-7 or diaza-1,5 bicyclo [4.3.0] nonene-5). in a solvent as mentioned above, or a mixture of these solvents, at a temperature comprised between 0ºC and the reflux temperature of the reaction mixture, either in a two-phase hydro-organic medium in the presence of an alkaline or alkaline earth base (soda, potash) or of an alkali or alkaline earth metal carbonate or bicarbonate at a temperature between 0 and 40ºC.

The amines of formula (II) can be obtained by hydrolysis of a corresponding urethane or carbamate of formula (IV)

Les méthodes choisies pour la transformation des carbamates (IV) en aminés (II) dépendent de la nature du groupement R'. Par exemple, si le groupement R' est un radical t-butyle, la transformation de (IV) en (II) sera effectuée en milieu acide (HCl dans l'éther, acide trifluoroacétique) ; si le groupement R' est un radical benzyle, la transformation de (IV) en (II) sera effectuée preferentiellement par hydrogénation catalytique, sous pression atmosphérique d'hydrogène, en utilisant le paladium (O) sur charbon comme catalyseur dans un solvant tel que l'éthanol.

The methods chosen for the transformation of carbamates (IV) into amines (II) depend on the nature of the group R '. For example, if the group R 'is a t-butyl radical, the transformation of (IV) into (II) will be carried out in an acid medium (HCl in ether, trifluoroacetic acid); if the group R ′ is a benzyl radical, the transformation of (IV) into (II) will preferably be carried out by catalytic hydrogenation, under atmospheric pressure of hydrogen, using paladium (O) on carbon as catalyst in a solvent such as ethanol.

The compounds of formula (I) can also be obtained directly from derivatives of formula (IV) when the esterified form of the residue R. and the carbamate function "R'OCON" can be deprotected simultaneously. Thus a preferred method consists in treating a derivative of formula (IV) in which R ' ₁ is - (CH ₂ ) _n -COOCH ₂ C ₆ H and R' is CH ₂ C ₆ H ₅ by atmospheric hydrogenation catalytic (paladium or carbon); the product of formula (II) (in which R '= (CH ₂ ) _n CO ₂ H) thus obtained is then condensed with an activated ester derived from the acid of formula (III) (for example, an ester of n- hydroxy succinimide) to lead to the derivative of formula (I). The methods used for the preparation of intermediates of formula (IV) depend on the nature of the residues X and Y.

The derivatives of formula (IV), with the exception of those for which -X- represents -NH- can be obtained from an acid (V) or a derivative of this acid

et d'une aminé de formule (VI)

and an amine of formula (VI)

by the well-known methods for peptide condensation and which have been applied beforehand for the preparation of (I ') from (II) and (III). Intermediaries (VI) are obtained from the corresponding carbamates (VII)

par des méthodes bien connues dépendant de la nature de R", comme indiqué précédemment pour la transformation du carbamate (IV) en aminé (II). Les carbamates (VII ) peuvent être préparés à partir d ' un acide (VIII ) ou d ' un dérivé de cet acide

by well known methods depending on the nature of R ", as indicated above for the transformation of carbamate (IV) into amine (II). The carbamates (VII) can be prepared from an acid (VIII) or a derivative of this acid

et d' une aminé de formule (IX)

and an amine of formula (IX)

par les méthodes bien connues pour la condensation peptidique et qui ont été appliquées précédemment pour la préparation de (I') à partir de (II) et (III).

by the well-known methods for peptide condensation and which have been applied previously for the preparation of (I ') from (II) and (III).

The derivatives of formula (IV) for which -X- represents -NH- can be obtained from an amine of formula (X)

et d'un acide de formule (XI), ou d'un dérivé de cet acide

and an acid of formula (XI), or a derivative of this acid

par les méthodes et techniques propres & la condensation peptidique et qui ont été présentées précédemment.

by the methods and techniques specific to peptide condensation and which have been presented previously.

The intermediates of formula (X) can be prepared from the amides (XII) while preserving the stereochemistry of the two asymmetric carbons

This transformation, well known under the name "Curtius rearrangement", can be carried out under different conditions according to well described methods, including the use of bis (trifluoroacetoxy) iodo benzene or of the azide obtained from the analogous hydrazino derivative. from (XII).

The amides (XII) can be prepared from the amides of formula (XIII)

and a carboxylic acid of formula (V) or a derivative of this acid by the methods and techniques well known in peptide synthesis and which have been presented previously.

Derivatives (V), (VIII), (IX). (XI) and (XIII) were prepared by the methods described. It is understood for those skilled in the art that, for the implementation of the methods according to the invention described above, it is necessary to choose protective groups (carbamates or esters) whose deprotection method will be compatible with other protecting groups or other labile functions present on the molecule considered. For example, the method chosen for the deprotection of carbamates (IV) into free amines (II) must be compatible with the ester function of the radical R ' ₁ . We will therefore choose, for example, a tert-butyl carbamate which is deprotected in an acid medium if the ester of the radical R ′ ₁ is a benzyl ester.

The enantiomers of the compounds of formula (I) are generally obtained from optically active protected amino acids such as the intermediates of formula (V). (VIII), (XII), (IX) when Z "= CO ₂ R 'and (XI) when Z" = NHCO ₂ R'. The starting amino acids used are chiral and belong to the L or D series, a configuration which is that found in the final products of formula (I).

The compounds of formula (I) can be purified by the usual known methods, for example by crystallization, chromatography or extraction.

The compounds of formula (I) have interesting pharmacological properties. These compounds have a strong affinity for gastrin and cholecystokinin (CCK) receptors and are therefore useful for the treatment and prevention of gastrin-related disorders in the gastrointestinal tract and CCK-related disorders in the system nervous.

