LU87262A1 - NOVEL SOMATOSTATIN DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS - Google Patents

Description

rr "'Λ * 7 Λ £" "0 ~ GRAND-DUCHY OF LUXEMBOURG, ΐ" Rrpvpit ÎSJo i Æ * ** - ...................... ............................... Γ "" 'CCtl ^ Mister Minister of 2 8 JUIH1988 ...... . of Economy and the Middle Classes „,. ·· - rea Intellectual Property Service

Title issued --------— | gp LÛXEMBÔÙko '^ / ^ «Invention Patent Application dt · 7 ---------------------------------- ---------------------------------------------------------- ----------------------------— Π) · I. Request

The so-called company: SANDOZ SA, Lichtstrasse 35e CH-4002 Basel »Switzerland, __ (2) 'represented by Mr. Louis EMRINGER, lawyer, residing in Luxembourg, _ acting in his capacity as agent ______-____________ -------- -—.— ------: --— (3) submitting) this vinßt- kuJJ: _ίJl ^ ΆJLÎJ} JL · IμJJUΆ £ .zV..L·Lg ^ A.lU £ _____ (4) at _____hours , to the Ministry of the Economy and the Middle Classes, in Luxembourg: 1. this request for obtaining a patent of invention concerning:

New somatostatin derivatives, their preparation and their________________ (5) use as medicines __________'___________________________________________ 2. the description in language_____________________________ of the invention in triplicate; 3. __________________./././____ drawing sheets, in triplicate; · 4. the receipt of the fees paid to the Luxembourg Registration Office, le — iJMJQ — I ... 9.ÂÂ__; 5. the delegation of power, dated _-------------- le — tA — iUÀB · —L9.ÂÂ-; 6. the successor document (authorization); claim (s) for the above patent application the priority of one (s) request (s) from (7) ________________________________! : ___ deposited (s) m (8) at._la .__ Rep — _P.ed., _ jd_ 'All.emagne_ le (9) .. ^. 9 ..._ j-uiix- ~ 1.9.87 — under ~ JLc ~ ..N °. ”- E -37--21- 406 ^ 3-et ™ le -2-9-jui-n — 1-987 -----————-- under the N ° (10 ) ___ É 37 21 407.1 ____________________________________ on behalf of (11) SANDOZ-P ATENT-GMBH, Humboldtstr, 3, D-7850 Lörrach, Germany elect) domicile for him / her and, if designated, for his / her representative, in Luxembourg the AJL, .LU.ß..jLLhjL „iJt ündzn 2652 Lux.e.mbou / Lg _____'____; _; (12) requests (nt) the grant of a patent for the subject described and represented in the abovementioned appendices, with postponement of this grant to —six ____________________________________ monthL (13)

The depositor / agent: -: ',. ; ................'- = - (14) ^ ‘TLProtest report.

The above patent application has been filed with the Ministry of the Economy and the Middle Classes,

Property Service MelketßS ^^ Ctsiembourg, dated: mm 4000

Xyr 'fc O JUNE 1300 ^ / i * \ Λ \ Pr. The Minister of ^ c mpmteej, of the Middle Classes, ^ \ The head of the intellectual property office, ~ A 68007' _ - ° - · _ ') /. - ____ - -. EXPLANATIONS RELATING TO THE FILE ^ eKePOT. ! X i - f λ γ ij, - (11 if applicable "Request for certificate of additio-to the main patent, to main patent application No.„. Λ ..,. ... of *. , * ..... „_. .V * - (2) enter the surname, first name, profession, - -! Fffj \ aaresst of the applicant, when the latter is an individual or the company name, legal form, address of the Tocia headquarters], when the applicant is a legal person - (3) enter J f \ - the surname, first name, address of the authorized representative, industrial property attorney, with special powers, if applicable: "represents by ............ acting as agent” ~ Λ - (4) date of filing in full - (5) title of invention · - ^ enter names, first names , addresses of the inventors or the indication "(see) separate designation (will follow)" Jprsim the disim \ T 1 ΐ i σηαίΐηη this fact naked cß will HanCiin rb-vMifnent <AnarA. ni, still Pinnientinn ”do not mention” tnrsniiAl'fnventeiirci'oneni, "ιμαμιιπ rfncimienrrif> finn.mentinn to ini'nHre h imi" H4eîonntir> nr • "‘ 100-7168 CLAIMING THE PRIORITY of TSC patent applications In the Federal Republic of Germany From 29. June 1987

DESCRIPTIVE MEMORY

filed in support of an application for

PATENT

at

LUXEMBOURG

in the name of: SANDOZ S.A.

for: New somatostatin derivatives, their preparation and their use as medicines · i w

The subject of the present invention is new peptide compounds derived from somatostatin, their preparation and their use as medicaments.

The invention relates in particular to the compounds of formula I

zi CH-S-y Y-S-CH

• · »2 1 2, 2 T

A - NH - CH - CO - N - CH - CO - B - c - D - E - NH - CH - F

1 2 3 4 5 6 7 in which A represents a residue of formula (al) or (01) ZR-CO- or R3HN- <pî-C0- i1 (“i) NHR2 (¾) in which R represents an alkylene group in Ci-Cix or C2-alkenylene -Ci i, Z represents a group -OH, -NR4 R5, -N © R4R5R6, -NHOH, guanidino or ureido,

Ri represents a C1-C5 alkylene group R2 represents hydrogen, a group -CO-NH2, -C (NH2) = NH or a carbohydrate residue, R3 represents hydrogen or a carbohydrate residue, R4 represents hydrogen, a C3-C3 alkyl group or a carbohydrate residue, r5 represents hydrogen or a C1-C3 alkyl group, and R6 represents a C1-C3 group, ^ N-CH (Zi) -C0- signifies i) a residue (L) or (D) -phenylalanine optionally substituted in the phenyl residue by halogen or by groups NO2, NH2, OH, C1-C3 alkyl and / or C1-C3 alkoxy, or ii) the rest a natural α-amino acid other than * »w 2 those defined under i) above, or the corresponding (D) -amino acid,

Zx in the remainder> N-CH (Ζχ) -CO- signifying the remaining part of said remainder i) or ii), A 'represents hydrogen or a Cx-C3 alkyl group,

Yx and Y2 together represent a direct bond or else Yx and Y2 represent, independently of one another, hydrogen or a residue corresponding to one of the formulas (1) to (5) below; R.

