Compounds with reduced ring size for use in diagnosing and treating melanoma, including metastatic melanoma and methods related to same

Patent metadata

Field	Value
Publication number	US-10464985-B2
Application number	US-201816039858-A
Country	US
Kind code	B2
Filing date	Jul 19, 2018
Priority date	Nov 30, 2009
Publication date	Nov 5, 2019
Grant date	Nov 5, 2019

Abstract

The present invention is directed to novel non-invasive diagnostic tools/compounds to image cancers, especially, melanoma, including metastatic melanoma in vivo. The present compounds exhibit enhanced uptake in cancerous cells and tissue and decreased renal uptake in kidney, evidencing favorable pharmacokinetics of compounds of the present invention. The compounds according to the present invention represent an advance in the diagnosis and treatment of melanoma, including metastatic melanoma using non-invasive molecular imaging techniques. The novel probes of the present invention are also useful for initiating therapy for melanoma as well as monitor patients' response to chemotherapy treatments and other interventions or therapies used in the treatment of melanoma/metastatic melanoma. Compounds according to the present invention may be used as diagnostic tools for a number of conditions and diseases states as well as therapeutic agents for treating such conditions and disease states.

First claim

The invention claimed is:

1. A method of treating melanoma in a patient in need thereof comprising administering to said patient an effective amount of a compound according to the chemical structure:
(Y 1 )—X-(ABC)-CycMSH hex

where Y 1 is a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) or hydrazinonicotinamide (HYNIC) group, wherein Y 1 incorporates or complexes with a radioisotope selected from the group consisting of 86 Y, 111 In, 225 Ac, 212 Bi, 213 Bi, 71 As, 72 As, 76 As, 77 As, 65 Zn, 48 V, 203 Pb, 209 Pb, 212 Pb, 166 Ho, 149 Pm, 153 Sm, 67 Ga, 68 Ga, 64 Cu, 67 Cu, 188 Re, 186 Re and 99m Tc;
X is absent or is a

 group;
ABC is GGNle when X is absent or is Nle when X is a

 group;
CycMSH hex is a cyclic peptide comprising six amino acids according to the general structure:

wherein W is a C—H group from an aspartic acid or glutamic acid residue, wherein the alkylene carboxylic acid sidechain of said aspartic acid or glutamic acid and the alkyleneamine sidechain of lysine or ornithine are bonded together to form an amide linkage as indicated;
X 1 is D-phenylalanine;
Y is arginine;
Z is tryptophan;
Z′ and the alkyleneamine to which Z′ is attached is Lys(CONH 2 ) or Orn(CONH 2 );
j is 1 or 2; and
r is 0 or 1; or
a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 , wherein Y 1 is a DOTA group and said compound is complexed with a radioisotope selected from the group consisting of 86 Y, 111 In, 225 Ac, 212 Bi, 213 Bi, 71 As, 72 As, 76 As, 77 As, 65 Zn, 48 V, 203 Pb, 209 Pb, 212 Pb, 166 Ho, 149 Pm and 153 Sm.

3. The method according to claim 1 , wherein Y 1 is a NOTA group and said compound is complexed with a radioisotope selected from the group consisting of 67 Ga, 68 Ga, 64 Cu, and 67 Cu.

4. The method according to claim 1 , wherein Y 1 is a HYNIC group and said compound is complexed with a radioisotope which is 188 Re, 186 Re and 99m Tc.

5. The method according to claim 1 , wherein j is 1 and r is 0.

6. The method according to claim 1 wherein j is 2 and r is 1.

7. The method according to claim 1 wherein j is 2 and r is 0.

8. The method according to claim 2 wherein j is 1 and r is 0.

9. The method according to claim 2 wherein j is 2 and r is 1.

10. The method according to claim 2 wherein j is 2 and r is 0.

11. The method according to claim 3 wherein j is 1 and r is 0.

12. The method according to claim 3 wherein j is 2 and r is 1.

13. The method according to claim 3 wherein j is 2 and r is 0.

14. The method according to claim 3 wherein j is 1 and r is 0.

15. The method according to claim 4 wherein j is 2 and r is 1.

16. The method according to claim 4 wherein j is 2 and r is 0.

17. The method according to claim 1 wherein X is absent and ABC is a GGNle group.

18. The method according to claim 1 wherein X is

and ABC is a Nle group.

