EP0579823A1

EP0579823A1 - New hexapeptidic derivatives, preparation, method and application as medicaments of said new derivatives

Info

Publication number: EP0579823A1
Application number: EP93905388A
Authority: EP
Inventors: Pierre Broto; Gilles Hamon; Eve 825 avenue du Comté-de-Nice MAHE; Dung Le-Nguyen
Original assignee: Roussel Uclaf SA
Current assignee: Sanofi Aventis France
Priority date: 1992-02-12
Filing date: 1993-02-11
Publication date: 1994-01-26
Also published as: FR2687155A1; WO1993016104A1; FR2687155B1; CA2107343A1; JPH06507186A; US5476840A

Abstract

Nouveaux dérivés peptidiques de formule générale (I): X1 X2 X3 Ile X5 X6, dans laquelle X1 représente un hydrogène, un résidu d'histidine, d'acétyl-histidine, ou de D-histidine, X2 représente un résidu d'alanine, de leucine, de tryptophane, de phenylalanine ainsi que leurs homologues en série D, X3 représente un résidu d'alanine, ainsi que son homologue en série D, X5 représente un résidu d'isoleucine, d'alanine, de valine, de norleucine, de leucine et d'acide aspartique ainsi que leurs homologues en série D, X6 représente un résidu de tryptophane, de leucine, d'isoleucine, de norleucine et leurs homologues en série D, procédé de préparation et application à titre de médicaments.New peptide derivatives of general formula (I): X1 X2 X3 Ile X5 X6, in which X1 represents a hydrogen, a residue of histidine, acetyl-histidine, or of D-histidine, X2 represents a residue of alanine, leucine, tryptophan, phenylalanine as well as their D series counterparts, X3 represents an alanine residue, as well as its D series counterpart, X5 represents an isoleucine, alanine, valine, norleucine residue, of leucine and aspartic acid as well as their D-series counterparts, X6 represents a residue of tryptophan, leucine, isoleucine, norleucine and their D-series counterparts, process for preparation and application as medicaments.

Description

New hexapeptide drifts. process for the preparation and application as medicaments of these new derivatives

The present application relates to new hexapep¬ tidic derivatives, the process for the preparation and the application as a medicament of these new derivatives.

It is known that endothelin is a potent vasoconstrictor extracted from aortic endothelium from pigs. This recently isolated peptide contains 21 amino acids, has 2 disulfide bridges and has the formula:

Cys Ser Cys Ser Ser Leu Met Asp Lys Glu Cys - 1 5 10

Val Tyr Phe Cys His Leu Asp Ile Ile Trp

15 20

(- A novel potent vasoconstrictor peptide produced by vascu- lar endothelial cells. M. Yanagisawa, H. Kurihara, S. Kimura, Y. To obe, M. Kobayashi, Y. Mitsui, Y. Yazaki, K. Goto & T. Masaki, Nature, (1988) 332, p. 411-415). This peptide is designated in the following under the name of ET1.

The nomenclature used is that of the IUPAC-IUB commission (1984) European J. Biochem 183, 9-37. This peptide which contains 21 amino acid residues, 2 disulfide bridges is capable of contracting at very low doses the smooth muscle cells (arteries and veins) of different species of mammals (man, dog, cat, pig, guinea pig, rat, rabbit ..). By trying to shorten the chain and replace certain amino acid residues of endothelin -with other amino acids, the Applicant has prepared by synthesis of new hexapeptide derivatives containing only five or six amino acids in which l vasoconstrictor activity has practically disappeared and which moreover present the property of blocking and binding to natural endothelin receptors. The products thus exhibit an activity which will oppose any action of a subsequent release of endothelin. These products also have the advantage of being able to be prepared by total synthesis in large quantities.

The present application thus relates to new hexapeptide derivatives corresponding to the general formula (I):

K _χ x ₂ X ₃ Ile x ₅ X ₆ (I)

in which X ₁ represents a hydrogen atom or a residue of histidine, acetyl-histidine, or D-histidine,

X ₂ represents a residue of alanine, leucine, tryptophane, phenylalanine and their D-series counterparts,

X ₃ represents an alanine residue as well as its D-series counterpart,

X ₅ represents a residue of isoleucine, alanine, valine, norleucine, leucine and aspartic acid as well as their D-series counterparts,

X ₆ represents a residue of tryptophan, leucine, isoleu¬ cine, norleucine and their D-series counterparts

Among the new hexapeptide derivatives, as defined above, there are in particular those characterized in that:

X- ^ represents a hydrogen atom, a residue of histidine or of D-histidine,

X ₂ represents an alanine or leucine residue, as well as their D-series counterparts, X ₃ represents an alanine residue as well as its D-series counterpart,

X ₅ represents an isoleucine residue as well as its D-series counterpart,

X ₆ represents a tryptophan residue, as well as its homolog in series D.