-CO-C- (CH2) b-H -GO-CH -C0-NHRc

Rb (CH2) n (1) (2) (3) -CO-NH-ÇH-COOR,. * \ 4 en \\

l -a "" * ', - ‘P’ ^ N

<4> (5) \ "; I

' * in which

Ra represents a methyl or ethyl group,

Rb represents hydrogen or a methyl or ethyl group, m signifies an integer from 1 to 4 inclusive, n signifies an integer from 1 to 5 inclusive,

Rc signifies a C1-C6 alkyl group,

Rd represents the substituent attached to the carbon atom a of a natural α-amino acid (including hydrogen),

Re represents a Cx-C5 alkyl group,

Ra 'and Rb' represent, independently of one another, hydrogen or a methyl or ethyl group, r8 and R9 represent, independently of one another, hydrogen, a halogen or an alkyl group in C1-C3 or alkoxy in Cx-C3, p signifies O or 1, q signifies 0 or 1, and * »3 rr signifies 0, 1 or 2, B signifies -Phe- optionally substituted in the ring by halogen or by groups NO2, NH2, OH, C1-C3 alkyl and / or C! -C3 alkoxy, or naphthyl-Ala, C signifies (L) -Trp- or (D) -Trp- optionally α-Ν-methylated and optionally substituted in the benzene ring by halogen or by NO2, NH2, OH, C1-C3 alkyl and / or C1-C3 alkoxy groups, D stands for -Lys-, Thia-Lys, yF-Lys, SF-Lys or Orn, optionally α-Ν-methylated, or a 4-arainocyclo-hexyl-Ala or 4-aminocyclohexyl-Gly residue, E means Thr, Ser, Val, Phe, Ile or a residue of the amino acid isobutyric, F signifies a group of formula -COOR7, -CH2OR10, -COtQ ^ or àRl2 -Xi in which R7 represents hydrogen or a C1-C3 alkyl group, R10 represents hydrogen or the remainder of a physiologically acceptable and physiologically hydrolyzable ester,

Ri 1 represents hydrogen or a C1-C3 alkyl group, phenyl or phenyl C7-Cio alkyl>

Ri 2 represents hydrogen or a C1-C3 alkyl group or -CH (Rj 3) -Xi,

Ri 3 · represents -CH2OH, - (CH2) 2-OH, - (CH2) 3-OH, or -CH (CH3) 0H or the substituent attached to the carbon atom a of a natural α-amino acid (including hydrogen) and

Xi represents a group of formula -COOR7, -CH2OR10 or w 4 -CO-N ^ in which R7 and Rio have the meanings given above,

Ri4 represents hydrogen or a C1-C3 alkyl group and

Ris represents hydrogen or a C1-C3 alkyl, phenyl or phenylalkyl C7-10 group, and Ri 6 represents hydrogen or a hydroxy group,

Ru must signify hydrogen or a methyl group when Rx2 signifies a group -CH (Ri3) -Xi, and in formula I the residues B, D and E have the configuration (L) and the residues in position 2 and 7 and the residues Yi 4) and Y2 4) each have, independently, the configuration (L) or (D), in free form or in the form of a salt or a complex.

By halogen is meant in the present application, fluorine, chlorine and bromine. According to usual practice, the amino acid residues designated by an abbreviation, for example -Phe-, -Cys- etc ..., should be understood as having the configuration (L), unless otherwise indicated. The term natural amino acid refers to an amino acid originating from a natural source or produced in another way, for example by synthesis or cell culture.

R4 and / or R3 preferably signify hydrogen or a methyl group. R6 preferably means a methyl group.

A 'preferably means hydrogen or a methyl group, especially hydrogen.

When A signifies a residue of formula (ax), it is preferably a ω-aminohexanoyl residue, possibly containing a carbohydrate residue.

When A signifies a residue of formula (ßx), it is preferably a residue derived from lysine, ornithine, arginine or citrulline.

A more preferably means a ω-amino-hexanoyl group.

When ^ N-CH (Ζχ) -CO- has the meaning i), it is preferably a residue (L) or (D) -phenylalanine, pentafluorophenylalanine or (L) or (D) tyrosine (where Ζχ means a benzyl or p-OH-benzyl group), more preferably a residue (D) -phenylalanine.

When} N-CH (Ζχ) -CO- has the meaning ii), the defined residue is preferably lipophilic. The preferred ii) radicals are the radicals in which Ζχ denotes an alkyl group having 3, preferably 4 or more carbon atoms, or a residue -CH2-A2 in which A2 denotes a naphthyl or pyridyl group.

More preferably, / N-CH (Zx) -CO- has the meaning i).

Preferably, Υχ and Y2 together represent a direct bond or else each symbol Υχ and Y2 independently signifies hydrogen or a residue of formula (1) or (3). More preferably, Υχ and Y2 together represent a direct bond.

In the compounds of formula I, the following meanings or their combinations are moreover preferred: B signifies Phe or Tyr C signifies - (D) Trp or 5-halo- (D) Trp, in particular D-Trp D signifies Lys or 4 -aminocyclohexyl-Ala E means Thr, Ser or Val, in particular Thr or Val F means Rn -CO-N ^ especially r 6 -CO-Nt ^ ^ V.CH (R13) Xi where Ru means hydrogen, Ri 2 has the meaning given above, Ri3 signifies -CH2OH, -CH (CH3) OH, iso-butyl, iso-propyl, -CH2CH2OH, - (CH2) 3OH or a residue derived from Trp, 5-fluoro-Trp, ß-Nal , Ala, MeAla or Gly, preferably -CH2OH or -CH (CH3) OH, especially -CH (CH3) OH,

Xi means ^ 14

-CO-N

Λ1 5 or -CH2 ORi o / specially -CH2ORi0 Ri0 means hydrogen,

Rio as an ester residue preferably means a formyl group, C2-C12 alkylcarbonyl, phenyl-C8-C12 alkylcarbonyl or benzoyl and / or the group -CH (Ri3) -Xi preferably has the L configuration.

The remains in position 2 and 7 preferably have the L configuration.

The appropriate carbohydrate residues (hereinafter referred to as X) represented by R2 and / or R3 and / or R4, comprise the following residues: a) X is the deoxy residue of a ketose of formula a)

Oc

the CH2 group of this residue being linked to the NH group of the compound of formula I

b) X is the deoxy residue of an aldose of formula b) 7

Y

• Q ~ “

the free valence of this residue being attached to the NH group of the compound of formula I

c) X is a residue of formula c) G3 - CO - NRy - in which G3CO signifies the residue of a uronic acid or of a polyhydroxymono- or dicarboxylic acid, and Ry signifies hydrogen or a C * alkyl group -C5 or C1-C4 alkanoyl, d) X signifies a residue of formula d), e), f) or g) i4 NH-Qn - (d) c'4. ^ 0Η5 · -Μ - (e)

'** ° v OH R

(g) in which

Ry means hydrogen or a C! -C5 alkyl or C1-C4 alkanoyl group, and Q / Q ', Q "and Q"' represent groups coupling the peptide residue with the carbohydrate residue, or e) X means a residue of formula h), i) or j) H0H2C- (CH0H) c-CY-CH2-NH- (h) HOH2 C- (CHOH) c-CH-CH 2 OH (i) NH- HOH2C- (CHOH ) c-CH-COOH (j)

Ah- 8 r in which Y signifies H2 or H, OH, c signifies 2, 3 or 4, and any of the free hydroxy groups in the polyol residue of formula h), i) or j) is optionally linked by a Glucosidic binding to a reducing mono-, di- or oligosaccharide or to an amino sugar.

