GIP receptor activating peptide

Abstract

The present invention provides a novel peptide compound having an activating effect on a GIP receptor and the use of the peptide compound as a drug. Specifically, a peptide or a salt thereof containing a sequence represented by formula (I) and a drug containing the peptide or a salt thereof are provided. 1 ‑Tyr‑A2‑Glu‑Gly‑Thr‑A6‑A7‑A8‑A9‑A10‑A11‑A12‑A13‑A14‑A15‑A16‑A17‑A18‑A19‑A20‑A2 1‑A22‑A23‑A24‑A25‑A26‑A27‑A28‑A29‑A30‑A31‑A32‑A33‑A34‑A35‑A36‑A37‑A38‑A39‑A40‑P 2 (I) wherein each symbol is as defined herein.

Description

Technical Field

[0001] Related Applications

[0002] The present invention relates to a novel peptide compound having an activating effect on a GIP receptor and the use of the peptide compound as a medicine. Background Art

[0003] Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are both peptides known as incretins. GLP-1 and GIP are secreted from L cells and K cells in the small intestine, respectively.

[0004] GLP-1 acts via the GLP-1 receptor and is known to have a glucose-dependent insulinotropic effect and an appetite suppressing effect. On the other hand, GIP is known to have a glucose-dependent insulinotropic effect via the GIP receptor, but the effect of GIP alone on appetite is still unclear.

[0005] Attempts have been made to find peptides and modified products thereof having GLP-1 receptor / GIP receptor co-agonist or glucagon receptor / GLP-1 receptor / GIP receptor tri-receptor agonist activity, and to develop these peptides as anti-obesity drugs, diabetes therapeutic drugs, or neurodegenerative disorder therapeutic drugs based on the structure of natural glucagon GIP or GLP-1 (Patent Documents 1 to 50, Non-Patent Documents 1 and 2). However, the peptide compounds of the present invention and compounds having a selective activation effect on the GIP receptor have not been disclosed.

[0006] List of References

[0007] Patent Literature

[0008] [Patent Document 1] WO2010 / 011439

[0009] [Patent Document 2] WO2010 / 148089

[0010] [Patent Document 3] WO2011 / 119657

[0011] [Patent Document 4] WO2012 / 088379

[0012] [Patent Document 5] WO2012 / 167744

[0013] [Patent Document 6] WO2013 / 164483

[0014] [Patent Document 7] WO2013 / 192129

[0015] [Patent Document 8] WO2013 / 192130

[0016] [Patent Document 9] WO2016 / 084826

[0017] [Patent Document 10] WO2014 / 192284

[0018] [Patent Document 11] WO2017 / 204219

[0019] [Patent Document 12] WO2016 / 066744

[0020] [Patent Document 13] WO2006 / 086769

[0021] [Patent Document 14] WO2007 / 109354

[0022] [Patent Document 15] WO2008 / 021560

[0023] [Patent Document 16] WO2009 / 042922

[0024] [Patent Document 17] WO2010 / 071807

[0025] [Patent Document 18] WO2011 / 094337

[0026] [Patent Document 19] WO2012 / 088116

[0027] [Patent Document 20] WO2013 / 003449

[0028] [Patent Document 21] WO2006 / 121904

[0029] [Patent Document 22] WO2007 / 028632

[0030] [Patent Document 23] WO2005 / 082928

[0031] [Patent Document 24] WO2000 / 069911

[0032] [Patent Document 25] WO2016 / 034186

[0033] [Patent Document 26] WO2017 / 075505

[0034] [Patent Document 27] WO2017 / 116204

[0035] [Patent Document 28] EP0479210

[0036] [Patent Document 29] WO2003 / 082898

[0037] [Patent Document 30] WO2007 / 028633

[0038] [Patent Document 31] WO2010 / 016935

[0039] [Patent Document 32] WO2010 / 016938

[0040] [Patent Document 33] WO2010 / 016940

[0041] [Patent Document 34] WO2010 / 016944

[0042] [Patent Document 35] WO2011 / 014680

[0043] [Patent Document 36] WO2012 / 055770

[0044] [Patent Document 37] WO2014 / 096145

[0045] [Patent Document 38] WO2014 / 096148

[0046] [Patent Document 39] WO2014 / 096149

[0047] [Patent Document 40] WO2014 / 096150

[0048] [Patent Document 41] WO2015 / 022420

[0049] [Patent Document 42] WO2015 / 067715

[0050] [Patent Document 43] WO2015 / 067716

[0051] [Patent Document 44] WO2015 / 086728

[0052] [Patent Document 45] WO2015 / 086729

[0053] [Patent Document 46] WO2015 / 086730

[0054] [Patent Document 47] US2016 / 0015788

[0055] [Patent Document 48] WO2016 / 077220

[0056] [Patent Document 49] WO2016 / 111971

[0057] [Patent Document 50] WO2016 / 198624

[0058] Non-patent literature

[0059] [Non-patent document 1] Nat Med., December 2013; 19(12): 1549, document number: 10.1038 / nm1213-1549.

[0060] [Non-patent document 2] Sci Transl Med., October 30, 2013; 5(209): 209ra151, document number: 10.1126 / scitranslmed.3007218. Summary of the invention

[0061] Technical issues

[0062] An object of the present invention is to provide a novel peptide compound which has a GIP receptor activating effect and is useful as a preventive / therapeutic agent or antiemetic agent for diabetes, obesity and diseases accompanied by vomiting or nausea.

[0063] Solutions to the problem

[0064] The inventors of the present invention have conducted extensive research to solve the above problems and have found that peptide compounds containing a sequence represented by formula (I) as novel compounds have excellent GIP receptor activation effects. In addition, the inventors have found that these compounds selectively activate GIP receptors and have an antiemetic effect, thereby completing the present invention.

[0065] More specifically, the present invention relates to the following [1] to

[26] .

[0066] [1] A peptide represented by formula (I):

[0067] P 1 -Tyr-A2-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A2 1-A22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-P 2 (SEQ ID NO: 165)

[0068] or a salt thereof,

[0069] in

[0070] P 1 represents a group represented by the following formula

[0071] -R A1 ,

[0072] -CO-R A1 ,

[0073] -CO-OR A1 ,

[0074] -CO-COR A1 ,

[0075] -SO-R A1 ,

[0076] -SO2-R A1 ,

[0077] -SO2-OR A1 ,

[0078] -CO-NR A2 R A3 ,

[0079] -SO2-NR A2 R A3 or

[0080] -C(=NR A1 )-NR A2 R A3

[0081] Where R A1 , R A2 and R A3 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;

[0082] P 2 represents -NH2 or -OH;

[0083] A2 represents Aib or D-Ala;

[0084] A6 represents Iva, Phe or Val;

[0085] A7 represents Ile, Lys or Val;

[0086] A8 represents Ser;

[0087] A9 represents Asp, Leu or Phe;

[0088] A10 represents Tyr;

[0089] A11 represents Aib or Ser;

[0090] A12 stands for Ile;

[0091] A13 represents Aib, Ala, Gln, Leu, Tyr or D-Iva;

[0092] A14 represents Leu;

[0093] A15 represents Asp, Glu, Lys, Ser or Tyr;

[0094] A16 represents Arg or Lys;

[0095] A17 represents Aib, Gln or Ile;

[0096] A18 represents Ala or His;

[0097] A19 represents Gln or Ser;

[0098] A20 represents Aib, Ala or Gln;

[0099] A21 represents Asn, Asp, Glu, Leu or Ser;

[0100] A22 represents Phe or αMePhe;

[0101] A23 represents Ile or Val;

[0102] A24 represents Arg, Asn, Asp, Lys or Lys(Ac);

[0103] A25 represents Trp;

[0104] A26 represents Aib, Iva or Leu;

[0105] A27 represents Leu;

[0106] A28 represents Ala, Arg, Lys or Lys(Ac);

[0107] A29 represents Gln or Gly;

[0108] A30 represents Arg, Gly, or missing;

[0109] A31 stands for Pro or missing;

[0110] A32 represents Ser or missing;

[0111] A33 represents Ser or missing;

[0112] A34 represents Gly or missing;

[0113] A35 represents Ala or deletion;

[0114] A36 stands for Pro or missing;

[0115] A37 stands for Pro or missing;

[0116] A38 stands for Pro or missing;

[0117] A39 represents Lys, Ser, or missing;

[0118] A40 represents Arg, Lys or missing; and

[0119] Any one or two amino acids selected from A8 to A30 optionally represent Lys (R), and R represents a substituent,

[0120] Assuming that A31 to A40 all represent deletions, A2 represents Aib.

[0121] [2] The peptide represented by formula (II) according to [1]:

[0122] P 1 -Tyr-A2-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A2 1-A22-A23-A24-A25-A26-A27-A28-A29-A30-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-A39-A40-P 2 (SEQ ID NO: 166)

[0123] or a salt thereof,

[0124] in

[0125] P 1 represents a group represented by the following formula

[0126] -R A1 ,

[0127] -CO-R A1 ,

[0128] -CO-OR A1 ,

[0129] -CO-COR A1 ,

[0130] -SO-R A1 ,

[0131] -SO2-R A1 ,

[0132] -SO2-OR A1 ,

[0133] -CO-NR A2 R A3 ,

[0134] -SO2-NR A2 RA3 or

[0135] -C(=NR A1 )-NR A2 R A3

[0136] Where R A1 , R A2 and R A3 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;

[0137] P 2 represents -NH2 or -OH;

[0138] A2 represents Aib or D-Ala;

[0139] A6 represents Iva, Phe or Val;

[0140] A7 represents Ile, Lys or Val;

[0141] A8 represents Ser;

[0142] A9 represents Asp, Leu or Phe;

[0143] A10 represents Tyr;

[0144] A11 represents Aib or Ser;

[0145] A12 stands for Ile;

[0146] A13 represents Aib, Ala, Gln, Leu, Tyr or D-Iva;

[0147] A14 represents Leu;

[0148] A15 represents Asp, Glu, Lys, Ser or Tyr;

[0149] A16 represents Arg or Lys;

[0150] A17 represents Aib, Gln or Ile;

[0151] A18 represents Ala or His;

[0152] A19 represents Gln or Ser;

[0153] A20 represents Aib, Ala or Gln;

[0154] A21 represents Asn, Asp, Glu, Leu or Ser;

[0155] A22 represents Phe or αMePhe;

[0156] A23 represents Ile or Val;

[0157] A24 represents Arg, Asn, Asp, Lys or Lys(Ac);

[0158] A25 represents Trp;

[0159] A26 represents Aib, Iva or Leu;

[0160] A27 represents Leu;

[0161] A28 represents Ala, Arg, Lys or Lys(Ac);

[0162] A29 represents Gln or Gly;

[0163] A30 represents Arg or Gly;

[0164] A39 represents Lys or Ser;

[0165] A40 represents Arg, Lys or missing; and

[0166] Any one or two amino acids selected from A8 to A30 optionally represent Lys (R), and R represents a substituent.

[0167] [3] The peptide represented by formula (III) according to [1]:

[0168] P 1 -Tyr-A2-GluGly-Thr-Val-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A2 1-A22-A23-A24-A25-A26-A27-A28-A29-A30-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-A39-A40-P 2 (SEQ ID NO: 167)

[0169] or a salt thereof,

[0170] in

[0171] P 1 represents a group represented by the following formula

[0172] -R A1 ,

[0173] -CO-R A1 ,

[0174] -CO-OR A1 ,

[0175] -CO-COR A1 ,

[0176] -SO-R A1 ,

[0177] -SO2-R A1 ,

[0178] -SO2-OR A1 ,

[0179] -CO-NR A2 R A3 ,

[0180] -SO2-NR A2 R A3 or

[0181] -C(=NR A1 )-NR A2 R A3

[0182] Where R A1 , R A2 and R A3 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;

[0183] P 2 represents -NH2 or -OH;

[0184] A2 represents Aib or D-Ala;

[0185] A7 represents Ile, Lys or Val;

[0186] A8 stands for Ser;

[0187] A9 represents Asp, Leu or Phe;

[0188] A10 represents Tyr;

[0189] A11 stands for Ser;

[0190] A12 stands for Ile;

[0191] A13 represents Aib, Ala, Gln, Leu or Tyr;

[0192] A14 represents Leu;

[0193] A15 represents Asp, Glu, Lys, Ser or Tyr;

[0194] A16 represents Lys;

[0195] A17 represents Gln or Ile;

[0196] A18 represents Ala or His;

[0197] A19 represents Gln or Ser;

[0198] A20 represents Aib or Gln;

[0199] A21 represents Glu or Leu;

[0200] A22 represents Phe;

[0201] A23 represents Ile or Val;

[0202] A24 represents Lys or Lys(Ac);

[0203] A25 represents Trp;

[0204] A26 represents Aib or Leu;

[0205] A27 represents Leu;

[0206] A28 represents Lys or Lys(Ac);

[0207] A29 represents Gly;

[0208] A30 represents Gly;

[0209] A39 represents Lys or Ser;

[0210] A40 represents Lys or missing; and

[0211] Any one or two amino acids selected from A8 to A30 optionally represent Lys (R), and R represents a substituent.

