Claims for Patent: 9,458,195

Summary for Patent: 9,458,195

Title:	Melanocortin receptor ligands
Abstract:	The present invention is directed to compounds according to formula, (R2R3)-A1-c(A2-A3-A4-A5-A6-A7-A8-A9)-A10-R1, and pharmaceutically-acceptable salts thereof that act as ligands for one or more of the melanocortin receptors, to methods of using such compounds to treat mammals and to pharmaceutical compositions comprising said compounds.
Inventor(s):	Zheng Xin Dong, Jacques-Pierre Moreau
Assignee:	Ipsen Pharma SAS
Application Number:	US13/074,565
Patent Claims:	1. A compound according to formula (I): (R2R3)-A1-c(A2-A3-A4-A5-A6-A7-A8-A9)-A10-R1 wherein: A1 is Arg, D-Arg, Cha, hCha, Chg, D-Chg, Ile, Leu, 2-Nal, Nle, Phe, D-Phe, hPhe, Val or deleted; A2 is Cys, Pen or Asp; A3 is D-Ala, D-Abu, D-Cha, D-Ile, D-Leu, D-Tle, or D-Val; A4 is His or 3-Pal; A5 is D-Phe, D-2-Nal or D-(Et)Tyr; A6 is Arg or hArg; A7 is Trp, 2-Nal, Bal, Bip or D-Trp; A8 is Gly, Ala, β-Ala, Gaba, Apn, Ahx or deleted; A9 is Cys, D-Cys, Pen or Lys; A10 is Thr or deleted; and R2 and R3 is, independently for each occurrence, H or acyl; R1 is —OH or —NH2; provided that (I). when A2 is Cys or Pen, then A9 is Cys, D-Cys, or Pen; (II). when A2 is Asp, then A9 is Lys; (III). when A1 is deleted, then R2 and R3 cannot both be H; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein said compound is: SEQ ID NO: 50 Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 50 Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 51 Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO: 51 Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO: 7 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 21 Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 22 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO: 28 Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH2; SEQ ID NO: 28 Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH2; SEQ ID NO: 29 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; SEQ ID NO: 30 Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 30 Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 30 Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 30 Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 30 Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 30 Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 36 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO: 16 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO: 16 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH2; SEQ ID NO: 20 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH2; SEQ ID NO: 49 Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO: 17 n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal- Cys)-NH2; SEQ ID NO: 17 n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp- Cys)-NH2; SEQ ID NO: 18 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH2; SEQ ID NO: 18 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH2; SEQ ID NO: 20 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH2; SEQ ID NO: 21 Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 22 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO: 22 Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; or SEQ ID NO: 29 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO: 46 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-OH; SEQ ID NO: 46 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-OH; SEQ ID NO: 46 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-OH; SEQ ID NO: 47 Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO: 29 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; or SEQ ID NO: 49 Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 1, wherein: A1 is Arg or D-Arg; or a pharmaceutically acceptable salt thereof. 4. A compound according to claim 3, wherein A3 is D-Ala; A4 is His; A7 is Trp, Bip, D-Trp or 2-Nal; A8 is Ala, β-Ala, Gaba, Apn or Ahx; or a pharmaceutically acceptable salt thereof. 5. A compound according to claim 4, wherein: R2 and R3 is, independently for each occurrence, H, acyl, n-propanoyl or n-butanoyl; or a pharmaceutically acceptable salt thereof. 6. A compound according to claim 1, wherein A2 is Cys or Asp; A3 is D-Ala; A4 is His; A5 is D-Phe or D-2-Nal; A6 is Arg; A7 is Trp; A8 is Ala, Gaba or deleted; A9 is Cys, Pen or Lys; A10 is deleted; or a pharmaceutically acceptable salt thereof. 7. A compound according to claim 6, wherein said compound is: SEQ ID NO: 50 Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 50 Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 51 Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO: 51 Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; or SEQ ID NO: 49 Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; or pharmaceutically acceptable salts thereof. 8. A compound according to claim 7, wherein said compound is: SEQ ID NO: 50 Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 51 Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; or SEQ ID NO: 49 Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; or a pharmaceutically acceptable salt thereof. 