Melanocortin-1 receptor-specific cyclic peptides

1. A cyclic peptide of the formula:

Z-Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Y

or a pharmaceutically acceptable salt thereof, wherein:

Z is H or an N-terminal group;

Xaa 1 is an amino acid with a side chain including a linear or branched alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl;

Xaa 2 and Xaa 6 are L- or D-isomer amino acids wherein the side chains thereof comprise a cyclic bridge;

Xaa 3 is L- or D-Pro, optionally substituted with hydroxyl, halogen, sulfonamide, alkyl, —O-alkyl, aryl, alkyl-aryl, alkyl-O-aryl, alkyl-O-alkyl-aryl, or —O-aryl, or Xaa 3 is an L- or D-isomer of an amino acid with a side chain including at least one primary amine, secondary amine, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, ether, sulfide, or carboxyl;

Xaa 4 is an L- or D-isomer amino acid with a side chain including phenyl, naphthyl or pyridyl, optionally substituted with one or more substituents independently selected from halo, (C 1 -C 10 )alkyl-halo, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylthio, aryl, aryloxy, nitro, nitrile, sulfonamide, amino, monosubstituted amino, disubstituted amino, hydroxy, carboxy, and alkoxy-carbonyl;

Xaa 5 is L- or D-Pro or Xaa 5 is an L- or D-isomer amino acid with a side chain including at least one primary amine, secondary amine, guanidine, urea, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, or ether;

Xaa 7 is optionally present, and if present is from one to three L- or D-isomer amino acid residues; and

Y is a C-terminal group.

2. A cyclic peptide of the formula:

Z-Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Y

or a pharmaceutically acceptable salt thereof, wherein:

Z is H or an N-terminal group;

Xaa 1 is optionally present, and if present is from one to three L- or D-isomer amino acid residues;

Xaa 2 and Xaa 6 are L- or D-isomer amino acids wherein the side chains thereof comprise a cyclic bridge;

Xaa 3 is L- or D-Pro, optionally substituted with hydroxyl, halogen, sulfonamide, alkyl, —O-alkyl, aryl, alkyl-aryl, alkyl-O-aryl, alkyl-O-alkyl-aryl, or —O-aryl, or Xaa 3 is an L- or D-isomer of an amino acid with a side chain including at least one primary amine, secondary amine, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, ether, sulfide, or carboxyl;

Xaa 4 is an L- or D-isomer amino acid with a side chain including phenyl, naphthyl or pyridyl, optionally substituted with one or more substituents independently selected from halo, (C 1 -C 10 )alkyl-halo, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylthio, aryl, aryloxy, nitro, nitrile, sulfonamide, amino, monosubstituted amino, disubstituted amino, hydroxy, carboxy, and alkoxy-carbonyl;

Xaa 5 is L- or D-Pro or Xaa 5 is an L- or D-isomer amino acid with a side chain including at least one primary amine, secondary amine, guanidine, urea, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, or ether;

Xaa 7 is an amino acid with a side chain including at least one aryl or heteroaryl, optionally substituted with one or more ring substituents, and when one or more substituents are present, are the same or different and independently hydroxyl, halogen, sulfonamide, alkyl, —O-alkyl, aryl, or —O-aryl; and

Y is a C-terminal group.

3. A cyclic peptide of the formula:

Z-Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Y

or a pharmaceutically acceptable salt thereof, wherein:

Z is an N-terminal group wherein the N-terminal group is a C 1 to C 17 acyl group, wherein the C 1 to C 17 comprises a linear or branched alkyl, cycloalkyl, alkylcycloalkyl, aryl or alkylaryl, a linear or branched C 1 to C 17 alkyl, aryl, heteroaryl, alkene, alkenyl, or aralkyl chain or an N-acylated linear or branched C 1 to C 17 alkyl, aryl, heteroaryl, alkene, alkenyl, or aralkyl chain;

Xaa 1 is optionally present, and if present is from one to three L- or D-isomer amino acid residues;

Xaa 2 and Xaa 6 are L- or D-isomer amino acids wherein the side chains thereof comprise a cyclic bridge;

Xaa 3 is L- or D-Pro, optionally substituted with hydroxyl, halogen, sulfonamide, alkyl, —O-alkyl, aryl, alkyl-aryl, alkyl-O-aryl, alkyl-O-alkyl-aryl, or —O-aryl, or Xaa 3 is an L- or D-isomer of an amino acid with a side chain including at least one primary amine, secondary amine, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, ether, sulfide, or carboxyl;

Xaa 4 is an L- or D-isomer amino acid with a side chain including phenyl, naphthyl or pyridyl, optionally substituted with one or more substituents independently selected from halo, (C 1 -C 10 )alkyl-halo, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylthio, aryl, aryloxy, nitro, nitrile, sulfonamide, amino, monosubstituted amino, disubstituted amino, hydroxy, carboxy, and alkoxy-carbonyl;

Xaa 5 is L- or D-Pro or Xaa 5 is an L- or D-isomer amino acid with a side chain including at least one primary amine, secondary amine, guanidine, urea, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, or ether;

Xaa 7 is optionally present, and if present is from one to three L- or D-isomer amino acid residues; and

Y is a C-terminal group.