19. The method according to claim 1 wherein said compound is co-administered in combination with an effective amount of dacarbazine (DTIC), interleukin-2 (IL-2), alpha-interferon and mixtures thereof.

20. A method of diagnosing the existence, absence or extent of melanoma in a patient comprising administering to said patient an imaging effective amount of a compound according to the chemical structure:
(Y 1 )—X-(ABC)-CycMSH hex

where Y 1 is a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) or hydrazinonicotinamide (HYNIC) group, wherein Y 1 incorporates or complexes with a radioisotope selected from the group consisting of 86 Y, 111 In, 225 Ac, 212 Bi, 213 Bi, 71 As, 72 As, 76 As, 77 As, 65 Zn, 48 V, 203 Pb, 209 Pb, 212 Pb, 166 Ho, 149 Pm, 153 Sm, 67 Ga, 68 Ga, 64 Cu, 67 Cu, 188 Re, 186 Re and 99m Tc;
X is absent or is a

 group;
ABC is GGNle when X is absent or is Nle when X is a

 group;
CycMSH hex is a cyclic peptide comprising six amino acids according to the general structure:

wherein W is a C—H group from an aspartic acid or glutamic acid residue, wherein the alkylene carboxylic acid sidechain of said aspartic acid or glutamic acid and the alkyleneamine sidechain of lysine or ornithine are bonded together to form an amide linkage as indicated;
X 1 is D-phenylalanine;
Y is arginine;
Z is tryptophan;
Z′ and the alkyleneamine to which Z′ is attached is Lys(CONH 2 ) or Orn(CONH 2 );
j is 1 or 2; and
r is 0 or 1; or
a pharmaceutically acceptable salt thereof;
imaging said patient to determine if tissue in said patient exhibits elevated expression of MSH receptors; and
diagnosing said patient as having melanoma if said tissue evidences elevated expression of MSH receptors in comparison to a standard.

21. The method according to claim 20 , wherein j is 1 or 2 and r is 0 or 1.

22. The method according to claim 20 wherein j is I or 2 and r is 1.

23. The method according to claim 20 wherein j is 1 or 2 and r is 0.

24. The method according to claim 20 wherein j is 1 and r is 0 or 1.

25. The method according to claim 20 wherein j is 2 and r is 0 or 1.

26. The method according to claim 20 wherein X is absent and ABC is a GGNle group.

27. The method according to claim 20 wherein X is

and ABC is a Nle group.

28. A method of monitoring therapy of a patient in the treatment of melanoma, the method comprising administering to a patient undergoing melanoma treatment an imaging effective amount of a compound according to the chemical structure:
(Y 1 )—X-(ABC)-CycMSH hex

where Y 1 is a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) or hydrazinonicotinamide (HYNIC) group, wherein Y 1 incorporates or complexes with a radioisotope selected from the group consisting of 86 Y, 111 In, 225 Ac, 212 Bi, 213 Bi, 71 As, 72 As, 76 As, 77 As, 65 Zn, 48 V, 203 Pb, 209 Pb, 212 Pb, 166 Ho, 149 Pm, 153 Sm, 67 Ga, 68 Ga, 64 Cu, 67 Cu, 188 Re, 186 Re and 99m Tc;
X is absent or is a

 group;
ABC is GGNle when X is absent or is Nle when X is a

Assignees

• Stc Unm

Inventors

• Miao Yubin
• Guo Haixun

Classifications

• A61P35/04

  specific for metastasis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K14/68 Primary

  Melanocyte-stimulating hormone [MSH] · CPC title

• C07K7/54

  with at least one abnormal peptide link in the ring · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title