FR2609717A1 - New tetrapeptides, process for preparing them and the new intermediates thus obtained, their application as medicinal products and compositions containing them - Google Patents

Abstract

The invention relates to new compounds of formula: in which R represents a hydrogen atom or an alkyl radical containing 1 to 5 carbon atoms, X represents a L-phenylalanine, L-tyrosine or L-tryptophan residue, Y an L-histidine, L-arginine or L-lysine residue, U an L-leucine, L-alanine, L-valine or L-isoleucine residue, B represents a pyridyl radical and A a hydrogen atom or a group for protecting the amine functional group of X, in all their possible diastereoisomeric forms as well as their addition salts with acids. The subject of the invention is also a process for preparing the products of formula I and the new intermediates thus obtained, their application as medicinal products and compositions containing them.

Description

 The present invention relates to new tetrapeptides, a process for their preparation, their application as medicaments, the compositions containing them and the new preparation intermediates obtained.

dans laquelle R représente un atome d'hydrogéne ou un radical alcoyle renfermant de 1 à 5 atomes de carbone, X représente un résidu de
L-phénylalanine, de L-tyrosine ou de L-tryptophane, Y un résidu de
L-histidine, de L-arginine ou de L-lysine, U un résidu de L-leucine, de
L-alanine, de L-valine ou de L-isoleucine, B représente un radical pyridinyle et A un atome d'hydrogéne ou un groupement protecteur de la fonction amine de X, sous toutes leurs formes diastéréoisomères possibles ainsi que leurs sels d'addition avec les acides
Dans la formule (I) donnée ci-dessus, B peut être un radical 2-pyridinyle, 3-pyridinyle ou 4-pyridinyle.The subject of the present invention is the compounds of formula (I)

in which R represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms, X represents a residue of
L-phenylalanine, L-tyrosine or L-tryptophan, Y a residue of
L-histidine, L-arginine or L-lysine, U a residue of L-leucine,
L-alanine, L-valine or L-isoleucine, B represents a pyridinyl radical and A a hydrogen atom or a group protecting the amine function of X, in all their possible diastereoisomeric forms as well as their addition salts with acids
In the formula (I) given above, B can be a 2-pyridinyl, 3-pyridinyl or 4-pyridinyl radical.

 When R is an alkyl radical, it is in particular a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl radical.

 R is preferably an isopropyl radical.

 By protective group A of the amino function is meant a group which can be easily removed, for example, by hydrolysis or reduction.

 Radicals which are capable of effectively protecting an amino radical are generally acid radicals, for example an acid radical derived from an aliphatic, aromatic, araliphatic or heterocyclic carboxylic acid such as acetic acid, benzoic acid or the pyridine-carboxylic acid or an acid radical derived from a carbonic acid such as The ethoxy-carbonyl, benzyloxycarbonyl (= Z), tert-butyloxy-carbonyl (= Boc), p-metryloxy-benzyloxy-carbonyl, fluorenyl methoxy carbonyl ( = FMOC), a phthalimido radical or an acyl radical deriving from a sulfonic acid such as the benzenesulfonyl or p-toluenesulfonyl radical, but it is also possible to use other radicals such as substituted or unsubstituted aryl or aralkyl radicals, for example the benzyl and triphenylmethyl radicals or radicals such as o-nitrophenyl sulfenyl and 2-benzoyl1-methylvinyl radicals.

 The addition salts with mineral or organic acids can be, for example, the salts formed with hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, acetic, propionic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric acids. , oxalic, glyoxylic, aspartic, alkanesulfonic such as methanesulfonic acid and arylsulfonic, such as benzene sulfonic acid.

The invention relates in particular to the compounds of formula (I) in which the carbon in position (5) of the tetrahydrofuranic ring is in configuration (S), as well as their addition salts with acids and those in which R represents a d atom hydrogen, B a 2-pyridinyl radical and A a tert-butyloxy-carbonyl radical (= Boc), as well as their addition salts with acids and very particularly the [5S] CS-fl-fCN-CN-C ( 1,1-dimethylethoxy) carbonyl] L-phenylalanyl3 L-histidyl3aminol 3-methylbutyl3 2-oxo tetrahydro 3-furanyl carbonyl]
N- (2-pyridinylmethyl) L-isoleucinamide.

