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1. AU2003202533 - Analogues of GLP-1

Office Australia
Application Number 2003202533
Application Date 27.03.2003
Publication Number 2003202533
Publication Date 10.04.2003
Publication Kind B2
IPC
C07K 14/605
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
KPEPTIDES
14Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
435from animals; from humans
575Hormones
605Glucagons
A61K 38/26
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
38Medicinal preparations containing peptides
16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
17from animals; from humans
22Hormones
26Glucagons
Applicants IPSEN Pharma S.A.S.
Inventors Dong, Zheng Xin
Agents Griffith Hack
Priority Data 09206601 07.12.1998 US
60111255 07.12.1998 US
Title
(EN) Analogues of GLP-1
Abstract
(EN)
A compound of formnula (RzR 3)-A 7 -AB-A-A'-A 1 '-A13 -A"4-A'5-A-A 17 8 -A"o-A 20-A 2 -A 22-A23-A 24-A 5-A 26-A27 A'5 -A 2-A30-A 3 2A3AuA5A3-JrAaA9 wherein A' is L-His, Ura, Paa, Pta, Amp, Tma-i-is, des-amino-His, or deleted;, A8 is Ala. 0-Ala, Aib, Aco, N-Me-Ala, N-Me-D-Ala or N-Me-Gly; A' is Glu, N-Me-Glu, N-Me-Asp or Asp; A"0 is Gly. Aco, fl-Ala or Aib;: A"1 is Thr or Ser. A 1 is PI-e, Acc, Aic, bib, 3-Pal, 4-Pal, B-Nal, Cha, Tmp or X'-Phe; A"isTr or Ser A' is Ser or bib; All is Asp or Glu; A' is Val, Acc. Ailb, Leu. lie, Tie, Nie, A bu, Ala or Cha; All is Ser or Thr, A" is Ser or Thc, A"9 is Tyr, Cha, Phe, 3-Pal, 4-Pal, Acc, I3-Nal or X'-Phe; is Leu. Acc, Aib. Nie, Ilie, Cha, Tie, Val, Phe or X1-Phe; A2' is Glu or Asp; A12 is Gly, Acc, 1-Ala, Glu or Abb; All is Gin, Asp, Amn or Glu; is Ala, Aib, Val, Abu, Tie or Acc; A'is Ala, Aib. Val, Abu. Tie, Acc. Lys, Ary, hArg, Orn, HN-CH((CH2,,-N(R'0 R")Y-0(0) or HN-CH((CH2,X-X 3 is Lys. Arg, hArg, Om, HN-CH((CH2,-N(R'0 or HN-CH((CH,).X-C(0); A 2 is Glu Asp, Leu, Aib or Lys; All is Phe. Pal. 13-Nal, X'-Phe, Aic. Acc. Aib. Cha or Trp; A~g is lie. Acc, Aib. Leu. Nie, Cha, Tie, Val. Abu. Ala or Phe; A' is Ala, Aib or Acc; A3 is Trp. /3-Nal, 3-Pal. 4-Pal, Phe, Aec, Aib or Cha;. A"2 is Leu, Acc. Aib. Nie, lie, Cha, Tie, Phe, X'-Phe or Ala; A"3 is Val, Ace, Aib, Leu, Ilie, Tie, Nie, Cha, Ala, Phe, Abu, Lys or X'-Phe; A"4 is Lys, Arg, hArg, Cmn, HN-CH((CH 2 10 or HN-CH((CH2,)-x 3 A' is Gly, 13-Ala, 0-Ala, Gaba, Ava, HN-(CHz)m,,C(O), Aib, Ace or a 0-amnino acid; A' is'L- or 0-Arg. 0- or L-Lys, 0- or L-hArg, 0- or L-Orn. HN-CH((CH2),-N(R10 HN-CH((CH 2h-X3 or deleted; A 31 is Gly. B3-Ala, Gaba, Ava. Aib, Acc, Ado. Arg, Asp. Aun, Aec, HN-(CH 2 )nc-C(C), HN-CH((0H 2X.