Among the latter, the peptide derivatives are preferably used in which:

X- _j _ represents a hydrogen atom or a histidine residue, X ₂ represents an alanine residue,

X ₃ represents an alanine or aspartic acid residue, X ₅ represents an isoleucine residue,

X ₆ represents a residue of tryptophan or of D-tryptophan. Among the new preferred hexapeptide derivatives of the invention, one more particularly retains one of the following peptide derivatives:

His Ala A at Ile Ile Trp, 1 5

Leu Ala Ile Ile Trp, 1 5

His Leu Ala Ile Ile D Trp, 1 5 Leu Ala Ile Ile D Trp,

1 5

Ala Ala Ile Ile Trp 5 5

Among the new hexapeptide derivatives as defined above, the following peptide derivative is most particularly retained:

His Ala Ala Ile Ile Trp. 1 5

The invention also relates to a process for the preparation of new hexapeptide derivatives as defined above, characterized in that a solid phase synthesis is carried out by sequentially introducing them onto a support of crosslinked polystyrene type. duly protected ino-acids, using a coupling agent, deprotects the amino acids, and releases from the resin the peptide chain thus formed, to obtain the peptide derivative of formula (I) thus sought. Under preferential conditions of implementation, the process described above is characterized in that: the support of the crosslinked polystyrene type is a resin of the "Boc-Trp-CM" type or of the "Boc-D-Trp- type CM "in which Boc is a tert-butyloxycarbonyl group, Trp is a tryptophyl group and D-Trp is a D-tryptophyl group and CM denotes the crosslinked polystyrene support,

the coupling agent is (benzotriazol-1-yloxy) tris (dimethylamino) phosphoniu hexafluorophosphate or Bop,

the release of the support from the peptide chain as well as the deprotection of the amino acids is carried out by means of hydrofluoric acid by operating at low temperature preferably around 0 ° C. The new hexapeptide derivatives which are the subject of the present invention have very interesting pharmacological properties; there is in particular a remarkable practically pure antagonistic effect against hypertension induced by endothelin and an anti-dry effect, the vasoconstrictive activity of endothelin being abolished.

Some of these properties are illustrated later in the experimental part.

These properties justify the use of the new hexapeptide derivatives corresponding to formula (I) above as medicaments.

A subject of the present invention is thus also the application, as medicaments, of the new hexapeptide derivatives as defined by the general formula (I) above. Among the drugs which are the subject of the invention, there are in particular the drugs, characterized in that they consist of the products of formula (I) in which X- ^ represents a hydrogen atom, a histidine residue or of D-histidine, X ₂ represents an alanine or leucine residue, as well as their D-series counterparts,

X ₃ represents an alanine residue, as well as its D-series counterpart, Xς represents an isoleucine residue, as well as its D-series counterpart,

X ₆ represents a residue of tryptophan, or of D-tryptophan.

Among the latter, it is preferable to use the drugs containing the new peptide derivatives such as defined above, in which:

X ₁ represents a hydrogen atom or a histidine residue, X ₂ represents an alanine or leucine residue, X ₃ represents an alanine residue, X ₅ represents an isoleucine residue,

Xg represents a residue of tryptophan or of D-tryptophan.

Among the preferred drugs of the invention, there are more particularly those consisting of one of the following peptide derivatives:

His Ala Ala Ile Ile Trp, 1 5

Leu Ala Ile Ile Trp, 1 5 His Leu Ala Ile Ile D Trp,

1 5

Leu Ala Ile Ile D Trp,

1 5

Ala Ala Ile Ile Trp. 1 5

Among the medicaments of the invention, the following peptide derivative is most particularly retained:

His Ala Ala Ile Ile Trp.