 The invention also relates to a process for the preparation of the compounds of formula (I).

In the process given below, a three-letter abbreviation is used to designate the alpha amino carboxylic acids U, X and Y according to the IUPAC nomenclature, the rules of which are published in particular in
Biochem. J. (1972) 126, 773-780.

 The following symbols have therefore been used to designate the alpha amino carboxylic acids.

dans toutes les formes énantiomères et diastéréoisomères possibles et dans laquelle A1 est un groupement protecteur de la fonction amine, à
L'action d'un malonate de formule CH2-CCOOR')2, R' étant un radical alcoyle renfermant de 1 à 5 atomes de carbone, pour obtenir un composé de formule III::

dans toutes les formes énantiomères et diastéréoisoméres possibles, dont on sépare éventuellement les diastéréoisomères et que l'on soumet éventuellement à un- halogénure d'alcoyle X1-RA, X1 étant un atome d'halogène et RA un radical alcoyle renfermant de 1 à 5 atomes de carbone pour obtenir un composé de formule IIIA dans laquelle RA est un radical alcoyle renfermant de 1 à 5 atomes de carbone :

et que L'on saponifie les composés de formule III ou IIIA, pour obtenir un acide de formule IV :

dans laquelle R est un atome d'hydrogène ou un radical alcoyle renfermant de 1 à 5 atomes de carbone, sous toutes les formes énantiomères et diastéréoisomères possibles, que l'on condense avec un composé de formule V ::
U-NH-CH2 B V dans laquelle B est un radical pyridinyle et U représente L-Leu, L-ile,
L-ala ou L-val, pour obtenir un compose de formule VI :

sous toutes Les formes diastéréoisomères possibles, dont on élimine le groupement protecteur A1 de la fonction amine et que l'on condense avec un acide alpha-amino carboxylique Y représentant L-His, L-Arg ou
L-Lys, dont la fonction amine est protégée par un groupement A2, pour obtenir un composé de formule VII ::

sous toutes les formes diastéréoisomères possibles, dont on élimine le groupement protecteur A2 de la fonction amine de Y et que l'on condense avec un acide alpha-amino carboxylique X représentant
L-Phe, L-Tyr ou L-Trp, dont la fonction amine est protégée par un groupement A, pour obtenir un composé de formule (I) dont on élimine, si désiré, le groupement protecteur A de la fonction amine de X, dans toutes les formes diastéréoisomères possibles, et que l'on traite si désiré avec un acide minéral ou organique pour en former le sel.Phe: phenylalanine
Tyr: tyrosine
Trp: tryptophan
His: histidine
Arg: arginine
Lily: lysine
Leu: Leucine
Island: Isoleucine
Ala: Alanine
Val: Valine
This process is characterized in that a compound of formula II is subjected

in all possible enantiomeric and diastereoisomeric forms and in which A1 is a protective group for the amine function, with
The action of a malonate of formula CH2-CCOOR ') 2, R' being an alkyl radical containing from 1 to 5 carbon atoms, to obtain a compound of formula III:

in all possible enantiomeric and diastereoisomeric forms, from which the diastereoisomers are optionally separated and which are optionally subjected to an alkyl halide X1-RA, X1 being a halogen atom and RA an alkyl radical containing from 1 to 5 carbon atoms to obtain a compound of formula IIIA in which RA is an alkyl radical containing from 1 to 5 carbon atoms:

and that the compounds of formula III or IIIA are saponified, to obtain an acid of formula IV:

in which R is a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms, in all the possible enantiomeric and diastereoisomeric forms, which is condensed with a compound of formula V:
U-NH-CH2 BV in which B is a pyridinyl radical and U represents L-Leu, L-ile,
L-ala or L-val, to obtain a compound of formula VI:

in all possible diastereoisomeric forms, from which the protective group A1 of the amine function is eliminated and which is condensed with an alpha-amino carboxylic acid Y representing L-His, L-Arg or
L-Lys, whose amine function is protected by an A2 group, to obtain a compound of formula VII:

in all possible diastereoisomeric forms, from which the protective group A2 of the amine function of Y is eliminated and which is condensed with an alpha-amino carboxylic acid X representing
L-Phe, L-Tyr or L-Trp, the amine function of which is protected by a group A, to obtain a compound of formula (I) from which the protective group A of the amine function of X is removed, if desired in all possible diastereoisomeric forms, and which are treated if desired with a mineral or organic acid to form the salt.