[0212] [4] The peptide represented by formula (IV) according to [1]:

[0213] P 1 -Tyr-Aib-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A2 1-A22-A23-A24-A25-A26-A27-A28-A29-A30-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-A40-P 2 (SEQ ID NO: 168)

[0214] or a salt thereof,

[0215] in

[0216] P1 represents a group represented by the following formula

[0217] -R Al ,

[0218] -CO-R A1 ,

[0219] -CO-OR A1 ,

[0220] -CO-COR A1 ,

[0221] -SO-R A1 ,

[0222] -SO2-R A1 ,

[0223] -SO2-OR A1 ,

[0224] -CO-NR A2 R A3 ,

[0225] -SO2-NR A2 R A3 or

[0226] -C(=NR A1 )-NR A2 R A3

[0227] Where R A1 , R A2 and R A3 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;

[0228] P 2 represents -NH2 or -OH;

[0229] A6 represents Iva, Phe or Val;

[0230] A7 stands for Ile or Val;

[0231] A8 represents Ser;

[0232] A9 represents Asp or Leu;

[0233] A10 represents Tyr;

[0234] A11 represents Aib or Ser;

[0235] A12 stands for Ile;

[0236] A13 represents Aib, Ala or D-Iva;

[0237] A14 represents Leu;

[0238] A15 represents Asp;

[0239] A16 represents Arg;

[0240] A17 represents Aib, Gln or Ile;

[0241] A18 represents Ala or His;

[0242] A19 represents Gln;

[0243] A20 represents Aib, Ala or Gln;

[0244] A21 represents Glu, Asn, Asp or Ser;

[0245] A22 represents Phe or αMePhe;

[0246] A23 represents Val;

[0247] A24 represents Arg, Asp or Asn;

[0248] A25 represents Trp;

[0249] A26 represents Leu or Iva;

[0250] A27 represents Leu;

[0251] A28 represents Ala or Arg;

[0252] A29 represents Gln or Gly;

[0253] A30 represents Arg or Gly;

[0254] A40 represents Arg or is missing; and

[0255] Any one or two amino acids selected from A8 to A30 optionally represent Lys (R), and R represents a substituent.

[0256] [5] The peptide represented by formula (V) according to [1]:

[0257] P 1-Tyr-Aib-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A2 1-A22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-P 2 (SEQ ID NO: 169)

[0258] or a salt thereof,

[0259] in

[0260] P 1 represents a group represented by the following formula

[0261] -R A1 ,

[0262] -CO-R A1 ,

[0263] -CO-OR A1 ,

[0264] -CO-COR A1 ,

[0265] -SO-R A1 ,

[0266] -SO2-R A1 ,

[0267] -SO2-OR A1 ,

[0268] -CO-NR A2 R A3 ,

[0269] -SO2-NR A2 R A3 or

[0270] -C(=NR A1 )-NR A2 R A3

[0271] Where R A1 , R A2 and R A3 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;

[0272] P 2 represents -NH2 or -OH;

[0273] A6 represents Iva, Phe or Val;

[0274] A7 represents Ile, Lys or Val;

[0275] A8 represents Ser;

[0276] A9 represents Asp, Leu or Phe;

[0277] A10 represents Tyr;

[0278] A11 represents Aib or Ser;

[0279] A12 stands for Ile;

[0280] A13 represents Aib, Ala, Gln, Leu, Tyr or D-Iva;

[0281] A14 represents Leu;

[0282] A15 represents Asp, Glu, Lys, Ser or Tyr;

[0283] A16 represents Arg or Lys;

[0284] A17 represents Aib, Gln or Ile;

[0285] A18 represents Ala or His;

[0286] A19 represents Gln or Ser;

[0287] A20 represents Aib, Ala or Gln;

[0288] A21 represents Asn, Asp, Glu, Leu or Ser;

[0289] A22 represents Phe or αMePhe;

[0290] A23 represents Ile or Val;

[0291] A24 represents Arg, Asn, Lys or Lys(Ac);

[0292] A25 represents Trp;

[0293] A26 represents Aib, Iva or Leu;

[0294] A27 represents Leu;

[0295] A28 represents Ala, Arg, Lys or Lys(Ac);

[0296] A29 represents Gln or Gly;

[0297] A30 represents Arg, Gly, or missing;

[0298] A31 to A40 represent deletions; and

[0299] Any one or two amino acids selected from A8 to A30 optionally represent Lys (R), and R represents a substituent.

[0300] [6] The peptide represented by formula (VI) according to [1]:

[0301] P 1 -Tyr-Aib-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A2 1-A22-A23-A24-A25-A26-A27-A28-A29-A30-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-A40-P 2 (SEQ ID NO: 170)

[0302] or a salt thereof,

[0303] in

[0304] P 1 represents a group represented by the following formula

[0305] -R A1 ,

[0306] -CO-R A1 ,

[0307] -CO-OR A1 ,

[0308] -CO-COR Al ,

[0309] -SO-R Al ,

[0310] -SO2-R A1 ,

[0311] -SO2-OR A1 ,

[0312] -CO-NR A2 R A3 ,

[0313] -SO2-NR A2 R A3 or

[0314] -C(=NR A1 )-NRA2 R A3

[0315] Where R A1 , R A2 and R A3 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;

[0316] P 2 represents -NH2 or -OH;

[0317] A6 represents Iva, Phe or Val;

[0318] A7 stands for Ile or Val;

[0319] A8 stands for Ser;

[0320] A9 represents Asp or Leu;

[0321] A10 represents Tyr;

[0322] A11 stands for Ser;

[0323] A12 stands for Ile;

[0324] A13 represents Aib or Ala;

[0325] A14 represents Leu;

[0326] A15 represents Asp;

[0327] A16 represents Arg or Lys;

[0328] A17 represents Aib, Gln or Ile;

[0329] A18 represents Ala or His;

[0330] A19 represents Gln;

[0331] A20 represents Aib or Gln;

[0332] A21 represents Asn, Glu or Asp;

[0333] A22 represents Phe;

[0334] A23 represents Val;

[0335] A24 represents Arg, Asn or Lys;

[0336] A25 represents Trp;

[0337] A26 represents Iva or Leu;

[0338] A27 represents Leu;

[0339] A28 represents Ala, Arg or Lys;

[0340] A29 represents Gln or Gly;

[0341] A30 represents Arg or Gly;

[0342] A40 represents Arg, Lys or missing; and

[0343] Any one or two amino acids selected from A8 to A30 optionally represent Lys (R), and R represents a substituent.

[0344] [7] The peptide represented by formula (I) according to [1]:

[0345] P 1 -Tyr-A2-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A2 1-A22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-P 2

[0346] or a salt thereof,

[0347] in

[0348] P 1 represents a group represented by the following formula

[0349] -R A1 ,

[0350] -CO-R A1 ,

[0351] -CO-OR A1 ,

[0352] -CO-COR A1 ,

[0353] -SO-R A1 ,

[0354] -SO2-R A1 ,

[0355] -SO2-OR A1 ,

[0356] -CO-NR A2 R A3 ,

[0357] -SO2-NR A2 R A3 or

[0358] -C(=NR A1 )-NR A2 R A3

[0359] Where R A1 , R A2 and R A3 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;

[0360] P 2 represents -NH2 or -OH;

[0361] A2 represents Aib or D-Ala;

[0362] A6 represents Iva, Phe or Val;

[0363] A7 represents Ile, Lys or Val;

[0364] A8 represents Ser;

[0365] A9 represents Asp, Leu or Phe;

[0366] A10 represents Tyr;

[0367] A11 represents Aib or Ser;

[0368] A12 stands for Ile;

[0369] A13 represents Aib, Ala, Gln, Leu, Tyr or D-Iva;

[0370] A14 represents Leu;

[0371] A15 represents Asp, Glu, Lys, Ser or Tyr;

[0372] A16 represents Arg or Lys;

[0373] A17 represents Aib, Gln or Ile;

[0374] A18 represents Ala or His;

[0375] A19 represents Gln or Ser;

[0376] A20 represents Aib, Ala or Gln;

[0377] A21 represents Asn, Asp, Glu, Leu or Ser;

[0378] A22 represents Phe or αMePhe;

[0379] A23 represents Ile or Val;

[0380] A24 represents Arg, Asn, Asp, Lys or Lys(Ac);

[0381] A25 represents Trp;

[0382] A26 represents Aib, Iva or Leu;

[0383] A27 represents Leu;

[0384] A28 represents Ala, Arg, Lys or Lys(Ac);

[0385] A29 represents Gln or Gly;

[0386] A30 represents Arg, Gly, or missing;

[0387] A31 stands for Pro or missing;

[0388] A32 represents Ser or missing;

[0389] A33 represents Ser or missing;

[0390] A34 represents Gly or missing;

[0391] A35 represents Ala or deletion;

[0392] A36 stands for Pro or missing;

[0393] A37 stands for Pro or missing;

[0394] A38 stands for Pro or missing;

[0395] A39 represents Lys, Ser or missing; and

[0396] A40 represents Arg, Lys or missing.

[0397] [8] The peptide represented by formula (I) according to [1]:

[0398] P 1 -Tyr-A2-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A2 1-A22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-P2

[0399] or a salt thereof,

[0400] in

[0401] P 1 represents a group represented by the following formula

[0402] -R A1 ,

[0403] -CO-R A1 ,

[0404] -CO-OR A1 ,

[0405] -CO-COR Al ,

[0406] -SO-R Al ,

[0407] -SO2-R Al ,

[0408] -SO2-OR A1 ,

[0409] -CO-NR A2 R A3 ,

[0410] -SO2-NR A2 R A3 or

[0411] -C(=NR A1 )-NR A2 R A3

[0412] Where R A1 , R A2 and R A3 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;

[0413] P 2 represents -NH2 or -OH;

[0414] A2 represents Aib or D-Ala;

[0415] A6 represents Iva, Phe or Val;

[0416] A7 represents Ile, Lys or Val;

[0417] A8 represents Ser;

[0418] A9 represents Asp, Leu or Phe;

[0419] A10 represents Tyr;

[0420] A11 represents Aib or Ser;

[0421] A12 stands for Ile;

[0422] A13 represents Aib, Ala, Gln, Leu, Tyr or D-Iva;

[0423] A14 represents Leu;

[0424] A15 represents Asp, Glu, Lys, Ser or Tyr;

[0425] A16 represents Arg or Lys;

[0426] A17 represents Aib, Gln or Ile;

[0427] A18 represents Ala or His;

[0428] A19 represents Gln or Ser;

[0429] A20 represents Aib, Ala or Gln;

[0430] A21 represents Asn, Asp, Glu, Leu or Ser;

[0431] A22 represents Phe or αMePhe;

[0432] A23 represents Ile or Val;

[0433] A24 represents Arg, Asn, Lys or Lys(Ac);

[0434] A25 represents Trp;

[0435] A26 represents Aib, Iva or Leu;

[0436] A27 represents Leu;

[0437] A28 represents Ala, Arg, Lys or Lys(Ac);

[0438] A29 represents Gln or Gly;

[0439] A30 represents Arg, Gly, or missing;

[0440] A31 stands for Pro or missing;

[0441] A32 represents Ser or missing;

[0442] A33 represents Ser or missing;

[0443] A34 represents Gly or missing;

[0444] A35 represents Ala or deletion;

[0445] A36 stands for Pro or missing;

[0446] A37 stands for Pro or missing;

[0447] A38 stands for Pro or missing;

[0448] A39 represents Lys, Ser, or missing;

[0449] A40 represents Arg, Lys or missing, and

[0450] Any one or two amino acids selected from A12, A14 and A17 optionally represent Lys (R), and R represents a substituent.

[0451] [9] The peptide or a salt thereof according to [1], wherein R represents XL-, L represents a divalent linker comprising PEG and / or an amino acid, and X represents a substituent.

[0452]

[10] The peptide or a salt thereof according to [1], wherein R represents XL-, L represents a bond or a divalent substituent, and X represents an optionally substituted hydrocarbon group.

[0453]

[11] The peptide represented by the following formula according to [1]: H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Aib-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 12), or a salt thereof.

[0454]

[12] The peptide represented by the following formula according to [1]: H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Gln-Ala-Gln-Aib-Glu-Phe-Val-Arg-Trp-Leu-Leu-Arg-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2 (SEQ ID NO: 36), or a salt thereof.

[0455]

[13] The peptide represented by the following formula according to [1]: Me-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Ile-Ala-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2 (SEQ ID NO: 65), or a salt thereof.

[0456]

[14] The peptide represented by the following formula according to [1]: Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2 (SEQ ID NO: 110), or a salt thereof.

[0457]

[15] The peptide represented by the following formula according to [1]: Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2 (SEQ ID NO: 119), or a salt thereof.

[0458]

[16] The peptide represented by the following formula according to [1]: Me-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2 (SEQ ID NO: 123), or a salt thereof.

[0459]

[17] The peptide represented by the following formula according to [1]: Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Eda-GGGGG-)-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 (SEQ ID NO: 354), or a salt thereof, wherein R represents a substituent.

[0460]

[18] The peptide represented by the following formula according to [1]: Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Oda-GGGGG-)-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 (SEQ ID NO: 362), or a salt thereof, wherein R represents a substituent.

