LIGANDS OF MELANOCORTIN RECEPTORSThe present invention is directed to a compound according to formula, (R2R3)-B1-A1-c(A2-A3-A4-A5-A6-A7-A8-A9)-A10-A11-A12-A13-B2-B3-R1, that act as ligands for one or more of the melanocortin receptors, the pharmaceutically- acceptable salts thereof, to methods of using such peptides to treat mammals and to pharmaceutical compositions useful therefore comprising said peptides.A compound according to formula (I)(R2R3)-B1-A1-c(A2-A3-A4-A5-A6-A7-A8-A9)-A1°-A11-A12-A13-B2-B3-R1 wherein:B1 is a peptide moiety which contains 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids, wherein at least 5 amino acids are independently selected from the group consisting of L-Arg, D-Arg, L-hArg and D-hArg, or B1 is optionally deleted;A1 is Ace, HN-(CH2)m-C(O), L- or D-amino acid or deleted; A2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp or GIu;A3 is GIy, GIu, Ala, β- Ala, Gaba, Aib, D-amino acid or deleted; A4 is His, 2-Pal, 3-PaI7 4-Pal, Taz, 2-Thi, 3-Thi or (X^X^X^Phe; A5 is D-Phe, D-I-NaI, D-2-Nal, D-Trp, D-BaI, D-^X^X^Phe, D-(Et)Tyr, D-Dip, D-Bip or D-Bpa ; AMs Arg, hArg, Dab, Dap, Lys, Orn or HN-CH((CH.)n-N(R4Rs))-C(O);A7 is Trp, 1-Nal, 2-Nal, BaI, Bip, Dip, Bpa, D-Trp, D-I-NaI, D-2-Nal, D-BaI, D- Bip, D-Dip or D-Bpa;A8 is GIy, D-AIa, Ace, Ala, j?-Ala, Gaba, Apn, Ahx, Aha, HN-(CH2)S-C(O) or deleted; A9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn or Lys;A10 is Ace, HN-(CH2)t-C(O), Pro, hPro, 3-Hyp, 4-Hyp, Thr, an L- or D-amino acid or deleted;A11 is Pro, hPro, 3-Hyp, 4-Hyp or deleted; A12 is Lys, Dab, Dap, Arg, hArg or deleted; A13 is Asp, GIu or deleted;B2 is a peptide moiety containing 1, 2, 3, 4, or 5 amino acids or deleted, B3 is a peptide moiety which contains 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids wherein at least 5 amino acids are independently selected from the group consisting of L-Arg, D-Arg, L-hArg and D-hArg, or is deleted; R1 is -OH or -NH2; R2 and R3 each is , independently for each occurrence, selected from the group consisting of H, (Ci-C3o)alkyl, (Q-Go)heteroalkyl, (G-Go)acyl, (C2-Go)alkenyl, (C2-Go)alkynyl, aryl(Ci-C3o)alkyl/ aryl(Ci-Go)acyl, substituted (Ci-Go)alkyl, substituted(Ci-Go)heteroalkyl, substituted (G-Go)acyl, substituted (C2-C3o)alkenyl/ substituted (C2-Go)alkynyl, substituted aryl(Ci-Go)alkyl and substituted aryl(Ci-C3o)acyl;R4 and R5 each is, independently for each occurrence, H, (Ci-Qo)alkyl, (Ci-Qo)heteroalkyl, (Ci-Qo)acyl, (C2-Qo)alkenyl, (C2-Qo)alkynyl, aryl(Ci-Qo)alkyl, aryl(Ci-Qo)acyl, substituted (Ci-Qo)alkyl, substituted (Ci-Qo)heteroalkyl, substituted(Ci-Qo)acyl, substituted (C2-Qo)alkenyl, substituted (C2-Qo)alkynyl, substituted