 In a preferred embodiment of the process of the invention: - The protective groups A1 and A2 can be chosen from the list given above for A.

- The malonate which reacts with the compound of formula II is ethyl malonate.

The reaction is carried out in the presence of a base which is preferably
sodium hydride. Other bases can also be used such as, for example, potassium hydride, alcoholates or alkali metal hydroxides.

- The alkyl halide X1-RA is preferably isopropyl iodide. Its additive reaction on the compound of formula III is carried out in the presence of sodium hydride.

- The saponification of the compounds of formulas III and IIIA is carried out by
Sodium hydroxide.

- The agents for unblocking amino functions are variable depending on the protective group used.

 When the protective group A1, A2 or A is the BOC group, the release is carried out by acid hydrolysis, in particular in the presence of hydrochloric acid. Trifluoroacetic acid can also be used. The reaction is carried out in solvents such as ether, methylene chloride.

Catalytic hydrogenation is used when the protecting group
A1, A2 or A is the group Z.

- The condensation of the acid of formula IV with the amine function of the product of formula V and of the amino acids Y or X, the amine functions of which are protected by a group A2 or A respectively with the compounds of formula VI or VII for which A1 and A2 = H, is carried out using 1-ethyl 3- (3-dimethyl aminopropyl) carbodiimide or dicyclohexylcarbodiimide activated by 1-hydroxy benzotriazole.

 The reaction is carried out in the presence of a base such as Nmethylmorpholine, N-ethylmorpholine or triethylamine. The activation of the carboxyl function of the acid of formula IV and of the amino acids Y or X can also be done in the form of a mixed anhydride using for example isobutyl chloroformate, or in the form of an ester N-hydroxy succinimide.

- The diastereoisomers are separated by usual methods.

 In particular, the two diastereoisomers of formula III are separated in which the carbon in position (5) of the tetrahydrofuran ring is in (S) or (R) configuration by chromatography.

 The compounds of formula (I) as defined above, as well as their addition salts with acids have interesting pharmacological properties. They present, in particular, very interesting inhibitory properties of human plasma renin.

These properties justify their application in therapy and
A subject of the invention is also, as medicaments, the products as defined by formula (I) above, as well as the addition salts with pharmaceutically acceptable acids of said products of formula (I).

The subject of the present invention is very particularly, as medicaments: -5S3 fS-C1-CCN-CN- (1,1-dimethylethoxy) carbonyl L-phenylalanyl]
L-histidylamino] 3-methylbutyL 2-oxo tetrahydro 3-furanyl] carbonyl]
N- (2-pyridinylmethyl) L-isoleucinamide as well as its addition salts with pharmaceutically acceptable acids.

 The medicaments which are the subject of the invention are useful in all diseases linked to a hypersecretion of renin, in particular in arterial hypertension and in hyperaldosteronism.

 The invention extends to pharmaceutical compositions containing, as active principle, the medicaments defined above.

 These pharmaceutical compositions can be administered by the oral, rectal, parenteral or local route by topical application to the skin and mucous membranes.

 These compositions can be solid or liquid and can be presented in the pharmaceutical forms commonly used in human medicine such as, for example, simple or coated tablets, capsules, granules, suppositories, injectables, ointments, creams, gels and aerosol preparations; they are prepared according to the usual methods. The active principle can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

 The dosage varies in particular depending on the route of administration, the condition treated and the subject concerned.

 For example in adults, it can vary between 0.001 to 10 mg / kg of body weight per day and more particularly between 0.01 to 1 mg / kg.