1 5

These drugs find, for example, their use in the treatment of all vascular spasms, in the treatment of cerebral post-hemorrhages, in the treatment of coronary spasms, peripheral vascular spasms as well as in the treatment of renal insufficiencies. These drugs can also be used in the treatment of myocardial infarction, in the prevention of post-angioplasty restenosis, in the treatment of atherosclerosis, certain forms of hypertension, as well as in the treatment of asthma.

The usual dose, which varies depending on the product used, the subject treated and the condition in question, may for example be from 1 to 300 g per day intravenously in humans.

A subject of the invention is also pharmaceutical compositions which contain at least one aforementioned derivative as active principle.

As active principle, the peptide derivatives corresponding to the general formula (I) can be incorporated into pharmaceutical compositions intended for the digestive or parenteral route. These pharmaceutical compositions may be, for example, solid or liquid and be in the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, capsules, capsules, granules, suppositories, injections, aerosols; they are prepared according to the usual methods. The active ingredient (s) can be incorporated 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.

Examples of implementation of the invention will now be given without implied limitation.

EXAMPLE 1: His Ala Ala Ile Ile Trp 1 5

STAGE A: Assembly of the peptide chain

A support of the “Boc-Trp-CM-support” type is used in which Boc is a tert-butyloxycarbonyl group, Trp represents a tryptophyl group and CM-support denotes the crosslinked polystyrene support. The support containing 0.6 mol Trp / g was prepared by the potassium fluoride method according to the technique described by Horiki K., Igano K. & Inouye K. (1978) Che istry Lett. , 165-168. All the amino acids are N-protected by the tert-butylcarbonyl group, the protective groups for the side chains were as follows:

- cyclohexyl ester for aspartic acid, - Nim-tertiobutyloxycarbonyl for histidine,

- tryptophan is not protected.

The coupling reactions were carried out using Bop or (benzotriazol-1-yloxy tris (di ethylamino) phosphonium hexafluorophosphate. A coupling cycle can be summarized as follows: Deprotectiσn: 1 - Treatment with a solution of trifluoroacetic acid

(50%) in dichloromethane containing 3% ethanediethiol for 1 minute. 2 - Draining then treatment with a solution of trifluoroacetic acid at 50% in dichloromethane containing

3% ethanedithiol for 30 minutes. 3 - Drain then wash with isopropanol containing 5% ethanedithiol. 4 - Wash with dichloromethane, 2 times. Coupling:

1 - Addition of Bop and Boc-amino acid.

2 - Addition of diisopropylethylamine (6 equivalents) then of solvent (dichloromethane or dimethylfor amide) with stirring.

3 - After negative reaction with ninhydrin, wash twice with dichloromethane.

Control tests using ninhydrin were carried out according to the method described by Kaiser, E., Colescott, R.L., Bossinger, CD. & Cook, P.I. (1970) Anal. Bioche. 24, 595-598.

Before treatment with hydrofluoric acid, the last Boc group is eliminated with trifluoroacetic acid.

Starting from 1 g of "Boc-Trp-CM-resin" resin, 1.5 g of protected peptide chain complex was obtained manually, resin which is used directly in the following stage. STAGE B: Release of the protected peptide chain-resin complex

1.5 g of a protected peptide chain-resin complex are reacted for 60 minutes with 15 ml of hydrofluoric acid 5 at 0 ° C. in the presence of anisole (1 ml). The resin is washed with ether; the crude peptide is extracted with a 20% aqueous solution of acetic acid. After lyophilization, 250 mg of crude product is obtained.

The fraction obtained is lyophilized and finally 30 mg of expected product is collected.

EXAMPLES 2 to 5:

By operating in the same manner as in Example 1, but with other amino acids, the other peptides which are listed below were prepared.

EXAMPLE 2: Leu Ala Ile Ile Trp

1 5

EXAMPLE 3 - His Leu Ala Ile Ile D Trp

1 5

EXAMPLE 4: Leu Ala Ile Ile D Trp

1 5

25

EXAMPLE 5: Ala Ala Ile Ile Trp.

1 5

Each product of Examples 1 to 5 was sequenced and its mass was checked by mass spectrometry. EXAMPLE 6:

An injectable solution corresponding to the following formula was prepared:

- Product of Example 1 1 mg

- sterile aqueous excipient 2 ml 35

EXAMPLE 7:

Tablets corresponding to the following formula were prepared: - Product of Example 1 2 mg

- excipient q.s.p. one tablet finished at 150 mg (composition of the excipient: lactose, starch, talc, magnesium stearate). 5

STUDY OF ENDOTHELIN RECEPTOR ACTIVITY

A membrane preparation is carried out from the posterior cortex plus the rat cerebellum. The tissue is ground with POLYTRON in a 50 mM Tris buffer pH = 7.4.