[0461]

[19] A medicament comprising the peptide according to [1] or a salt thereof.

[0462]

[20] The drug according to

[19] , which is an activator of the GIP receptor.

[0463]

[21] The drug according to

[19] , which is a suppressant for vomiting or nausea.

[0464]

[22] A method for suppressing vomiting or nausea in a mammal, comprising administering to the mammal an effective amount of the peptide or a salt thereof according to [1].

[0465]

[23] A method for activating a GIP receptor in a mammal, comprising administering to the mammal an effective amount of the peptide or a salt thereof described in [1].

[0466]

[24] Use of the peptide or a salt thereof described in [1] for the manufacture of an inhibitor of vomiting or nausea.

[0467]

[25] The peptide or a salt thereof described in [1] is used for suppressing vomiting or nausea.

[0468]

[26] The drug of

[21] , the method of

[22] , the use of

[24] or the peptide of

[25] , wherein the vomiting or nausea is caused by one or more conditions or causes selected from the following (1) to (6):

[0469] (1) Diseases such as gastroparesis, hypomotility, peritonitis, abdominal tumors, constipation, gastrointestinal obstruction, cyclic vomiting syndrome, chronic unexplained nausea and vomiting, acute and chronic pancreatitis, hyperkalemia, cerebral edema, intracranial lesions, metabolic disorders, gastritis caused by infection, postoperative diseases, myocardial infarction, migraine, intracranial hypertension and intracranial hypotension (e.g., altitude sickness);

[0470] (2) Drugs such as (i) alkylating agents (e.g., cyclophosphamide, carmustine, lomustine, chlorambucil, streptozotocin, dacarbazine, ifosfamide, temozolomide, busulfan, bendamustine, and melphalan), cytotoxic antibiotics (e.g., dactinomycin, doxorubicin, mitomycin-C, bleomycin, epirubicin, actinomycin D, amrubicin, idarubicin, daunorubicin, and pirarubicin), antimetabolites (e.g., cytarabine, methotrexate, 5-fluorouracil, (ii) opioid analgesics (e.g., morphine); (iii) dopamine receptor D1D2 agonists (e.g., apomorphine); and (iv) cannabis and cannabinoid products, including cannabis hyperemesis gravis.

[0471] (3) Radiation sickness or radiation therapy to the chest, abdomen, etc. for the treatment of cancer;

[0472] (4) Toxic substances or toxins;

[0473] (5) pregnancy, including hyperemesis gravidarum; and

[0474] (6) Vestibular disorders, such as motion sickness or dizziness.

[0475] This specification includes all or part of the contents disclosed in the specification and / or drawings of Japanese Patent Application No. 2017-072556 to which the priority of this application is claimed.

[0476] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

[0477] Advantageous Effects of the Invention

[0478] Compound (I) selectively activates GIP receptors and demonstrates significant hypoglycemic and antiemetic effects in vivo. BRIEF DESCRIPTION OF THE DRAWINGS

[0479] [Figure 1-1] Figure 1-1 shows the effect of compound 6 on conditioned taste aversion (CTA) in mice.

[0480] [Figure 1-2] Figure 1-2 shows the effect of compound 117 on conditioned taste aversion (CTA) in mice.

[0481] [Figure 2-1] Figure 2-1 shows the effect of compound 6 on cisplatin-induced acute vomiting in ferrets.

[0482] [Fig. 2-2] Fig. 2-2 shows the effect of compound 117 on cisplatin-induced acute vomiting in ferrets. Each value represents the mean ± SD (n = 4).

[0483] [Fig. 2-3] Fig. 2-3 shows the effect of compound 117 on cisplatin-induced acute vomiting in ferrets. Each value represents the mean ± SD (n = 7).

[0484] [Figure 3] Figure 3 shows the dose-dependent effect of compound 6 on the morphine-induced emesis model (ferret).

[0485] [Figure 4] Figure 4 shows the effects of compounds 75, 104 and 117 (1 nmol / kg) and compound 59 (3 nmol / kg) on ​​morphine-induced emesis in ferrets when administered subcutaneously.

[0486] [Figure 5] Figure 5 shows the effects of compounds 59 and 113 on morphine-induced emesis in ferrets when administered subcutaneously.

[0487] [Fig. 6-1] Fig. 6-1 shows the effects of compounds 341, 349, 253, 268, 284, 292 and 314 on morphine-induced vomiting in ferrets when administered subcutaneously. It shows the results of morphine administration 4 hours after administration of each compound. Each value represents mean ± SD (n = 4).

[0488] [Fig. 6-2] Fig. 6-2 shows the effects of compounds 341 and 349 on morphine-induced vomiting in ferrets when administered subcutaneously. It shows the results of morphine administration 120 hours after administration of each compound. Each value represents mean ± SD (n = 4).

[0489] [ Fig. 7-1 ] Fig. 7-1 shows the inhibition of PYY-1119-induced emesis by administration of Compound 6 in beagle dogs.

[0490] [ Fig. 7-2] Fig. 7-2 shows the inhibition of PYY-1119-induced emesis by administration of Compound 117 in beagle dogs.

[0491] [ Fig. 8A] Fig. 8A shows the amino acid sequence of the compound according to the present invention.

[0492] [ Fig. 8B] Fig. 8B shows the amino acid sequence of the compound according to the present invention.

[0493] [ Fig. 8C ] Fig. 8C shows the amino acid sequence of the compound according to the present invention.

[0494] [ Fig. 8D] Fig. 8D shows the amino acid sequence of the compound according to the present invention.

[0495] [Fig. 9-1A] Fig. 9-1A, Fig. 9-1B, and Fig. 9-1C show the amino acid sequences of compounds 158 to 230 according to the present invention. Fig. 9-1A shows these sequences from the N-terminus to position 13.

[0496] [Figure 9-1B] Figure 9-1A, Figure 9-1B, Figure 9-1C show the amino acid sequences of compounds 158 to 230 according to the present invention. Figure 9-1B shows positions 14 to 22 of these sequences following Figure 9-1A.

[0497] [Figure 9-1C] Figure 9-1A, Figure 9-1B, Figure 9-1C show the amino acid sequences of compounds 158 to 230 according to the present invention. Figure 9-1C shows these sequences from position 23 to the C-terminus following Figure 9-1B.

[0498] [Fig. 9-2A] Fig. 9-2A, Fig. 9-2B, and Fig. 9-2C show the amino acid sequences of compounds 231 to 303 according to the present invention. Fig. 9-2A shows these sequences from the N-terminus to position 13.

[0499] [Figure 9-2B] Figure 9-2A, Figure 9-2B, Figure 9-2C show the amino acid sequences of compounds 231 to 303 according to the present invention. Figure 9-2B shows positions 14 to 22 of these sequences following Figure 9-2A.

[0500] [Fig. 9-2C] Fig. 9-2A, Fig. 9-2B, and Fig. 9-2C show the amino acid sequences of compounds 231 to 303 according to the present invention. Fig. 9-2C shows these sequences from position 23 to the C-terminus following Fig. 9-2B.

[0501] [Fig. 9-3A] Fig. 9-3A, Fig. 9-3B, and Fig. 9-3C show the amino acid sequences of compounds 304 to 376 according to the present invention. Fig. 9-3A shows these sequences from the N-terminus to position 13.

[0502] [Figure 9-3B] Figure 9-3A, Figure 9-3B, Figure 9-3C show the amino acid sequences of compounds 304 to 376 according to the present invention. Figure 9-3B shows positions 14 to 22 of these sequences following Figure 9-3A.

[0503] [Figure 9-3C] Figure 9-3A, Figure 9-3B, Figure 9-3C show the amino acid sequences of compounds 304 to 376 according to the present invention. Figure 9-3C shows these sequences from position 23 to the C-terminus following Figure 9-3B.

[0504] [Fig. 9-4A] Fig. 9-4A, Fig. 9-4B, and Fig. 9-4C show the amino acid sequences of compounds 377 to 449 according to the present invention. Fig. 9-4A shows these sequences from the N-terminus to position 13.

[0505] [Figure 9-4B] Figure 9-4A, Figure 9-4B, Figure 9-4C show the amino acid sequences of compounds 377 to 449 according to the present invention. Figure 9-4B shows positions 14 to 22 of these sequences following Figure 9-4A.

[0506] [Figure 9-4C] Figure 9-4A, Figure 9-4B, Figure 9-4C show the amino acid sequences of compounds 377 to 449 according to the present invention. Figure 9-4C shows these sequences from position 23 to the C-terminus following Figure 9-4B.

[0507] [Fig. 9-5A] Fig. 9-5A, Fig. 9-5B, and Fig. 9-5C show the amino acid sequences of compounds 450 to 522 according to the present invention. Fig. 9-5A shows these sequences from the N-terminus to position 13.

[0508] [Figure 9-5B] Figure 9-5A, Figure 9-5B, Figure 9-5C show the amino acid sequences of compounds 450 to 522 according to the present invention. Figure 9-5B shows positions 14 to 22 of these sequences following Figure 9-5A.

[0509] [Figure 9-5C] Figure 9-5A, Figure 9-5B, Figure 9-5C show the amino acid sequences of compounds 450 to 522 according to the present invention. Figure 9-5C shows these sequences from position 23 to the C-terminus following Figure 9-5B. DETAILED DESCRIPTION

[0510] The definition of each substituent used in the present specification is described in detail below. Unless otherwise specified, each substituent has the following definition.

[0511] In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine.

[0512] In this manual, “C 1-6Examples of the "alkyl" group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl.

[0513] In this specification, “optionally halogenated C 1-6 Examples of the "alkyl group" include C optionally having 1 to 7, preferably 1 to 5 halogen atoms. 1-6 Specific examples thereof include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and 6,6,6-trifluorohexyl.

[0514] In this manual, “C 2-6 Examples of the “alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.

[0515] In this manual, “C 2-6 Examples of the “alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.

[0516] In this manual, “C 3-10 Examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and adamantyl.

[0517] In this specification, “optionally halogenated C 3-10 Examples of the "cycloalkyl" include C 3-10 Specific examples thereof include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0518] In this manual, “C 3-10Examples of "cycloalkenyl" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.

[0519] In this manual, “C 6-14 Examples of the "aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

[0520] In this manual, “C 7-16 Examples of the "aralkyl" group include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

[0521] In this manual, “C 1-6 Examples of the "alkoxy" group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

[0522] In this specification, “optionally halogenated C 1-6 Examples of the "alkoxy group" include C 1-6 Specific examples thereof include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

[0523] In this manual, “C 3-10 Examples of the "cycloalkyloxy" group include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

[0524] In this manual, “C 1-6 Examples of the "alkylthio group" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.

[0525] In this specification, “optionally halogenated C 1-6 Examples of the "alkylthio group" include C 1-6 Specific examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio.

[0526] In this manual, “C 1-6 Examples of "alkyl-carbonyl" include acetyl, propionyl, butyryl, 2-methylpropionyl, pentanoyl, 3-methylbutyryl, 2-methylbutyryl, 2,2-dimethylpropionyl, hexanoyl and heptanoyl.

[0527] In this specification, “optionally halogenated C1-6 Examples of the "alkyl-carbonyl group" include C 1-6 Specific examples thereof include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propionyl, butyryl, valeryl and hexanoyl.

[0528] In this manual, “C 1-6 Examples of the "alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl.

[0529] In this manual, “C 6-14 Examples of "aryl-carbonyl" include benzoyl, 1-naphthoyl and 2-naphthoyl.

[0530] In this manual, “C 7-16 Examples of the "aralkyl-carbonyl" group include phenylacetyl and phenylpropionyl.

[0531] In the present specification, examples of the "5- to 14-membered aromatic heterocyclic carbonyl group" include a nicotinoyl group, an isonicotinoyl group, a thenoyl group and a furoyl group.

[0532] In the present specification, examples of the "3- to 14-membered non-aromatic heterocyclic carbonyl group" include a morpholinylcarbonyl group, a piperidinylcarbonyl group and a pyrrolidinylcarbonyl group.

[0533] In this specification, "mono- or di-C 1-6 Examples of the "alkyl-carbamoyl group" include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

[0534] In this specification, "mono- or di-C 7-16 Examples of the "aralkyl-carbamoyl group" include benzylcarbamoyl and phenethylcarbamoyl.

[0535] In this manual, “C 1-6 Examples of the "alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl groups.

[0536] In this specification, “optionally halogenated C 1-6 Examples of the "alkylsulfonyl group" include C 1-6Specific examples thereof include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl.

[0537] In this manual, “C 6-14 Examples of the "arylsulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

[0538] In the present specification, examples of the “substituent” include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxyl group, an optionally substituted mercapto (SH) group and an optionally substituted silyl group.

[0539] In the present specification, examples of the "hydrocarbon group" (including the "hydrocarbon group" of the "optionally substituted hydrocarbon group") include C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 Aryl and C 7-16 Aralkyl.

[0540] In the present specification, examples of the “optionally substituted hydrocarbon group” include a hydrocarbon group optionally having one or more substituents selected from the following substituent A.

