Piperazine melanocortin-specific compounds
Melanocortin receptor-specific piperazine or ketopiperazine compounds having the structure: and stereoisomer and pharmaceutically acceptable salts thereof, where X is CH 2 or C═O, R 1 , R 2 , and R 3 are as described in the specification, preferably where R 3 is a D-amino acid with at least one substituted or unsubstituted phenyl or naphthyl aromatic ring, and where R 3 optionally further includes an amine capping group, a second amino acid residue or a second amino acid residue with an amine capping group, which compounds are agonists, antagonists or mixed agonists and antagonists at one or more melanocortin receptors, and having utility in the treatment of melanocortin receptor-related disorders and conditions. Methods of synthesis of compounds of structure (I), pharmaceutical compositions containing a compound of structure (I) and methods relating to the use thereof are also disclosed.
1. A compound having the structure:
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein
R 1 is -L 1 -J or, if X is CH 2 , is H or -L 1 -J;
R 2 is (CH 2 ) y —W or, if X is CH 2 , is H or -L 1 -J, on the proviso that R 1 and R 2 are not both H;
R 3 is -L 2 -Q;
L 1 is a linker selected from the group consisting of —(CH 2 ) y —, —O—(CH 2 ) y —, —O—, —NH—(CH 2 ) y —, —(C═O)(CH 2 ) y —, —(C═O)—O—(CH 2 ) y —, and —CH 2 (C═O)NH;—:
J is a ring structure selected from the group consisting of substituted or unsubstituted aromatic carbocyclic rings, substituted or unsubstituted non-aromatic carbocyclic rings, substituted or unsubstituted aromatic fused carbobicyclic ring groups, substituted or unsubstituted aromatic carbocyclic ring groups wherein the rings are joined by a bond or —O—, and substituted or unsubstituted aromatic fused heterobicyclic ring groups; wherein in each instance each ring in the ring structure consists of 5 or 6 ring atoms;
W is selected from the group consisting of NH 2 , NH(C═NH)NH 2 , —NHCOCH 3 , —CONHCH 3 , —NH(C═NH)NHMe, —NH(C═NH)NHEt, —NH(C═NH)NHPr, —NH(C═NH)NHPr—I, —NH(C═NH)NH 2 , —NH(C═O)OCH 3 , —NH(C═O)CH 3 , —-NH(C═O)NH 2 , —NH(C═O)NHCH 3 ,
L 2 is a linker selected from the group consisting of
Q is an aromatic carbocyclic ring selected from the group consisting of phenyl, substituted phenyl, naphthyl and substituted naphthyl;
R 4 is H, —R 5 or —R 5 —R 6 ;
R 5 is an amino acid residue or an amine capping group, provided that if R 6 is present, R 5 is an amino acid residue;
R 6 is H or an amine capping group;
X is CH 2 or C═O; and
y is at each occurrence independently from 1 to 6.
2. The compound of claim 1 wherein J is a substituted or unsubstituted ring structure selected from the group consisting of
3. The compound of claim 1 wherein at least one ring of the group J is substituted with one or more halogen, alkyl or aryl groups.
4. The compound of claim 1 wherein R 1 is selected from the group consisting of
5. The compound of claim 1 wherein R 1 is selected from the group consisting of
6. The compound of claim 1 wherein R 2 is selected from the group consisting of
7. The compound of claim 1 where Q is
wherein R 7a and R 7b are optional ring substituents, and when one or both are present, are the same or different and independently hydroxyl, halogen, alkyl, or aryl groups attached directly or through an ether linkage.
8. The compound of claim 7 wherein the alkyl group is —CH 3 or —OCH 3 .
9. The compound of claim 1 wherein R 5 or R 6 is an amine capping group selected from the group consisting of hexyl, hexanoyl, heptanoyl, acetyl, phenylacetyl, cyclohexylacetyl, naphthylacetyl, cinnamoyl, benzyl, benzoyl, cinnamoyl, 12-Ado, 7′-amino heptanoyl, 6-Ahx, Amc and 8-Aoc.
10. The compound of claim 1 wherein R 3 is a D-amino acid with an aromatic carbocyclic ring selected from the group consisting of phenyl, substituted phenyl, naphthyl and substituted naphthyl.
11. The compound of claim 1 wherein R 3 is a D-amino acid with an amine capping group and an aromatic carbocyclic ring selected from the group consisting of phenyl, substituted phenyl, naphthyl and substituted naphthyl.
