Cyclic undecapeptide pro-drugs and uses thereof

1. A pro-drug consisting of a cyclic undecapeptide in which the peptide chain comprises at least one amino acid residue of general formula (I) below:

in which:

the carbon atom C a constitutes one of the links of the undecapeptide ring;

the substituents Y each represent a hydrogen atom or together constitute a bond;

the substituents R 1 and R 3 represent, independently of one another, a hydrogen atom, an aralkyl group, an alkaryl group, a heteroalkyl group, a heterocyclic group, an alkylheterocyclic group, a heterocyclic alkyl group or a linear or branched alkyl group having from 1 to 6 carbon atoms, optionally substituted with at least one of the groups chosen from —COOH, —CONHR 8 , —NHC═NH(NH 2 ), —NHC═NR 8 (NH 2 ), —NH 2 , —NHR 8 , —NR 8 2 , —N + R 8 3 , —OH, —OPO(OR 8 ) 2 , —OPO(OH)(OR 8 ), —OPO(OH) 2 , —OSO(OR 8 ) 2 , —OSO(OH)(OR 8 ), —OSO(OH) 2 , and the various salified forms of these groups, each of the substituents R 8 representing, independently of one another, a linear or branched alkyl group having from 1 to 6 carbon atoms;

the substituents R 2 and R 4 represent, independently of one another a hydrogen atom, an alkaryl group, or a linear or branched alkyl group having from 1 to 6 carbon atoms;

the substituents R 5 and R 6 represent, independently of one another, a hydrogen atom, an aralkyl group, or a linear or branched alkyl group having from 1 to 6 carbon atoms; and

the substituent R 7 represents an aralkyl group, an alkaryl group, a heteroalkyl group, a heterocyclic group, an alkylheterocyclic group, a heterocyclicalkyl group or a linear or branched alkyl group having from 1 to 6 carbon atoms, said groups being optionally substituted with at least one of the groups chosen from —COOH, —CONHR 8 , —NHC═NH(NH 2 ), —NHC═NR 8 (NH 2 ), —NH 2 , —NHR 8 , —NR 8 2 , —N + R 8 3 , —OH, —OPO(OR 8 ) 2 , —OPO(OH)(OR 8 ), —OPO(OH) 2 , —OSO(OR 8 ) 2 , —OSO(OH)(OR 8 ), —OSO(OH) 2 , and the various salified forms of these groups.

2. The pro-drug as claimed in claim 1 , characterized in that, in general formula (I) defining said amino acid residue, at least one of the substituents R 1 and R 3 represents an aralkyl group, an alkaryl group, a heteroalkyl group, a heterocyclic group, an alkylheterocyclic group, a heterocyclic alkyl group or a linear or branched alkyl group having from 1 to 6 carbon atoms, each of said groups being substituted with at least one of the groups chosen from —COOH, —CONHR 8 , —NHC═NH(NH 2 ), —NHC═NR 8 (NH 2 ), —NH 2 , —NHR 8 , —NR 8 2 , —N + R 8 3 , —OH, —OPO(OR 8 ) 2 , —OPO(OH)(OR 8 ), —OPO(OH) 2 , —OSO(OR 8 ) 2 , —OSO(OH)(OR 8 ), —OSO(OH) 2 , and the various salified forms of these groups.

3. The pro-drug as claimed in claim 2 , characterized in that said aralkyl, alkaryl, heteroalkyl, heterocyclic, alkylheterocyclic, heterocyclicalkyl or alkyl groups are substituted with at least one of the groups chosen from —NR 8 2 , —N + R 8 3 , —OPO(OH) 2 or the various salified forms of these groups.

4. The pro-drug as claimed in claim 3 , characterized in that at least one of said substituents R 1 and R 3 represents a linear alkyl group having from 1 to 6 carbon atoms substituted with at least one of the groups chosen from —NR 8 2 , —N + R 8 3 , —OPO(OH) 2 or the various salified forms of these groups.

5. The pro-drug as claimed in claim 1 , characterized in that, in general formula (I) defining said amino acid residue, the substituents R 5 and R 6 cannot simultaneously represent a hydrogen atom.

6. The pro-drug as claimed in claim 1 , characterized in that, in general formula (I) defining said amino acid residue, at least one of said substituents R 5 and R 6 represents a linear or branched alkyl group having from 1 to 6 carbon atoms, and the substituent R 7 represents an aralkyl group or a linear or branched alkyl group having from 1 to 6 carbon atoms.