Thus, the compounds of the present invention can be used for the treatment and prevention of irritable bowel syndrome, acute pancreatitis, ulcers and disorders of intestinal motility, certain tumors of the lower esophagus, colon and bowel, psychoses, anxiety disorders and Parkinson's disease. Example 1

 N (3, 4 dichlorobenzoyl) -DGlu-gNle-des-amino-Trp

1A: synthesis of Z-DGlu (OBzl) -Nle-NH ₂

To a solution of Z-DGlu (OBzl) -ONp (2.95 g; 6 mmol) in 10 ml of DMF are successively added H-Nle-NH ₂ .HCl (1.09 g; 6.54 mmol) H0BT (0.81 g; 6 mmol) and diisopropylethylamine (2.15 ml, 12.54 mmol). The solution is stirred at 20ºC for 2 hours, the solvent is removed by evaporation under reduced pressure and the residue is washed with 200 ml of a 1/1 mixture of ethyl acetate and ether. The precipitate thus formed is filtered, washed with the same mixture of solvents, a saturated aqueous bicarbonate solution, water, a 1M aqueous solution of KHSO ₄ and water. The precipitate is dried under vacuum over P ₂ O ₅ to give 2.63 g (91%) of product 1A.

mp 175-177ºC; [α] _D : + 2.9 (c 0.97 DMF); Rf: 0.68 (ethyl acetate).

Elementary analysis (C ₂₆ H ₃₃ N ₃ O ₆ ):

hold. : C, 64.57; H, 6.89; N, 8.69.

found: C, 64.28; H, 6.78; N, 8.55.

1B: synthesis of Z-DGlu (OBzl) -gNle-des-amino-Trp

To a suspension of the dipeptide Z-DGlu (OBzl) -Nle-NH ₂ (1.3 g; 2.69 mmol) in 10 ml of a 1/1 acetonitrile and water mixture, is added 1.21 g (2.82 mmol) of [bis-trifluoroacetoxy ) iodo] benzene. After 3 hours at 20 ° C, a clear solution appears. The solvents are removed by evaporation under reduced pressure to give a residue which is triturated with 3 X 50 ml of dry ether. The resulting white precipitate is dried under vacuum over P ₂ O ₅ . This dry solid (0.703 g) is added to a solution of 3-indole-propionic acid (0.246 g; 1.3 mmol) in 10 ml of DMF, followed per 0.575 g (1-3 mmol) of BOP and 2.53 mmol (0.28 ml) of NMM. After 3 hours of stirring of the reaction medium at 20ºC, the desired product precipitates following the addition of 100 ml of a saturated aqueous bicarbonate solution. The precipitate is collected after filtration, washed with 50 ml of an aqueous bicarbonate solution, water (2 X 30 ml), a 1M aqueous solution in KHSO ₄ (2 X 50 ml), water (2 X 50 ml). and dried under vacuum over P ₂ O ₅ to give 0.705 g of product 1B.

mp 145-148ºC; [α] _D : - 1.5 (c 1.09 DMF); Rf: 0.72 (ethyl acetate).

Elementary analysis (C ₃₆ H ₄₂ N ₄ O ₆ ):

hold. : C, 68.98; H, 6.77; N. 8.94

found: C, 68.69; H. 6.75; N, 8.72.

1C: synthesis of 3,4 dichloro-benzoic acid, N-hydroxysuccinimide ester To a solution of 3.4 dichlorobenzoic acid (5 g; 26.2 mmol) in 50 ml of dimethoxyethane are added 3-31 g of N-hydroxysuccinimide (28.82 mmol) and 5.4 g of dicyclohexylcarbodiimiάe (26.2 mmol). After 20 hours of stirring at 20ºC, the precipitate formed by the dicyclohexylurea is removed by filtration and the solvent is evaporated under reduced pressure. The oil thus obtained is dissolved in 200 ml of ethyl acetate and the organic phase is washed with water, with a 1M solution of KHSO ₄ (2 X 50 ml) and 2 X 50 ml of water, dried over potassium sulfate and concentrated under reduced pressure to give 5.87 g (73%) of 1C ester. Rf: 0.56 (EtOAc / hex = 1/1).

1D: synthesis of N (3,4-dichlorobenzoyl) -DGlu-gNle-des-amino-Trp (example 1)

Compound 1B (0.627 g; 1 mmol) is dissolved in 10 ml of a mixture of DMF / ACOH / H ₂ O in the proportions 10/1/1 containing 50 mg of paladium on charcoal and hydrogenated for 4 hours at 20ºC under atmospheric pressure. The reaction medium is filtered through celite and concentrated under reduced pressure to give a residue which is dissolved in 5 ml of DMF. To this solution are added 0.23 g (0.8 mmol) of 3.4 dichlorobenzoic acid, N-hydroxysuccinimide ester and 0.52 ml of diisopropylethylamine (3 mmol). The reaction medium is stirred at 20ºC for 20 hours, then 100 ml of a 1M aqueous solution in KHSO ₄ are added. The precipitate thus formed is collected by filtration, washed with water (2 X 50 ml), with ether and hexane and dried under vacuum to give 0.354 g (77%) of product 1.

mp 150 (dec); [α] _D : - 16.1 (c 1.2 DMF); Rf: 0.7 (chloroform, methanol, acetic acid: 85/10/5).

Elementary analysis (C ₂₈ H ₃₂ N ₄ O ₅ Cl ₂ ):

hold. : C. 58.42; H, 5.61; N, 9.73

found: C, 58.21; H. 5-91; N, 9.69.