12. The compound of claim 1 wherein R 3 is a dipeptide consisting of a D-amino acid including an aromatic carbocyclic ring selected from the group consisting of phenyl, substituted phenyl, naphthyl and substituted naphthyl and a second amino acid residue, wherein the D-amino acid is bonded to the ring nitrogen.
13. The compound of claim 1 wherein R 3 is a dipeptide consisting of a D-amino acid including an aromatic carbocyclic ring selected from the group consisting of phenyl, substituted phenyl, naphthyl and substituted naphthyl and a second amino acid residue with an amine capping group.
14. The compound of claim 10 , 11 , 12 or 13 wherein the D-amino acid is selected from the group consisting of Phe, Phe(2-Cl), Phe(4-Cl), Phe(2,4-diCl), Phe(2,4-diF), Phe(3,4-diCl), Phe(4-N02), Phe(4-Me), Phe(4-Phenyl), HPhe, pF-Phe, Phe(4-Br), Phe(4-CF 3 ), Phe(3,4-diF), Phe(4-I), Phe(2-Cl, 4-Me), Phe(2-Me, 4-Cl), Phe(2-F, 4-Cl), Phe(2,4-diMe), Phe(2-Cl, 4CF 3 ), and Phe(3,4di-OMe).
15. The compound of claim 10 , 11 , 12 or 13 wherein the D-amino acid is selected from the group consisting of Pgl, Trp, Nal 1, Nal 2, Bip, Dip, Bpa, Ser(Bzl), Ser(2-Naphthyl), Ser(Phenyl), Ser(4-Cl-Phenyl), Ser(2-Cl-Phenyl), Ser(p-Cl-Phenyl), Lys(Z), Lys(Z-2′Br), Lys(Bz), Thr(Bzl), Tic, Tiq, Cys(Bzl), Tyr(2,6-DiCl-Bzl) and Tyr(Bzl).
16. The compound of claim 12 or 13 wherein the second amino acid residue in the dipeptide is selected from the group of L-amino acids consisting of Abu, 2-Abz, 3-Abz, 4-Abz, Achc, Acpc, Aib, Amb, Arg(Tos), Asp(anilino), Asp(3-Cl-anilino), Asp(3,5-diCl-anilino), 11-Aun, AVA, Beta-hHyp(Bzl), Cha, Chg, Cmpi, Disc, Dpr(beta-Ala), GAA, GBZA, B-Gpa, GVA(Cl), His, hSer, Ser(Bzl), Tic, hHyp, Hyp(Bzl), Inp, 2-Naphthylacetyl, (Nlys)Gly, OcHx, Pip, 4-phenylPro, 5-phenylPro, Pyr, Sar, Tie, Tiq, Atc, Igl, Hyp(O-2-Naphthyl), Hyp(O-Phenyl), 2-Aic, Idc, 1-Aic, Beta-homoSer(Bzl), Ser(O-2-Naphthyl), Ser(O-Phenyl), Ser(O-4-Cl-Phenyl), Ser(O-2-Cl-Phenyl), Thr(Bzl), Tic, Beta-homoThr(Bzl), Thr(O-2-Naphthyl), Thr(O-Phenyl), Thr(O-4-Cl-Phenyl) and Thr(O-2-Cl-Phenyl), Nle, Leu, Ile, Val and Beta-Ala.
17. The compound of claim 11 or 13 wherein the amine capping group is selected from the group consisting of hexyl, hexanoyl, heptanoyl, acetyl, phenylacetyl, cyclohexylacetyl, naphthylacetyl, cinnamoyl, benzyl, benzoyl, 7′-amino heptanoyl, 12-Ado, 6-Ahx, Amc, and 8-Aoc.