The products of formula III and 111A in which A1 is a protective group and of formula VI and VII in which A1 and
A2 represent a protective group which can be replaced by a hydrogen atom, are new chemicals.

 The subject of the invention is therefore these products as new industrial products, in particular as intermediate products, necessary for the implementation of the process of the invention.

 The starting product of formula II for which A1 = Z is described in European patent 0143746.

 The one for which A1 = Boc is described in European patent 0172347.

 The starting materials of formula II are prepared by the methods described in these two patents.

The following examples illustrate the invention, without, however,
Limit.

 Example 1: [5S] [[5- [1 - [[N- [N - [(1,1-dimethylethoxy) carbonyl L-phnylalanyl] L-histidyl] amino] 3-methytbutyl] 2-oxo tetrahydro 3- furanyl] carbonyl] N- (2-pyridinyLmethyL) L-isoleucinamide.

Stage A: C5S (S *) + 5R (S *) 5- [1 - [[1,1-dimethyl ethoxy) carbonyl amine 3-methylbutyl] 2-oxo tetrahydro furan 3-carboxylate.

 Stirred for 2 hours 1.05 g of sodium hydride in 40 cm3 of tetrahydrofuran, 6.62 cm3 of ethyl malonate added dropwise, then 4 g of mixture 1S (S *) + 1S (R *) 3 -methyl 1- (2-oxiranyl) butyl carbamate (1,1-dimethyl ethyl) (described in European patent 172 347) dissolved in 40 cm3 of tetrahydrofuran, also added dropwise. The mixture is stirred at reflux of tetrahydrofuran for approximately 14 hours and the reaction is hydrolyzed by the addition of 1 cm 3 of a saturated solution of ammonium chloride. The tetrahydrofuran is eliminated, the residue is taken up in ethyl acetate, washed with water, with a saturated solution of sodium chloride, dried, and ethyl acetate is eliminated.

 The 10 g of crude product thus obtained is purified by chromatography on silica (eluent: hexane 8 - ethyl acetate 2).

 4.04 g of 5 S isomer (S *) having an Rf of 0.56 and 0.6 g of a mixture of 5 S isomer (S *) and 5 R isomer (S *) are thus obtained. ) with an Rf of 0.54.

Stage B: ES S (S *) acid 5 - [1 [[((1,1-dimethylethoxy) carbonyl amine 3-methylbutyl] 2-oxo tetrahydro furan 3-carboxylic.

 2.7 g of product obtained in Stage A are introduced into 45 cm3 of ethanol and 6.13 cm3 of 2N sodium hydroxide, stirred for approximately 14 hours, acidified to pH 3 with hydrochloric acid "N", extracted with 3 times 50 cm3 of ether. The organic phase is washed with a saturated sodium chloride solution until neutral pH, dried, the ether is removed under reduced pressure and 2.4 g of the expected product are obtained.

Stage C: C5 S3 CC5 - E1EC1,1-dimethylethoxy) carbonyl] amine 3-methylbutyl 2-oxo tetrahydro 3-furanyl3 carbonyl N-C2-pyri di nylmethy I)
L-isoleucinamide.

Mix for 15 hours at room temperature - 970 mg of N - (2-pyridinylmethyl) L-isoleucinamide hydrochloride
prepared as indicated in the European patent MERCK 0081783, - 15 cm 3 of methylene chloride, - 1.19 cm 3 of N-ethyl morpholine, - 670 mg of 1-hydroxy benzotriazole, - 1.04 g of product obtained in stage B, - 690 mg of 1-ethyl 3- (3-dimethyl amino propyl) carbodi imide hydrochloride.

 Then distilled to dryness under reduced pressure, purified the product obtained by chromatography on silica (eluent: methylene chloride 9-methanol 1) and collected 1.26 g of an oil having an Rf of 0.45.

Stage D: [5 S [[5-C1 [[N - [(1,1-dimethylethoxy] carbonyl
L-tistidylamino 3-methylbutyl] 2-oxo tetrahydro 3-furanyl3 carbonyl)
N- (2-pyridinylmethyl) L-isoleucinamide.