Example 2

 N (3,4 dichlorobenzoyl) -Glu-gNle-des-amino-Trp

2A: synthesis of Z-Glu (OBzl) -Nle-NH ₂

To a solution of Z-Glu (OBzl) -OH (2.34 g; 6.3 mmol) in 10 ml of DMF are successively added 1.1 g of HCl, H-Nle-NH ₂ (1.1 g; 6.6 mmol)

2.78 g of BOP (6.3 mmol) and 1.45 ml of NMM (12.9 mmol). The solution is stirred at 20ºC for 2 hours. The precipitate formed after addition of

100 ml of aqueous bicarbonate is filtered, washed with a saturated bicarbonate solution, water, a 1M solution in KHSO ₄ , water, dried under vacuum over P ₂ O ₅ to give 2.85 g (93%) of desired product 2A.

mp 175-177ºC; [α] _D : - 2.3 (c 0.92 DMF); Rf: 0.62 (ethyl acetate).

Elementary analysis (C ₂₆ H ₃₃ N ₃ O ₆ ):

hold. : C, 64.57; H. 6.89; N, 8.69

found: C, 64.49; H, 6.82; N, 8.62.

2B: synthesis of Z-Glu (OBzl) -g4le-des-amino-Trp

The product 2B (1.36 g) was obtained from the derivative 2A (1.4 g) by the method described above for the preparation of 1B. mp 165-170ºC; [α] _D : - 2.6 (c 1 .09 DMF); Rf 0.70 (ethyl acetate).

Elementary analysis (C ₃₆ H ₄₂ N ₄ O ₆ ):

hold. : C, 68.98; H. 6.77; N. 8.94

found: C, 68.75; H. 6.68; N. 8.81.

2C: synthesis of N (3,4-dichlorobenzoyl) -Glu-gNle-des-amino-Trp

 Product 2C (Example 2) was obtained (0.385 g) from product 2B

(0.627 g) by the method previously described for obtaining 1D

(example 1) from 1B.

mp 170-175ºC (dec.); [α] _D : + 13.9 (c 1 DMF); Rf: 0.17 (EtOAc, py.

HAc. H ₂ O: 80/20/5/10).

Elementary analysis (C ₂₈ H ₃₂ N ₄ O ₅ CI ₂ ):

hold. : C, 58.42; H, 5-61; N, 9.73

found: C, 58.31; H, 5.62; N, 9.83.

Example 3

 N (3,4-dichlorobenzoyl) -DGlu-gDNle-des-amino-Trp

3A: synthesis of Z-DGlu (OBzl) -DNle-NH ₂

1.81 g of Z-DGlu (OBz) -DNle-NH ₂ were prepared from 1 g of TFA,

H-D Nle-NH- according to the method previously described for the synthesis of

1A.

mp 176-178ºC; [α] _D : - 2.7 (c 0.94 DMF); Rf: 0.58 (ethyl acetate).

Elementary analysis (C ₂₆ H ₃₃ N ₃ O ₆ ):

hold. : C, 64.57; H. 6.89; N, 8.69

found: C, 64.58; H, 6.82; N, 8.76. 3B: synthesis of Z-DGlu (OBzl) -gDNle-des-amino-Trp

 The product 3j_ (1.42 g) was prepared from the derivative 3A (1.4 g) by the method described above for the preparation of 1B.

mp 170-172ºC; [α] _D : + 3.0 (c 1.37 DMF); Rf: 0.79 (ethyl acetate).

Elementary analysis (C ₃₆ H ₄₃ N ₄ O ₆ ):

hold. : C, 68.98; H. 6.77; N, 8.94

found: C, 68.83; H, 6.65; N. 8.69.

3C: synthesis of N (3,4-dichlorobenzoyl) -DGlu-gDNle-des-amino-Trp

 (example 3).

 The product 3C (example 3) was obtained (0.362 g) from Z-D-Glu

(OBzl) -gDNle-des-amino-Trp (0.627 g) by the method previously described for obtaining 1D from 1B.

mp 170-173ºC; [α] _D : - 13-6 (c 1 DMF); Rf: 0.13 (EtOAc, py. HAc,

H ₂ O 80/20/5/10).

Elementary analysis (C ₂₈ H ₃₂ N ₄ O ₅ Cl ₂ ):

hold. : C. 58.42; H, 5-61; N, 9.?3

found: C, 58.19; H. 5.61; N, 9.88.

Example 4

 N (3,4 dichlorobenzoyl) -Glu-gDNle-des-amino-Trp

4A: synthesis of Z-Glu (OBzl) -DNle-des-amino-Trp

The product 4A (1.65 g) was prepared from Z-DGlu (OBzl) -OH (1.41 g) according to the method previously described for the preparation of 2A. mp 178-180ºC; [α] _D : - 1.5 (c 0.98 DMF); Rf: 0.62 (ethyl acetate). Elementary analysis (C ₂₆ H ₃₃ N ₃ O ₆ ):

hold. : C, 64.57; H, 6.89; N. 8.69

found: C. 64.38; H. 6.76; N. 8.55.

4B: synthesis of Z-Glu (QBzl) -gDNle-des-amino-Trp

The product 4B (1.47 g) was obtained from the derivative-4A (Z-Glu (OBzl) - DNle-NH ₂ ; 1.4 g) according to the method described for the preparation of product 1B.

mp 1.68-170ºC; [α] _D : - 1.2 (c 1.09 DMF); Rf: 0.83 (ethyl acetate).