9. A compound according to claim 8, wherein said compound is: SEQ ID NO: 50 Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; or a pharmaceutically acceptable salt thereof. 10. A compound according to claim 8, wherein said compound is: SEQ ID NO: 51 Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; or a pharmaceutically acceptable salt thereof. 11. A compound according to claim 8, wherein said compound is: SEQ ID NO: 49 Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; or a pharmaceutically acceptable salt thereof. 12. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 13. A pharmaceutical composition according to claim 12, wherein said compound is a selective melanocortin-4 receptor agonist or a pharmaceutically acceptable salt thereof. 14. A pharmaceutical composition according to claim 13, wherein said compound is a selective melanocortin-4 receptor agonist or a pharmaceutically acceptable salt thereof with a functional activity characterized by an EC50 at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin-1 receptor, the human melanocortin-3 receptor and the human melanocortin-5 receptor. 15. A pharmaceutical composition according to claim 14, wherein the functional activity of the melanocortin-4 receptor agonist is characterized by an EC50 at least 17-fold more selective for the human melanocortin-4 receptor than for the human melanocortin-3 receptor. 16. A pharmaceutical composition according to claim 14, wherein the functional activity of the melanocortin-4 receptor agonist is characterized by an EC50 at least 90-fold more selective for the human melanocortin-4 receptor than for the human melanocortin-3 receptor. 17. A pharmaceutical composition according to claim 14, wherein the functional activity of the melanocortin-4 receptor agonist is characterized by an EC50 at least 200-fold more selective for the human melanocortin-4 receptor than for the human melanocortin-5 receptor. 18. A pharmaceutical composition according to claim 14, wherein the functional activity of the melanocortin-4 receptor agonist is characterized by an EC50 at least 3000-fold more selective for the human melanocortin-4 receptor than for the human melanocortin-5 receptor. 19. A compound according to formula II: (R2R3)-A1-c(A2-A3-A4-A5-A6-A7-A8-A9)-NH2 wherein: A1 is Nle or deleted; A2 is Cys or Asp; A3 is D-Ala; A4 is His; A5 is D-Phe; A6 is Arg; A7 is Trp, 2-Nal or Bal; A8 is Gly, Ala, D-Ala, β-Ala, Gaba or Apn; A9 is Cys or Lys; each of R2 and R3 is independently selected from the group consisting of H or (C1-C6)acyl; provided that (I). when R2 is (C1-C6)acyl, then R3 is H; (II). when A2 is Cys, then A9 is Cys; and (III). when A2 is Asp, then A9 is Lys, or a pharmaceutically acceptable salt thereof. 20. A compound according to claim 19, wherein said compound is: SEQ ID NO: 54 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH2; SEQ ID NO: 54 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)- NH2; SEQ ID NO: 54 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)- NH2; SEQ ID NO: 54 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)- NH2; SEQ ID NO: 54 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO: 56 Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO: 56 Ac-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH2; SEQ ID NO: 57 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO: 57 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)- NH2; SEQ ID NO: 57 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)- NH2; or SEQ ID NO: 58 Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Ala-Lys)-NH2; or a pharmaceutically acceptable salt thereof. 21. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 22. A pharmaceutical composition according to claim 21, wherein said compound is a selective melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof. 23. A pharmaceutical composition according to claim 22, wherein said compound is a selective melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof, with a functional activity characterized by an EC50 at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, the human melanocortin 3 receptor and the human melanocortin 5 receptor. 24. A pharmaceutical composition according to claim 23, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor. 25. A pharmaceutical composition according to claim 23, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC50 at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor. 26. A pharmaceutical composition according to claim 23, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC50 at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor. 27. A pharmaceutical composition according to claim 23, wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC50 at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.