- unlocking:
1.26 g of product obtained in Stage C is dissolved in 40 cm3 of methylene chloride, cooled to +5 C, and a stream of hydrochloric acid is bubbled for 10 minutes.

 Distilled to dryness under reduced pressure, added ether, drained and 1.26 g of deblocked product C is obtained.

- condensation:
The procedure is carried out in the same manner as in Stage C from 1.26 g of unblocked product obtained above in 30 cm 3 of methylene chloride, of 1.4 cm 3 of ethyl morpholine, of 486 mg of 1-hydroxy benzotriazole, 674 mg Boc-L. Histidine and 504 mg of 1-ethyl 3-C3-dimethylamino propyl) carbodiimide. 600 mg of a colorless oil having a
Rf. 0.3 by chromatography on silica (eluent: methylene chloride 9-methanol 1).

Stage E: [5S] [[5- [1 - [[N- [N - [(1,1-dimethylethoxy) carbonyl) L-phenylalanyl] L-histidyl) amino) 3-methylbutyl) 2-oxo tetrahydro 3 furanyl) carbonyl) N-C2-pyridinylmethyl) L-isoleucinamide.

- unlocking:
The amino function of the product obtained in stage D is unblocked in the same way as for the product obtained in stage C. 700 mg of unlocked product D are obtained.

- condensation
The procedure is carried out in the same way as in stage D from 700 mg of product D released, 30 cm3 of methylene chloride, 3 cm3 of ethyl morpholine, 162 mg of 1-hydroxy benzotriazole, 225 mg of Boc Lphenylalanine, and 245 mg of 1-ethyl 3- (3-dimethylamino propyl) carbodi imide.

 350 mg of expected product is obtained.

Analysis:
CX HX NX
Calculated 62.8 7.3 13.9
Found 62.8 7.5 13.5
Example 2:
CS-fl-CtN-CN-C (1,1-dimethylethoxy) carbonyl L-phenylalanyl3
L-histidyl] amino] 3-methylbutyl] 3- (1-methylethyl) 2-oxo tetrahydro 3-furanyl] carbonyl] N- (2-pyridinylmethyl) L-isoleucinamide.

Stage A: [5S (S *)] [5- [1 - [[(1,1-dimethylethoxy) carbonyl amine 3-methylbutyl] 3- (1-methylethyl) 2-oxo tetrahydrofuran 3-carboxylate.

 3 g of product obtained in Stage A of Example 1 dissolved in 20 cm 3 of tetrahydrofuran are stirred for 1 hour at room temperature over 310 mg of sodium hydride in 15 cm 3 of tetrahydrofuran.

 Then added 4.4 cm3 of isopropyl iodide, heated to 50 ° C. for 25 hours, added 0.88 cm3 of isopropyl iodide, heated to 50 ° C. for another 4 hours, cooled to room temperature, then added 15 cm3 of an aqueous solution of citric acid at 10 X.

 The tetrahydrofuran is removed, the aqueous phase is extracted with ether, the ethereal phase is washed with water, dried, the ether evaporated.

 3.35 g of crude product are obtained which are purified by chromatography on silica (eluent: hexane 85 - ethyl acetate 25). 1.8 g of expected product are obtained having an Rf of 0.23.

Stage B: [5S (S *)] 5 - [1 - [[1,1-dimethylethoxy) carbonyl amine 3-methylbutyl] 3- (1-methylethyl) 2-oxo tetrahydrofuran 3carboxylic acid.

 The operation is carried out as indicated in stage B of example 1 from 1.43 g of product obtained in the preceding stage in 20 cm3 of ethanol, and 2.78 cm3 of 2N sodium hydroxide.

 1.3 g of expected product with an Rf are obtained. 0.1 by chromatography on silica (eluent: methylene chloride 9-methanoL 1).

Stage C: [5S [[5- [1 - [[1,1-dimethylethoxy) carbonyl amino3 3-methylbutyl] 3-C1-methylethyl 2-oxo tetrahydro 3-furanyl] carbonyl] N- (2-pyridinylmethyl) L- isoleucinamide.