18. A compound having the structure:
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein
R 1 is -L 1 -J;
R 2 is (CH 2 ) y —W;
R 3 is -L 2 -Q;
L 1 is a linker selected from the group consisting of —(CH 2 ) y —, —O—(CH 2 ) y —, —O—, —NH—(CH 2 ) y —, —(C═O)(CH 2 ) y —, —(C═O)—O—(CH 2 ) y —, and —CH 2 (C═O)NH—;
J is a ring structure selected from the group consisting of substituted or unsubstituted aromatic carbocyclic rings, substituted or unsubstituted non-aromatic carbocyclic rings, substituted or unsubstituted aromatic fused carbobicyclic ring groups, substituted or unsubstituted aromatic carbocyclic ring groups wherein the rings are joined by a bond or —O—, and substituted or unsubstituted aromatic fused heterobicyclic ring groups; wherein in each instance each ring in ring structure consists of 5 or 6 ring atoms;
W is selected from the group consisting of NH 2 , NH(C═NH)NH 2 , —NHCOCH 3 , —CONHCH 3 , —NH(C═NH)NHMe, —NH(C═NH)NHEt, —NH(C═NH)NHPr, —NH(C═NH)NHPr—I, —NH(C═NH)NH 2 , —NH(C═O)OCH 3 , —NH(C═O)CH 3 , —NH(C═O)NHCH 2 , —NH(C═O)NHCH 3 ,
L 2 is a linker selected from the group consisting of
Q is an aromatic carbocyclic ring selected from the group consisting of phenyl, substituted phenyl, naphthyl and substituted naphthyl;
R 4 is H, —R 5 or —R 5 —R 6 ;
R 5 is an amino acid residue or an amine capping group, provided that if R 6 is present, R 5 is an amino acid residue;
R 6 is H or an amine capping group; and y is at each occurrence independently from 1 to 6;
wherein the carbon atom marked with an asterisk can have any stereochemical configuration.
19. The compound of claim 18 wherein J is a substituted or unsubstituted ring structure selected from the group consisting of
20. The compound of claim 18 wherein at least one ring of the group J is substituted with one or more halogen, alkyl or aryl groups.
21. The compound of claim 18 wherein R 1 is selected from the group consisting of
22. The compound of claim 18 wherein R 1 is selected from the group consisting of
23. The compound of claim 18 wherein R 2 is selected from the group consisting of
24. The compound of claim 18 where Q is
wherein R 7 a and R 7 b are optional ring substituents, and when one or both are present, are the same or different and independently hydroxyl, halogen, alkyl, or aryl groups attached directly or through an ether linkage.
25. The compound of claim 24 wherein the alkyl group is —CH 3 or —OCH 3 .
26. The compound of claim 18 wherein R 5 or R 6 is an amine capping group selected from the group consisting of hexyl, hexanoyl, heptanoyl, acetyl, phenylacetyl, cyclohexylacetyl, naphthylacetyl, cinnamoyl, benzyl, benzoyl, cinnamoyl, 12-Ado, 7′-amino heptanoyl, 6-Ahx, Amc and 8-Aoc.
27. The compound of claim 18 wherein R 3 is a D-amino acid with an aromatic carbocyclic ring selected from the group consisting of phenyl, substituted phenyl, naphthyl and substituted naphthyl.
28. The compound of claim 18 wherein R 3 is a D-amino acid with an amine capping group and an aromatic carbocyclic ring selected from the group consisting of phenyl, substituted phenyl, naphthyl and substituted naphthyl.
29. The compound of claim 18 wherein R 3 is a dipeptide consisting of a D-amino acid including an aromatic carbocyclic ring selected from the group consisting of phenyl, substituted phenyl, naphthyl and substituted naphthyl and a second amino acid residue, wherein the D-amino acid is bonded to the ring nitrogen.
30. The compound of claim 18 wherein R 3 is a dipeptide consisting of a D-amino acid including an aromatic carbocyclic ring selected from the group consisting of phenyl, substituted phenyl, naphthyl and substituted naphthyl and a second amino acid residue with an amine capping group.
31. The compound of claim 27 , 28 , 29 or 30 wherein the D-amino acid is selected from the group consisting of Phe, Phe(2-Cl), Phe(4-Cl), Phe(2,4-diCl), Phe(2,4-diF), Phe(3,4-diCl), Phe(4-NO 2 ), Phe(4-Me), Phe(4-Phenyl), HPhe, pF-Phe, Phe(4-Br), Phe(4-CF 3 ), Phe(3,4-diF), Phe(4-I), Phe(2-Cl, 4-Me), Phe(2-Me, 4Cl), Phe(2-F, 4Cl), Phe(2,4-diMe), Phe(2-Cl, 4-CF 3 ), and Phe(3,4di-OMe).