Elementary analysis (C ₃₆ H ₄₂ N ₄ O ₆ ):

hold. : C, 68.98; H, 6.71; N. 8.94

found: C, 68.78; H, 6.89; N. 8.99.

4C: synthesis of N (3.4-dichlorobenzoyl) -Glu-gDNle-des-amino-Trp

(example 4).

 The product 4C or example 4 (0.436 g) was obtained from the intermediate 4B (0.627 g) by the method previously described for obtaining ID from 1B.

mp 168-171ºC; [α] _D : * 14.4 (c 1.1 DMF) Rf: 0.81 (CHCl _3. MeOH. HAC 85/10/15).

Elementary analysis (C ₂₈ H ₃₂ N ₄ O ₅ Cl ₂ ):

hold. : C, 58.42; H, 5.61; N. 9.73

found: C. 58.26; H. 5.58; N. 9.62.

Example 5

 N (3,4-dichlorobenzoyl) -Glu-Nle-Tryptamine

5A : synthèse de Boc-Nle-Tryptamine

5A: synthesis of Boc-Nle-Tryptamine

Tryptamine (1.02 g; 6.39 mmol) is added to a solution of Boc-Nle-OSu (2 g; 6.09 mmol) in 10 ml of DMF. The solution is stirred at 20ºC for 5 hours, the solvent is evaporated under reduced pressure and the residue is dissolved in 200 ml of ethyl acetate. The organic phase is washed with a saturated aqueous bicarbonate solution, water, a 1M solution in KHSO ₄ . water, then dried over sodium sulfate, filtered and concentrated in vacuo to give a residual oil which crystallizes from an ether / hexane mixture (1.95 g; 86%). mp 106-107ºC; [α] 8.58 (c 0.92 DMF); Rf: 0.52 (ethyl acetate / hexane: 1/1).

Elementary analysis (C ₂₁ H ₃₁ N ₃ O ₃ ):

hold. : C, 67-52; H, 8.38; N, 11.25

found: C, 67.36; H. 8-32; N. 11.03.

5B: synthesis of Z-Glu (OBzl) -Nle-Tryptamine

Boc-Nle-Tryptamine 5_A (0.8 g; 2.14 mmol) is dissolved in 5 ml of TFA. After 30 minutes of stirring at 20ºC, the trifluoroacetic acid is eliminated by evaporation under vacuum and the residual oil is triturated with ether and then dried under vacuum in the presence of potassium hydroxide. The residue thus obtained (0-71 g) is dissolved in 5 ml of DMF and added to a solution containing 0.679 g (1.83 mmol) of Z-Glu (OBzl) -OH, 0.808 g of BOP and 0.41 ml of NMM. The reaction medium is stirred for 4 hours at 20 ° C. then the desired product is precipitated by the addition of 100 ml of saturated sodium bicarbonate. The precipitate is separated by filtration, washed with 2 X 50 ml of saturated sodium bicarbonate, 2 X 30 ml of water, 2 X 50 ml of a 1M aqueous solution in KHSO ₄ . 2 X 50 ml of water, then dried under vacuum over P ₂ O ₅ to give 0.992 g (86%) of product 5B.

mp 107-108ºC; [α] _D : - 6.5 (c 1 DMF); Rf: 0.72 (EtOAc, Hexane: 7/3).

Elementary analysis (C ₃₆ H ₄₂ N ₄ O ₆ ):

hold. : C, 68.98; H. 6.77; N. 8.94

found: C, 68.67; H, 6.72; N, 8.77. 5C: synthesis of N (3,4-dichlorobenzoyl) -Glu-Nle-Tryptamine

 (example 5)

 Compound 5B (0.5 g; 0.79 mmol) is dissolved in a mixture of DMF /

HAC / H ₂ O. 20: 3: 3 containing 30 mg of 10% Pd / C and hydrogenated for 3 hours at 20ºC at atmospheric pressure. The reaction medium is filtered, concentrated under reduced pressure to give a residue which is dissolved in 5 ml of DMF. To this solution are added 0.250 g (0.71 mmol) of 3.4 dichlorobenzoic acid, N-hydroxysuccinimide ester and 0.52 ml of DIEA. The reaction mixture is stirred for 20 hours at 20 ° C. and then treated with 100 ml of a molar solution of KHSO ₄ . The precipitate thus formed is collected after filtration, washed with water, ether and hexane, then dried under vacuum over P ₂ O ₅ to give 0.37 g (92%) of product 5C or Example 5.

mp 145-150ºC; [α] _D : + 8.1 (c 1.08 DMF); Rf 0.70 (CHCl ₃ , MeOH. HAC

85/10/15).

Elementary analysis (C ₂₈ H ₃₂ N ₄ O ₅ Cl ₂ ):

hold. : C, 58.42; H, 5.61; N, 9.73

found: C, 58.12; H. 5.42; N, 9.89.

Example 6

 N (3, 4-dichlorobenzoyl) -DGlu-Nle-Tryptamine

6A: synthesis of Z-DGlu (OBz) -Nle-Tryptamine

A solution of TFA, Nle-Tryptamine (0.379 g; 0.98 mmol) in 5 ml of DMF is added to a solution comprising 0.458 g (0.93 mmol) of Z-DGlu (OBzl) -ONp, 0.125 g (0.93 mmol) of HOBt and 0.34 ml of DIEA. After 5 hours of stirring at 20ºC, the solvent is removed under reduced pressure and the residue is dissolved in 200 ml of ethyl acetate. The organic phase is washed with 2 X 50 ml of saturated bicarbonate, 2 X 30 ml of water then dried over sodium sulfate, filtered, concentrated under reduced pressure to give a residue which is triturated with ether and then an ether / hexane mixture. The solid thus obtained is dried under vacuum over

P ₂ O ₅ to give 0.520 g (82%) of product 6A.

mp 100-105ºC (dec); [α] _D : - 9.6 (c 0.95 DMF); Rf: 0.75 (EtOAc / Hexane: 7/3).

