Analogues of GLP-1

Analogues of GLP-1

  • CN 1,329,620 A
  • Filed: 12/07/1999
  • Published: 01/02/2002
  • Est. Priority Date: 12/07/1998
  • Status: Abandoned Application
First Claim
Patent Images

1. a formula (I) compound(R 2R 3)-A 7-A 8-A 9-A 10-A 11-A 12-A 13-A 14-A 15-A 16-A 17-A 18-A 19-A 20-A 21-A 22-A 23-A 24-A 25-A 26-A 27-A 28-A 29-A 30-A 31-A 32-A 33-A 34-A 35-A 36-A 37-A 38-A 39-R 1

  • (I)Wherein;

    A 7Be L-His, Ura, Paa, Pta, Amp, Tma-His, des-amino-His, or deletion;

    A 8Be Ala, D-Ala, Aib, Acc, N-Me-Ala, N-Me-D-Ala or N-Me-Gly;

    A 9Be Glu, N-Me-Glu, N-Me-Asp or Asp;

    A 10Be Gly, Acc, β

    -Ala or Aib;

    A 11Be Thr or Ser;

    A 12Be Phe, Acc, Aic, Aib, 3-Pal, 4-Pal, β

    -Nal, Cha, Trp or X 1-Phe;

    A 13Be Thr or Ser;

    A 14Be Ser or Aib;

    A 15Be Asp or Glu;

    A 16Be Val, Acc, Aib, Leu, Ile, Tle, Nle, Abu, Ala or Cha;

    A 17Be Ser or Thr;

    A 18Be Ser or Thr;

    A 19Be Tyr, Cha, Phe, 3-Pal, 4-Pal, Acc, β

    -Nal or X 1-Phe;

    A 20Be Leu, Acc, Aib, Nle, Ile, Cha, Tle, Val, Phe or X 1-Phe;

    A 21Be Glu or Asp;

    A 22Be Gly, Acc, β

    -Ala, Glu or Aib;

    A 23Be Gln, Asp, Asn or Glu;

    A 24Be Ala, Aib, Val, Abu, Tle or Acc;

    A 25Be Ala, Aib, Val, Abu, Tle, Acc, Lys, Arg, hArg, Orn, HN-CH ((CH 2) n-N (R 10R 11)) C (O) or HN-CH ((CH 2) e-X 3)-C (O);

    A 26Be Lys, Arg, hArg, Orn, HN-CH ((CH 2) n-N (R 10R 11))-C (O) or HN-CH ((CH 2) e-X 3)-C (O);

    A 27Be Glu Asp, Leu, Aib or Lys;

    A 28Be Phe, Pal, β

    -Nal, X 1-Phe, Aic, Acc, Aib, Cha or Trp;

    A 29Be Ile, Acc, Aib, Leu, Nle, Cha, Tle, Val, Abu, Ala or Phe;

    A 30Be Ala, Aib or Acc;

    A 31Is Trp, β

    -Nal, 3-Pal, 4-Pal, Phe, Acc, Aib or Cha;

    A 32Be Leu, Acc, Aib, Nle, Ile, Cha, Tle, Phe, X 1-Phe or Ala;

    A 33Be Val, Acc, Aib, Leu, Ile, Tle, Nle, Cha, Ala, Phe, Abu, Lys or X 1-Phe;

    A 34Be Lys, Arg, hArg, Orn, HN-CH ((CH 2) n-N (R 10R 11))-C (O) or HN-CH ((CH 2) e-X 3)-C (O);

    A 35Be Gly, β

    -Ala, D-Ala, Gaba, Ava, HN-(CH 2) m-C (O), Aib, Acc or a D-amino acid;

    A 36Be L-or D-Arg, D-or L-Lys, D-or L-hArg, D-or L-or Orn, HN-CH ((CH 2) n-N (R 10R 11))-C (O), HN-CH ((CH 2) e-X 3)-C (O) or deletion;

    A 37Be Gly, β

    -Ala, Gaba, Ava, Aib, Acc, Ado, Arg, Asp, Aun, Aec, HN-(CH 2) m-C (O), HN-CH ((CH 2) n-N (R 10R 11))-C (O), a D-amino acid, or deletion;

    A 38Be D-or L-Lys, D-or L-Arg, D-or L-hArg, D-or L-Orn, HN-CH ((CH 2) n-N (R 10R 11)) C (O), HN-CH ((CH 2) e-X 3)-C (O) Ava, Ado, Aec or deletion;

    A 39Be D-or L-Lys, D-or L-Arg, HN-CH ((CH 2) n-N (R 10R 11))-C (O), Ava, Ado, or Aec;

    Each X that occurs 1Be selected from (C respectively 1-C 6) alkyl, OH and halogen;

