Cyclic peptidomimetic urokinase receptor antagonists

1. A method of inhibiting angiogenesis which comprises administering to a subject in need thereof an effective amount of a compound of formula (I)

wherein X 21 -X 30 are monomeric building blocks, preferably aminocarboxylic acid residues and are derived from a structure in which X 21 =D-Cys, X 22 =Asn, X 23 =Lys, X 24 =Tyr, X 25 =Phe, X 26 =Ser, X 27 =Asn, X 28 =Ile, X 29 =Cys and X 30 =Trp, Y is a spacer and m is 0 or 1, and the monomeric building blocks are linked via —CONR 1 or —NR 1 CO bonds, in which R 1 in each case independently is hydrogen, methyl or ethyl, and pharmaceutically acceptable salts and derivatives thereof, with the proviso that at least one of the amino acid residues X 21 -X 30 is replaced by one of the amino acid residues listed below:

X 21 : Asp, Glu, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), D-penicillanine (D-Pen), allylglycine (Alg), ornithine (Orn), Lys;

X 22 : Asp, Glu;

X 23 : Dab, Dap, His, citrulline (Cit), homocitrulline (Hci), norleucine (Nle);

X 24 : homophenylalanine (Hph), 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), thienylalanine (Thi), Trp, phenylglycin (Phg), 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), Cha (cyclohexylalanine);

X 25 : Trp, Tic, Thi, Hph, Phg;

X 26 : Val;

X 27 : Asp, Glu;

X 28 : Cha, 2-aminobutyric acid (Abu), tert-leucine (Tle), α-aminoisobutyric acid (Aib); and

X 29 : Asp, Glu, Dap, Dab, Alg, D-Pen, Orn, Lys,

wherein angiogensis is inhibited in cells expressing a urokinase receptor (uPAR).

2. The method of claim 1 , wherein at least one of the amino acid residues X 21 -X 30 has one of the meanings listed below:

X 21 : D-Pen;

X 23 : Dap, Dab, Cit, Hci, Nle, His;

X 24 : Thi, Hph, Phg, 1-Nal, 2-Nal, Cha;

X 25 : Thi;

X 27 : Asp;

X 28 : Val, Cha.

3. The method of claim 1 , wherein at least one of the amino acid residues X 21 -X 30 has one of the meanings listed below:

X 21 : D-Pen;

X 23 : Dab, Nle, Cit, Hci;

X 24 : 1-Nal, 2-Nal, Cha;

X 25 : Thi;

X 28 : Cha.

4. The method of claim 1 , wherein X 21 -X 30 are monomeric building blocks, preferably aminocarboxylic acid residues and are derived from a structure in which X 21 =D-Cys, X 22 =Asn, X 23 =Dap, Dab or Nle, X 24 =Tyr, X 25 =Phe, X 26 =Ser, X 27 =Asn, X 28 =Ile, X 29 =Cys and X 30 =Trp, Y is a spacer and m is 0 or 1, and the monomeric building blocks are linked via —CONR 1 or —NR 1 CO bonds, in which R 1 in each case independently is hydrogen, methyl or ethyl, and pharmaceutically acceptable salts and derivatives thereof.

5. The method of claim 1 , wherein no more than 6 of the amino acid residues X 22 , X 23 , X 24 , X 25 , X 26 , X 27 , X 28 and X 30 are replaced with the amino acid residues as defined in claim 1 .

6. The method of claim 1 , wherein no more than 2 of the amino acid residues X 24 , X 25 , X 28 and X 30 are replaced with the amino acid residues as defined in claim 1 .

7. A method of delivering a substance to cells expressing a urokinase receptor (uPAR) which comprises administering a target vehicle containing the substance to an individual, wherein the targeting vehicle comprises a compound of the formula (I)

wherein X 21 -X 30 are monomeric building blocks, preferably aminocarboxylic acid residues and are derived from a structure in which X 21 =D-cys, X 22 =ASN, X 23 =Lys, X 24 =Tyr, X 25 =Phe, X 26 -Ser, X 27 -Asn, X 28 =Ile, X 29 =Cys and X 30 =Trp, Y is a spacer and m is 0 or 1, and the monomeric building blocks are linked via —CONR 1 or —NR 1 CO bonds, in which R 1 in each case independently is hydrogen, methyl or ethyl, and pharmaceutically acceptable salts and derivatives thereof, which the proviso that at least one of the amino acid residues X 21 -X 30 is replaced by one of the amino acid residues listed below:

X 21 : Asp, Glu, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), D-penicillanine (D-Pen), allylglycine (Alg), ornithine (Orn), Lys;

X 22 : Asp, Glu;

X 23 : Dab, Dap, His, citrulline (Cit), homocitrulline (Hci), norleucine (Nle);

X 24 : homophenylalanine (Hph), 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), thienylalanine (Thi), Trp, phenylglycin (Phg), 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), Cha (cyclohexylalanine);

X 25 : Trp, Tic, Thi, Hph, Phg;

X 26 : Val;

X 27 : Asp, Glu;

X 28 : Cha, 2-aminobutyric acid (Abu), tert-leucine (Tie), α-aminoisobutyric acid (Aib);

X 29 : Asp, Glu, Dap, Dab, Alg, D-Pen, Orn, Lys.

8. The method of claim 7 , wherein at least one of the amino acid residues X 21 -X 30 has one of the meanings listed below:

X 21 : D-Pen;

X 23 : Dap, Dab, Cit, Hci, Nle, His;

X 24 : Thi, Hph, Phg, 1-Nal, 2-Nal, Cha;

X 25 : Thi;

X 27 : Asp;

X 28 : Val, Cha.

9. The method of claim 7 , wherein at least one of the amino acid residues X 21 -X 30 has one of the meanings listed below:

X 21 : D-Pen;

X 23 : Dab, Nle, Cit, Hci;

X 24 : 1-Nal, 2-Nal, Cha;

X 25 : Thi;

X 28 : Cha.

10. The method of claim 7 , wherein X 21 -X 30 are monomeric building blocks, preferably aminocarboxylic acid residues and are derived from a structure in which X 21 =D-Cys, X 22 =Asn, X 23 =Dap, Dab or Nle, X 24 =Tyr, X 25 =Phe, X 26 =Ser, X 27 =ASN, X 28 =Ile, X 29 =Cys and X 30 =Trp, Y is a spacer and m is 0 or 1, and the monomeric building blocks are liked via —CONR 1 or —NR 1 CO bonds, in which R 1 in each case independently is hydrogen, methyl or ethyl, and pharmaceutically acceptable salts and derivatives thereof.

11. The method of claim 7 , wherein no more than 6 of the amino acid residues X 22 , X 23 , X 24 , X 25 , X 26 , X 27 , X 28 and X 30 are replaced with the amino acid residues as defined in claim 7 .

12. The method of claim 7 , wherein no more than 2 of the amino acid residues X 24 , X 25 , X 28 and X 30 are replaced with the amino acid residues as defined in claim 7 .