In all of the formulas a) to g) shown above, only one carbohydrate residue has been represented per formula. The invention however also covers carbohydrate residues containing from 1 to 3 residues of mono-saccharides which can be linked together in the form of di-saccha-ride or tri-saccharide.

In all the remains represented above, the symbol indicates that the bond can be in position a or ß.

In formula a), the residue hX- preferably represents i) a residue of formula ai) "N" V / ·

Xf ·· .¾% in which one of the symbols Ga and Gb signifies hydrogen and the other OH, one of the symbols Gc and Gd signifies hydrogen and the other OH or a glucosyloxy residue in which the glucosyl residue can derive from a mono-, di- or oligosaccha- 9 ψ reducing ride, one of the symbols Ge and Gf means hydrogen and the other OH, one of the symbols Gg and Gh represents hydrogen and the other hydrogen or CH2OH, for example in which the symbols Ga to Gh are chosen in such a way that the remainder of formula a2) corresponds to a residue obtainable by transposition of Amadori from a mono- , di- or oligosaccharide natural or accessible by synthesis.

As examples of carbohydrate residues of formula ai, mention may be made of deoxyfructosyl, deoxyta-gatosyl, deoxysorbosyl, a-glucosyl- (1-4) -deoxyfructosyl, a-glucosyl (1-4) -a-glucosyl- (1- 4) -deoxyfructosyl.

ii) A remainder of formula a2)

* / \ OE

V <=. Q (* 2> ν'-1

Gd Gb in which one of the symbols Ga and Gb signifies hydrogen and the other OH, one of the symbols Gc and Gd signifies hydrogen and the other OH or glucosyloxy in which the glu-cosyl residue can derive of a reducing mono-, di- or oligosaccharide, one of the residues Ge and Gf signifies hydrogen and the other hydrogen, COOH, CH2OH, CH2-0-P (0) - (OH) 2 or CH2O-glucosyle, in which the glucosyl residue can be derived from a reducing mono-, di- or oligosaccharide, for example in which the symbols Ga to Gf are chosen in such a way that the remainder of formula a2) corresponds to a residue which can be obtained by transposition of Amadori from a mono-, di- or oligosaccharide natural or accessible by synthesis.

The residues of formula a2) can be obtained for example by transposition of Amadori from saccharides such as gentiobiose, melibiose, ribose, xylose, or from uronic acids such as glucuronic or galacturonic acid.

In formula b), the residue of formula Q- * preferably represents i) a residue of formula bx) Y V *

Nf * (bl) in which one of the symbols Ga or Gb signifies hydrogen and the other a direct bond, one of the symbols Gc or Gd signifies hydrogen and the other OH, one of the symbols Ge or Gf means hydrogen and the other OH or glucosyloxy, in which the glucosyl residue can derive from a reducing mono-, di- or oligosaccharide, one of the symbols Gg and Gh means hydrogen and the other CH2OH or CH2-0-glucosyl, in which the glucosyl residue can derive from a reducing mono-, di- or oligosaccharide, for example in which the symbols Ga to Gj, are chosen in such a way that the rest of formula bi) corresponds to a residue which can be obtained by Heyns transposition from a natural mono-, di- or oligoketosis or accessible by synthesis, ii) a residue of formula b2 'ry yy ° d ° b in which l one of the symbols Ga and Gb signifies hydrogen and the other a direct bond, one of the symbols Gc and Gd signifies hydrogen and the other OH, one of the symbols Ge and Gf signifies ie hydrogen and the other CH2OH or CH2-O-glucosyl in which the glucosyl residue can be derived from a reducing mono-, di- or oligosaccharide, for example in which the symbols Ga to Gf are chosen so that the residue b2) corresponds to a residue which can be obtained by transposition of Heyns from a mono-, di- or oligoketosis natural or accessible by synthesis.

The residues of formula b2) or b2) can be obtained for example by transposition of Heyns from a carbohydrate such as D-fructose, lactulose, L-sorbose, D-tagatose or D-ribulose.

In formula c, the polyhydroxymono- or dicarboxylic acid contains for example at least 3 r 12 hydroxy groups and may also contain other substituents, for example amino or acetylamino groups.

As examples of such polyhydroxycarboxylic acids, mention may be made of onic acids derived from carbohydrates such as gluconic acid, or aric acids such as glucaric acid, as well as quinic acid, acetylmuranic acid, acetylneuraminic acid and D-glucosaminic acid.

As examples of uronic acids, mention may be made of glucuronic acid and galacturonic acid.

In the remains of formula d) to g), G4, G4 ', G4 "and G4"' have the meanings given above for Gi or G2.

The symbol Q or Q 'links the group -NH- of the compound of formula I with an NH2 or OH group of the carbohydrate residue and signifies for example the residue of a dicarboxylic acid or preferably a residue -CbH2b-CO- in which b means 0 to 6. The rest can be branched.

Q1 means for example a residue - © - n "-co-ch2-ch2-co-, or in particular a residue -CbH2b-CO- (b for example from 1 to 6). Q means for example a residue -CH2-CO-. Q especially means -CO- or -CS-; -NH-Q "- and -NH-Q" '- signify a residue which links the group -NH- of the compound of formula I with the carbohydrate residue, especially the residues of ω-aminocarboxylic acids. They can mean, for example, a residue -NH-CbH2b-CO-.

The residues of formula h), i) or j) are preferably those of formula h), especially those in which c signifies 3.

The compounds of formula I can exist in free form, in salt form or in complex form. The acid addition salts are those formed for example r 13 with organic acids, polymeric acids and mineral acids. Such salts include, for example, hydrochlorides and acetates. The complexes are those formed from the compounds of formula I by the addition of mineral substances, for example mineral salts or hydroxides such as calcium and zinc salts, and / or by the addition of polymeric organic substances.

The present invention also relates to a process for preparing the compounds of formula I. These compounds can be prepared according to processes known in peptide chemistry or by analogous processes, for example according to a process characterized in that i) the or the protective groups present in a protected polypeptide having the sequence indicated in formula I, ii) two peptide units are paired by an amide bond, each of which contains at least one amino acid or amino alcohol residue in protected form or unprotected, a peptide unit containing a residue A and the peptide-units being such that a protected or unprotected polypeptide having the sequence indicated in formula I is obtained and, if necessary, step i) is carried out of the process, iii) the group F of a protected or unprotected polypeptide having the sequence indicated in formula I is transformed into another group F and, if necessary, step i) of the process is carried out, iv ) at least one optionally protected residue is introduced into a protected or unprotected peptide and, if necessary, stage i) of the process is carried out, or v) a compound of formula I is oxidized, in which the mercapto groups of the residues Cys are in free form, which gives a polypeptide of formula I in which Yx and Y2 together form a direct bond, and the compound of formula I resulting is recovered in r 14 free form or in the form of a salt or in form d 'a complex.

