ANALOGUES OF GLUCOSE-DEPENDENT INSULINOTROPIC POLYPEPTIDE (GIP) MODIFIED AT N-TERMINAL

摘要

There is provided a novel series of analogues of glucose-dependent insulinotropic polypeptide, pharmaceutical compositions containing said compounds, and the use of said compounds as GIP-receptor agonists or antagonists for treatment of GIP-receptor mediated conditions, such as non-insulin dependent diabetes mellitus and obesity.

主权项

1. A compound of formula (I),
(R2R3)-A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-A41-A42-A43-R1,  (I)wherein:
A1 is Cpa, His, 4Hppa, 2-Pal, 3-Pal, 4-Pal, (X4,X5,X6,X7,X8)Phe, Taz, 3Thi, 7HO-Tic, Tyr(Ac), Tyr(Me), β-Tyr, 3Br-Tyr, 3,5Br-Tyr, 3Cl-Tyr, 2F-Tyr, 3F-Tyr, hTyr, 3I-Tyr, 3,5I-Tyr, αMe-Tyr, 2,6Me-Tyr, 3MeO-Tyr, 3NH2-Tyr, 3NO2-Tyr, 3OH-Tyr, or 3(HO—(CH2)Tyr; A2 is Ala, Abu, D-Abu, Acc, Aib, β-Ala, D-Ala, Gaba, Gly, Ser, D-Ser, Thr, D-Thr, Val, or D-Val; A3 is Glu, Aib, Asp, N-Me-Asp, Dhp, Dmt, N-Me-Glu, 3Hyp, 4Hyp, 4Ktp, Pro, hPro, Thz, or Tic; A4 is Gly, Acc, Aib, or β-Ala; A5 is Thr, Acc, Aib, or Ser; A6 is Phe, Acc, Aib, Aic, Cha, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, (X4,X5,X6,X7,X8)Phe, or Trp; A7 is Ile, Abu, Acc, Aib, Ala, Cha, Leu, Nle, Phe, Tle, or Val; A8 is Ser, Aib, or Thr; A9 is Asp, Aib, or Glu; A10 is Tyr, Acc, Cha, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, Phe, or (X4,X5,X6,X7,X8)Phe; A11 is Ser, Acc, Aib, Nle, or Thr; A12 is Ile, Abu, Acc, Aib, Ala, Cha, Leu, Nle, Phe, Tle, or Val; A13 is Ala, Acc, Aib, β-Ala, D-Ala, Gly, or Ser; A14 is Met, Abu, Acc, Aib, Ala, Cha, Ile, Leu, Nle, Phe, Tle, or Val; A15 is Asp, Aib, or Glu; A16 is Lys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3); A17 is Ile, Abu, Acc, Aib, Ala, Cha, Leu, Nle, Phe, Tle, or Val; A18 is His, Amp, Arg, 2-Pal, 3-Pal, 4-Pal, Phe, or Tyr; A19 is Gln, Aib, or Asn; A20 is Gln, Aib, or Asn; A21 is Asp, Aib, or Glu; A22 is Phe, Acc, Aib, Aic, Cha, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, (X4,X5,X6,X7,X8)Phe, or Trp; A23 is Val, Abu, Acc, Aib, Ala, Cha, Ile, Leu, Nle, or Tle; A24 is Asn, Aib, or Gln; A25 is Trp, Acc, Aib, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, Phe, or (X4,X5,X6,X7,X8)Phe; A26 is Leu, Acc, Aib, Cha, Ile, Nle, Phe, (X4,X5,X6,X7,X8)Phe, or Tle; A27 is Leu, Acc, Aib, Cha, Ile, Nle, Phe, (X4,X5,X6,X7,X8)Phe, or Tle; A28 is Ala, Acc, or Aib; A29 is Gln, Aib, Asn, or deleted; A30 is Lys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted; A31 is Gly, Aib, Acc, β-Ala, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted; A32 is Lys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted; A33 is Lys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted; A34 is Asn, Aib, Gln, Ser, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted; A35 is Asp, Aib, Glu, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted; A36 is Trp, Acc, Aib, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, Phe, (X4,X5,X6,X7,X8)Phe, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted; A37 is Lys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted; A38 is His, Amp, 2-Pal, 3-Pal, 