Elementary analysis (C ₃₆ H ₄₂ N ₄ O ₆ ):

hold. : C, 68.98; H, 6.74; N, 8.94

found: C, 68.59; H, 6.65; N, 8.8.

6B: synthesis of N (3,4-dichlorobenzoyl) -DGlu-Nle-Tryptamine

 (example 6).

 Derivative 6B (0.354 g) was prepared from derivative 6A (0.45 g) by the method previously described for the preparation of 5C.

6B:

mp 140ºC (dec); [α] _D : - 29.4 (c 1 DMF); Rf: 0.72 (CHCl ₃ , MeOH. HAC

85/10/15).

Elementary analysis (C ₂₈ H ₃₂ N ₄ O ₅ Cl ₂ ):

hold. : C, 58.42; H, 5.61; N. 9.73

found: C, 58.09; H, 5.60; N, 9.46.

Example 7

 N (3,4-dichlorobenzoyl, -DGlu-DNle-Tryptamine

7A: synthesis of Boc-DNle-Tryptamine

 Tryptamine (1.02 g; 6.39 mmol) is added to a solution of

Boc-DNle-OSu (2 g; 6.09 mmol) in 10 ml of DMF. The solution is stirred at 20ºC for 5 hours, the solvent is evaporated under reduced pressure and the residue is dissolved in 200 ml of ethyl acetate, washed with a saturated aqueous bicarbonate solution, water, a 1M solution of KHSO ₄ in water, and water. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. The residual oil is crystallized from an ether / hexane mixture to give 1.82 g (79%) of product 7A.

mp 110-112ºC; [α] _D : + 8.2 (c 1.03 DMF); Rf: 0.55 (ethyl acetate / hexane: 1/1).

Elementary analysis (C ₂₁ H ₃₁ N ₃ O ₃ ):

hold. : C, 67-52; H, 8.38; N, 11.25

found: C, 67.41; H, 8.33; N, 11.12.

7B: synthesis of Z-DGlu (OBzl) -Nle-Tryptamine

The derivative 7A (0.8 g; 2.14 mmol) is dissolved in 5 ml of trifluoroacetic acid. After 30 min at 20ºC, the trifluoroacetic acid is eliminated by evaporation under reduced pressure and the residual oil is triturated with dry ether and then dried under vacuum over P ₂ O ₅ . The residue (0.65 g; 1.7 mmol) is dissolved in 5 ml of DMF and added to a solution containing Z-DGlu (OBzl) -ONp (0.796 g; 1.61 mmol), HOBT

(0.217 g; 1.61 mmol) and the DIEA (0.58 ml; 3.4 mmol). The reaction medium is stirred for 5 hours at 20 ° C., the solvent is removed by distillation under reduced pressure and the residue is dissolved in 200 ml of ethyl acetate. The organic phase is washed with a saturated aqueous bicarbonate solution (2 X 50 ml), water (2 X 30 ml), an aqueous IM solution in KHSO ₄ (2 X 50 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue which is washed several times with dry ether with an ether / hexane mixture. The solid thus obtained is dried under vacuum over P_, 0_ to give 0.954 g

(94%) of product 7B.

mp 150ºC (dec); [α] _D : + 7.1 (c 1 DMF); Rf: 0.72 (EtOAc. Hexane: 7/3).

Elementary analysis (C ₃₆ H ₄₂ N ₄ O ₆ ):

hold. : C, 68.98; H, 6.77; N, 8.94

found: C, 68.59; H, 6.48; N, 8.68. 7C: synthesis of N (3,4-dichlorobenzoyl) -DGlu-DNle-Tryptamine

 (example 7).

 The derivative 7C (0.627 g) was prepared from the derivative 7B (0.824 g) by the method previously described for the preparation of 5C.

 7C:

mp 120ºC; [α] _D : - 5.6 (c 1.03 DMF); Rf: 0.68 (CHCl _3. MeOH. HAC

85/10/15).

Elementary analysis (C ₂₈ H ₃₂ N ₄ O ₅ Cl ₂ ):

hold. : C, 58.42; H, 5.61; N. 9.73

found: C, 58.21; H, 5.58; N. 9.66.

Example 8

 N (3,4-dichlorobenzo.yl) -Glu-DNle-Tryptamine

 8A: synthesis of ZGlu (OBzl) -DNle-Tryptamine

 The derivative 8A (Z-Glu (OBzl) -DNle-Tryptamine, 0.868 g) was prepared from BOC-DNle-Tryptamine (0.8 g) by the method previously described for the preparation of 5B.

 8A:

mp 90-93ºC; [α] _D : + 8.5 (c 1 DMF); Rf: 0.70 (EtOAc / Hexane: 7/3).

Elementary analysis (C ₃₆ H ₄₂ N ₄ O ₆ ):

hold. : C, 68.98; H, 6.77; N, 8.94

found: C, 68.72; H. 6.68; N, 8.81.

8B: synthesis of N (3,4-dichlorobenzoyl) -Glu-DNle-Tryptamine

(example 8).

The product 8B or example 8 (0.497 g) was obtained from intermediate 8A (0.75 g) by the method previously described for the synthesis of 5C. 8B:

mp 105-110ºC; [α] _D : + 28.1 (c 1 DMF); Rf: 0.75 (CHCl ₃ , MeOH. HAC:

85/10/15).