[0541] Substituent A

[0542] (1) halogen atoms,

[0543] (2) Nitro,

[0544] (3) cyano group,

[0545] (4) oxo group,

[0546] (5) hydroxyl group,

[0547] (6) optionally halogenated C 1-6 Alkoxy,

[0548] (7)C 6-14 Aryloxy (e.g. phenoxy, naphthoxy),

[0549] (8)C 7-16 Aralkyloxy (eg benzyloxy),

[0550] (9) a 5- to 14-membered aromatic heterocyclic oxy group (e.g., a pyridyloxy group),

[0551] (10) a 3- to 14-membered non-aromatic heterocyclic oxy group (e.g., morpholinyloxy, piperidinyloxy),

[0552] (11)C 1-6 Alkyl-carbonyloxy (e.g. acetyloxy, propionyloxy),

[0553] (12)C 6-14 Aryl-carbonyloxy (e.g. benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy),

[0554] (13)C 1-6 Alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),

[0555] (14) Single or Dual C 1-6 Alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy),

[0556] (15)C 6-14 Aryl-carbamoyloxy (e.g. phenylcarbamoyloxy, naphthylcarbamoyloxy),

[0557] (16) a 5- to 14-membered aromatic heterocyclic carbonyloxy group (e.g., nicotinoyloxy group),

[0558] (17) a 3- to 14-membered non-aromatic heterocyclic carbonyloxy group (e.g., morpholinylcarbonyloxy group, piperidinylcarbonyloxy group),

[0559] (18) optionally halogenated C 1-6 Alkylsulfonyloxy (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy),

[0560] (19) optionally C 1-6 Alkyl substituted C 6-14 Arylsulfonyloxy (e.g., phenylsulfonyloxy, toluenesulfonyloxy),

[0561] (20) optionally halogenated C 1-6 Alkylthio,

[0562] (21) a 5- to 14-membered aromatic heterocyclic group,

[0563] (22) a 3- to 14-membered non-aromatic heterocyclic group,

[0564] (23) Formyl group,

[0565] (24) carboxyl group,

[0566] (25) optionally halogenated C 1-6 Alkyl-carbonyl,

[0567] (26)C 6-14 Aryl-carbonyl,

[0568] (27) a 5- to 14-membered aromatic heterocyclic carbonyl group,

[0569] (28) a 3- to 14-membered non-aromatic heterocyclic carbonyl group,

[0570] (29)C 1-6 Alkoxy-carbonyl,

[0571] (30)C 6-14 Aryloxy-carbonyl (e.g. phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl),

[0572] (31)C 7-16 Aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, phenethoxycarbonyl),

[0573] (32) Carbamoyl,

[0574] (33) thiocarbamoyl group,

[0575] (34) Single or Double C 1-6 Alkyl-carbamoyl,

[0576] (35)C 6-14 Aryl-carbamoyl (e.g. phenylcarbamoyl),

[0577] (36) a 5- to 14-membered aromatic heterocyclic carbamoyl group (e.g., a pyridylcarbamoyl group, a thienylcarbamoyl group),

[0578] (37) 3- to 14-membered non-aromatic heterocyclic carbamoyl (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl),

[0579] (38) optionally halogenated C 1-6 Alkylsulfonyl,

[0580] (39)C 6-14 Arylsulfonyl,

[0581] (40) a 5- to 14-membered aromatic heterocyclic sulfonyl group (e.g., a pyridylsulfonyl group, a thienylsulfonyl group),

[0582] (41) optionally halogenated C 1-6 Alkylsulfinyl,

[0583] (42)C 6-14 Arylsulfinyl (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl),

[0584] (43) a 5- to 14-membered aromatic heterocyclic sulfinyl group (e.g., a pyridylsulfinyl group, a thienylsulfinyl group),

[0585] (44) amino group,

[0586] (45) Single or Double C 1-6 Alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino),

[0587] (46) Single or Double C 6-14 Arylamino (e.g. phenylamino),

[0588] (47) a 5- to 14-membered aromatic heterocyclic amino group (e.g., a pyridylamino group),

[0589] (48)C 7-16 Aralkylamino (eg benzylamino),

[0590] (49) carboxamido group,

[0591] (50)C 1-6 Alkyl-carbonylamino (e.g. acetylamino, propionylamino, butyrylamino),

[0592] (51)(C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino (e.g. N-acetyl-N-methylamino),

[0593] (52)C 6-14 Aryl-carbonylamino (e.g. phenylcarbonylamino, naphthylcarbonylamino),

[0594] (53)C 1-6 Alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino),

[0595] (54)C 7-16 Aralkyloxy-carbonylamino (eg benzyloxycarbonylamino),

[0596] (55)C 1-6 Alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino),

[0597] (56) Optional C 1-6 Alkyl substituted C 6-14 Arylsulfonylamino (e.g., phenylsulfonylamino, toluenesulfonylamino),

[0598] (57) optionally halogenated C 1-6 alkyl,

[0599] (58)C 2-6 Alkenyl,

[0600] (59)C 2-6 Alkynyl,

[0601] (60)C 3-10 Cycloalkyl,

[0602] (61)C 3-10 Cycloalkenyl and

[0603] (62)C 6-14 Aryl.

[0604] The number of the above-mentioned substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. When the number of these substituents is two or more, the corresponding substituents may be the same or different.

[0605] In the present specification, examples of the “heterocyclic group” (including the “heterocyclic group” of the “optionally substituted heterocyclic group”) include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group and (iii) a 7- to 10-membered bridged heterocyclic group, each containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom as ring-constituting atoms other than a carbon atom.

[0606] In the present specification, examples of the “aromatic heterocyclic group” (including the “5- to 14-membered aromatic heterocyclic group”) include a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom as ring-constituting atoms other than a carbon atom.

[0607] Preferred examples of the “aromatic heterocyclic group” include a 5- or 6-membered monocyclic aromatic heterocyclic group such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and

[0608] 8-14 membered fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic group, such as benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridyl, thienopyridyl, furopyridyl, pyrrolopyridyl, pyrazolopyridyl, oxazolopyridyl, thiazolopyridyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl , furanopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazoloprimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiazyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.

[0609] In the present specification, examples of the “non-aromatic heterocyclic group” (including the “3- to 14-membered non-aromatic heterocyclic group”) include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom as ring-constituting atoms other than a carbon atom.

[0610] Preferred examples of the “non-aromatic heterocyclic group” include a 3- to 8-membered monocyclic non-aromatic heterocyclic group such as aziridinyl, oxiranyl, thioranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothiophenyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepanyl, and 9 to 14-membered fused polycyclic (preferably bicyclic or tricyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, dihydroindolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, yl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolinyl and the like.

[0611] In the present specification, preferred examples of the "7- to 10-membered bridged heterocyclic group" include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl.

[0612] In the present specification, examples of the “nitrogen-containing heterocyclic group” include a “heterocyclic group” containing at least one nitrogen atom as a ring-constituting atom.

[0613] In the present specification, examples of the "optionally substituted heterocyclic group" include a heterocyclic group optionally having one or more substituents selected from the substituent A mentioned above.

[0614] The number of substituents in the "optionally substituted heterocyclic group" is, for example, 1 to 3. When the number of these substituents is two or more, the corresponding substituents may be the same or different.

[0615] In the present specification, examples of "acyl" include each optionally having "1 or 2 groups selected from C1-6 alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 Aryl, C 7-16 substituents of aralkyl, 5- to 14-membered aromatic heterocyclic and 3- to 14-membered non-aromatic heterocyclic groups, each of which optionally has 1 to 3 atoms selected from halogen atoms, optionally halogenated C 1-6 The invention also includes a "substituent of" an alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group" formyl group, carboxyl group, carbamoyl group, thiocarbamoyl group, sulfinyl group, sulfonyl group, sulfamoyl group and phosphono group.

[0616] Examples of the "acyl group" also include a hydrocarbon-sulfonyl group, a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and a heterocyclylsulfinyl group.

[0617] Here, the hydrocarbon-sulfonyl group refers to a hydrocarbon-bonded sulfonyl group, the heterocyclic sulfonyl group refers to a heterocyclic group-bonded sulfonyl group, the hydrocarbon-sulfinyl group refers to a hydrocarbon-bonded sulfinyl group, and the heterocyclic sulfinyl group refers to a heterocyclic group-bonded sulfinyl group.

[0618] Preferred examples of "acyl" include formyl, carboxyl, C 1-6 Alkyl-carbonyl, C 2-6 Alkenyl-carbonyl (e.g. crotonyl), C 3-10 Cycloalkyl-carbonyl (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3-10 Cycloalkenyl-carbonyl (e.g. 2-cyclohexenecarbonyl), C 6-14 Aryl-carbonyl, C 7-16 Aralkyl-carbonyl, 5- to 14-membered aromatic heterocyclylcarbonyl, 3- to 14-membered non-aromatic heterocyclylcarbonyl, C 1-6 Alkoxy-carbonyl, C6-14 Aryloxy-carbonyl (e.g. phenoxycarbonyl, naphthoxycarbonyl), C 7-16 Aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, phenethoxycarbonyl), carbamoyl, mono- or di-C 1-6 Alkyl-carbamoyl, mono- or di-C 2-6 Alkenyl-carbamoyl (e.g. diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl (e.g. cyclopropylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl (e.g. phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl, 5- to 14-membered aromatic heterocyclic carbamoyl (e.g., pyridylcarbamoyl), thiocarbamoyl, mono- or di-C 1-6 Alkyl-thiocarbamoyl (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl (e.g. diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl (e.g. phenylthiocarbamoyl), mono- or di-C 7-16 Aralkyl-thiocarbamoyl (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl (e.g., pyridylthiocarbamoyl), sulfinyl, C 1-6 Alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl), sulfo, C 1-6 Alkylsulfonyl, C 6-14 Arylsulfonyl, phosphonyl and mono- or di-C 1-6 Alkylphosphonyl (eg, dimethylphosphonyl, diethylphosphonyl, diisopropylphosphonyl, dibutylphosphonyl).

[0619] In the present specification, examples of the "optionally substituted amino group" include an amino group optionally having "1 or 2 groups selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-16 Aralkyl, C 1-6 Alkyl-carbonyl, C 6-14 Aryl-carbonyl, C 7-16 Aralkyl-carbonyl, 5- to 14-membered aromatic heterocyclylcarbonyl, 3- to 14-membered non-aromatic heterocyclylcarbonyl, C 1-6Alkoxy-carbonyl, 5- to 14-membered aromatic heterocyclic group, carbamoyl, mono- or di-C 1-6 Alkyl-carbamoyl, mono- or di-C 7-16 Aralkyl-carbamoyl, C 1-6 Alkylsulfonyl and C 6-14 The substituents of the arylsulfonyl group each optionally have 1 to 3 amino groups selected from the substituent group A.

[0620] Preferred examples of the optionally substituted amino group include amino, mono- or di-(optionally halogenated C 1-6 alkyl)amino (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6 Alkenylamino (e.g. diallylamino), mono- or di-C 3-10 Cycloalkylamino (e.g. cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 Arylamino (e.g. phenylamino), mono- or di-C 7-16 Aralkylamino (e.g. benzylamino, dibenzylamino), mono- or di- (optionally halogenated C 1-6 Alkyl)-carbonylamino (e.g. acetylamino, propionylamino), mono- or di-C 6-14 Aryl-carbonylamino (e.g. benzoylamino), mono- or di-C 7-16 Arylalkyl-carbonylamino (e.g., benzylcarbonylamino), mono- or di-5- to 14-membered aromatic heterocyclylcarbonylamino (e.g., nicotinoylamino, isonicotinoylamino), mono- or di-3- to 14-membered non-aromatic heterocyclylcarbonylamino (e.g., piperidinylcarbonylamino, mono- or di-C 1-6 Alkoxy-carbonylamino (e.g. tert-butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino (e.g. pyridylamino), carbamoylamino, (mono- or di-C 1-6 alkyl-carbamoyl)amino (e.g. methylcarbamoylamino), (mono- or di-C 7-16 Aralkyl-carbamoyl)amino (e.g., benzylcarbamoylamino), C 1-6 Alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino), C 6-14 Arylsulfonylamino (e.g., phenylsulfonylamino), (C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino (e.g. N-acetyl-N-methylamino) and (C 1-6 Alkyl)(C 6-14 aryl-carbonyl)amino (e.g. N-benzoyl-N-methylamino).

[0621] In the present specification, examples of the “optionally substituted carbamoyl group” include a group optionally having “1 or 2 groups selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-16 Aralkyl, C 1-6 Alkyl-carbonyl, C 6-14 Aryl-carbonyl, C 7-16 Aralkyl-carbonyl, 5- to 14-membered aromatic heterocyclylcarbonyl, 3- to 14-membered non-aromatic heterocyclylcarbonyl, C 1-6 Alkoxy-carbonyl, 5- to 14-membered aromatic heterocyclic group, carbamoyl, mono- or di-C 1-6 Alkyl-carbamoyl and mono- or di-C 7-16 The substituents of the aralkyl-carbamoyl group each optionally have 1 to 3 carbamoyl groups selected from the substituent group A.