The above method can be carried out for example in a manner analogous to the methods described below in the examples.

The amino acids or peptide units used as starting materials and containing on the nitrogen atom a residue of formula ai) or ßi can be prepared according to known methods by reacting the corresponding amino acids or peptides not containing of the remainder of formula ax) or ß2), for example using the corresponding acid or the reactive derivative of the corresponding acid, for example an acid of formula ZR-COOH or a reactive derivative of this acid, such as an ester activated, or an amino acid of formula

Ri7HN-CH-C0R16 I1 nhr2 in which R17 signifies a protective group and Ri6 signifies a hydroxy group or a group activating the carboxy group. As examples of residues of activated esters or groups activating the carboxy group, mention may for example be made of 4-nitrophenyl, pentachlorophenyl, pentafluorophenyl, succinimidyl or 1-hydroxy-benzotriazolyl groups.

The introduction of the groups Υχ and Y2 into the SH groups of the Cys residues in positions 2 and 7 can be carried out according to the methods known for acylation reactions, for example by treating a polypetide containing a free SH group with a reactive derivative an acid, especially an acid halide, to introduce the residues 1), 2) and 5) (where p = 0) as defined above for Yi and Y2, or with an isocyanate to introduce the residues 3), 4) and 5) (where p = 1) as defined above for Yi and Y2. The compounds in which Yi 15 and Y2 have the meaning 4) can be prepared using the amino acid isocyanates, which can be obtained in a manner known per se, for example by reaction of an amino acid with phosgene and removal of HCl.

The peptide units used as starting materials or the compounds of formula I comprising a carbohydrate residue of formula a) can be prepared by reacting in a slightly acid medium a protected peptide having a free amino group with a reducing mono-, di- or oligosaccharide or a corresponding uronic acid or ester of uronic acid (transposition of Amadori), and possibly subsequent removal of the protective group.

This reaction can be carried out according to the methods known for a transposition of Amadori. The added acid can be for example glacial acetic acid. When the reaction is carried out with uronic acid, an additional acid can be added. It is preferable to use an excess of carbohydrate, for example ten equivalents for one equivalent of peptide compound. The reaction can be carried out in a polar solvent such as methanol, preferably at temperatures between about 50 and 70 ° C.

The peptide units or the compounds of formula I comprising a carbohydrate residue of formula b) can be prepared by reaction in a slightly acid medium of a protected peptide having a free amino group with a ketose (Heyns transposition). The reaction can be carried out under the same conditions as those indicated for the transposition of Amadori.

The peptide units or the compounds of formula I comprising a carbohydrate residue of formula c) can be prepared by reaction of a protected peptide having a free amino group, with an acid of formula G3-C00H or a reactive derivative of such an acid , and possibly elimination of the protective group (s). This reaction is a conventional amidation reaction which can be carried out in a manner known per se. The amides can, for example, preferably be prepared from free acids in the presence of hydroxybenzotriazole and dicyclohexylcarbodiimide.

The peptide units or the compounds of formula I comprising a carbohydrate residue of formula d), e), f) or g) can be prepared a) by reaction of the peptide with the bridging element and reaction of the product obtained with the carbohydrate, or b) by reacting the carbohydrate with the bridge element and then reacting the glucosylated bridge element with the peptide.

These reactions can be carried out according to known methods.

The peptide units or the peptides of formula I comprising a carbohydrate residue of formula d) in which Q signifies -CO- or -CS-, can be prepared for example by coupling of the corresponding glucosylated isocyanate or isothiocya-nate of formula

G * N = C = L

in which L signifies O or S and G4 has the meaning given above and in which the free hydroxy groups present in G4 are protected for example by acylation, with a protected peptide containing a free amino group and subsequent removal of the protective groups.

The reaction can be carried out according to known methods for the preparation of urea derivatives.

The peptide units or the compounds of formula I comprising a carbohydrate residue of formula f) or g), r 17 can be obtained for example by transposition of Amadori or Heyns, for example as described above for the preparation of the compounds comprising a residue carbohydrate of formula a) or b).

The peptide units or the compounds of formula I comprising a carbohydrate residue of formula h), i) or j) can be prepared for example a ') by reductive amination of an aldose, a deoxyaldose or a ketose with the peptide comprising a free amino group, b ') by reduction of the hemi-acetal group in a compound comprising a carbohydrate residue of formula a) or b), or c') by reaction of the peptide with a linear aminocarboxylic acid derived from a carbohydrate , any product participating in the reaction can, if desired, be temporarily protected.

Reductive amination and reduction can be carried out according to known methods. The reductive amination can be carried out for example with NaBH3CN.

The operation is preferably carried out at a pH of 7. The reduction of the hemi-acetal group can be carried out with a borohydrid, for example with NaBH4. It is preferably carried out at a pH of around 6.

The starting materials used in the processes described above are known or can be obtained according to known methods or in a similar manner to the methods described in the literature or in the examples below.

The following examples illustrate the present invention without in any way limiting its scope. All temperatures are given in degrees Celsius and the a2 0D values are not corrected. The following abbreviations have been used:

Boc = tert, -butyloxycarbonyl DMF = dimethylformamide

Fmoc = 9-fluorenylmethoxycarbonyl r 18

AcOH »acetic acid

MeOH = methanol

Thr-ol - threoninal residue = ch3 ~ choh-ch (ch2oh) -nh- TFA = »trifluoroacetic acid

All the peptides are obtained in the form of polyacetate polyhydrates having a peptide content of 70 to 90%.

Liquid chromatography (HPLC) indicates that the peptides contain less than 5% of other peptides.

The factor "F" mentioned in the following examples indicates the peptide content in the product obtained (F = 1 indicates a peptide content of 100%). The difference up to 1001 [(1 -F) x 100] is made up of acetic acid and water.

Example 1 H2N- (CH2) 5-CO-DPhe-éys-Phe-DTrp-Lys-Thr-Cys-Thr-ol i- a) 0.56 g of H-DPhe-Cys-Phe-DTrp-Lys is dissolved (BOC) - 1

Thr-Cys-Thr-ol, 0.5 mmol of Fmoc-e-aminocaproic acid and 115 mg of hydroxybenzotriazole in 10 ml of DMF and cooled to -30 °. To this solution is added a solution of 115 mg of dicyclohexylcarbodiimide in 5 ml of DMF (cooled to -10 °).