10 After 30 minutes at 25 ° C (B.M.) the homogenate is centrifuged at 30,000 g for 15 minutes (2 centrifugations with intermediate recovery in the Tris pH 7.4 buffer). The pellets are resuspended in an incubation buffer (25 mM Tris, pepstatin A 5 microg / ml, aprotinin

15 3 microg / ml, 0.1 mM PMSF, 3mM EDTA, EGTA ImM pH 7.4).

Aliquots of 2 ml are distributed in hemolysis tubes and 1251 Endothelin (approximately 50,000 dpm / tube) and the product to be studied are added. (The product is first tested at 3 * 10 ~ ⁵ M in triplicate). When the tested product moves

20 by more than 50% the radioactivity linked specifically to the receptor, it is tested again according to a range of 7 concentrations in order to determine the concentration which inhibits by 50% the radioactivity linked specifically to the receptor. The inhibitory concentration 50% is thus determined.

The non-specific binding is determined by adding endothelin at 10 ~ ⁶ M (in triplicate). Incubate at 25 ° C for 60 minutes, return to a water bath at 0 ° C for 5 minutes, filter under reduced pressure, rinse with Tris 7.4 buffer and count the radioactivity in the presence of the scintillant Triton.

The result is expressed directly in inhibitory concentration 50% (IC50), that is to say in concentration of studied product expressed in nM, necessary to displace 50% of the specific radioactivity fixed on the receptor studied.

Ir-

35 Result;

The IC 50 values found for the products of Examples 1 and 2 are given in Table I below, in nanoles. TABLE I

STUDY OF VASOCONSTRUCTIVE ACTIVITY AND ANTAGONISM OF THE EFFECTS OF ENDOTHELIN IN DEMEDULATED RAT

Male Sprague-Dawley rats are anesthetized with ne butal (60 mg / kg) injected intraperitoneally. The animals are then demulled, put under respiratory assistance (1 ml / 100 g - 50 breaths per minute), then the vague nerves are cut. A carotid artery is catheterized to record blood pressure and the test products are injected into the pudendal vein. . Study of vasoconstrictor activity

The animals receive endothelin 1 or the test compound in cumulative injections by venous route, the administrations being spaced 2 minutes apart. The increase in mean arterial pressure (BP) induced by each compound is measured and expressed as a percentage change from the initial pressure. • Study of the endothelin antagonist activity

Ten minutes after the intravenous injection of the solvent or of the compounds to be tested, the animals receive administrations of endothelin 1 cumulatively (1, 3, 10 and 30 Mg / kg i.v.) every 2 minutes.

The antagonistic activity is expressed as a percentage of inhibition of the pressure response of endothelin administered alone, at doses of 3 and 10 μg / kg. Results:

The vasoconstrictor activity of the compound of Example 1 is given in Table II below: Table II

The antagonist activity of the compound of Example 1 is given in Table III below:

Table III

LIST OF SEQUENCES

(1) GENERAL INFORMATION:

(i) DEPOSITOR:

(A) NAME: ROUSSEL-UCLAF

(B) STREET: 35, Boulevard des Invalides

(C) CITY: PARIS

(E) COUNTRY: FRANCE

(F) POSTAL CODE: 75007

(ii) TITLE OF THE INVENTION:

New hexapeptide derivatives, process for the preparation and application as medicaments of these new derivatives.