[0622] Preferred examples of the optionally substituted carbamoyl group include carbamoyl, mono- or di-C 1-6 Alkyl-carbamoyl, mono- or di-C 2-6 Alkenyl-carbamoyl (e.g. diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl (e.g. cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl (e.g. phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl, mono- or di-C 1-6 Alkyl-carbonyl-carbamoyl (e.g., acetylcarbamoyl, propionylcarbamoyl), mono- or di-C 6-14 Aryl-carbonyl-carbamoyl (eg benzoylcarbamoyl) and 5- to 14-membered aromatic heterocyclylcarbamoyl (eg pyridylcarbamoyl).

[0623] In the present specification, examples of the "optionally substituted thiocarbamoyl group" include a group optionally having "1 or 2 groups selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-16 Aralkyl, C 1-6 Alkyl-carbonyl, C 6-14 Aryl-carbonyl, C 7-16 Aralkyl-carbonyl, 5- to 14-membered aromatic heterocyclylcarbonyl, 3- to 14-membered non-aromatic heterocyclylcarbonyl, C 1-6 Alkoxy-carbonyl, 5- to 14-membered aromatic heterocyclic group, carbamoyl, mono- or di-C 1-6Alkyl-carbamoyl and mono- or di-C 7-16 The substituents of the aralkyl-carbamoyl group each optionally have 1 to 3 thiocarbamoyl groups selected from the substituents of the substituent group A.

[0624] Preferred examples of the optionally substituted thiocarbamoyl group include thiocarbamoyl, mono- or di-C 1-6 Alkyl-thiocarbamoyl (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl (e.g. diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl (e.g. phenylthiocarbamoyl), mono- or di-C 7-16 Aralkyl-thiocarbamoyl (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), mono- or di-C 1-6 Alkyl-carbonyl-thiocarbamoyl (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or di-C 6-14 Aryl-carbonyl-thiocarbamoyl (eg benzoylthiocarbamoyl) and 5- to 14-membered aromatic heterocyclylthiocarbamoyl (eg pyridylthiocarbamoyl).

[0625] In the present specification, examples of the “optionally substituted sulfamoyl group” include a group optionally having “1 or 2 groups selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-16 Aralkyl, C 1-6 Alkyl-carbonyl, C 6-14 Aryl-carbonyl, C 7-16 Aralkyl-carbonyl, 5- to 14-membered aromatic heterocyclylcarbonyl, 3- to 14-membered non-aromatic heterocyclylcarbonyl, C 1-6 Alkoxy-carbonyl, 5- to 14-membered aromatic heterocyclic group, carbamoyl, mono- or di-C 1-6 Alkyl-carbamoyl and mono- or di-C 7-16 The substituents of the aralkyl-carbamoyl group each optionally have 1 to 3 sulfamoyl groups selected from the substituents of substituent A.

[0626] Preferred examples of the optionally substituted sulfamoyl group include sulfamoyl, mono- or di-C 1-6Alkyl-sulfamoyl (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C 2-6 Alkenyl-sulfamoyl (e.g. diallylsulfamoyl), mono- or di-C 3-10 Cycloalkyl-sulfamoyl (e.g. cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C 6-14 Aryl-sulfamoyl (e.g. phenylsulfamoyl), mono- or di-C 7-16 Aralkyl-sulfamoyl (e.g., benzylsulfamoyl, phenethylsulfamoyl), mono- or di-C 1-6 Alkyl-carbonyl-sulfamoyl (e.g., acetylsulfamoyl, propionylsulfamoyl), mono- or di-C 6-14 Aryl-carbonyl-sulfamoyl (eg benzoylsulfamoyl) and 5- to 14-membered aromatic heterocyclylsulfamoyl (eg pyridylsulfamoyl).

[0627] In the present specification, examples of the "optionally substituted hydroxyl group" include a group optionally having "selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-16 Aralkyl, C 1-6 Alkyl-carbonyl, C 6-14 Aryl-carbonyl, C 7-16 Aralkyl-carbonyl, 5- to 14-membered aromatic heterocyclylcarbonyl, 3- to 14-membered non-aromatic heterocyclylcarbonyl, C 1-6 Alkoxy-carbonyl, 5- to 14-membered aromatic heterocyclic group, carbamoyl, mono- or di-C 1-6 Alkyl-carbamoyl, mono- or di-C 7-16 Aralkyl-carbamoyl, C 1-6 Alkylsulfonyl and C 6-14 The substituents of the arylsulfonyl group each optionally have 1 to 3 hydroxyl groups selected from the substituent group A.

[0628] Preferred examples of the optionally substituted hydroxyl group include hydroxyl, C 1-6 Alkoxy, C 2-6 alkenyloxy (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), C 3-10 Cycloalkyloxy (e.g. cyclohexyloxy), C 6-14 Aryloxy (e.g. phenoxy, naphthoxy), C 7-16 Aralkyloxy (e.g., benzyloxy, phenethyloxy), C 1-6 Alkyl-carbonyloxy (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C6-14 Aryl-carbonyloxy (e.g. benzoyloxy), C 7-16 Aralkyl-carbonyloxy (e.g., benzylcarbonyloxy), 5- to 14-membered aromatic heterocyclylcarbonyloxy (e.g., nicotinoyloxy), 3- to 14-membered non-aromatic heterocyclylcarbonyloxy (e.g., piperidinylcarbonyloxy), C 1-6 Alkoxy-carbonyloxy (e.g., tert-butoxycarbonyloxy), 5- to 14-membered aromatic heterocyclyloxy (e.g., pyridyloxy), carbamoyloxy, C 1-6 Alkyl-carbamoyloxy (e.g. methylcarbamoyloxy), C 7-16 Aralkyl-carbamoyloxy (e.g., benzylcarbamoyloxy), C 1-6 Alkylsulfonyloxy (e.g., methylsulfonyloxy, ethylsulfonyloxy) and C 6-14 Arylsulfonyloxy (eg phenylsulfonyloxy).

[0629] In the present specification, examples of the “optionally substituted sulfanyl group” include a group optionally having “selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-16 Aralkyl, C 1-6 Alkyl-carbonyl, C 6-14 aryl-carbonyl and 5- to 14-membered aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from sulfanyl and halogenated sulfanyl.

[0630] Preferred examples of the optionally substituted sulfanyl group include a sulfanyl (—SH) group, a C 1-6 Alkylthio, C 2-6 alkenylthio (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C 3-10 Cycloalkylthio (e.g. cyclohexylthio), C 6-14 Arylthio (e.g. phenylthio, naphthylthio), C 7-16 Aralkylthio (e.g. benzylthio, phenethylthio), C 1-6 Alkyl-carbonylthio (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C 6-14 Aryl-carbonylthio (eg benzoylthio), 5- to 14-membered aromatic heterocyclylthio (eg pyridylthio) and halogenated thio (eg pentafluorothio).

[0631] In the present specification, examples of the “optionally substituted silyl group” include a silyl group optionally having “1 to 3 groups selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C6-14 Aryl and C 7-16 The substituents of the aralkyl group each optionally have 1 to 3 silyl groups selected from the substituent group A.

[0632] Preferred examples of the optionally substituted silyl group include tri-C 1-6 Alkylsilyl (eg, trimethylsilyl, tert-butyl(dimethyl)silyl).

[0633] Regarding compound 1, formula (I): P 1 -Tyr-A2-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A2 1-A22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-P 2 The definition of each symbol in (SEQ ID NO: 165) is described in detail below.

[0634] P 1 is a group represented by the formula:

[0635] -R A1 ,

[0636] -CO-R A1 ,

[0637] -CO-OR A1 ,

[0638] -CO-COR A1 ,

[0639] -SO-R A1 ,

[0640] -SO2-R A1 ,

[0641] -SO2-OR A1 ,

[0642] -CO-NR A2 R A3 ,

[0643] -SO2-NR A2 R A3 or

[0644] -C(=NR A1 )-NR A2 R A3

[0645] Where R Al , R A2 and R A3 Each is independently a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.

[0646] P 1 Preferred is an acetyl group, a methyl group or a hydrogen atom.

[0647] P 2 Represents -NH2 or -OH.

[0648] A2 represents Aib or D-Ala.

[0649] A6 represents Iva, Phe or Val.

[0650] A7 represents Ile, Lys or Val.

[0651] A8 stands for Ser.

[0652] A9 represents Asp, Leu or Phe.

[0653] A10 stands for Tyr.

[0654] A11 represents Aib or Ser.

[0655] A12 stands for Ile.

[0656] A13 represents Aib, Ala, Gln, Leu, Tyr or D-Iva.

[0657] A14 represents Leu.

[0658] A15 represents Asp, Glu, Lys, Ser or Tyr.

[0659] A16 represents Arg or Lys.

[0660] A17 represents Aib, Gln or Ile.

[0661] A18 represents Ala or His.

[0662] A19 represents Gln or Ser.

[0663] A20 represents Aib, Ala or Gln.

[0664] A21 represents Asn, Asp, Glu, Leu or Ser.

[0665] A22 represents Phe or αMePhe.

[0666] A23 represents Ile or Val.

[0667] A24 represents Arg, Asn, Asp, Lys or Lys(Ac).

[0668] A25 represents Trp.

[0669] A26 represents Aib, Iva or Leu.

[0670] A27 represents Leu.

[0671] A28 represents Ala, Arg, Lys or Lys(Ac).

[0672] A29 represents Gln or Gly.

[0673] A30 represents Arg, Gly or missing.

[0674] A31 stands for Pro or lack thereof.

[0675] A32 represents Ser or deletion.

[0676] A33 represents Ser or deletion.

[0677] A34 represents Gly or is missing.

[0678] A35 represents Ala or is missing.

[0679] A36 stands for Pro or lack thereof.

[0680] A37 stands for Pro or lack thereof.

[0681] A38 stands for Pro or lack thereof.

[0682] A39 represents Lys, Ser or missing.

[0683] A40 represents Arg, Lys or missing.

[0684] Assuming that A31 to A40 all represent deletions, A2 represents Aib.

[0685] Any one or two amino acids selected from A8 to A30 optionally represent Lys (R). R represents a substituent.

[0686] Preferably, R represents XL-, wherein L represents a divalent linker comprising or consisting of PEG and / or amino acids, and X represents a substituent. Known PEG linkers, amino acid linkers or combinations thereof can be used as divalent linkers as long as they are capable of connecting Lys to the substituent. Alternatively, preferably, R represents XL-, wherein L represents a bond or a divalent substituent, and X represents an optionally substituted hydrocarbon group, or a salt thereof. Known divalent substituents can be used, including but not limited to alkylene, carbonyl, oxycarbonyl, imino, alkylimino, sulfonyl, oxy, sulfide group, ester bond, amide bond, carbonate bond or a combination thereof. More preferably, R represents XL-, wherein L is selected from

[0687]

[0688] A glycine linker comprising one or two to nine linked glycines or a combination of one or more than one of single bonds, and X represents C6-C 20 Mono- or di-acids, or acetyl.

[0689] Specifically, R represents XL-, wherein , Teda-GGGGG-, Teda-GGGGGG-, Peda-GGGG-(Peda: C15 diacid), Peda-GGGGG-, Peda-GGGGGG-, Heda-GGGG-(Heda: C1 6 diacid), Heda-GGGGG-, Heda-GGGGGG-, Hepda-GGGG-(Hepda: C17 diacid), Hepda-GGGGG-, Hepda-GGGGGG-, Oda-GGGG-(Oda: C18 diacid), Oda-GGGGG-, Oda-GGGGGG-, Eda-GGGG-(Eda: C20 diacid), Eda-GGGGG-, Eda-GGGGGG-, Eda-GGGGGGG-. As an alternative, it is particularly preferred that R represents XL-, wherein L represents a glycine linker comprising five or six linked glycines, and X represents C 16 -C 20 Linear saturated dicarboxylic acids.

[0690] Furthermore, when any one or two amino acids selected from A8 to A30 optionally represent Lys(R), preferably, one amino acid selected from A12, A14 and A17 represents Lys(R), and more preferably, one amino acid selected from A14 and A17 represents Lys(R).

[0691] Preferred examples of the compound (I) include peptides represented by the following formula (II) or salts thereof.

[0692] Formula (II):

[0693] P 1 -Tyr-A2-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A2 1-A22-A23-A24-A25-A26-A27-A28-A29-A30-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-A39-A40-P 2 (SEQ ID NO: 166)

[0694] In formula (II), P 1 As defined above.

[0695] P 2 As defined above.

[0696] A2 represents Aib or D-Ala.

[0697] A6 represents Iva, Phe or Val.

[0698] A7 represents Ile, Lys or Val.

[0699] A8 stands for Ser.

[0700] A9 represents Asp, Leu or Phe.

[0701] A10 stands for Tyr.

[0702] A11 represents Aib or Ser.

[0703] A12 stands for Ile.

[0704] A13 represents Aib, Ala, Gln, Leu, Tyr or D-Iva.

[0705] A14 represents Leu.

[0706] A15 represents Asp, Glu, Lys, Ser or Tyr.

[0707] A16 represents Arg or Lys.

[0708] A17 represents Aib, Gln or Ile.

[0709] A18 represents Ala or His.

[0710] A19 represents Gln or Ser.