Elementary analysis (C ₂₈ H ₃₂ N ₄ O ₅ Cl ₂ ):

hold. : C, 58.42; H, 5.61; N, 9.73

found: C, 58.32; H, 5.48; N, 9.62.

Example 9

 N (3,4-dichlorophenylacteyl) -DGlu-DNle-Tryptamine

3,4-dichlorophenylacetic acid (0.250 g; 1 mmol), N-hydroxysuccinimide (0.196 g; 0.95 mmol) are dissolved in 10 ml of DMF at 0 ° C. The reaction medium is stirred at 20ºC for 20 hours then filtered (in order to remove the precipitate of DCU). D-Glu-DNle-Tryptamine (resulting from the hydrogenation of 0.627 g of Z-DGlu (OBzl) -DNle-Tryptamine as described above) dissolved in 5 ml of DMF and DIEA (0.18 ml; 2 mmol) are added successively to the filtrate. The reaction medium is stirred for 20 hours at 20 ° C., then treated with 100 ml of an aqueous IM solution of KHSO ₄ . The precipitate thus formed is isolated by filtration, washed with water (2 X 50 ml), with ether and with hexane, then dried under vacuum over P ₂ O ₅ to give 0.482 g (86%) of product 9.

mp 150-152ºC (dec); [α] _D : + 9.8 (c 1 DMF); Rf: 0.46 [ethyl acetate).

Elementary analysis (C ₂₉ H ₃₄ N ₄ O ₅ Cl ₂ ):

hold. : C, 59.06; H, 5.82; N, 9.50

found: C, 60.69; H, 6.03; N, 9.60. Example 10

 N (3,4-dichlorophenoxyacteyl) -D-Glu-D-Nle-Tryptamine

3,4-dichlorophenoxyacetic acid (0.221 g; 1 mmol), N-hydroxysuccinimide (0.138 g; 1.2 mmol) and DCC (0.196 g; 0.95 mmol) are dissolved in 10 ml of DMF at 0 ° C. The reaction mixture is stirred at 20 ° C for 20 hours, filtered (to remove the precipitate of DCU) and D-Glu-DNle-Tryptamine (from the hydrogenation of 0.627 g of Z-DGlu (OBzl) -DNle- Tryptamine as described above) dissolved in 5 ml of DMF is added thereto, followed by DIEA (0.18 ml). After 20 hours at 20 ° C. 100 ml of an IM solution of KHSO ₄ is added to the reaction medium; the precipitate thus formed is isolated by filtration, washed with water (2 × 50 ml), with ether and with hexane and dried under vacuum to give 0.471 g of product 10 (82%).

mp 105-108ºC; [α] _D : + 2.0 (c 1.04 DMF); Rf: 0.52 (ethyl acetate).

Elementary analysis (C ₂₉ H ₃₄ N ₄ O ₆ Cl ₂ ):

hold. : C, 59.50; H. 5.67; N. 9.25

found: C, 59.32; H, 6.64; N. 9.10.

Example 11

 U (2-naphthylacetyl) -D-Glu-D-Nle-Tryptamine

Le produit 11 (0.429 g) a été préparé à partir de l'acide 2-naphtylacétique (0.186 g) selon la méthode préalablement décrite pour la préparation de l'exemple 9.

Product 11 (0.429 g) was prepared from 2-naphthylacetic acid (0.186 g) according to the method previously described for the preparation of Example 9.

11:

mp 138-140ºC (dec); [α] _D : + 11.4 (c 0.98 DMF); Rf: 0.37 (CHCl ₃ , MeOH, HAC: 120/10/5)

Elementary analysis (C ₃₃ H ₃₈ N ₄ O ₅ .2H ₂ O):

hold. : C. 65.34; H, 6.99; N. 9.23

found: C, 65.80; H, 6.49; N, 9.49.

Example 12

 N (1-naphthylacetyl) -DGlu-DNle-Tryptamine

Product 12 (0.461 g) was prepared from 1-naphthylacetic acid (0.186 g) according to the method previously described for the preparation of Example 9.

12:

mp 125-130ºC (dec); [α] _D : + 6.6 (c 0.96 DMF); Rf: 0.38 (CHCl ₃ , MeOH, HAC: 120/10/5)

Elementary analysis (C ₃₃ H ₃₈ N ₄ O ₅ .2H ₂ O):

hold. : C, 65.34; H, 6-99; N, 9.23

found: C. 65.15; H, 6.56; N, 10.80.

Example 13

 N (1-naphthoyl) -DGlu-DNle-Trypttmine

Le produit 13 (0.402 g) a été préparé à partir de l'acide 1-naphtoïque (0.172 g) selon la méthode précédemment décrite pour la préparation de

Product 13 (0.402 g) was prepared from 1-naphthoic acid (0.172 g) according to the method previously described for the preparation of

9.

13:

mp 150ºC (dec); [α] _D : + 2.5 (c 1.02 DMF); Rf: 0.25 (CHCl _3. MeOH,

HAC: 120/10/5)

Elementary analysis (C ₃₂ H ₃₆ N ₄ O ₅ .2H ₂ O):

hold. : C. 64.83; H. 6.81; N. 9-45

found: C, 64.32; H. 6.55; N. 9.82.

Example 14

 N (2-naphthoyl) -DGlu-DNle-Tryptamine

 Example 14 (0.428 g) was prepared from 2-naphthoic acid (0.172 g) according to the method previously described for the preparation of Example 9.