-N(R' 0 a 0-amino acid, or deleted; A3 is D- or L-Lys, D- or L-Arg, 0- or L-hArg. D- or L-Omn, HN-CH((CH 2 1'R1 HN-CH((CH 2 3 Ava, Ado, Aec or deleted; is 0- or L-Lys, 0- or L-Arg, HN-CH((CH2 Ava, Ado, or Aec; X1 for each occurrence is independenby selected from the group consisting of (Cr-C6)alkyl, OH and halo; R' is OH, NH 2 (C1-CAalkoxy. or NH-X 2 -CH2-Z wherein X2 is a (Ci-C1 )hydrocarbon moiety, and Z' is H. OH, 002 H or CONK12 or -C(O)-NHR' 2 wherein X4 is, independently for each occurrence, -NH-or and wherein f is, independently for each occurrence, an integer from 1 to 29 inclusive: each of R2 and R3 is independently selected from the group consisting of H, (C'c C3.4alkyl, (C2-C3,)alkerfyl, phenyl(C1 -C,0 )alkyl. naphthyl(C1-C3,jakyl, hydroxy(C1 C3,)alkyl. hydroxy(C,-C30)alkenyl. hydroxyphenyl(C 1-C3jalkyl, and t hydroxynaphthyl(C1 -Q,)alkyl; or one of R 2 and R' is (OH 32-N"-C=N(CH 3 2 (C, C,)acyl. (C,-C,,,)a~kylsutfonyl. C(O)X5 or wherein Y is H, OH or NH,; r is 0 to 4; q is 0 to 4; and X5 is (C -C%)alkyl, (C-C,)alkenyl, phenyl(C,-C,)alkyl naphthyl(C,-C,,)alkyl, hydroxy(C, -Cx)alkyl, hydroxy(C,-Cw)alkenyl. hydroxyphenyl(C,-C)alkyl or hydroxynaphthyl(C,-Cac)alkyl; e is, independently for each occurrence, an integer from 1 to 4 inclusive; mn is, independently for each occurrence, an integer from 5 to,24 inclusive; n is, independently for each occurrence, an integer from 1 to 5, inclusive; each of R" and R" is, independently for each occurrence, H, (C,-C,)alkyl, C or R' 2 and R" each is, independently for each occurrence, (C,-C,)alkyl; provided that: when A7 is Ura, Paa or Pta, then R2 and R3 are deleted; when R1" is (C,-C 0)acyl, (C-C3o)alkylsulfonyl. or H then R" is H or (C,-C3 )alkyl; at least one amino acid of.a compound of formula is not the same as the native sequence of hGLP-1(7-36. -37 or -38)NH, or hGLP-1(7-36, -37 or -38)OH (ii) a compound of formula is not an analogue of hGLP-1(7-36, -37 or -38)NH, or hGLP-1 (7-36, -37 or -38)OH wherein a single position has been substituted by Ala; 8 (iii) a compound of formula is not Lysf)hGLP-1(7-38)-E, (Lys2 (Nc alkanoyl))hGLP-1(7-36, -37 or (Lys"(N.-alkanoyl))hGLP-1(7-36, -37 or 38)-E, (Lys-bis(NrAlkanoyl))hGLP-1(7-36, -37 or (Arg2, LysM (Ncalkanoyl))hGLP-1 (8-36, -37 or (Argm", Lys(N-alkanoyl))hGLP-1(7-36. -37 or -38)-E or (Arg"' Lys9(Nalkanoyl))hGLP-1(7-38)-E, wherein E is -OH or -NH,: (iv) a compound of formula is not Z'-hGLP-1(7-36. -37 or -38)-OH. Z'-hGLP-1(7 36. -37 or wherein Z' is selected from the group consisting of: (ArgL"). (Arg2f). (LysL). (Argm, Lysf), (Arg", (D-Lys") (D-Argm). Lys") or (Arg 2m t , Lys"), (0 (Asp"); at least one of (D-Ala') and and (Tyr7 (N-acyl-His'), (N-alkyl-His'), (N-acyl-D-His) or (N-alkyl-D-His'); a compound of formula is not a combination of any two of the substitutions listed in groups to and (vi) a compound of formula is not (N-Me-Ala')hGLP-1 (8-36 or (GIu' 5)hGLP-1(7-36 or-37). (Asp")hGLP-1(7-36 or-37) (Phe3 )hGLP-1(7-36 or -37 or (Aibs.35)hGLP-1 (7-36)NH 2 or a pharmaceutically acceptable salt thereof.