4. A cyclic peptide of the formula:

Z-Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Y

or a pharmaceutically acceptable salt thereof, wherein:

Z is H or an N-terminal group;

Xaa 1 is optionally present, and if present is from one to three L- or D-isomer amino acid residues;

Xaa 2 and Xaa 6 are L- or D-isomer amino acids wherein the side chains thereof comprise a cyclic bridge;

Xaa 3 is L- or D-Pro, optionally substituted with hydroxyl, halogen, sulfonamide, alkyl, —O-alkyl, aryl, alkyl-aryl, alkyl-O-aryl, alkyl-O-alkyl-aryl, or —O-aryl, or Xaa 3 is an L- or D-isomer of an amino acid with a side chain including at least one primary amine, secondary amine, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, ether, sulfide, or carboxyl;

Xaa 4 is D-Phe, optionally substituted with one or more substituents independently selected from halo, (C 1 -C 10 )alkyl-halo, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylthio, aryl, aryloxy, nitro, nitrile, sulfonamide, amino, monosubstituted amino, disubstituted amino, hydroxy, carboxy, and alkoxy-carbonyl;

Xaa 6 is an L- or D-isomer of Arg, Lys, Orn, Dab or Dap;

Xaa 7 is an L- or D-isomer of Trp, NaI 1 or NaI 2; and

Y is a C-terminal group.

5. The cyclic peptide of claim 4 wherein Xaa 3 is an L- or D-isomer of His.

6. The cyclic peptide of claim 4 wherein Z is a C 1 to C 7 acyl group and Xaa 1 is an L- or D-isomer of Nle.

7. A cyclic peptide of the formula:

Z-Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Y

or a pharmaceutically acceptable salt thereof, wherein:

Z is H or a C 1 to C 17 acyl group, wherein the C 1 to C 17 comprises a linear or branched alkyl, cycloalkyl, alkylcycloalkyl, aryl or alkylaryl, a linear or branched C 1 to C 17 alkyl, aryl, heteroaryl, alkene, alkenyl, or aralkyl chain or an N-acylated linear or branched C 1 to C 17 alkyl, aryl, heteroaryl, alkene, alkenyl, or aralkyl chain;

Xaa 1 is an L- or D-isomer amino acid residue with a side chain including a linear or branched alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl;

Xaa 2 and Xaa 6 are L- or D-isomer amino acids wherein one of Xaa 2 and Xaa 6 is an L- or D-isomer of Asp, hGlu or Glu and the other of Xaa 2 and Xaa 6 is an L- or D-isomer of Lys, Orn, Dab or Dap and wherein the side chains of Xaa 2 and Xaa 6 comprise a cyclic bridge;

Xaa 3 is L- or D-Pro, optionally substituted with hydroxyl, halogen, sulfonamide, alkyl, —O-alkyl, aryl, alkyl-aryl, alkyl-O-aryl, alkyl-O-alkyl-aryl, or —O-aryl, or Xaa 3 is an L- or D-isomer of an amino acid with a side chain including at least one primary amine, secondary amine, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, ether, sulfide, or carboxyl;

Xaa 4 is D-Phe, optionally substituted with one or more substituents independently selected from halo, (C 1 -C 10 )alkyl-halo, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylthio, aryl, aryloxy, nitro, nitrile, sulfonamide, amino, monosubstituted amino, disubstituted amino, hydroxy, carboxy, and alkoxy-carbonyl;

Xaa 6 is an L- or D-isomer of Arg, Lys, Orn, Dab or Dap;

Xaa 7 is an L- or D-isomer of Trp, NaI 1 or NaI 2; and

Y is a hydroxyl, an amide, or an amide substituted with one or two linear or branched C 1 to C 17 alkyl, cycloalkyl, aryl, alkyl cycloalkyl, aralkyl, heteroaryl, alkene, alkenyl, or aralkyl chains.

8. A pharmaceutical composition comprising a cyclic peptide or pharmaceutically acceptable salt thereof of claim 1 and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition comprising a cyclic peptide or pharmaceutically acceptable salt thereof of claim 7 and a pharmaceutically acceptable carrier.