After a reaction time of 24 hours, during which the mixture reaches room temperature, the dicyclohexylurea which has formed is filtered off and the filtrate is diluted with water to 10 times its volume. The precipitated reaction product is filtered off, washed and dried over phosphorus pentoxide. The crude product thus obtained is used without further purification for the following reaction.

b) Elimination of the Fmoc group

0.5 g of the crude product obtained under a) is treated for 10 minutes at room temperature with 5 ml of DMF / r 19 piperidine 4/1 vol / vol (clear solution) and then mixed with 100 ml of diisopropyl ether . The precipitated reaction product is then filtered, washed and dried. The crude product thus obtained is used without further purification for the following reaction.

c) Elimination of the BOC group

300 mg of the crude product obtained under b) are treated for 5 minutes at room temperature with 5 ml of 100% TFA (completely dissolved) and then mixed with 50 ml of diisopropyl ether. After adding 2 ml of HCl / diethyl ether, the product which has precipitated is filtered, washed and dried under high vacuum. The final product is chromatographed on silica gel (CHC13 / MeOH / H20 / AcOH 7/3 / 0.5 / 0.5), with subsequent elimination of the salts on Duolite (gradient: H20 / AcOH 95/5) -> H20 / dioxane / AcOH 45/50/5). The title compound is obtained in the form of acetate (white lyophilisate).

[a] 20D = -32 ° (c = 0.5 in 95% AcOH); F - 0.79.

Example 2 H2N- (CH2) 3-CO-DPhe-èys-Phe-DTrp-Lys-Thr-Cys-Thr-ol

By following a procedure analogous to that described in Example 1 (a and c) and by reaction with BOC-NH- (CH2) 3COOH instead of Fmoc-NH- (CH2) 5-COOH, the title compound is obtained in the form of a white lyophilisate. [a] 20D m -34.4 ° (c = 0.5 in 95% AcOH), F 0 0.93.

Example 3 H2N- (CH2) 10-CO-DPhe-èys-Phe- (D) Trp-Lys-Thr-Cys-Thr-ol

The title compound is obtained by operating as described in Example 2, but using BOC-NH- (CH2) 10-COOH. [a] 20D = -37.2 ° (c = 0.5 in 95% AcOH); F "0.89.

Example 4 1-j H-Lys-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol "- a) 0.56 g of H-DPhe-Cys-Phe-DTrp-Lys (BOC) is dissolved ) - ψ 20 -1

Thr-Cys-Thr-ol and 0.5 mmol of Fmoc-Lys (BOC) -OH and 115 mg of hydroxybenzotriazole in 10 ml of DMF and cooled to -30 °. To this solution is added a solution of 115 mg of dicyclohexylcarbodiimide in 5 ml of DMF (cooled to -10 °).

After a reaction time of 24 hours, during which the mixture reaches room temperature, the dicyclohexylurea which has formed is filtered and the filtrate is diluted with water to 10 times its volume. The precipitated reaction product is filtered, washed and dried over phosphorus pentoxide. The crude product thus obtained is used without further purification for the following reaction.

b) Elimination of the Fmoc group

0.5 g of the crude product obtained under a) is treated for 10 minutes at room temperature with 5 ml of DMF / piperidine 4/1 vol / vol (clear solution) and then mixed with 100 ml of diisopropyl ether. The precipitated product is filtered, washed and dried. The crude product thus obtained is used without further purification for the following reaction.

c) Elimination of the BOC group

300 mg of the crude product obtained (1b) are treated for 5 minutes at room temperature with 5 ml of 100% TFA (completely dissolved) and then mixed with 50 ml of diisopropyl ether. After adding 2 ml of HCl / diethyl ether, the precipitate is filtered, washed and dried under high vacuum. The final product is then purified by chromatography on silica gel using CHCl3 / MeOH / H2O / AcOH 7/3 / 0.5 / 0.5 as eluent, with subsequent elimination of the salts on Duolite (gradient: H2O / AcOH 95 / 5) H2O / dioxane / AcOH 45/50/5). The title compound is obtained in the form of a white lyophilisate.

[a] 20D = -23.8 ° (c = 0.63 in 95% AcOH); F = 0.86.

Example 5 r 21 H-DLys-DPhe-tys-Phe-DTrp-Lys-Thr-Cys-Thr-ol

The title compound is obtained in the form of a white lyophilisate by following the method of Example 4 but using Fmoc-DLys (BOC) -OH.

[a] 20D = -26.4 ° (c = 0.54 in 95% AcOH); F = 0.81.

Example 6 | --------— | H-Arg-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol

The title compound is obtained by following the method of Example 2 but using Boc-Arg-OH, HCl t a] 20d = -18.0 ° (c = 1, in 95% AcOH); F "0.84.

Example 7 NH 0

II II --- 1 H2N-C-NH- (CH2) sC-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol The title compound is obtained by following the process of Example 2 , but using

NH

H2 N-Ü-NH- (CH 2) s-C00HfHCl · -25.2 ° (c = 1, in 95% AcOH); F 0, 0.87.

Example 8 0 0 H2N-C-NH- (CH2) 5-C-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol

The title compound is obtained by following the method of Example 2, but using 0

II

H2N-C-NH- (CH2) 5-COOH.

ta) 20 !, = -40.3 ° (c = 1, in 95% AcOH); F = 0.85.

Example 9

Na-Desoxy-D-fructosyl-Lys-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-

Thr-ol

In 25 ml of methanol / acetic acid 9/1 (vol / vol), 250 mg of H-Lys (Boc) -DPhe-Cys-Phe-DTrp-Lys (Boc) -Thr-Cys-Thr-ol are dissolved. in Example 4b) and 250 mg r 22 of D (+) glucose are added. The reaction mixture is heated at 65 ° for 6 hours and the solvent is then removed by evaporation under reduced pressure. After rapid chromatography on silica gel, the resulting protected N-Boc compound is used for the following reaction without further purification. The elimination of the Boc group is carried out in the usual manner (see example le or 4c) and gives the title compound.

[a] 2 0 D = -21.8 ° (c = 0.95 in 95% AcOH); F = 0.92.

Example 10 0

Na-Desoxy-D-fructosyl-NH- (CH2) 5-Î-DPhe-cjrs-Phe-DTrp-Lys-lir-Cys

Thr-ol

The title compound is obtained by following the method of Example 9, but using H2 N- (CH2) 5-C-DPhe-Cys-Phe-DTrp-Lys (Boc) -Thr-Cys-Thr-ol

S

as a starting material.

[a] 2 0 D = -44.4 ° (c = 0.8 in 95% AcOH); F = 0.87.

r 23

The compounds of formula I in free form or in the form of a pharmaceutically acceptable salt or complex, hereinafter designated the compounds of the invention, have interesting pharmacological properties and can therefore be used in therapy as medication. In particular, they exert an activity which inhibits the secretion of growth hormone, as is shown for example by the drop in the levels of growth hormone in serum in rats.