aryl(Ci-Qo)alkyl, substituted aryl(Ci-Go)acyl, (Ci-Qo)alkylsulfonyl or -C(NH)-NH2; n is, independently for each occurrence, 1, 2, 3, 4 or 5; m is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; s is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; t is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; X1, X2, X3, X4 and X5 each is, independently for each occurrence, H, F, Cl, Br, I,(Ci-io)alkyl, substituted (Ci-io)alkyl, (C2-io)alkenyl, substituted (C2-io)alkenyl, (G- io)alkynyl, substituted (C2-io)alkynyl, aryl, substituted aryl, OH, NH2, NO2 or CN; provided that:(I) when R4 is (Ci-Qo)acyl, aryl(Ci-C4o)acyl, substituted (Ci-Qo)acyl, substituted aryl(Ci-Qo)acyl, (G-Qo)alkylsulfonyl or -C(NH)-NH2, then R5 is H, (Ci- αo)alkyl, (Ci~C4o)heteroalkyl, (G-C4o)alkenyl, (G-C4o)alkynyl, aryl(Ci-Qo)alkyl, substituted (Ci-C4o)alkyl, substituted (Ci-C4o)heteroalkyl, substituted (C2-Qo)alkenyl, substituted (C2-Oo)alkynyl or substituted aryl(Ci-Qo)alkyl;(II) when R2 is (Ci-C3o)acyl, aryl(Ci-C3o)acyl, substituted (Ci-C3o)acyl or substituted aryl(G-C3o)acyl, then R3 is H, (Ci-C3o)alkyl, (Ci-C3o)heteroalkyl, (C2-C3o)alkenyl, (C2-C3o)alkynyl, aryl(G-C3o)alkyl, substituted (Ci-C3o)alkyl, substituted (G-C3o)heteroalkyl, substituted (C2-C3o)alkenyl, substituted (C2-C3o)alkynyl or substituted aryl(Ci-C3o)alkyl;(III) neither B1 nor B2 contains one or more of the following amino acid sequences: Arg-(Lys)2-(Arg)2-Gln-(Arg)3, Tyr-Ala-Arg-Lys-Ala-(Arg)2-Gln-Ala- (Arg)2, Tyr-Ala-Arg-(Ala>-(Arg)2-(Ala)2-(Arg)2, Tyr-Ala-(Arg)9, Tyr-(Ala)3-(Arg>, Tyr-Ala-Arg-Ala-Pro-(Arg)2-Ala-(Arg)3 or Tyr-Ala-Arg-Ala-Pro-(Arg)2-Pro-(Arg)2;(IV) either B1 or B2 or both must be present in said compound;(V) when A2 is Cys, D-Cys, hCys, D-hCys, Pen or D~Pen, then A9 is Cys, D-Cys, hCys, D-hCys, Pen or D-Pen; and(VI) when A2 is Asp or GIu, then A9 is Dab, Dap, Orn or Lys; or a pharmaceutically acceptable salt thereof.
멜라노코르틴 수용체의 리간드본 발명은 하나 이상의 멜라노코르틴 수용체에 대해 리간드로서 작용하는 식: (R2R3)-B1-A1-c(A2-A3-A4-A5-A6-A7-A8-A9)-A10-A11-A12-A13-B2-B3-R1에 따른 화합물, 약제학적으로 허용가능한 그의 염, 포유류를 치료하기 위한 상기 화합물의 이용 방법, 및 상기 화합물을 포함하는 포유류 치료에 이용가능한 약학 조성물에 관한 것이다.식 (I)의 화합물 또는 약제학적으로 허용가능한 그의 염: 식 (I) (R2R3)-B1-A1-c(A2-A3-A4-A5-A6-A7-A8-A9)-A10-A11-A12-A13-B2-B3-R1 상기 식 (I)에서, B1은 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 또는 15개의 아미노산을 포함하며 5개 이상의 아미노산은 독립적으로 L-Arg, D-Arg, L-hArg 및 D-hArg으로 이루어진 군으로부터 선택되는 펩티드 모이어티이거나, 또는 B1은 선택적으로 삭제되며; A1은 Acc, HN-(CH2)m-C(O), L-아미노산 또는 D-아미노산이거나, 삭제되며; A2는 Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp 또는 Glu이며; A3는 Gly, Glu, Ala, β-Ala, Gaba, Aib 또는 D-아미노산이거나, 삭제되며; A4는 His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, 또는 (X1,X2,X3,X4,X5)Phe이며; A5는 