(iii) NUMBER OF SEQUENCES: 5

(iv) COMPUTER-READABLE FORM:

(A) TYPE OF SUPPORT: 5.25 inch Floppy Disk

(B) COMPUTER: IBM PC compatible

(C) OPERATING SYSTEM: PC-DOS / MS-DOS

(D) SOFTWARE: Wordperfect 5.1

EPO

(V) CURRENT DEMAND DATA: DEPOSIT NUMBER: FR 92 01558

(2) INFORMATION FOR SEQ ^ID NO: 1

(i) CHARACTERISTICS OF THE SEQUENCE:

(A) LENGTH: 6 amino acids

(B) TYPE: peptide

(C) NUMBER OF STRANDS: single

(D) CONFIGURATION: linear

(ii) TYPE OF MOLECULE: peptide

(Xi) DESCRIPTION OF SEQUENCE SEQ ID N ^* 1:

His Ala Ala Ile Ile Trp 1 5 LIST OF SEQUENCES

(1) GENERAL INFORMATION:

(i) DEPOSITOR:

(A) NAME: ROUSSEL-UCLAF

(B) STREET: 35, Boulevard des Invalides

(C) CITY: PARIS

(E) COUNTRY: FRANCE

(F) POSTAL CODE: 75007

(ii) TITLE OF THE INVENTION:

(iϋ) NUMBER OF SEQUENCES: 5

(iv) COMPUTER-READABLE FORM:

(A) TYPE OF SUPPORT: 5.25 inch Floppy Disk

(B) COMPUTER: IBM PC compatible

(C) OPERATING SYSTEM: PC-DOS / MS-DOS

(D) SOFTWARE: Wordperfect 5.1

EPO

(V) CURRENT DEMAND DATA: DEPOSIT NUMBER: FR 92 01558

(2) INFORMATION FOR SEQ ID NO: 2

(i) CHARACTERISTICS OF THE SEQUENCE:

(A) LENGTH: 5 amino acids

(B) TYPE: peptide

(C) NUMBER OF STRANDS: single

(D) CONFIGURATION: linear

(ii) TYPE OF MOLECULE: peptide

(xi) DESCRIPTION OF SEQUENCE SEQ ID N'2:

Leu Ala Ile Ile Trp 1 5 LIST OF SEQUENCES

(1) GENERAL INFORMATION:

(i) DEPOSITOR:

(A) NAME: ROUSSEL-UCLAF

(B) STREET: 35, Boulevard des Invalides

(C) CITY: PARIS

(E) COUNTRY: FRANCE

(F) POSTAL CODE: 75007

(ii) TITLE OF THE INVENTION:

(iϋ) NUMBER OF SEQUENCES: 5

(iv) COMPUTER-READABLE FORM:

(A) TYPE OF SUPPORT: 5.25 inch Floppy Disk

(B) COMPUTER: IBM PC compatible

(C) OPERATING SYSTEM: PC-DOS / MS-DOS

(D) SOFTWARE: Wordperfect 5.1

EPO

(V) CURRENT DEMAND DATA: DEPOSIT NUMBER: FR 92 01558

(2) INFORMATION FOR SEQ ^ID NO: 3

(i) CHARACTERISTICS OF THE SEQUENCE:

(A) LENGTH: 7 amino acids

(B) TYPE: peptide

(C) NUMBER OF STRANDS: single

(D) CONFIGURATION: linear

(ii) TYPE OF MOLECULE: peptide

(xi) DESCRIPTION OF SEQUENCE SEQ ID N ^' 3:

His Leu Ala Ile Ile D Trp

1 5 LIST OF SEQUENCES

(1) GENERAL INFORMATION:

(i) DEPOSITOR:

(A) NAME: ROUSSEL-UCLAF

(B) STREET: 35, Boulevard des Invalides

(C) CITY: PARIS

(E) COUNTRY: FRANCE

(F) POSTAL CODE: 75007

(ii) TITLE OF THE INVENTION:

(iii) NUMBER OF SEQUENCES: 5

(iv) COMPUTER-READABLE FORM:

(A) TYPE OF SUPPORT: 5.25 inch Floppy Disk

(B) COMPUTER: IBM PC compatible

(C) OPERATING SYSTEM: PC-DOS / MS-DOS

(D) SOFTWARE: Wordperfect 5.1

EPO

(V) CURRENT DEMAND DATA: DEPOSIT NUMBER: FR 92 01558

(2) INFORMATION FOR SEQ ID NO: 4

(i) CHARACTERISTICS OF THE SEQUENCE:

(A) LENGTH: 6 amino acids

(B) TYPE: peptide

(C) NUMBER OF STRANDS: single

(D) CONFIGURATION: linear

(ii) TYPE OF MOLECULE: peptide

(Xi) DESCRIPTION OF SEQUENCE SEQ ID N'4:

Leu Ala Ile Ile D Trp 1 5 LIST OF SEQUENCES

(1) GENERAL INFORMATION:

(i) DEPOSITOR:

(A) NAME: ROUSSEL-UCLAF

(B) STREET: 35, Boulevard des Invalides

(C) CITY: PARIS

(E) COUNTRY: FRANCE

(F) POSTAL CODE: 75007

(ii) TITLE OF THE INVENTION:

(iii) NUMBER OF SEQUENCES: 5

(iv) COMPUTER-READABLE FORM:

(A) TYPE OF SUPPORT: 5.25 inch Floppy Disk

(B) COMPUTER: IBM PC compatible

(C) OPERATING SYSTEM: PC-DOS / MS-DOS

(D) SOFTWARE: Wordperfect 5.1

EPO

(V) CURRENT DEMAND DATA: DEPOSIT NUMBER: FR 92 01558

(2) INFORMATION FOR SEQ ID N ^* : 5

(i) CHARACTERISTICS OF THE SEQUENCE:

(A) LENGTH: 5 amino acids

(B) TYPE: peptide

(C) NUMBER OF STRANDS: single

(D) CONFIGURATION: linear

(ii) TYPE OF MOLECULE: peptide

(xi) DESCRIPTION OF SEQUENCE SEQ ID N ^" 5:

Ala Ala Ile Ile Trp 1 5

Claims

CLAIMS 1) New hexapeptide derivatives corresponding to the general formula (I):

_χ X _{2 3} Ile X ₅ X _g (I)

in which X- ^ represents a hydrogen atom or a residue of histidine, acetyl-histidine, or D-histidine, X ₂ represents a residue of alanine, leucine, tryptophane, phenylalanine as well than their D-series counterparts,

X ₃ represents an alanine residue, as well as its D-series counterpart,

Xg represents a residue of tryptophan, leucine, isoleu¬ cine, norleucine and their D-series counterparts

2) Hexapeptide derivatives according to claim 1, characterized in that:

X- ^ represents a hydrogen atom, a residue of histidine or of D-histidine, ₂ represents a residue of alanine or of leucine, as well as their homologs in series D, X ₃ represents a residue of alanine, thus than its D series counterpart,

X ₅ represents an isoleucine residue, as well as its homolog in series D, g represents a residue of tryptophan, as well as its ologue in series D.

• 3) Hexapeptide derivatives according to claim 1 or 2, characterized in that:

X ^ represents a hydrogen atom or a histidine residue,

X ₂ represents an alanine residue, X ₃ represents an alanine residue,

X ₅ represents an isoleucine residue,

X ₆ represents a residue of tryptophan or of D-tryptophan.

4) Peptide derivatives according to claims 3, characterized in that they consist of one of the following peptide derivatives:

His Ala Ala Ile Ile Trp, 1 5

Leu Ala Ile Ile Trp,

1 5

His Leu Ala Ile Ile D Trp,

1 5 Leu Ala Ile Ile D Trp,

1 5

Ala Ala Ile Ile Trp.

1 5

5) Hexapeptide derivatives according to any one of claims 1, 2 or 3, characterized in that it consists of the following peptide derivative:

His Ala Ala Ile Ile Trp. 1 5

6) Process for the preparation of new hexapeptide derivatives as defined in claim 1, characterized in that a solid phase synthesis is carried out by sequentially introducing the duly protected amino acids onto a support of crosslinked polystyrene type, using a coupling agent, deprotects the amino acids, and releases from the resin the peptide chain thus formed, to obtain the peptide derivative of formula (I) thus sought. 7) Method according to claim 6, characterized in that:

the support of the crosslinked polystyrene type is a resin of the "Boc-Trp-CM" type or of the "Boc-D-Trp-CM" type in which Boc is a tert-butyloxycarbonyl group, Trp is a tryptophyl and D-Trp group is a D-tryptophyl group and CM denotes the crosslinked polystyrene support,

- the release of the support from the peptide chain as well as deprotection of amino acids is carried out by means of hydrofluoric acid by operating at low temperature preferably at around 0 ° C.

8) Medicines, characterized in that they consist of the new hexapeptide derivatives as defined by the general formula (I) of claim 1.

9) Medicines, characterized in that they consist of new hexapeptide derivatives as defined in any one of claims 2, 3, 4 or 5.

10) Pharmaceutical compositions, characterized in that they contain, as active principle, at least one of the medicaments as defined in any one of claims 8 or 9.