The test is carried out with male rats. The test substance is administered in various doses increasing logarithmically, using at least 5 rats per dose. 1 hour after subcutaneous administration of the test substance, blood is drawn. Growth hormone levels in the blood are determined using the radioimmunoassay method. In this test, the compounds of formula I are active after administration by the subcutaneous route of a dose of between 0.01 and 100 jt / g / kg, for example at 1 // g / kg.

In addition, the inhibitory activity on the secretion of growth hormone of the compounds of the invention was also examined after oral administration to male rats having estradiol implants. The test is carried out as follows:

A tube of silastic (length 50 mm, diameter 3 mm) at 50 mg of estradiol is implanted under ether anesthesia under the dorsal skin of male rats of OFA strain weighing approximately 300 g. At various time intervals (1 to 6 months later), the fasted animals are subjected to various tests. The test substance is administered orally at a dose between 30 and 5,000 // g / kg.

r 24

The growth hormone level in the serum is determined according to the radioimmunoassay method 1 and 2 hours after the oral administration.

The compounds of the invention are therefore indicated for the use in the treatment of disorders having an etiology comprising or associated with excessive secretion of growth hormone, for example in the treatment of acromegaly as well as in the treatment of diabetes mellitus, especially its vascular complications, for example angiopathy, proliferative retinopathy, the phenomenon of dawn and nephropathy.

The compounds of the invention also inhibit gastric and pancreatic secretion, for example exocrine and endocrine pancreatic secretion, as appears from the conventional tests carried out on rats having a gastric and pancreatic fistula. In this test, the compounds are active after oral administration at a dose of between 0.1 and 10 mg / kg.

The compounds of the invention are therefore also indicated for use in the treatment of gastrointestinal disorders, for example for the treatment of ulcer, pancreatic fistula, irritable bowel syndrome, dumping syndrome, acute pancreatitis and hormone-producing gastrointestinal tumors (eg, vi-pome, glucagonoma, insulinoma, carcinoid tumors, etc.) as well as gastrointestinal bleeding.

The compounds of the invention also inhibit the proliferation and / or keratinization of epidermal cells and are therefore indicated for use in the treatment of dermatological diseases associated with proliferation and / or pathological keratinization of cells of the skin. epidermis, especially in the treatment of psoriasis.

In addition, the compounds of the invention are indicated for use in the treatment of degenerative senile dementia, also known as senile dementia of the Alzheimer type (DSTA), as well as cluster headaches.

The compounds of the invention are also effective in the treatment of various types of tumors, in particular tumors containing somatostatin receptors, for example meningioma.

For all the above indications, the appropriate daily dose is between approximately 2 μς and approximately 20 mg, for example between approximately 10 and approximately 5,000 μ ^ subcutaneously and between approximately 300 and 5,000 μq orally , the compounds of the invention being advantageously administered in divided doses up to 4 times a day in the form of unit doses containing for example from approximately 0.5 μg to approximately 10 mg of active substance, or in a form to sustained release.

The compound of Example 1 is the preferred compound.

Inhibition of growth hormone secretion is the preferred indication.

The compounds of the invention can be administered in free form or in the form of a pharmaceutically acceptable salt or complex. Such salts or complexes can be prepared according to the usual methods and have the same activity as the free form.

The invention also relates to the compounds of the invention for use as medicaments, Γ 26 especially for the treatment of disorders having an etiology comprising or associated with excessive secretion of growth hormone, for example acromegaly, diabetes mellitus or angiopathy, for the treatment of gastrointestinal disorders, for example ulcer, acute pancreatitis, pancreatic fistula, irritable bowel syndrome, dumping syndrome and gastro-entero-pancreatic tumors producing d hormones and gastrointestinal bleeding, for the inhibition of the proliferation and / or keratinization of epidermal cells, for example psoriasis, the treatment of degenerative senile dementia or cluster headaches and the treatment of various types of tumors, for example meningioma.

As medicaments, the compounds of the invention can be administered in the form of a pharmaceutical composition containing, as active substance, a compound of the invention in free form or in the form of a pharmaceutically acceptable salt or complex , in combination with a pharmaceutically acceptable carrier or diluent. Such compositions, which also form part of the invention, can be prepared according to the usual methods. The compounds can be administered according to any of the usual routes, in particular parenterally, for example in the form of solutions or injectable suspensions, or in the form of a nasal spray or suppositories.

In a group of compounds of the invention A signifies the residue of a ω-aminocarboxylic acid containing from 3 to 12 carbon atoms,> N-CH (Zi) -C0- signifies i) a residue (L) - or ( D) -phenylalanine optionally substituted by ogène 17 halogen or by NO2, NH2, OH, C1-C3 alkyl and / or C1-C3 alkoxy or ii) the remainder of a natural α-andnoacid other than those defined under i) above, or the corresponding (D) -amino acid, A 'signifies hydrogen or a C1-C3 alkyl group, Yx and Y2 together represent a direct bond or Yj. and Y2 each signify, independently of one another, a residue corresponding to the formulas (1) to (5) defined above, B signifies -Phe- optionally substituted in the cycle by halogen or by NO2 groups , NH2, OH, C1-C3 alkyl and / or C1-C3 alkoxy, C has the meaning indicated above, D means -Lys- optionally aN-methylated, E means Thr, Ser, Val, F means a group of formula -COOR7, -CH2ORio, -CON ^ or -CON-L_ Xx in which R7, Rio, Ru, Ri 2 and Xi are as defined above, the residues B, D and E have the configuration (l) and the residues in position 2 and 7 and the residues Yi 4) and Y2 4) each have, independently, the configuration (L) or (D), in free form, or in the form of a salt or a complex.

In another group of compounds of the invention A signifies H-Lys- or H- (D) Lys-,> N-CH (Zi) -CO- signifies i) a residue (L) - or (D) -phenylalanine r 28 optionally substituted by halogen or by NO2, NH2, OH, C1-C3 alkyl and / or C1-C3 alkoxy, or ii) the remainder of a natural α-amino acid other than those defined under i), or the corresponding (D) -amino acid, A 'signifies hydrogen or a C1-C3 alkyl group, Yi and Y2 together signify a direct bond or signify each, independently of one another, the hydrogen or a residue corresponding to the formulas 1) to 5) defined above, B signifies -Phe- optionally substituted in the ring by halogen or by groups NO2, NH2, OH, alkyl in Oχ-03 and / or alkoxy in Ci-C3, C has the meaning indicated above, D means Lys optionally aN-methylated E means Thr, Ser, Val, F means a group of formula -coor7, -ch2or10, -con or .coi_LXl in which R7, Rio / Ru, Ri 2 and Xi are as defined above, the residues B, D and E have the configuration (l) and the residues in position 2 and 7 and the residues Yi 4) and Y2 4) each have, independently of one another, the configuration (L) or ( D), in free form, or in the form of a salt or a complex.