[0711] A20 represents Aib, Ala or Gln.

[0712] A21 represents Asn, Asp, Glu, Leu or Ser.

[0713] A22 represents Phe or αMePhe.

[0714] A23 represents Ile or Val.

[0715] A24 represents Arg, Asn, Asp, Lys or Lys(Ac).

[0716] A25 represents Trp.

[0717] A26 represents Aib, Iva or Leu.

[0718] A27 represents Leu.

[0719] A28 represents Ala, Arg, Lys or Lys(Ac).

[0720] A29 represents Gln or Gly.

[0721] A30 represents Arg or Gly.

[0722] A39 represents Lys or Ser.

[0723] A40 represents Arg, Lys or missing.

[0724] Any one or two amino acids selected from A8 to A30 optionally represent Lys(R), and R is as defined above.

[0725] Preferred other examples of the compound (I) include a peptide represented by the following formula (III) or a salt thereof.

[0726] Formula (III):

[0727] P 1 -Tyr-A2-Glu-Gly-Thr-Val-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A2 1-A22-A23-A24-A25-A26-A27-A28-A29-A30-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-A39-A40-P 2 (SEQ ID NO: 167)

[0728] In formula (III), P 1As defined above.

[0729] P 2 As defined above.

[0730] A2 represents Aib or D-Ala.

[0731] A7 represents Ile, Lys or Val.

[0732] A8 stands for Ser.

[0733] A9 represents Asp, Leu or Phe.

[0734] A10 stands for Tyr.

[0735] A11 stands for Ser.

[0736] A12 stands for Ile.

[0737] A13 represents Aib, Ala, Gln, Leu or Tyr.

[0738] A14 represents Leu.

[0739] A15 represents Asp, Glu, Lys, Ser or Tyr.

[0740] A16 represents Lys.

[0741] A17 represents Gln or Ile.

[0742] A18 represents Ala or His.

[0743] A19 represents Gln or Ser.

[0744] A20 represents Aib or Gln.

[0745] A21 represents Glu or Leu.

[0746] A22 represents Phe.

[0747] A23 represents Ile or Val.

[0748] A24 represents Lys or Lys(Ac).

[0749] A25 represents Trp.

[0750] A26 represents Aib or Leu.

[0751] A27 represents Leu.

[0752] A28 represents Lys or Lys(Ac).

[0753] A29 represents Gly.

[0754] A30 represents Gly.

[0755] A39 represents Lys or Ser.

[0756] A40 represents Arg or is missing.

[0757] Any one or two amino acids selected from A8 to A30 optionally represent Lys(R), and R is as defined above.

[0758] In addition, other preferred examples of the compound (I) include a peptide represented by the following formula (IV) or a salt thereof.

[0759] Formula (IV):

[0760] P 1 -Tyr-Aib-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A2 1-A22-A23-A24-A25-A26-A27-A28-A29-A30-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-A40-P 2 (SEQ ID NO: 168)

[0761] In formula (IV), P 1 As defined above.

[0762] P 2 As defined above.

[0763] A6 represents Iva, Phe or Val.

[0764] A7 stands for Ile or Val.

[0765] A8 stands for Ser.

[0766] A9 represents Asp or Leu.

[0767] A10 stands for Tyr.

[0768] A11 represents Aib or Ser.

[0769] A12 stands for Ile.

[0770] A13 represents Aib, Ala or D-Iva.

[0771] A14 represents Leu.

[0772] A15 stands for Asp.

[0773] A16 represents Arg.

[0774] A17 represents Aib, Gln or Ile.

[0775] A18 represents Ala or His.

[0776] A19 represents Gln.

[0777] A20 represents Aib, Ala or Gln.

[0778] A21 represents Glu, Asn, Asp or Ser.

[0779] A22 represents Phe or αMePhe.

[0780] A23 stands for Val.

[0781] A24 represents Arg, Asp or Asn.

[0782] A25 represents Trp.

[0783] A26 represents Leu or Iva.

[0784] A27 represents Leu.

[0785] A28 represents Ala or Arg.

[0786] A29 represents Gln or Gly.

[0787] A30 represents Arg or Gly.

[0788] A40 represents Arg or is missing.

[0789] Any one or two amino acids selected from A8 to A30 optionally represent Lys(R), and R is as defined above.

[0790] In addition, other preferred examples of compound (I) include a peptide represented by the following formula (V) or a salt thereof.

[0791] Formula (V):

[0792] P 1 -Tyr-Aib-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A9 1-A22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-P 2 (SEQ ID NO: 169)

[0793] In formula (V), P 1 As defined above.

[0794] P 2 As defined above.

[0795] A6 represents Iva, Phe or Val.

[0796] A7 represents Ile, Lys or Val.

[0797] A8 stands for Ser.

[0798] A9 represents Asp, Leu or Phe.

[0799] A10 stands for Tyr.

[0800] A11 represents Aib or Ser.

[0801] A12 stands for Ile.

[0802] A13 represents Aib, Ala, Gln, Leu, Tyr or D-Iva.

[0803] A14 represents Leu.

[0804] A15 represents Asp, Glu, Lys, Ser or Tyr.

[0805] A16 represents Arg or Lys.

[0806] A17 represents Aib, Gln or Ile.

[0807] A18 represents Ala or His.

[0808] A19 represents Gln or Ser.

[0809] A20 represents Aib, Ala or Gln.

[0810] A21 represents Asn, Asp, Glu, Leu or Ser.

[0811] A22 represents Phe or αMePhe.

[0812] A23 represents Ile or Val.

[0813] A24 represents Arg, Asn, Lys or Lys(Ac).

[0814] A25 represents Trp.

[0815] A26 represents Aib, Iva or Leu.

[0816] A27 represents Leu.

[0817] A28 represents Ala, Arg, Lys or Lys(Ac).

[0818] A29 represents Gln or Gly.

[0819] A30 represents Arg, Gly or missing.

[0820] A31 to A40 all represent deletions.

[0821] Any one or two amino acids selected from A8 to A30 optionally represent Lys(R), and R is as defined above.

[0822] Particularly preferred examples of the compound (I) include a peptide represented by the following formula (VI) or a salt thereof.

[0823] Formula (VI):

[0824] P 1 -Tyr-Aib-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A2 1-A22-A23-A24-A25-A26-A27-A28-A29-A30-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-A40-P 2 (SEQ ID NO: 170)

[0825] In formula (VI), P 1 As defined above.

[0826] P 2 As defined above.

[0827] A6 represents Iva, Phe or Val.

[0828] A7 stands for Ile or Val.

[0829] A8 stands for Ser.

[0830] A9 represents Asp or Leu.

[0831] A10 stands for Tyr.

[0832] A11 stands for Ser.

[0833] A12 stands for Ile.

[0834] A13 represents Aib or Ala.

[0835] A14 represents Leu.

[0836] A15 stands for Asp.

[0837] A16 represents Arg or Lys.

[0838] A17 represents Aib, Gln or Ile.

[0839] A18 represents Ala or His.

[0840] A19 represents Gln.

[0841] A20 represents Aib or Gln.

[0842] A21 represents Asn, Glu or Asp.

[0843] A22 represents Phe.

[0844] A23 stands for Val.

[0845] A24 represents Arg, Asn or Lys.

[0846] A25 represents Trp.

[0847] A26 represents Iva or Leu.

[0848] A27 represents Leu.

[0849] A28 represents Ala, Arg or Lys.

[0850] A29 represents Gln or Gly.

[0851] A30 represents Arg or Gly.

[0852] A40 represents Arg, Lys or missing.

[0853] Any one or two amino acids selected from A8 to A30 optionally represent Lys(R), and R is as defined above.

[0854] In addition, other preferred examples of compound (I) include a peptide represented by the above formula (I), or a salt thereof,

[0855] Where P 1 As defined above,

[0856] P 2 As defined above,

[0857] A2 represents Aib or D-Ala,

[0858] A6 represents Iva, Phe or Val,

[0859] A7 represents Ile, Lys or Val,

[0860] A8 stands for Ser,

[0861] A9 represents Asp, Leu or Phe,

[0862] A10 stands for Tyr,

[0863] A11 stands for Aib or Ser,

[0864] A12 stands for Ile,

[0865] A13 represents Aib, Ala, Gln, Leu, Tyr or D-Iva,

[0866] A14 represents Leu,

[0867] A15 represents Asp, Glu, Lys, Ser or Tyr,

[0868] A16 represents Arg or Lys,

[0869] A17 represents Aib, Gln or Ile,

[0870] A18 represents Ala or His,

[0871] A19 represents Gln or Ser,

[0872] A20 represents Aib, Ala or Gln,

[0873] A21 represents Asn, Asp, Glu, Leu or Ser,

[0874] A22 represents Phe or αMePhe,

[0875] A23 represents Ile or Val,

[0876] A24 represents Arg, Asn, Asp, Lys or Lys(Ac),

[0877] A25 represents Trp,

[0878] A26 represents Aib, Iva or Leu,

[0879] A27 represents Leu,

[0880] A28 represents Ala, Arg, Lys or Lys(Ac),

[0881] A29 represents Gln or Gly,

[0882] A30 represents Arg, Gly or missing,

[0883] A31 stands for Pro or missing,

[0884] A32 represents Ser or missing,

[0885] A33 represents Ser or missing,

[0886] A34 represents Gly or missing,

[0887] A35 represents Ala or missing,

[0888] A36 stands for Pro or missing,

[0889] A37 stands for Pro or missing,

[0890] A38 stands for Pro or missing,

[0891] A39 represents Lys, Ser or missing, and

[0892] A40 represents Arg, Lys or missing.

[0893] Assuming that A31 to A40 all represent deletions, A2 represents Aib.

[0894] In addition, other preferred examples of compound (I) include a peptide represented by the above formula (I), or a salt thereof,

[0895] Where P 1 As defined above,

[0896] P 2 As defined above,

[0897] A2 represents Aib or D-Ala,

[0898] A6 represents Iva, Phe or Val,

[0899] A7 represents Ile, Lys or Val,

[0900] A8 stands for Ser,

[0901] A9 represents Asp, Leu or Phe,

[0902] A10 stands for Tyr,

[0903] A11 stands for Aib or Ser,

[0904] A12 stands for Ile,

[0905] A13 represents Aib, Ala, Gln, Leu, Tyr or D-Iva,

[0906] A14 represents Leu,

[0907] A15 represents Asp, Glu, Lys, Ser or Tyr,

[0908] A16 represents Arg or Lys,

[0909] A17 represents Aib, Gln or Ile,

[0910] A18 represents Ala or His,

[0911] A19 represents Gln or Ser,

[0912] A20 represents Aib, Ala or Gln,

[0913] A21 represents Asn, Asp, Glu, Leu or Ser,

[0914] A22 represents Phe or αMePhe,

[0915] A23 represents Ile or Val,

[0916] A24 represents Arg, Asn, Lys or Lys(Ac),

[0917] A25 represents Trp,

[0918] A26 represents Aib, Iva or Leu,

[0919] A27 represents Leu,

[0920] A28 represents Ala, Arg, Lys or Lys(Ac),

[0921] A29 represents Gln or Gly,

[0922] A30 represents Arg, Gly or missing,

[0923] A31 stands for Pro or missing,

[0924] A32 represents Ser or missing,

[0925] A33 represents Ser or missing,

[0926] A34 represents Gly or missing,

[0927] A35 represents Ala or missing,

[0928] A36 stands for Pro or missing,

[0929] A37 stands for Pro or missing,

[0930] A38 stands for Pro or missing,

[0931] A39 represents Lys, Ser or missing, and

[0932] A40 represents Arg, Lys or missing.

[0933] Assuming that A31 to A40 all represent deletions, A2 represents Aib.

[0934] Any one or two amino acids selected from A12, A14 and A17 optionally represent Lys(R), and R is as defined above.

[0935] Still other more preferred examples of compound (I) include a peptide represented by the following formula (VII) or a salt thereof.

[0936] Formula (VII):

[0937] P 1 -Tyr-Aib-Glu-Gly-Thr-A6-A7-Ser-A9-Tyr-Ser-Ile-A13-Leu-Asp-A16-A17-A18-Gln-A20-A 21-Phe-Val-A24-Trp-A26-Leu-A28-A29-A30-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-A40-P 2 (SEQ ID NO: 567)

[0938] In formula (VII), P 1 As defined above.

[0939] P 2 As defined above.

[0940] A6 represents Iva, Phe or Val.

[0941] A7 stands for Ile or Val.

[0942] A9 represents Asp or Leu.

[0943] A13 represents Aib or Ala.

[0944] A16 represents Arg or Lys.

[0945] A17 represents Aib, Gln or Ile.

[0946] A18 represents Ala or His.

[0947] A20 represents Aib or Gln.

[0948] A21 represents Asn, Glu or Asp.

[0949] A24 represents Arg, Asn or Lys.

[0950] A26 represents Iva or Leu.

[0951] A28 represents Ala, Arg or Lys.

[0952] A29 represents Gln or Gly.

[0953] A30 represents Arg or Gly.

[0954] A40 represents Arg, Lys or missing.

[0955] Still other more preferred examples of compound (I) include a peptide represented by the following formula (VIII) or a salt thereof.