14:

ap 120ºC (dec); [α] _D : - 5.5 (c 1 DMF); Rf: 0.25 (CHCl ₃ , MeOH. HAC

120/10/5)

Elementary analysis (C ₃₂ H ₃₆ N ₄ O ₅ .2H ₂ O):

hold. : C, 64.83; H, 6.81; N, 9.45

found: C. 64.28; H. 6.55; N. 9.76. Evaluation of the gastric anti-secretory effect in vitro:

The isolated stomach of mice allows the in vitro pharmacological study of substances stimulating or inhibiting gastric secretion independently of the influence which the vagus nerve exerts on the fundic glands. (Burice K.T., Parsons M.E., J. Physiol. 1976; 258: 453-465; Szelenyi I., Thiemer K., Pharmacology 1979; 10: 315-322)

The anti-secretory activity of the compounds was measured on the secretion of H ions whose parietal cells were stimulated by Pentagastrin. For these purposes, SWISS male mice weighing between 20 and 28 g, fed 24 hours before the experiment with a 10% liquid solution of wheat germ are anesthetized with urethane (1.8 g / kg at a rate of 10 ml / kg). After median laparotomy, the stomach is catheterized at the level of the cardia and the pylorus then immediately immersed in a bath (100 ml) of buffered survival (NaCl: 113 mM, KCl: 5 mM. CaCl ₂ : 2.5 mM. Mg SO ₄ : 1.2 mM, Glucose: 5.6 mM) maintained at 37 ° C and oxygenated with Carbogen. The gastric lumen is perfused at a constant rate of 1 ml / min in the physiological direction with an unbuffered solution (NaCl: 141.2 mM, KCl: 5 mM, CaCl ₂ : 2.5 mM, MgSO ₄ : 1.2 mM, Glucose: 5.6 mM) maintained at 37ºC and gasified by a flow of O ₂ . The pH of the serosal and xaucosal solutions are 7.4 and 6.5 respectively.

The acidity of the effluent is measured continuously by pH-metry; the optimal distension of the stomach is ensured by the perfusion system which maintains an intragastric pressure of 12 cm of water.

After a stabilization period of 15 to 20 min, the product tested, at the chosen dose or the vehicle solvent (NaOH 0.02 N) is introduced into the bath in a volume not exceeding 0.5 ml; 20 min later, Pentagastrin at a dose of 10 M is administered under the same conditions (t = 0). The latter causes stimulation of the acid secretion with a peak situated in the interval of 15 min following the start of the stimulation. The secretion of H ⁺ ions is expressed according to the maximum concentration peak (μmol / l), obtained under stimulation with Pentagastrin (the basal value being deduced). The results of the treated batches are expressed in% of variation compared to the control batch (Pentagastrine only).

The results obtained are listed in the table below.

In brackets: number of animals

 Statistics according to Wilcoxon test: * P = 0.055. ** P = 0.0065

Conclusion:

As a result, the above-mentioned products are capable, in vitro, of antagonizing the effects of Pentagastrin on the parietal cells.

Evaluation of the Anti-ulcer effect:

One of the most commonly used models of acute experimental ulcers is ingestion of Ethanol. Ethanol is a necrotizing agent which weakens the "gastric mucosal barrier" by altering its defensive factors: hyperemic lesions of the fundic mucosa are histologically associated with cytolysis of the epithelium accompanied intra-mucosal hemolysis.

 The method is adapted from that of Robert et al. (Gastroenterology. Vol.

77. Pages 433-443. 1979).

Mixed NMRI mice weighing between 22 and 25 g subjected to a 24-hour hyric diet are used.

At t = 0, the products which are the subject of this patent are administered per os by gavage, in solution in 0.02 N NaOH (constituting the vehicle solvent), at a rate of 10 ml / kg.

For control batches, the vehicle solvent (Placebo) is administered alone, under the same conditions.

30 min after administration of the product at the chosen dose, or of the placebo, 95% ethanol is administered to the animals per os by gavage, at a rate of 10 ml / kg.

An hour later the animals are sacrificed and the stomachs are quickly removed, opened according to the great curvature and rinsed under a stream of clear water.

Then these are spread out and the gastric lesions are quantified thanks to a digital image analysis system. The system calculates, for each stomach, the total ulcerated surface and reports it to the total surface of the stomach: this defines the ulceration index which is used to calculate the percentage of variation of the treated batches compared to the control batches.

The results obtained are listed in the table below.

In brackets: number of animals

Statistics according to Wilcoxon test: * P = 0.0046, ** P = 0.0010

The present invention also relates to medicaments consisting of at least one compound of formula (I) in the pure state or in the form of a composition in which it is associated with any other pharmaceutically compatible product, which may be inert or physiologically active. The medicaments according to the invention can be used orally, parenterally, rectally or topically.

As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, cachets) or granules can be used. In these compositions, the active principle according to the invention is' mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon. These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.

As liquid compositions for oral administration, use may be made of pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin. These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.

The sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents, can be used. These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating agents into the composition sterilants, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

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

In human therapy, the compounds according to the invention are particularly useful for the treatment and prevention of disorders associated with CCK in the nervous system and the gastrointestinal system. These compounds can therefore be used in the treatment and prevention of psychoses, anxiety disorders, Parkinson's disease, tardive diskinesia, irritable bowel syndrome, acute pancreatitis, ulcers and intestinal motility disorders. certain tumors of the lower esophagus, colon and intestine, as a potentiator of the analgesic activity of narcotic and non-narcotic analgesic drugs and as a regulator of appetite.

The doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 0.05 g and 1 g per day orally for an adult with unit doses ranging from 10 mg to 500 mg of active substance.