Claims (10)

29 1.- The compounds corresponding to formula I *! »· CV * -»! τ, -sc "* -HH-c8-eo-K-ä-co-ecoE-ra-CTJ-r (I) 1 2 3 4 5 6 7 in which A represents a residue of formula (al) or (ßl ) ZR-CO- or R3HN- ^ H-C0- (αχ) llHR2 (ßi) in which R represents a C ^ Cu alkylene group or C2-Cn alkenylene, Z represents a group -OH, -NR4R5, -N © R4R5R6, -NHOH, guanidino or ureido, Ri represents a C1-C5 alkylene group R2 represents hydrogen, a group -CO-NH2 / -C (NH2) = NH or a carbohydrate residue, r3 represents hydrogen or a carbohydrate residue, R4 represents hydrogen, a C1-C3 alkyl group or a carbohydrate residue, R5 represents hydrogen or a C1-C3 alkyl group, and R6 represents a C1-C3 group,> N-CH (Zi) -CO- signifies i) a residue (L) or (D) -phenylalanine optionally substituted in the phenyl residue by halogen or by NO2, NH2, OH, C1-C3 alkyl and / or alkoxy groups in Ci-C3, or ii) the remainder of a natural α-amino acid other than those defined in i) above, or the corresponding (D) -amino acid, Ζχ in the remainder> N-CH (Ζχ) -CO- signifying the remaining part of said remainder i) or ii), A 'represents hydrogen or a Cx-C3 alkyl group, Yx and Y2 together represent a direct bond or although Yx and Y2 represent, independently of one another, hydrogen or a residue corresponding to one of the formulas (1) to (5) below; Ra -C0 - ^ - (CH2) m-H -CO-Cff ^ i -C0-NHRc Rb (CH2) n <1) (2) (3) -CO-NH-CH-COOR. / î "\ jl · * ·" ν "w") \% ^ in which Ra represents a methyl or ethyl group, Rb represents hydrogen or a methyl or ethyl group, m signifies an integer from 1 to 4 inclusive, n signifies an integer from 1 to 5 inclusive, Rc signifies a Cx-C6 alkyl group, Rd signifies the substituent attached to the carbon atom a of a natural α-amino acid (including hydrogen), Re represents a Cx-C5 alkyl group, Ra 'and Rb' represent, independently of one another, hydrogen or a methyl or ethyl group, R8 and R9 represent, independently of one another, hydrogen, halogen or Cx-C3 alkyl or Cx-C3 alkoxy, p signifies O or 1, q signifies O or 1, and r signifies O, 1 or 2, 31 B signifies -Phe- optionally substituted in the ring with halogen or with groups NO2, NH2, OH, C1-C3 alkyl and / or C1-C3 alkoxy, or naphthyl-Ala, C signifies (L) -Trp- or (D) - Trp- optionally aN-methylated and optionally substituted in cyc benzene by halogen or by NO2, NH2, OH, C1-C3 alkyl and / or C1-C3 alkoxy, D stands for -Lys-, Thia-Lys, yF-Lys, $ F-Lys or Orn, optionally α-Ν-methylated, or a 4-aminocyclo-hexyl-Ala or 4-aminocyclohexyl-Gly residue, E signifies Thr, Ser, Val, Phe, Ile or a residue of amino-isobutyric acid, F signifies a group of formula _ -COOR7, -CH2OR10, -CON ^ JS N * ,, -CO-N-1-Xi in which R7 represents hydrogen or a C1-C3 alkyl group, Rio represents hydrogen or residue of a physiologically acceptable and physiologically hydrolyzable ester, Ri 1 represents hydrogen or a C1-C3 alkyl group, phenyl or phenyl-C7-C10 alkyl / Ri 2 represents hydrogen or a C1-C3 alkyl group or -CH (R13) -Xx, Ri 3 represents -CH2OH, - (CH2) 2-OH, - (CH2) 3-OH or -CH (CH3) 0H or the substituent attached to the carbon atom a d ' a natural α-amino acid (including hydrogen) and Xi represents a group of formula -COOR7, -CH2ORi0 or 32 -CO- N ^ ^ RlS in which r7 and R10 have the meanings given above, Ri4 represents hydrogen or a Cx-C3 alkyl group and r15 represents hydrogen or a Cx-C3 alkyl group, phenyl or phenylalk.C7 -10, and rx6 represents hydrogen or a hydroxy group, Rxx having to signify hydrogen or a methyl group when Rx2 signifies a group -CH (R13) -XX / and in formula I the residues B, D and E have the configuration ^) and the residues in position 2 and 7 and the residues Yx 4) and Y2 4) each have, independently, the configuration (L) or (D), in free form or in the form of a salt or a complex. 2.- A compound according to claim 1, characterized in that A signifies the residue of a ω-aminocarboxylic acid containing from 3 to 12 carbon atoms,> N-CH (Zx) -C0- signifies i) a residue ( L) - or (D) -phenylalanine optionally substituted by halogen or by NO2, NH2, OH, Cx-C3 alkyl and / or Cx-C3 alkoxy, or ii) the remainder of a- natural amino acid other than those defined under i) above, or the corresponding D-amino acid, A 'signifies hydrogen or a Cx-C3 alkyl group, Yx and Y2 together signify a direct bond or Yx and Y2 mean, independently of one another, hydrogen or a residue corresponding to one of the formulas (1) to (5) defined in claim 1, B means Phe optionally substituted in the ring 33 by halogen or by groups NO2, NH2, OH, C1-C3 alkyl and / or C1-C3 alkoxy, C has the meaning given in claim 1, D signifies Lys optionally aN-methylated, E signifies Thr, Ser or Val, F signifies ie a group of formula -COOR7 "-CHzORio, -CON ^^ or -CON-- Xx in which R7, Rio" Ri 1, Ri 2 and have the meanings given in claim 1, and the residues B, D and E have the configuration (l) and the residues in position 2 and 7 and the residues Yx 4) and Y2 4) each have, independently, the configuration (L) or (D). 3.- A compound according to claim 1, characterized in that A) signifies H-Lys- or H- (D) Lys-,> N-CH (Zi) -CO- signifies i) a residue (L) - or (D) -phenylalanine optionally substituted by halogen or by NO2, NH2, OH, C1-C3 alkyl and / or C1-C3 alkoxy groups, or ii) the remainder of an α-amino acid natural other than those defined under i) above, or the corresponding (D) -amino acid, A 'signifies hydrogen or a C1-C3 alkyl group, Yi and Y2 together signify a direct bond or else Yi and Y2 mean, independently of one another, hydrogen or a residue corresponding to one of the formulas (1) to (5) defined in claim 1, B means Phe optionally substituted in the ring by halogen or by groups NO2, NH2, OH, C1-C3 alkyl and / or C1-C3 alkoxy, C has the meaning given in claim 1, 34 D signifies Lys optionally aN-methylated, E signifies Thr, Ser or Val, F means a group of formula -COOR7, -CH2ORio, -COn / or Rl ! -COFl · - Xi in which R7, R10, Ru, Ri 2 and Xt have the meanings given in claim 1, the residues B, D and E have the configuration (l) and the residues in position 2 and 7 and the remains Y2 4) and Y2 4) each have, independently / the configuration (L) or (D). 4.