    R 1Be OH, NH 2, (C 1-C 30) alkoxyl group, or NH-X 2-CH 2-Z 0, X wherein 2Be (C 1-C 12) the hydrocarbon part, Z 0Be H, OH, CO 2H or CONH 2Or-C (O)-NHR 12, wherein each X that occurs 4Be respectively-C (O)-,-NHC (O)-or-CH 2-, wherein each f that occurs is respectively 1-29 integer, comprises 29;

    R 2And R 3Be selected from H, (C separately respectively 1-C 30) alkyl, (C 2-C 30) alkenyl, phenyl (C 1-C 30) alkyl, naphthyl (C 1-C 30) alkyl, hydroxyl (C 1-C 30) alkyl, hydroxyl (C 2-C 30) alkenyl, hydroxyphenyl (C 1-C 30) alkyl and hydroxyl naphthyl (C 1-C 30) alkyl;

    Or R 2And R 3One of be (C 1-C 30) acyl group, (C 1-C 30) alkyl sulphonyl, C (O) X 5, Or Wherein Y is H, OH or NH 2R is 0-4;

    Q is 0-4;

    X 5Be (C 1-C 30) alkyl, (C 2-C 30) alkenyl, phenyl (C 1-C 30) alkyl, naphthyl (C 1-C 30) alkyl, hydroxyl (C 1-C 30) alkyl, hydroxyl (C 2-C 30) alkenyl, hydroxyphenyl (C 1-C 30) alkyl or hydroxyl naphthyl (C 1-C 30) alkyl;

    Each e that occurs is respectively 1-4 integer, comprises 4;

    Each m that occurs is respectively 5-24 integer, comprises 24;

    Each n that occurs is respectively 1-5 integer, comprises 5;

    Each R that occurs 10And R 11Be respectively H, (C 1-C 30) alkyl, (C 1-C 30) acyl group, (C 1-C 30) alkyl sulphonyl ,-C ((NH) (NH 2)) or And Each R that occurs 12And R 13Be respectively (C 1-C 30) alkyl;

    Condition is;

    Work as A 7Be Ura, Paa or Pta then delete R 2And R 3Work as R 10Be (C 1-C 30) acyl group, (C 1-C 30) alkyl sulphonyl ,-C ((NH) (NH 2)) or R then 11Be H or (C 1-C 30) alkyl;

    (ⅰ

    ) amino acid of at least a formula (I) compound and hGLP-1 (7-36 ,-37 or-38) NH 2Or the native sequences difference of hGLP-1 (7-36 ,-37 or-38) OH;

    (ⅱ

    ) formula (I) compound is not hGLP-1 (7-36 ,-37 or-38) NH 2Or the analogue of hGLP-1 (7-36 ,-37 or-38) OH, wherein single position is replaced by Ala;

    (ⅲ

    ) formula (I) compound is not (Arg 26,34, Lys 38) hGLP-1 (7-38)-E, (Lys 26(N ε

    -chain triacontanol base)) hGLP-1 (7-36 ,-37 or-38)-E, (Lys 34(N ε

    -chain triacontanol base)) hGLP-1 (7-36 ,-37 or-38)-E, (Lys 26,34-two (N ε

    -chain triacontanol base)) hGLP-1 (7-36 ,-37 or-38)-E, (Arg 26, Lys 34(N ε

    -chain triacontanol base)) hGLP-1 (8-36 ,-37 or-38)-E, (Arg 26,34, Lys 36(N ε

    -chain triacontanol base)) hGLP-1 (7-36 ,-37 or-38)-E or (Arg 26,34, Lys 38(N ε

    -chain triacontanol base)) hGLP-1 (7-38)-E, wherein E be-OH or-NH 2(ⅳ

    ) formula (I) compound is not Z 1-hGLP-1 (7-36 ,-37 or-38)-OH, Z 1-hGLP-1 (7-36 ,-37 or-38)-NH 2, Z wherein 1Be selected from;

    (a) (Arg 26), (Arg 34), (Arg 26,34), (Lys 36), (Arg 26, Lys 36), (Arg 34, Lys 36), (D-Lys 36), (Arg 36), (D-Arg 36), Arg 26,34, Lys 36) or (Arg 26,36, Lys 34);

    (b)(Asp 21);

    (c) (Aib 8), (D-Ala 8) and (Asp 9) at least a;

    And (d) (Tyr 7), (N-acyl group-His 7), (N-alkyl-His 7), (N-acyl group-D-His 7) or (N-alkyl-D-His 7);

    (ⅴ

    ) formula (I) compound is not any two kinds combination of the listed substituent of (a)-(d) group;

    And(ⅵ

    ) formula (I) compound is not (N-Me-Ala 8) hGLP-1 (8-36 or-37), (Glu 15) hGLP-1 (7-36 or-37), (Asp 21) hGLP-1 (7-36 or-37) or (Phe 31) hGLP-1 (7-36 or-37), or its pharmacy acceptable salt.

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