Melphalan derivatives and their use as cancer chemotherapeutic drugs
The invention refers to new alkylating di- and tripeptides based on a melphalan unit, and one or two additional amino acids or amino acid derivatives, which can be used in the treatment of carcinogenic diseases. Further, the invention refers to a pharmaceutical composition comprising the alkylating peptides of the invention.
1. A di- or tripepetide having the formula I:
wherein R 1 is alkyloxy, cycloalkyloxy, aryloxy, arylalkyloxy, NH 2 , alkylamino, cycloalkylamino, or arylamino; R 2 is
wherein R 3 is independently NH 2 , OH, O-alkyl, N-alkyl, O-acyl, NH-acyl, N(CH 2 CH 2 Cl ) 2 , NO 2 , F, CF 3 or H, and n is 1 or 2; X is
wherein R 5 is H; R 4 is a natural or modified cyclic or aromatic amino acid, or H; and pharmaceutically acceptable salts thereof.
2. A di- or tripepetide having the formula V:
wherein R 1 is alkyloxy, cycloalkyloxy, aryloxy, arylalkyloxy, NH 2 , alkylamino, cycloalkylamino, or arylamino; R 3 is NH 2 , OH, O-alkyl, N-alkyl, O-acyl, NH-acyl, N(CH 2 CH 2 Cl) 2 , NO 2 , F, CF 3 or H: and R 4 is a natural or modified cyclic or aromatic amino acid, or H; and pharmaceutically acceptable salts thereof.
3. A method of manufacturing a medicament, comprising:
formulating the peptide according to claim 1 with a pharmaceutically acceptable excipient.
4. The peptide according to claim 1 , wherein R 3 is F.
5. The peptide according to claim 2 , wherein R 1 is alkyloxy; R 3 is F, CF 3 , H, OH, O-alkyl, NO 2 , N(CH 2 CH 2 Cl) 2 , NH-acyl or NH 2 ; and R 4 is H.
6. The peptide according to claim 5 , which is L-melphanyl-p-L-fluoro-phenylalanine ethyl ester or a pharmaceutically acceptable salt thereof.
7. The peptide according to claim 5 , which is L-melphanyl-p-L-fluoro-phenylalanine isopropyl ester or a pharmaceutically acceptable salt thereof.
8. The peptide according to claim 2 , wherein R 1 is alkyloxy; R 3 is F, CF 3 , H, OH, O-alkyl, NH-acyl, NO 2 , N(CH 2 CH 2 Cl) 2 or NH 2 ; and R 4 is a natural or modified cyclic or aromatic amino acid.
9. The peptide according to claim 8 , which is L-prolin-L-melphanyl-p-fluorophenylalanine ethyl ester or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition for the treatment of malignant tumours, comprising at least one peptide compound according to claim 1 , together with at least one pharmaceutically acceptable carrier and/or excipient.
11. The pharmaceutical composition according to claim 10 , for the treatment of breast cancer, lung cancer, ovarian cancer, leukemias, lymphomas and multiple myeloma.
12. A method of treating malignant tumours, comprising:
administering a pharmaceutically effective dose of the peptide according to claim 1 to a subject in need thereof.
13. A method of manufacturing a medicament, comprising:
formulating the peptide according to claim 2 with a pharmaceutically acceptable excipient.
14. The peptide according to claim 2 , wherein R 3 is F.
15. A pharmaceutical composition for the treatment of malignant tumors, comprising at least peptide compound according to claim 2 , together with at least one pharmaceutically acceptable carrier and/or excipient.
16. The pharmaceutical composition according to claim 15 , for the treatment of breast cancer, lung cancer, ovarian cancer, leukemias, lymphomas and multiple myeloma.
17. A method of treating malignant tumours, comprising:
administering a pharmaceutically effective dose of the peptide according to claim 2 to a subject in need thereof.