Protein-Binding Anthracycline Peptide Derivatives and Drugs Containing Them

1 . An anthracycline-peptide derivative of Formula I:

wherein

R 1 ═H, OH, or OCH 3 ;

R 2 ═H or OH;

m=0-5;

n=0-6;

P 1 -P 10 is a peptide sequence cleavable by PSA consisting of L- and/or D-amino acids; and

PM is protein-binding group.

2 . The anthracycline-peptide derivative according to claim 1 , wherein the anthracycline component is doxorubicin, daunorubicin, 4′-epirubicin, idarubicin, or carubicin.

3 . The anthracycline-peptide derivative according to claim 1 , wherein the anthracycline component is doxorubicin.

4 . The anthracycline-peptide derivative according to claim 1 , wherein PM is a maleinimide group, a 2-dithiopyridyl group, a halogen acetamide group, a halogen acetate group, a disulfide group, an acrylic acid ester group, a monoalkyl maleic acid ester group, a monoalkyl maleaminic acid amide group, a N-hydroxysuccinimidyl ester group, an isothiocyanate group, or an aziridine group, which can optionally be substituted.

5 . The anthracycline-peptide derivative according to claim 2 , wherein PM is a maleinimide group, which can optionally be substituted.

6 . The anthracycline-peptide derivative according to claim 1 , wherein n<2 and m=2-5.

7 . The anthracycline-peptide derivative according to claim 1 , wherein n=4 and m=0.

8 . The anthracycline-peptide derivative according to claim 1 , wherein P 1 in the peptide sequence (P 1 -P 10 ) is Arg, His, Met, Ser, Tyr, Thr, Phe, Gly, GIn, or Lys.

9 . The anthracycline-peptide derivative according to claim 7 , wherein P 1 in the peptide sequence is Arg.

10 . The anthracycline-peptide derivative according to claim 1 , wherein P 1 , P 2 , P 3 , P 4 , P 5 , and P 6 in the peptide sequence are the same or different and stand for Ser, Tyr, Thr, Asn, Gln, Gly, or Phe.

11 . The anthracycline-peptide derivative according to claim 1 , wherein P 1 , P 2 , P 3 , P 4 , P 5 , and P 6 in the peptide sequence are the same or different and stand for Ser or Tyr.

12 . The anthracycline-peptide derivative according to claim 1 , wherein the peptide sequence P 1 -P 10 comprises six, seven, or eight amino acids.

13 . The anthracycline-peptide derivative according to claim 1 , wherein the peptide sequence is Arg-Ser-Ser-Tyr-Tyr-Ser-Arg, Arg-Arg-Ser-Ser-Tyr-Tyr-Ser-Gly, Ser-Ser-Tyr-Tyr-Ser-Gly, Asn-Ser-Ser-Tyr-Phe-Gln, Arg-Ser-Ser-Tyr-Tyr-Gln-Arg, or Arg-Ser-Ser-Tyr-Tyr-Tyr-Arg.

14 . The anthracycline-peptide derivative according to claim 1 , wherein the peptide sequence is Arg-Ser-Ser-Tyr-Tyr-Ser-Arg.

15 . A process for the production of a doxorubicin-peptide derivative according to claim 1 , the process comprising reacting doxorubicin with a peptide derivative of General Formula II:

wherein

m=0-5;

n=0-6;

P 1 -P 10 is a peptide sequence consisting of L- and/or D-amino acids; and

PM is a protein-binding group,

in the presence of carboxylic acid activation reagents.

16 . The process according to claim 15 , wherein PM is a maleinimide group.

17 . The process for the production of doxorubicin-peptide derivatives, said process comprising reacting doxorubicin with a peptide of General Formula III:

wherein

m=0-5;

n=0-6;

P 3 -P 10 is a peptide sequence, consisting of L- and/or D-amino acids; and

PM is a protein-binding group,

in the presence of carboxylic acid activation reagents.

18 . The process according to claim 17 , wherein PM is a maleinimide group.

19 . The process according to any one of- claims 15 or 17 , wherein the carboxylic acid activation reagent is selected from N,N′-dicyclohexylcarbodiimide, N,N′-diisopropylcarbodiimide, N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridino-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate (HATU), or (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, preferably N,N-diisopropylcarbodiimide.

20 . A composition comprising the anthracycline-peptide derivative of claim 1 , optionally together with pharmaceutical auxiliary substances and/or solvents.

21 . A method for the treatment of cancer diseases comprising administering to a subject in need of treatment of cancer disease a composition comprising the anthracycline-peptide derivative of claim 1 .

22 . A process for the production of a composition, the process comprising converting a compound of claim 1 into a therapeutically compatible solution.