- A compound according to any one of claims 1 to 3, characterized in that B means Phe or Tyr C means (D) -Trp D means Lys E means Thr, Ser or Val F means Rl 1 -CO-N ^ ^ vCH (R13) X1 WHERE R11 is hydrogen, Ri3 is CH2OH, CH (CH3) OH, i-butyl, i-propyl, CH2CH2OH, (CH2) 3OH or a residue derived from Trp or 5-fluoro-Trp , and Xi signifies Z1 '-CO-N rH nD \ or ch2or10, Ri 5 where Rx4 and Ri5 have the meanings given in claim 1, Rxo signifies hydrogen, Rio as ester residue signifies a formyl group , C2-Ci2 alkylcarbonyl, phenylalkylcar-bonyl in Ce-Ci2 or benzoyl, and the group -CH (Ri3) -X! at configuration (L). 5. A compound according to claim 1 or 4, characterized in that the carbohydrate residue is chosen from a) the deoxy residue of a ketose of formula a) <v ··> ““ * (a, the group CH2 of this residue being linked to the NH group of the compound of formula I b) the deoxy residue of an aldose of formula b) "2 (b> · (the free valence of this residue being attached to the NH group of the compound of formula I c) a residue of formula c) G3 - CO - NRy - * (c) in which G3CO signifies the residue of a uronic acid or of a polyhydroxymono- or dicarboxylic acid, and Ry signifies hydrogen or a C 1 -C alkyl group C5 or C1-C4 alkanoyl, d) a residue of formula d), e), f) or g) 36; 'Λ * y? 4 / - NH-QN - (d; C'4. \> ^ 0 -ς · -Ν - (e) “· * / • v * h /" V "4 ... / \ h (f; ^ 2" ΗΓ * "* 'in which Ry means hydrogen or an alkyl group C1-C5 or C1-C4 alkanoyl, and Q / Q ', Q "and Q"' represent groups coupling the peptide residue with the carbohydrate residue, or e) a residue of formula h), i) or j) H0H2C- (CH 0H) c-CY-CH2-NH- (h) H0H2C- (CH0H) c-CH-CH20H (i) NH- H0H2C- (CH0H) c-CH-C00H (j) NH- in which Y means H2 or H , OH, c signifies 2, 3 or 4, and any of the free hydroxy groups in the polyol residue of formula h), i) or j) is optionally linked by a glucosidic bond to a mono-, di- or oligosaccharide reducer or an amino sugar. 6.- A compound according to claim 5, characterized in that in formula a), the remainder 37 Ος represents i) a remainder of formula aj,) Ju. ^ * S.A_ e \ _ (ai> ° <% in which one of the symbols Ga and Gb signifies hydrogen and the other OH, one of the symbols Gc and Gd signifies hydrogen and the other OH or a glucosyloxy residue in which the glucosyl residue can be derived from a reducing mono-, di- or oligosaccharide, one of the symbols Ge and Gf means hydrogen and the other OH, one of the symbols Gg and Gj , represents hydrogen and the other hydrogen or CH2OH, ii) a residue of formula a2) FV j \ = c <* >> \ 38 in which one of the symbols Ga and Gb signifies hydrogen and l other OH, one of the symbols Gc and Gd signifies hydrogen and the other OH or glucosyloxy in which the glu-cosyl residue can derive from a reducing mono-, di- or oligosaccharide, one of the residues G . and Gf means hydrogen and the other hydrogen, COOH, CH2OH, CH2-OP (0) - (OH) 2 or CH20-glucosyl, in which the glucosyl residue can be derived from a mono-, di- or reducing oligosaccharide, and in formula b), the remainder of formula Q ~ oh represents i) a residue of formula bx) | Λ> 6 \ - “<” ü in which one of the symbols Ga or Gb signifies hydrogen and the other a direct bond, one of the symbols Gc or Gd signifies l hydrogen and the other OH, one of the symbols G * or Gf signifies hydrogen and the other OH or glucosyloxy, in which the glucosyl residue can be derived from a reducing mono-, di- or oligosaccharide, 39. one of the symbols Gg and Gh signifies hydrogen and the other CH2OH or CH2-O-glucosyl, in which the glucosyl residue can derive from a reducing mono-, di- or oligosaccharide, ii) a residue of formula b2 & · Ed "b in which one of the symbols Ga and Gb signifies hydrogen and the other a direct bond, one of the symbols Gc and Gd signifies hydrogen and the other OH, one of the symbols Ge and Gf mean hydrogen and the other CH2OH or CH2-O-glucosyl in which the glucosyl residue can be derived from a reducing mono-, di- or oligosaccharide. 7, - A compound chosen from H2N- (CH2) 5-CO-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol H-Lys-DPhe-dys-Phe-DTrp-Lys-Thr-Cyfe -Thr-ol H-DLys-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol Na-Desoxy-D-fructosyl-Lys-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr -ol and 0 Na-Desoxy-D-fructosyl-NH- (CH2) 5- (Ü-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-®l in free form or in the form of a salt or a complex 40 8. A process for preparing the compounds specified in claim 1 and their salts and their complexes, characterized in that i) the protective group or groups present in a protected polypeptide having the sequence indicated in formula I, ii are removed ) two peptide units are coupled by an amide bond, each of which contains at least one amino acid or amino alcohol residue in protected or unprotected form, a peptide unit containing a residue A and the peptide units being such that a protected or unprotected polypeptide having the sequence indicated in formula I is obtained and, if necessary, stage i) of the process is carried out, iii) the group F is transformed from a protected or unprotected polypeptide having the sequence indicated in formula i, in another group F and, if necessary, step i) of the process is carried out, iv) at least one optionally protected residue is introduced into a protected or unprotected peptide and, if necessary , we implement step i) of the process, or v) a compound of formula X is oxidized, in which the mercapto groups of the Cys residues are in free form, which gives a polypeptide of formula I in which Yi and Y2 together form a direct bond , and the resulting compound of formula I is recovered in free form or in the form of a salt or in the form of a complex. 9. A compound according to any one of claims 1 to 7, in free form or in the form of a pharmaceutically acceptable salt or complex, for use as a medicament. 10. A pharmaceutical composition, characterized in that it comprises, as active substance, a compound according to any one of claims 1 to 7, in 41 free form or in the form of a pharmaceutically acceptable salt or complex, in combination with a pharmaceutically acceptable carrier or diluent.