[0956] Formula (VIII):

[0957] P 1 -Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(R)-Asp-Arg-Aib-A18-Gln-Ai b-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-A40-P 2 (SEQ ID NO: 568);

[0958] In formula (VIII), P 1 As defined above.

[0959] P 2 As defined above.

[0960] A18 represents Ala or His.

[0961] A40 represents Arg or is missing.

[0962] R stands for XL-.

[0963] -L- stands for -GGGGG- or -GGGGGG-.

[0964] X stands for Heda, Hepda, Oda or Eda.

[0965] Still other more preferred examples of compound (I) include a peptide represented by the following formula (IX) or a salt thereof.

[0966] Formula (IX):

[0967] P 1-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(R)-A18-Gln-Ai b-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-A40-P 2 (SEQ ID NO: 569);

[0968] In formula (IX), P 1 As defined above.

[0969] P 2 As defined above.

[0970] A18 represents Ala or His.

[0971] A40 represents Arg or is missing.

[0972] R stands for XL-.

[0973] -L- stands for -GGGGG- or -GGGGGG-.

[0974] X stands for Heda, Hepda, Oda or Eda.

[0975] Specifically, preferred specific examples of compound (I) include peptides represented by the following formula:

[0976] H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Aib-Gl u-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO: 12);

[0977] H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Gln-Ala-Gln-Aib-Gl u-Phe-Val-Arg-Trp-Leu-Leu-Arg-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO: 36);

[0978] Me-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Ile-Ala-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:65);

[0979] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:110);

[0980] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Scr-Asp-Tyr-Scr-Ile-Aib-Leu-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:119);

[0981] Me-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:123);

[0982] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Heda-GGGGG-)-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Al a-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:458);

[0983] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Heda-GGGGGG-)-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:470);

[0984] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Hepda-GGGGGG-)-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:478);

[0985] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Hepda-GGGGGG-)-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:479);

[0986] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Oda-GGGGG-)-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:454);

[0987] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Oda-GGGGGG-)-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:452);

[0988] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Eda-GGGGG-)-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:354);

[0989] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Eda-GGGGGG-)-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:355);

[0990] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Heda-GGGGG-)-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:520);

[0991] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Heda-GGGGGG-)-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:522);

[0992] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Hepda-GGGGG-)-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:521);

[0993] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Hepda-GGGGGG-)-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:523);

[0994] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Oda-GGGGG-)-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:495);

[0995] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Oda-GGGGGG-)-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:497);

[0996] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Eda-GGGGG-)-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Al a-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:488);

[0997] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Eda-GGGGGG-)-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:534);

[0998] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Heda-GGGGG-)-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:536);

[0999] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Heda-GGGGGG-)-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:537);

[1000] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Hep da-GGGGG-)-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:538);

[1001] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Hepda-GGGGGG-)-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:519);

[1002] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Oda-GGGGG-)-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:539);

[1003] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Oda-GGGGGG-)-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:492);

[1004] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Eda-GGGGG-)-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:486);

[1005] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Eda-GGGGGG-)-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:533);

[1006] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Heda-GGGGG-)-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:540);

[1007] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Heda-GGGGGG-)-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:541);

[1008] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Hepda-GGGGGG-)-Asp-Arg-Aib-His-Gln -Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:542);

[1009] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Hepda-GGGGGG-)-Asp-Arg-Aib-His-Gl n-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:527);

[1010] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Oda-GGGGG-)-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:543);

[1011] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Oda-GGGGGG-)-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:495);

[1012] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Eda-GGGGG-)-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:544);

[1013] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Eda-GGGGGG-)-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:535);

[1014] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Heda-GGGGG-)-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:545);

[1015] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Heda-GGGGGG-)-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:507);

[1016] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Hepda-GGGGGG-)-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:546);

[1017] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Hepda-GGGGGG-)-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:508);

[1018] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Oda-GGGGG-)-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:362);

[1019] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Oda-GGGGGG-)-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:509);

[1020] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Eda-GGGGG-)-Ala-Gl n-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:547);

[1021] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Eda-GGGGGG-)-Ala-G ln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:548);

[1022] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Heda-GGGGG-)-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:549);

[1023] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Heda-GGGGGG-)-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:516);

[1024] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Hepda-GGGGG-)-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:515);

[1025] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Hepda-GGGGGG-)-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:517);

[1026] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Oda-GGGGG-)-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:504);

[1027] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Oda-GGGGGG-)-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:505);

[1028] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Eda-GGGGG-)-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:506);

[1029] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Eda-GGGGGG-)-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO:550);

[1030] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Heda-GGGGG-)-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:551);

[1031] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Heda-GGGGGG-)-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:552);

[1032] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Hepda-GGGGG-)-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:553);

[1033] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Hepda-GGGGGG-)-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:554);

[1034] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Oda-GGGGG-)-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:555);

[1035] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Oda-GGGGGG-)-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:556);

[1036] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Eda-GGGGG-)-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:557);

[1037] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Eda-GGGGGG-)-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:558);

[1038] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Heda-GGGGG-)-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:559);

[1039] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Heda-GGGGGG-)-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:560);

[1040] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lcu-Asp-Arg-Lys(Hepda-GGGGG-)-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:561);

[1041] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Hepda-GGGGGG-)-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO:562);

[1042] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Oda-GGGGG-)-His-Gln- Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO: 563);

[1043] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Oda-GGGGGG-)-His-Gln -Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO: 499);

[1044] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Eda-GGGGG-)-His-Gln- Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO: 564);

[1045] or

[1046] Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Eda-GGGGGG-)-His-Gln -Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO: 565);

[1047] or a salt thereof.

[1048] Furthermore, other particularly preferred examples of the compound (I) include a peptide represented by the following formula (X) or a salt thereof.

[1049] Formula (X):

[1050] P 1 -Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-A14-Asp-Arg-A17-A18-Gln-Aib- Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-A40-P 2 (SEQ ID NO: 566)

[1051] In formula (X), P 1 As defined above.

[1052] P 2 As defined above.

[1053] A14 represents Leu.

[1054] A17 stands for Aib.

[1055] A18 represents Ala or His.

[1056] A40 represents Arg or is missing.

[1057] Any one amino acid selected from A14 and A17 represents Lys(R).

[1058] R stands for XL-.

[1059] L represents a glycine linker comprising five or six linked glycines.

[1060] X is for C 16 -C 20 Linear saturated dicarboxylic acids.

[1061] In addition, examples of compound (I) include peptides represented by SEQ ID NO:1, SEQ ID NO:2 or SEQ ID NO:3.

[1062] Compound (I) can be prepared according to a peptide synthesis method known per se. The peptide synthesis method may be, for example, any of a solid phase synthesis process and a liquid phase synthesis process. That is, the target peptide can be produced according to the desired sequence by repeatedly condensing a partial peptide or amino acid that can constitute compound (I) and a remainder (which may be composed of two or more amino acids). When the product with the desired sequence has a protecting group, the target peptide can be produced by eliminating the protecting group. Examples of known protecting group condensation methods and elimination methods include the methods described in (1)-(5) below.

[1063] (1) M.Bodanszky and MAOndetti: Peptide Synthesis, IntersciencePublishers, New York (1966)

[1064] (2)Schroeder and Luebke: The Peptide, Academic Press, New York (1965)

[1065] (3) Nobuo Izumiya et al.: Peptide Gosei-no-Kiso to Jikken (Basics and experiments of peptide synthesis), published by Maruzen Co. (1975)

[1066] (4) Haruaki Yajima and Shunpei Sakakibara: Seikagaku Jikken Koza (Biochemical Experiment) 1, Tanpakushitsu no Kagaku (Chemistry of Proteins) IV, 205 (1977)

[1067] (5) Haruaki Yajima Editor: Zoku Iyakuhin no Kaihatsu (A sequel to Development of Pharmaceuticals), Volume 14, Peptide Synthesis, published by Hirokawa Shoten

[1068] After the reaction, compound (I) can be purified and isolated using conventional purification methods such as combined solvent extraction, distillation, column chromatography, liquid chromatography, recrystallization, etc. When the peptide obtained by the above-mentioned method is in a free form, it can be converted into a suitable salt by a known method; conversely, when the peptide is obtained in the form of a salt, the salt can be converted into a free form or other salts by a known method.

[1069] The starting compound may also be a salt. Examples of such a salt include those exemplified as salts of compound (I) mentioned below.

[1070] For the condensation of protected amino acids or peptides, various activating agents that can be used for peptide synthesis can be used, and these activating agents are particularly preferably triphosphonium salts, tetramethyluronium salts, carbodiimides, etc. Examples of triphosphonium salts include benzotriazol-1-yloxytris(pyrrolizino)phosphonium hexafluorophosphate (PyBOP), bromotris(pyrrolizino)phosphonium hexafluorophosphate (PyBroP), 7-azabenzotriazol-1-yloxytris(pyrrolizino)phosphonium hexafluorophosphate (PyAOP), and examples of tetramethyluronium salts include 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 2-(1H- ... -yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(5-norbornane-2,3-dicarboxylimide)-1,1,3,3-tetramethyluronium tetrafluoroborate (TNTU), O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), and examples of carbodiimides include N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIPCDI), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI·HCl) and the like. For condensation using these, it is preferred to add a racemization inhibitor [e.g., N-hydroxy-5-norbornene-2,3-dicarboxylic imide (HONB), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOBt), ethyl 2-cyano-2-(hydroxyimino)acetate (Oxyma), etc.]. The solvent to be used for the condensation can be appropriately selected from those known to be usable for peptide condensation reactions. For example, acid amides such as anhydrous or aqueous N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc., halogenated hydrocarbons such as dichloromethane, chloroform, etc., alcohols such as trifluoroethanol, phenol, etc., sulfoxides such as dimethyl sulfoxide, etc., tertiary amines such as pyridine, etc., ethers such as dioxane, tetrahydrofuran, etc., nitriles such as acetonitrile, propionitrile, etc., esters such as methyl acetate, ethyl acetate, etc., appropriate mixtures of these substances, etc. can be used. The reaction temperature is appropriately selected from the range known to be useful for peptide conjugation reactions, and is usually selected from the range of about -20°C to 90°C. A 1.5 to 6-fold excess of the activated amino acid derivative is usually used. In solid phase synthesis, when the test using the ninhydrin reaction reveals that the condensation is insufficient, sufficient condensation can be performed by repeating the condensation reaction without eliminating the protecting group. If the condensation is insufficient even after repeating the reaction, the unreacted amino acid may be acylated with acetic anhydride, acetylimidazole or the like so that the influence on the subsequent reaction can be avoided.

[1071] Examples of the protecting group for the amino group of the starting amino acid include benzyloxycarbonyl (Z), tert-butoxycarbonyl (Boc), tert-pentyloxycarbonyl, isobornyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl (Cl-Z), 2-bromobenzyloxycarbonyl (Br-Z), adamantyloxycarbonyl, trifluoroacetyl, phthaloyl, formyl, 2-nitrophenylsulfinyl, diphenylphosphinothioyl, 9-fluorenylmethoxycarbonyl (Fmoc), trityl and the like.

[1072] In addition to the C mentioned above 1-6 Alkyl, C 3-10 Cycloalkyl, C 7-14 Examples of the carboxyl protecting group for the starting amino acid include allyl, 2-adamantyl, 4-nitrobenzyl, 4-methoxybenzyl, 4-chlorobenzyl, phenacyl, benzyloxycarbonylhydrazide, tert-butoxycarbonylhydrazide, tritylhydrazide and the like in addition to the aralkyl group.

[1073] The hydroxyl group of serine or threonine can be protected, for example, by esterification or etherification. Examples of groups suitable for esterification include lower (C 2-4 ) alkanoyl (such as acetyl, etc.), aromatic acyl (such as benzoyl, etc.), and groups derived from organic acids, etc. In addition, examples of groups suitable for etherification include benzyl, tetrahydropyranyl, tert-butyl (Bu t ), trityl (Trt), etc.

[1074] Examples of the protecting group for the phenolic hydroxyl group of tyrosine include Bzl, 2,6-dichlorobenzyl, 2-nitrobenzyl, Br-Z, tert-butyl and the like.

[1075] Examples of the protecting group of histidine imidazole include p-toluenesulfonyl (Tos), 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), dinitrophenyl (DNP), benzyloxymethyl (Bom), tert-butoxymethyl (Bum), Boc, Trt, Fmoc and the like.

[1076] Examples of protecting groups for the guanidino group of arginine include Tos, Z, 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), p-methoxybenzenesulfonyl (MBS), 2,2,5,7,8-pentamethylchroman-6sulfonyl (Pmc), mesitylene-2-sulfonyl (Mts), 2,2,4,6,7-E-methyldihydrobenzofuran-5-sulfonyl (Pbf), Boc, Z, NO2, and the like.

[1077] Examples of the protecting group for the side chain amino group of lysine include Z, Cl-Z, trifluoroacetyl, Boc, Fmoc, Trt, Mtr, 4,4-dimethyl-2,6-dioxocyclohexylidene (Dde) and the like.

[1078] Examples of the protecting group for the indolyl group of tryptophan include formyl (For), Z, Boc, Mts, Mtr and the like.