10. The cyclic peptide of claim 1 wherein the N-terminal group is a C 1 to C 17 acyl group, wherein the C 1 to C 17 comprises a linear or branched alkyl, cycloalkyl, alkylcycloalkyl, aryl or alkylaryl, a linear or branched C 1 to C 17 alkyl, aryl, heteroaryl, alkene, alkenyl, or aralkyl chain or an N-acylated linear or branched C 1 to C 17 alkyl, aryl, heteroaryl, alkene, alkenyl, or aralkyl chain.

11. The cyclic peptide of claim 1 wherein one of Xaa 2 and Xaa 6 is an L- or D-isomer of Asp, hGlu or Glu and the other of Xaa 2 and Xaa 6 is an L- or D-isomer of Lys, Orn, Dab or Dap.

12. The cyclic peptide of claim 1 wherein Xaa 2 and Xaa 6 are each independently Cys, D-Cys, Pen or D-Pen.

13. The cyclic peptide of claim 1 wherein Y is a hydroxyl, an amide, or an amide substituted with one or two linear or branched C 1 to C 17 alkyl, cycloalkyl, aryl, alkyl cycloalkyl, aralkyl, heteroaryl, alkene, alkenyl, or aralkyl chains.

14. A pharmaceutical composition comprising a cyclic peptide or pharmaceutically acceptable salt thereof of claim 2 and a pharmaceutically acceptable carrier.

15. The cyclic peptide of claim 2 wherein the N-terminal group is a C 1 to C 17 acyl group, wherein the C 1 to C 17 comprises a linear or branched alkyl, cycloalkyl, alkylcycloalkyl, aryl or alkylaryl, a linear or branched C 1 to C 17 alkyl, aryl, heteroaryl, alkene, alkenyl, or aralkyl chain or an N-acylated linear or branched C 1 to C 17 alkyl, aryl, heteroaryl, alkene, alkenyl, or aralkyl chain.

16. The cyclic peptide of claim 2 wherein one of Xaa 2 and Xaa 6 is an L- or D-isomer of Asp, hGlu or Glu and the other of Xaa 2 and Xaa 6 is an L- or D-isomer of Lys, Orn, Dab or Dap.

17. The cyclic peptide of claim 2 wherein Xaa 2 and Xaa 6 are each independently Cys, D-Cys, Pen or D-Pen.

18. The cyclic peptide of claim 2 wherein Y is a hydroxyl, an amide, or an amide substituted with one or two linear or branched C 1 to C 17 alkyl, cycloalkyl, aryl, alkyl cycloalkyl, aralkyl, heteroaryl, alkene, alkenyl, or aralkyl chains.

19. A pharmaceutical composition comprising a cyclic peptide or pharmaceutically acceptable salt thereof of claim 3 and a pharmaceutically acceptable carrier.

20. The cyclic peptide of claim 3 wherein one of Xaa 2 and Xaa 6 is an L- or D-isomer of Asp, hGlu or Glu and the other of Xaa 2 and Xaa 6 is an L- or D-isomer of Lys, Orn, Dab or Dap.

21. The cyclic peptide of claim 3 wherein Xaa 2 and Xaa 6 are each independently Cys, D-Cys, Pen or D-Pen.

22. The cyclic peptide of claim 3 wherein Y is a hydroxyl, an amide, or an amide substituted with one or two linear or branched C 1 to C 17 alkyl, cycloalkyl, aryl, alkyl cycloalkyl, aralkyl, heteroaryl, alkene, alkenyl, or aralkyl chains.

23. A pharmaceutical composition comprising a cyclic peptide or pharmaceutically acceptable salt thereof of claim 4 and a pharmaceutically acceptable carrier.

24. The cyclic peptide of claim 4 wherein the N-terminal group is a C 1 to C 17 acyl group, wherein the C 1 to C 17 comprises a linear or branched alkyl, cycloalkyl, alkylcycloalkyl, aryl or alkylaryl, a linear or branched C 1 to C 17 alkyl, aryl, heteroaryl, alkene, alkenyl, or aralkyl chain or an N-acylated linear or branched C 1 to C 17 alkyl, aryl, heteroaryl, alkene, alkenyl, or aralkyl chain.

25. The cyclic peptide of claim 4 wherein one of Xaa 2 and Xaa 6 is an L- or D-isomer of Asp, hGlu or Glu and the other of Xaa 2 and Xaa 6 is an L- or D-isomer of Lys, Orn, Dab or Dap.

26. The cyclic peptide of claim 4 wherein Xaa 2 and Xaa 6 are each independently Cys, D-Cys, Pen or D-Pen.

27. The cyclic peptide of claim 4 wherein Y is a hydroxyl, an amide, or an amide substituted with one or two linear or branched C 1 to C 17 alkyl, cycloalkyl, aryl, alkyl cycloalkyl, aralkyl, heteroaryl, alkene, alkenyl, or aralkyl chains.