7. The pro-drug as claimed in claim 6 , characterized in that said substituents R 5 and R 6 represent, independently of one another, a hydrogen atom or a methyl group.

8. The pro-drug as claimed in claim 1 , characterized in that said peptide chain comprises a single amino acid residue of general formula (I) forming an undecapeptide ring with a linear sequence of ten amino acids of general formula (II) below:

-T-U-V-W-MeLeu-Ala-X-MeLeu-Z-MeVal-  (II)

in which:

T is chosen from the amino acids Ala, Abu, Nval, Val and Thr;

U is chosen from the amino acids Sar, (D)MeSer, (D)MeAla and (D)MeSer(OCOR 9 ), with R 9 representing a hydrogen atom, an alkaryl group, or a linear or branched alkyl group having from 1 to 6 carbon atoms;

V represents an amino acid of general formula (N—R 10 )aa, aa being chosen from the amino acids Val, Leu, Ile, Thr, Phe, Tyr and Thr, and R 10 being a linear or branched alkyl group having from 1 to 6 carbon atoms;

W is chosen from the amino acids Val, Nval and Leu;

X is chosen from the amino acids (D)Ala, (D)Ser, (D)Hiv, (D)Val and (D)Thr; and

Z is chosen from the amino acids Leu and MeLeu.

9. The pro-drug as claimed in claim 8 , characterized in that said linear sequence of ten amino acids is chosen from the following sequences of formulae (III) to (XIV):

-Abu-Sar-MeLeu-Val-MeLeu-Ala-(D)Ala-MeLeu-MeLeu-MeVal-  (III);

-Abu-(D)MeAla-EtVal-Val-MeLeu-Ala-(D)Ala-MeLeu-MeLeu-MeVal-  (IV);

-Thr-Sar-MeLeu-Val-MeLeu-Ala-(D)Ala-MeLeu-MeLeu-MeVal-  (V);

-Val-Sar-MeLeu-Val-MeLeu-Ala-(D)Ala-MeLeu-MeLeu-MeVal-  (VI);

-Nval-Sar-MeLeu-Val-MeLeu-Ala-(D)Ala-MeLeu-MeLeu-MeVal-  (VII);

-Val-(D)MeAla-MeLeu-Val-MeLeu-Ala-(D)Ala-MeLeu-MeLeu-MeVal-  (VIII);

-Val-Sar-MeLeu-Val-MeLeu-Ala-(D)Val-MeLeu-Leu-MeVal-  (IX);

-Val-Sar-MeLeu-Val-MeLeu-Ala-(D)Thr-MeLeu-Leu-MeVal-  (X);

-Abu-(D)MeSer(OAc)-MeLeu-Val-MeLeu-Ala-(D)Ala-MeLeu-Leu-MeVal-  (XI);

-Abu-Sar-MeLeu-Val-MeLeu-Ala-(D)Ser-MeLeu-MeLeu-MeVal-  (XII);

-Thr-Sar-MeLeu-Leu-MeLeu-Ala-(D)-Hiv-MeLeu-Leu-MeVal-  (XIII);

and

-Abu-Sar-MeLeu-Val-MeLeu-Ala-(D)-Val-MeLeu-Leu-MeVal-  (XIV).

10. The pro-drug as claimed in claim 1 , having formulae (XV) below:

11. The pro-drug as claimed in claim 1 , having formulae (XVI) below:

12. A method of treating a pathological condition of the eye in a mammal, comprising administering to a mammal in need thereof, a therapeutically effective amount of a medicinal product comprising the pro-drug of claim 1 .

13. The method of claim 12 , wherein the pathological condition is selected from the group consisting of: dry keratoconjunctivitis, Sjögren's syndrome, allergic keratoconjunctivitis, conjunctivitis producing mucous, synechia, herpetic stromal keratitis, immune-related keratitis and Thygeson's keratitis.

14. A method for prolonging organ allograft survival in a mammal, comprising administering to a mammal in need thereof, a therapeutically effective amount of a medicinal product comprising the pro-drug of claim 1 .

15. The method of claim 14 , wherein the organ allograft is selected from the group consisting of: kidney, heart, liver, pancreas, lung, small intestine, and bone marrow.