32. The compound of claim 27 , 28 , 29 or 30 wherein the D-amino acid is selected from the group consisting of Pgl, Trp, Nal 1, Nal 2, Bip, Dip, Bpa, Ser(Bzl), Ser(2-Naphthyl), Ser(Phenyl), Ser(4-Cl-Phenyl), Ser(2-Cl-Phenyl), Ser(p-Cl-Phenyl), Lys(Z), Lys(Z-2′Br), Lys(Bz), Thr(Bzl), Tic, Tiq, Cys(Bzl), Tyr(2,6-DiCl-Bzl) and Tyr(Bzl).
33. The compound of claim 29 or 30 wherein the second amino acid residue is selected from the group of L-amino acids consisting of Abu, 2-Abz, 3-Abz, 4-Abz, Achc, Acpc, Aib, Amb, Arg(Tos), Asp(anilino), Asp(3-Cl-anilino), Asp(3,5-diCl-anilino), 11-Aun, AVA, Beta-hHyp(Bzl), Cha, Chg, Cmpi, Disc, Dpr(beta-Ala), GAA, GBzA, B-Cpa, GVA(Cl), His, hSer, Ser(Bzl), Tic, hHyp, Hyp(Bzl), Inp, 2-Naphthylacetyl, (Nlys)Gly, OcHx, Pip, 4-phenylPro, 5-phenylPro, Pyr, Sar, Tle, Tiq, Atc, Igl, Hyp(O-2-Naphthyl), Hyp(O-Phenyl), 2-Aic, Idc, 1-Aic, Beta-homoSer(Bzl), Ser(O-2-Naphthyl), Ser(O-Phenyl), Ser(O-4-Cl-Phenyl), Ser(O-2-Cl-Phenyl), Thr(Bzl), Tic, Beta-homoThr(Bzl), Thr(O-2-Naphthyl), Thr(O-Phenyl), Thr(O-4-Cl-Phenyl) and Thr(O-2-Cl-Phenyl), Nle, Leu, Ile, Val and Beta-Ala.
34. The compound of claim 28 or 30 wherein the amine capping group selected from the group consisting of hexyl, hexanoyl, heptanoyl, acetyl, phenylacetyl, cyclohexylacetyl, naphithylacetyl, cinnamoyl, benzyl, benzoyl, 7′-amino heptanoyl, 12-Ado, 6-Ahx, Amc, and 8-Aoc.
35. A compound having the structure:
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein
R, is -L 1 -J;
R 2 is (CH 2 ) y —W;
R 6 is H or an amine capping group;
R 7a and R 7b are optional ring substituents, and when one or both are present, are the same or different and independently hydroxyl, halogen, alkyl, or aryl groups attached directly or through an ether linkage;
L, is a linker selected from the group consisting of —(CH 2 ) y —, —O—(CH 2 ) y —, —O—, —NH—(CH 2 ) y —, —(C═O)(CH 2 ) y —, —(C═O)—O—(CH 2 ) y —, and —CH 2 (C═O)NH—;
J is a ring structure selected from the group consisting of substituted or unsubstituted aromatic carbocyclic rings, substituted or unsubstituted non-aromatic carbocyclic rings, substituted or unsubstituted aromatic fused carbobicyclic ring groups, substituted or unsubstituted aromatic carbocyclic ring groups wherein the rings are joined by a bond or —O—, and substituted or unsubstituted aromatic fused heterobicyclic ring groups; wherein in each instance each ring in the ring structure consists of 5 or 6 ring atoms;
W is selected from the group consisting of NH 2 , NH(C═NH)NH 2 , —NHCOCH 3 , —CONHCH 3 , —NH(C═NH)NHMe, —NH(C═NH)NHEt, —NH(C═NH)NHPr, —NH(C═NH)NHPr—I, —NH(C═NH)NH 2 , —NH(C═O)OCH 3 , —NH(C═O)CH 3 , —NH(C═O)NH 2 , —NH(C═O)NHCH 3 ,
y is at each occurrence independently from 1 to 6;
wherein the carbon atoms marked with an asterisk can have any stereochemical configuration.
36. The compound of claim 35 wherein J is a substituted or unsubstituted ring structure selected from the group consisting of
37. The compound of claim 35 wherein at least one ring of the group J is substituted with one or more halogen, alkyl or aryl groups.
38. The compound of claim 35 wherein R 1 is selected from the group consisting of
39. The compound of claim 35 wherein R 1 is selected from the group consisting of
40. The compound of claim 35 wherein R 2 is selected from the group consisting of
41. The compound of claim 35 wherein R 6 is an amine capping group selected from the group consisting of hexyl, hexanoyl, heptanoyl, acetyl, phenylacetyl, cyclohexylacetyl, naphthylacetyl, cinnamoyl, benzyl, benzoyl, cinnamoyl, 12-Ado, 7′-amino heptanoyl, 6-Ahx, Amc and 8-Aoc.