In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated. The following examples illustrate compositions according to the invention: Example A

 Using the usual technique, capsules containing 50 mg of active product having the following composition are prepared:

 - N (3,4 dichlorobenzoyl) -D-Glu-D-Nle-Tryptamine ................................ ........ 50 mg

- cellulose ................................................ ........................................ .......... ...... 18 mg

- lactose ................................................ ........................................ .......... ....... 55 mg

- colloidal silica ............................................... .......................................... 1 mg

- sodium carboxymethyl starch ............................................... ....... ......... 10 mg

- talc ................................................ ........................................ .......... ............ 10 mg

- magnesium stearate .............................................. ........................... 1 mg

Example B

 Tablets dosed with 50 g of active product having the following composition are prepared, according to the usual technique.

 - N (3,4 dichlorobenzoyl) -D-Glu-g-D-Nle-des-amino-Tryptophan .. 50 mg

- lactose ............................. ................... ................................ .................. ............. 104 mg

- cellulose ................................................ .................................................. ............. 40 mg

- polyvidone ................................................ .................................................. ............. 10 mg

- sodium carboxymethyl starch ............................................... ............................. 22 mg

- talc ................................................ ............................................. ..... ..................... 10 mg

- magnesium stearate .............................................. .................................... 2 mg

- colloidal silica ............................................... .................................................. . 2 mg

- mixture of hydroxymethylcellulose, glycerin, titanium oxide

 (72-3.5-24.5) q.s.p. 1 film-coated tablet finished at 245 mg.

Example C

 A solution for injection containing 10 mg of active product having the following composition is prepared:

 - N (3,4 dichlorobenzoyl) -D-Glu-D-Nle-Tryptamine ................................ ................ 50 mg

- benzoic acid ............................................... .................................................. 80 mg

- benzyl alcohol ............................................... .................................................. 20.06 cm ³

- sodium benzoate .............................................. ................................................. 80 mg

- 95% ethanol ............................................. .................................................. ...... 0.4 cm ³

- sodium hydroxide.............................................. ................................................ 24 mg - propylene glycol............................................... .................................................. ... 1.6 cm ³

- water ................................................ .................................................. ....................... qs 4 cm ³

Claims

1. New pseudopeptide derivatives of general formula (I)

in which,  Z represents a phenyl, benzyl, indanyl, cycloalkyl, polycycloalkyl, indolylalkyl, naphthyl, naphthylmethyl, phenoxy methyl, naphtoxymethyl radical, optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio radicals, R ₁ represents (CH ₂ ) _n CO ₂ H in which n is between 1 and 5, R ₂ represents an alkyl radical, branched or linear, X represents -NH- or -CO-,  Y represents -NH- or -CO-, it being understood that X and Y are different from each other,  Z 'represents a hydrogen atom, or a methyl radical, Z "represents a hydrogen atom or CO ₂ R ₃ or NHCO ₂ R ₃ , it being understood that if Y = NH, Z" cannot be NHCOR ₃ and that if Y = CO, Z "cannot be COR ₃ , R ₃ represents an alkyl, cycloalkyl, polycycloalkyl, phenyl radical, optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, alkylthio and nitro radicals, _and their physiologically acceptable salts. 2. Pseudopeptides according to claim 1, characterized in that Z represents a 3,4-dichlorophenyl radical. 3. Pseudopeptides according to one of claims 1 and 2, characterized in that R ₁ represents (CH ₂ ) ₂ CO ₂ H,  4. Pseudopeptides according to one of claims 1 to 3, characterized in that R_ represents a butyie radical, linear or branched.  5. Pseudopeptides according to one of claims 1 to 4, characterized in that Z 'and Z "each represent a hydrogen.  6. Pseudopeptides according to one of claims 1 to 5, characterized in that X represents -CO- and Y represents -NH-.  7. Pseudopeptides according to one of claims 1 to 5, characterized in that X represents -NH- and Y represents -CO-.  8. Pseudopeptides according to one of claims 1 to 7, characterized in that they correspond to formula (I) in which the asymmetric centers of the carbons linked to the substituents R. and R. are of configuration D.  9. Process for preparing the compounds of formula (I) according to one of claims 1 to 8, characterized in that an amino derivative of formula II is reacted

in which R-, X, Y, Z 'and Z "have the same meanings as in claim 1 and in which R' ₁ is equivalent to R ₁ or is an esterified form of R ₁ , on an acid of formula (III ) or a derivative of this acid,

wherein Z has the same meanings as in claim 1, followed by hydrolysis of the ester represented by R ' ₁ when R' ₁ is an esterified form of R ₁ .  10. Pharmaceutical compositions containing, as active ingredients, a pseudo-peptide of formula (I) according to one of claims 1 to 8, in combination with an acceptable pharmaceutical vehicle.  11. Use of a pseudopeptide of formula I according to one of claims 1 to 8 for the manufacture of a medicament intended for the treatment of duodenal ulcers.  12. Use of a pseudopeptide of formula I according to one of claims 1 to 8 for the manufacture of a medicament intended for the treatment of gastric ulcers.  13. Use of a pseudopeptide of formula I according to one of claims 1 to 8 for the manufacture of a medicament for the treatment of Zollinger-Ellison syndrome.  14. Use of a pseudopeptide of formula I according to one of claims 1 to 8 for the manufacture of a medicament for the treatment of gastro-duodenal bonds linked to stress.  15. Use of a pseudopeptide of formula I according to one of claims 1 to 8 for the manufacture of a medicament intended for the treatment of esophagitis by gastroesophageal reflux.