4-Pal, Phe, Tyr, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)sNH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)sNH—C(O)—(CH2)t—CH3), or deleted; A39 is Asn, Aib, Gln, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted; A40 is Ile, Acc, Aib, Ser, Thr, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted; A41 is Thr, Acc, Aib, Asn, Gln, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted; A42 is Gln, Acc, Aib, Asn, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), or deleted; A43 is Acc, Ado, Aib, Ala, Asn, Asp, His, Gln, Phe, Thr, Trp, HN—CH((CH2)n—N(R4R5))—C(O), Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl), Cys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), hCys(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Pen(succinimide-N—(CH2)x—C(O)—NH—(CH2)y—CH3), Cys(succinimide-N—(CH2)s—NH—C(O)—(CH2)t—CH3), hCys(succinimide-N—(CH2)sNH—C(O)—(CH2)t—CH3), Pen(succinimide-N—(CH2)sNH—C(O)—(CH2)t—CH3), or deleted; R1 is OH, NH2, (C1-C30)alkoxy, or NH—X2—CH2—Z0, wherein X2 is a (C0-C30) hydrocarbon moiety and Z0 is H, OH, CO2H, or CONH2; each of R2, R3, R4 and R5 is independently selected from the group consisting of H, (C1-C30)alkyl, (C1-C30)heteroalkyl, (C1-C30)acyl, (C2-C30)alkenyl, (C2-C30)alkynyl, aryl(C1-C30)alkyl, aryl(C1-C30)acyl, substituted (C1-C30)alkyl, substituted (C1-C30)heteroalkyl, substituted (C1-C30)acyl, substituted (C2-C30)alkenyl, substituted (C2-C30)alkynyl, substituted aryl(C1-C30)alkyl, and substituted aryl(C1-C30)acyl; provided that when R2 is (C1-C30)acyl, aryl(C1-C30)acyl, substituted (C1-C30)acyl, or substituted aryl(C1-C30)acyl, then R3 is H, (C1-C30)alkyl, (C1-C30)heteroalkyl, (C2-C30)alkenyl, (C2-C30)alkynyl, aryl(C1-C30)alkyl, substituted (C1-C30)alkyl, substituted (C1-C30)heteroalkyl, substituted (C2-C30)alkenyl, substituted (C2-C30)alkynyl, or substituted aryl(C1-C30)alkyl; further provided that when R4 is (C1-C30)acyl, aryl(C1-C30)acyl, substituted (C1-C30)acyl, or substituted aryl(C1-C30)acyl, then R5 is H, (C1-C30)alkyl, (C1-C30)heteroalkyl, (C2-C30)alkenyl, (C2-C30)alkynyl, aryl(C1-C30)alkyl, substituted (C1-C30)alkyl, substituted (C1-C30)heteroalkyl, substituted (C2-C30)alkenyl, substituted (C2-C30)alkynyl, or substituted aryl(C1-C30)alkyl; n is, independently for each occurrence, an integer from 1 to 5 inclusive; s, t, x and y each is, independently for each occurrence, an integer from 1 to 30 inclusive; X4, X5, X6, X7 and X8 each is, independently for each occurrence, H, F, CF3, Cl, Br, I, (C1-10)alkyl, substituted (C1-10)alkyl, aryl, substituted aryl, OH, NH2, —CH2NH2, NO2, or CN; provided that when A1 is 4Hppa, then R2 and R3 are deleted; further provided that the compound contains more than one amino acid substitutions or modifications at positions 1, 2 and 3; and further provided that if the amino acid at position 1 is modified, it is not modified by: (a) N-terminal alkylation; (b) N-terminal acetylation; (c) N-terminal acylation; (d) the addition of an N-terminal isopropyl group; or (e) the addition of an N-terminal pyroglutamic acid; or a pharmaceutically acceptable salt thereof.