The procedure is carried out as indicated in stage C of Example 1 from 1 g
N- (2-pyridinylmethyl) L-isoleucinamide hydrochloride of 1 cm3
ethyl morpholine, 459 mg of 1-hydroxybenzotriazole, 1 g of
product obtained in Stage B, 700 mg of 1-ethyl 3- (3-dimethylaminopropyl) carbodiimide hydrochloride.

1.4 g of an oil are collected having an Rf of 0.4 in
chromatography on silica (eluent: methylene chloride 9-methanol: 1).

Stage D: [5S] [[5- [1 - [[N - [(1,1-dimethylethoxy) carbonyl
L-histidyl] amino] 3-methylbutyl] 3-Ci-methylethyl) 2-oxo tetrahydro 3-furanyU carbonyl N- (2-pyridinylmethyl) L-isoleucinamide.

- unlocking:
The operation is carried out as indicated in stage D of Example 1 from 1.4 g of product obtained in stage C and 1.35 g of product C is released.

- condensation:
The operation is carried out as indicated in stage C of Example 1 from 1.35 g of product C released, 50 cm3 of methylene chloride, 1 cm3 of ethyl morpholine, 405 mg of 1-hydroxybenzotriazole, of 689 mg of Boc Histidine and 575 mg of 1-ethyl 3- (3dimethylamino propyl) carbodiimide hydrochloride.

 1.26 g of expected product is obtained having an Rf of 0.4 by chromatography on silica (eluent: methylene chloride 95 methanol 5).

Stage E: CS-C1-CCN-CC (1,1-dimethylethoxy) carbonyl L-phenylalanyl L-histidyl3aminol 3-methylbutyl3 3- (1-methylethyl) 2-oxo tetrahydro 3-furanyl) carbonyl N- (2-pyridinylmethyl ) L-isoleucinamide.

- unlocking
The operation is carried out as indicated in stage D of Example 1 from 1.26 g of product obtained in stage D and 1g of product D released.

- condensation:
The procedure is carried out in the same way as in Stage E of Example 1, starting with 1 g of product D released, 50 cm3 of methylene chloride, 1 cm3 of ethylmorpholine, 292 mg of 1-hydrobenzotriazole, 556 mg of Boc phenylalanine and 460 mg of 1-ethyl 3 (3-dimethylamino propyl) carbodiimide hydrochloride. 900 mg of expected product is obtained in the form of a colorless oil.

Analysis
C% H% N%
Calculated 63.9 7.6 13.2
Found 63.4 7.8 13.1
Pharmacological study:
Measurement of anti-renin activity in vitro:
The measurement of renin activity is based on the radioimmunoassay technique of Haber et al (New England Nuclear, Angiotensin I, radioimmunoassay kit, reference NEA-022) which measures the activity of the primary product of renin, l angiotensin I. The measurement of anti-renin activity is therefore based on the ability of the products to inhibit the production of angiotensin I in vitro.

 Tests are carried out with human venous blood as a source of renin. The blood is collected in cooled tubes containing EDTA. Centrifuge, collect the plasma and store it at -20nC.

For the test, 1 ml of thawed plasma is added to 2 ml of Tris-HCl buffer (pH 7.4) at O-4 C containing 8-hydroxy quinoline, dimercaprol and EDTA, respectively at final concentrations 0.02 X, 0.005 X and 0.1 mM. The rest of the method is the same as that described by the manufacturers of the assay kit for angiotensin I by radioimmunoassay.

 After mixing the plasma and the buffer at 0-4riC, a 1 ml aliquot is incubated at 37 C for 60 minutes. All the tubes are then placed at 0-4nC and 100 ml of the tubes which have been incubated at 37nC and at 0-4nC are withdrawn for the angiotensin I formation test.

 The renin activity for each sample is evaluated by measuring the difference between the value of angiotensin I formed at 37 C and that existing at 0-4C.

The renin activity values are expressed in ng
Angiotensin I / ml / h. The renin inhibitors are added to the 2 ml of tris-HCL buffer at several concentrations and the controls (100 × activity) are carried out in the presence of solvent (acetic acid).