D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X1,X2,X3,X4,X5)Phe, D-(Et)Tyr, D-Dip, D-Bip 또는 D-Bpa이며; A6은 Arg, hArg, Dab, Dap, Lys, Orn 또는 HN-CH((CH2)n-N(R4R5))-C(O)이며; A7은 Trp, 1-Nal, 2-Nal, Bal, Bip, Dip, Bpa, D-Trp, D-1-Nal, D-2-Nal, D-Bal, D-Dip 또는 D-Bip이며; A8은 Gly, D-Ala, Acc, Ala, β-Ala, Gaba, Apn, Ahx, Aha, HN-(CH2)s-C(O)이거나, 삭제되며; A9는 Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn 또는 Lys이며; A10은 Acc, HN-(CH2)t-C(O), Pro, hPro, 3-Hyp, 4-Hyp, Thr, L- 또는 D-아미노산이거나, 삭제되며; A11은 Pro, hPro, 3-Hyp 또는 4-Hyp이거나, 삭제되며; A12는 Lys, Dab, Dap, Arg 또는 hArg이거나, 삭제되며; A13은 Asp 또는 Glu이거나, 삭제되며; B2는 1, 2, 3, 4 또는 5개의 아미노산을 포함하는 펩티드 모이어티이거나, 삭제되며, B3은 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 또는 15개의 아미노산을 포함하며 5개 이상의 아미노산은 독립적으로 L-Arg, D-Arg, L-hArg 및 D-hArg로 이루어진 군으로부터 선택되는 펩티드 모이어티이거나, 삭제되며; R1은 -OH 또는 -NH2이며; R2 및 R3는 각각 각 경우에 독립적으로, H, (C1-C30)알킬, (C1-C30)헤테로알킬, (C1-C30)아실, (C2-C30)알케닐, (C2-C30)알키닐, 아릴(C1-C30)알킬, 아릴(C1-C30)아실, 치환된 (C1-C30)알킬, 치환된 (C1-C30)헤테로알킬, 치환된 (C1-C30)아실, 치환된 (C2-C30)알케닐, 치환된 (C2-C30)알키닐, 치환된 아릴(C1-C30)알킬 및 치환된 아릴(C1-C30)아실로 이루어진 군으로부터 선택되며; R4 및 R5는 각각 각 경우에 독립적으로, H, (C1-C40)알킬, (C1-C40)헤테로알킬, (C1-C40)아실, (C2-C40)알케닐, (C2-C40)알키닐, 아릴(C1-C40)알킬, 아릴(C1-C40)아실, 치환된 (C1-C40)알킬, 치환된 (C1-C40)헤테로알킬, 치환된 (C1-C40)아실, 치환된 (C2-C40)알케닐, 치환된 (C2-C40)알키닐, 치환된 아릴(C1-C40)알킬, 치환된 아릴(C1-C40)아실, (C1-C40)알킬설포닐 또는 -C(NH)-NH2이며; n은 각 경우에 독립적으로, 1, 2, 3, 4 또는 5이며; m은 각 경우에 독립적으로, 1, 2, 3, 4, 5, 6 또는 7이며; s는 각 경우에 독립적으로, 1, 2, 3, 4, 5, 6 또는 7이며; t는 각 경우에 독립적으로, 1, 2, 3, 4, 5, 6 또는 7이며; X1, X2, X3, X4 및 X5는 각각 각 경우에 독립적으로 H, F, Cl, Br, I, (C1-10)알킬, 치환된 (C1-10)알킬, (C2-10)알케닐, 치환된 (C2-10)알케닐, (C2-10)알키닐, 치환된 (C2-10)알키닐, 아릴, 치환된 아릴, OH, NH2, NO2 또는 CN이며; 단, 하기를 만족한다: (I). R4가 (C1-C40)아실, 아릴(C1-C40)아실, 치환된 (C1-C40)아실, 치환된 아릴(C1-C40)아실, (C1-C40)알킬설포닐 또는 -C(NH)-NH2이면, R5는 H, (C1-C40)알킬, (C1-C40)헤테로알킬, (C2-C40)알케닐, (C2-C40)알키닐, 아릴(C1-C40)알킬, 치환된 (C1-C40)알킬, 치환된 (C1-C40)헤테로알킬, 치환된 (C2-C40)알케닐, 치환된 (C2-C40)알키닐, 또는 치환된 아릴(C1-C40)알킬이고; (II). R2가 (C1-C30)아실, 아릴(C1-C30)아실, 치환된 (C1-C30)아실, 또는 치환된 아릴(C1-C30)아실이면, R3은 H, (C1-C30)알킬, (C1-C30)헤테로알킬, (C2-C30)알케닐, (C2-C30)알키닐, 아릴(C1-C30)알킬, 치환된 (C1-C30)알킬, 치환된 (C1-C30)헤테로알킬, 치환된 (C2-C30)알케닐, 치환된 (C2-C30)알키닐, 또는 치환된 아릴(C1-C30)알킬이고; (III) B1 및 B2 둘다 아미노산 서열: Arg-(Lys)2-(Arg)2-Gln-(Arg)3, Tyr-Ala-Arg-Lys-Ala-(Arg)2-Gln-Ala-(Arg)2, Tyr-Ala-Arg-(Ala)2-(Arg)2-(Ala)2-(Arg)2, Tyr-Ala-(Arg)9, Tyr-(Ala)3-(Arg)7, Tyr-Ala-Arg-Ala-Pro-(Arg)2-Ala-(Arg)3 및 Tyr-Ala-Arg-Ala-Pro-(Arg)2-Pro-(Arg)2 중 하나 이상을 포함하지 않으며; (IV) B1 및 B2 중 어느 하나 또는 둘다는 상기 화합물에 존재하여야 하며; (V) A2가 Cys, D-Cys, hCys, D-hCys, Pen 또는 D-Pen이면, A9는 Cys, D-Cys, hCys, D-hCys, Pen 또는 D-Pen이고; (VI) A2가 Asp 또는 Glu이면, A9는 Dab, Dap, Orn 또는 Lys이다.