42. A compound having the structure:
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein
R, is -L 1 -J;
R 2 is (CH 2 ) y —W;
R 5 is an amino acid residue;
R 5 is H or an amine capping group;
R 7a and R 7b are optional ring substituents, and when one or both are present, are the same or different and independently hydroxyl, halogen, alkyl, or aryl groups attached directly or through an ether linkage;
L 1 is a linker selected from the group consisting of —(CH 2 ) y —, —O—(CH 2 ) y —, —O—, —NH—(CH 2 ) y —, —(C═O)(CH 2 ) y —, —(C═O)—O—(CH 2 ) y , and —CH 2 (C═O)NH—;
J is a ring structure selected from the group consisting of substituted or unsubstituted aromatic carbocyclic rings, substituted or unsubstituted non-aromatic carbocyclic rings, substituted or unsubstituted aromatic fused carbobicyclic ring groups, substituted or unsubstituted aromatic carbocyclic ring groups wherein the rings are joined by a bond or —O—, and substituted or unsubstituted aromatic fused heterobicyclic ring groups; wherein in each instance each ring in the ring structure consists of 5 or 6 ring atoms;
W is selected from the group consisting of NH 2 , NH(C═NH)NH 2 , —NHCOCH 3 , —CONHCH 3 , —NH(C═NH)NHMe, —NH(C═NH)NHEt, —NH(C═NH)NHPr, —NH(C═NH)NHPr—I, —NH(C═NH)NH 2 , —NH(C═O)OCH 3 , —NH(C═O)CH 3 , —NH(C═O)NH 2 , —NH(C═O)NHCH 3 ,
y is at each occurrence independently from 1 to 6;
wherein the carbon atoms marked with an asterisk can have any stereochemical configuration.
43. The compound of claim 42 wherein J is a substituted or unsubstituted ring structure selected from the group consisting of
44. The compound of claim 42 wherein at least one ring of the group J is substituted with one or more halogen, alkyl or aryl groups.
45. The compound of claim 42 wherein R 1 is selected from the group consisting of
46. The compound of claim 42 wherein R 1 is selected from the group consisting of
47. The compound of claim 42 wherein R 2 is selected from the group consisting of
48. The compound of claim 42 wherein R 6 is an amine capping group selected from the group consisting of hexyl, hexanoyl, heptanoyl, acetyl, phenylacetyl, cyclohexylacetyl, naphthylacetyl, cinnamoyl, benzyl, benzoyl, cinnamoyl, 12-Ado, 7′-amino heptanoyl, 6-Ahx, Amc and 8-Aoc.
49. The compound of claim 42 wherein R 5 is selected from the group of L-amino acids consisting of Abu, 2-Abz, 3-Abz, 4-Abz, Achc, Acpc, Aib, Amb, Arg(Tos), Asp(anilino), Asp(3-Cl-anilino), Asp(3,5-diCl-anilino), 11-Aun, AVA, Beta-hHyp(Bzl), Cha, Chg, Cmpi, Disc, Dpr(beta-Ala), GAA, GBZA, B-Gpa, GVA(Cl), His, hSer, Ser(Bzl), Tic, hHyp, Hyp(Bzl), Inp, 2-Naphthylacetyl, (Nlys)Gly, OcHx, Pip, 4-phenylPro, 5-phenylPro, Pyr, Sar, Tle, Tiq, Atc, Igl, Hyp(O-2-Naphthyl), Hyp(O-Phenyl), 2-Aic, Idc, 1-Aic, Beta-homoSer(Bzl), Ser(O-2-Naphthyl), Ser(O-Phenyl), Ser(O-4-Cl-Phenyl), Ser(O-2-Cl-Phenyl), Thr(Bzl), Tic, Beta-homoThr(Bzl), Thr(O-2-Naphthyl), Thr(O-Phenyl), Thr(O-4-Cl-Phenyl) and Thr(O-2-Cl-Phenyl), Nle, Leu, Ile, Val and Beta-Ala.
50. A composition comprising a compound of any one of claims 1 , 18 , 35 and 42 in combination with a pharmaceutically acceptable carrier.