The results are expressed in molar concentration of the inhibitor necessary to inhibit 50 X (IC50) of the angiotensin I formed in 60 minutes, in comparison with the solvent
The IC50 of the product of Example 1 is 0.65 M.

Reference: Haber E, Koerner T., Page LB Kliman B and Parnode A (1964)
J. Clin. Endocrinal-Metab 29: 1349.

Claims (10)

1 /. Compounds of formula (I):

 in which R represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms, X represents a residue of L-phenylalanine, L-tyrosine or L-tryptophan, Y a residue of L-histidine, L-arginine or L-lysine, U a residue of L-leucine, L-alanine, L-valine or L-isoleucine, B represents a pyridinyl radical and A a hydrogen atom or a group protecting the amine function of X, in all their possible diastereoisomeric forms as well as their addition salts with acids. 2 /. Compounds of formula (I), as defined in claim 1, in which the carbon in position (5) of the tetrahydrofuranic ring is in configuration (S), as well as their addition salts with acids. 3 /. Compounds of formula (I), as defined in claims 1 or 2 in which R represents a hydrogen atom, B a 2pyridinyl radical and A a tert-butyloxy-carbonyl radical (= Boc), as well as Their addition salts with acids. 4 /. [5S] [[5- [1 - [[N- [N - [(1,1-dimethylethoxy) carbonyl L-phenylalanyl] L-histidyl amine 3-methylbutyl] 2-oxo tetrahydro 3-furanyl carbonyl N- (2-pyridinylmethyl) L-isoleucinamide. 5 /. Process for the preparation of the compounds of formula (I), characterized in that a compound of formula II is subjected:

 in all possible enantiomeric and diastereoisomeric forms and in which A1 is a protective group for the amine function, with The action of a malonate of formula CH2-CCOOR ') 2, R' being an alkyl radical containing from 1 to 5 carbon atoms, to obtain a compound of formula III:

 in all possible enantiomeric and diastereoisomeric forms, from which the diastereoisomers are optionally separated and which are optionally subjected to an alkyl halide X1-RA, X1 being a halogen atom and RA an alkyl radical containing from 1 to 5 atoms of carbon to obtain a compound of formula IIIA in which RA is an alkyl radical containing from 1 to 5 carbon atoms:

 and that the compounds of formula III or IIIA are saponified, to obtain an acid of formula IV:

 in which R is a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms, in all the possible enantiomeric and diastereoisomeric forms, which is condensed with a compound of formula V:  U-NH-CH2 B V in which B is a pyridinyl radical and U represents L-leu, L-ile, L-ala or L-val, to obtain a compound of formula VI

 in all possible diastereoisomeric forms, from which the protective group A1 of the amine function is eliminated and which is condensed with an alpha-amino carboxylic acid Y representing L-His, L-Arg or L-Lys, whose amine function is protected by an A2 group, to obtain a compound of formula VII:

 in all possible diastereoisomeric forms, from which the protective group A2 of the amine function of Y is eliminated and which is condensed with an alpha-amino carboxylic acid X representing L-Phe, L-Tyr or L-Trp, the amine function of which is protected by a group A, in order to obtain a compound of formula (I) from which the protective group A of the amine function of X is removed, if desired in all Possible diastereoisomeric forms, which are treated if desired with a mineral or organic acid to form the salt. 6 /. As medicaments, the compounds of formula (I) as defined in claim 1, in all their possible diastereoisomeric forms, as well as their addition salts with pharmaceutically acceptable acids. 7 /. As medicaments, the compounds of formula (I) as defined in claims 2 and 3 as well as their addition salts with pharmaceutically acceptable acids. 8 /. As a medicament, the compound of claim 4. 9 /. Pharmaceutical compositions containing, as active principle, a medicament according to one of Claims 6 to 8. 10 /. As intermediate products, the products of formula III, IIIA or IV in which A1 represents a group protecting the amine function and of formula VI and VII in which A1 and A2 represent a group protecting the amine function which can optionally be eliminated and replaced by a hydrogen atom.