[1079] Examples of protecting groups for asparagine and glutamine include Trt, xanthene (Xan), 4,4'-dimethoxybenzhydryl (Mbh), 2,4,6-trimethoxybenzyl (Tmob), and the like.

[1080] Examples of activated carboxyl groups in the starting materials include corresponding acid anhydrides, azides, active esters [esters with alcohols (e.g., pentachlorophenol, 2,4,5-trichlorophenol, 2,4-dinitrophenol, cyanomethyl alcohol, p-nitrophenol, HONB, N-hydroxysuccinimide, 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt))], etc. Examples of activated amino groups in the starting materials include corresponding phosphoramides.

[1081] Examples of methods for removing (eliminating) the protecting group include catalytic reduction of a hydrogen gas stream in the presence of a catalyst such as Pd-black or Pd-carbon; acid treatment using anhydrous hydrogen fluoride, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid (TFA), trimethylsilyl bromide (TMSBr), trimethylsilyl trifluoromethanesulfonate, tetrafluoroboric acid, tri(trifluoro)boric acid, boron tribromide or a solution of a mixture thereof; base treatment using diisopropylethylamine, triethylamine, piperidine, piperazine, etc.; and reduction with sodium in liquid ammonia, etc. The elimination reaction by the above acid treatment is usually carried out at a temperature of -20°C to 40°C; the acid treatment is effectively carried out by adding a cation scavenger such as anisole, phenol, anisole thioether, m-cresol and p-cresol; dimethyl sulfide, 1,4-butanedithiol, 1,2-ethanedithiol, triisopropylsilane, etc. In addition, the 2,4-dinitrophenyl group serving as the protecting group of imidazole of histidine is removed by treatment with thiophenol; the formyl group serving as the protecting group of indole of tryptophan is removed by treatment with an acid in the presence of 1,2-ethanedithiol, 1,4-butanedithiol, or the like, and by deprotection treatment with a base such as dilute sodium hydroxide or dilute aqueous ammonia.

[1082] Protection of functional groups that should not participate in the reaction between the starting material and the protecting group, elimination of the protecting group, activation of the functional group participating in the reaction, and the like can be appropriately selected from known protecting groups and known means.

[1083] In the method for preparing the amide of the peptide, the amide is formed by solid phase synthesis using a resin for amide synthesis, or the α-carbonyl of the carboxyl terminal amino acid is amidated, and the peptide chain is extended to the desired peptide length toward the amino side, after which a peptide in which only the protecting group of the N-terminal α-amino group of the peptide chain is removed and a peptide in which only the protecting group of the C-terminal carboxyl group of the peptide chain is removed are prepared, and the two peptides are condensed in the above-mentioned mixed solvent. Regarding the details of the condensation reaction, the above also applies. After purifying the protected peptide obtained by condensation, all protecting groups can be removed by the above-mentioned method to obtain the desired crude polypeptide. By purifying the crude peptide using various known purification means, and freeze-drying the main fraction, the desired amide of the peptide can be prepared.

[1084] When compound (I) exists as configurational isomers such as enantiomers, diastereomers, conformers, etc., they are also included in compound (I), and each can be separated by means known per se or the above separation method and purification method as needed. In addition, when compound (I) is in the form of a racemate, it can be separated into S-form and R-form by conventional optical resolution. When compound (I) includes stereoisomers, both individual isomers and mixtures of each isomer are also included in compound (I).

[1085] Compound (I) can be chemically modified by a method known per se and using a substituent and polyethylene glycol. For example, a chemically modified compound (I) can be produced by introducing a substituent into a Cys residue, an Asp residue, a Glu residue, a Lys residue, etc. of compound (I) and / or conjugating polyethylene glycol to the residue, etc. In addition, a linker structure may exist between compound (I) and the substituent and polyethylene glycol.

[1086] Compound (I) modified by substituents and / or polyethylene glycol (PEG) produces effects such as promoting the biological activity of therapeutically and diagnostically important peptides, prolonging their blood circulation time, reducing their immunogenicity, enhancing their solubility, and enhancing their resistance to metabolism.

[1087] The molecular weight of PEG is not particularly limited, and is generally about 1K to about 1000K Daltons, preferably about 10K to about 100K Daltons, more preferably about 20K to about 60K Daltons.

[1088] Modification of compound (I) by a substituent can be performed by introducing a substituent based on known oxidation reaction and reduction reaction.

[1089] As a method for modifying compound (I) by PEG, a method well known in the art can be used, and, for example, the method described below can be used.

[1090] (1) A pegylation agent having an active ester (for example, SUNBRIGHT MEGC-30TS (trade name), NOF Corp.) is bonded to the amino group of compound (I).

[1091] (2) A pegylation agent having an aldehyde (for example, SUNBRIGHT ME-300AL (trade name), NOF Corp.) is bonded to the amino group of compound (I).

[1092] (3) A divalent cross-linking reagent (e.g., GMBS (Dojindo Laboratories), EMCS (Dojindo Laboratories), KMUS (Dojindo Laboratories), SMCC (Pierce)) is bonded to compound (I), and then a pegylation reagent having a thiol group (e.g., SUNBRIGHT ME-300-SH (trade name), NOF Corp.) is bonded thereto.

[1093] (4) A thiol group is introduced into compound (I) by means of an SH-introducing agent (e.g., D-cysteine ​​residue, L-cysteine ​​residue, Traut's reagent), and then the thiol group is reacted with a pegylation reagent having a maleimide group (e.g., SUNBRIGHT ME-300MA (trade name), NOF Corp.).

[1094] (5) A thiol group is introduced into compound (I) by an SH-introducing agent (e.g., D-cysteine ​​residue, L-cysteine ​​residue, Trout's reagent), and then the thiol group is reacted with a pegylation reagent having an iodoacetamide group (e.g., SUNBRIGHT ME-300IA (trade name), NOF Corp.).

[1095] (6) An ω-aminocarboxylic acid, α-amino acid or the like is introduced as a linker into the N-terminal amino group of compound (I), and the amino group derived from the linker is then reacted with a pegylation reagent having an active ester (e.g., SUNBRIGHT MEGC-30TS (trade name), NOF Corp.).

[1096] (7) An ω-aminocarboxylic acid, α-amino acid or the like is introduced as a linker into the N-terminal amino group of compound (I), and the amino group derived from the linker is then reacted with a pegylation reagent having an aldehyde group (e.g., SUNBRIGHT ME-300AL (trade name), NOF Corp.).

[1097] Furthermore, compound (I) may be a solvate (eg, a hydrate) or a non-solvate (eg, a non-hydrate).

[1098] Isotopes (e.g. 3 H. 14 C. 35 S. 125 I) etc. to label compound (I).

[1099] Alternatively, compound (I) may be in a deuterated form, wherein 1 H is converted to 2 H(D).

[1100] Compound (I) labeled or substituted with an isotope can be used as, for example, a tracer for positron emission tomography (PET) (PET tracer), and can be used in the field of medical diagnosis and the like.

[1101] For the peptides mentioned in this article, according to conventional peptide notation, the left end is the N-terminus (amino terminus) and the right end is the C-terminus (carboxyl terminus). The C-terminus of the peptide can be an amide (-CONH2), a carboxyl group (-COOH), a carboxylate group (-COO - ), alkylamide (-CONHR a ) and esters (-COOR a ). In particular, amide (-CONH2) is preferred.

[1102] Compound (I) may be in the form of a salt. Examples of such salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.

[1103] Preferable examples of the metal salt include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like.

[1104] Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylenediamine and the like.

[1105] Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

[1106] Preferable examples of the salt with an organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.

[1107] Preferable examples of the salt with a basic amino acid include salts with arginine, lysine, ornithine, etc. Preferable examples of the salt with an acidic amino acid include salts with aspartic acid, glutamic acid, etc.

[1108] Among the salts mentioned above, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, inorganic salts such as alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, magnesium salts, barium salts, etc.), ammonium salts, etc. are preferred; and when the compound has a basic functional group, for example, salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., or salts formed with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. are preferred.

[1109] Compound (I) may be in the form of a prodrug.

[1110] A prodrug refers to a compound that is converted into compound (I) by a reaction due to an enzyme, gastric acid, etc. under physiological conditions in a living body, that is, a compound that is converted into compound (I) by oxidation, reduction, hydrolysis, etc. by an enzyme; a compound that is converted into compound (I) by hydrolysis, etc. due to gastric acid, etc.

[1111] Examples of the prodrug of compound (I) include compounds in which the amino group of compound (I) is acylated, alkylated or phosphorylated (for example, compounds in which the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidinylmethylated, pivaloyloxymethylated or tert-butylated); compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated or borated (for example, compounds in which the hydroxyl group of compound (I) is acetylated, palmitoylated, propionylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated); compounds in which the carboxyl group of compound (I) is esterified or amidated (for example, compounds in which the carboxyl group of compound (I) is C 1-6 alkyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalyl esterification, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl esterification, cyclohexyloxycarbonylethyl esterification or methyl amidation compounds), etc. Among them, it is preferable to use a compound in which the carboxyl group of compound (I) is replaced by C 1-6 Compounds in which an alkyl group such as methyl, ethyl, tert-butyl, etc. is esterified. These compounds can be produced from compound (I) by a method known per se.

[1112] The prodrug of compound (I) may also be a prodrug converted to compound (I) under physiological conditions, such as those described in IYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol. 7, Design of Molecules, pp. 163-198 (published by HIROKAWA SHOTEN (1990)).

[1113] In the present specification, the prodrug may form a salt. Examples of such a salt include those exemplified as the salt of compound (I).

[1114] Compound (I) may be a crystal. Compound (I) also includes a crystal having a single crystal form or a mixture of multiple crystal forms. Crystals can be produced by crystallizing Compound (I) according to a crystallization method known per se.

[1115] In addition, compound (I) may be a pharmaceutically acceptable co-crystal or co-crystal salt. Here, a co-crystal or a co-crystal salt refers to a crystalline substance composed of two or more specific substances that are solid at room temperature, each of which has different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, stability, etc.). Co-crystals and co-crystal salts can be produced by co-crystallization known per se.

[1116] The crystal of Compound (I) is excellent in physicochemical properties (eg, melting point, solubility, stability) and biological properties (eg, pharmacokinetics (absorption, distribution, metabolism, excretion), efficacy expression), and is therefore particularly useful as a drug.

[1117] Compound (I) and its prodrug (hereinafter sometimes abbreviated as the compound of the present invention) have a GIP receptor activating effect.

[1118] The compounds of the present invention have a highly selective activation effect on GIP receptors in vivo.

[1119] GIP is a gastrointestinal hormone called incretin, which has a promoting effect on insulin secretion from the pancreas. Incretin is closely related to glucose metabolism, so compounds with GIP receptor activation can be used to prevent and treat symptoms related to abnormal glucose metabolism, including diabetes and obesity. In addition, the compounds of the present invention have GIP receptor selective activation and inhibit vomiting by activating GABAergic neurons in the area postrema.

[1120] More specifically, the compounds of the present invention have hypoglycemic effects, antiemetic effects and the like.

[1121] The compounds of the present invention have high chemical stability and excellent persistence of in vivo effects.

[1122] The compounds of the present invention can be used as GIP receptor activators.

[1123] In the present invention, a GIP receptor activator (GIP receptor agonist) refers to an agent having a GIP receptor activating effect. In addition, a GIP receptor selective activator (GIP receptor selective agonist) particularly refers to an agent whose EC50 for the GIP receptor is 1 / 1000 or less, preferably 1 / 10000 or less, of the EC50 for the GLP-1 receptor.

[1124] The compounds of the present invention have low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity), show some side effects, and can be safely administered to mammals (e.g., humans, cows, horses, dogs, cats, monkeys, mice, rats), etc. as agents for preventing or treating the various diseases mentioned below.

[1125] By virtue of the above-mentioned activation effect on the GIP receptor, the compound of the present invention can be used as an agent for treating or preventing various diseases including diabetes and obesity. The compound of the present invention can be used as an agent for preventing or treating, for example, the following diseases: symptomatic obesity, obesity based on simple obesity, disease states or diseases associated with obesity, eating disorders, diabetes (e.g., type 1 diabetes, type 2 diabetes, gestational diabetes, obese diabetes), hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hyperLDL-cholesterolemia, hypoHDL-cholesterolemia, postprandial hyperlipidemia), hypertension, heart failure, diabetic complications [e.g., neuropathy, nephropathy, retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious diseases (e.g., respiratory tract infection, urinary tract infection, gastrointestinal infection, dermal soft tissue infection, lower limb infection), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorder, peripheral blood circulation disorder], metabolic syndrome (disease states having 3 or more selected from the following: hypertriglyceridemia (TG) blood, hypoHDL cholesterol (HDL-C) blood, hypertension, abdominal obesity and impaired glucose tolerance), sarcopenia, etc.

[1126] Examples of symptomatic obesity include endocrine obesity (e.g., Cushing syndrome, hypothyroidism, insulinoma, obesity type II diabetes, pseudohypoparathyroidism, hypogonadism), central obesity (e.g., hypothalamic obesity, frontal lobe syndrome, Kleine-Levin syndrome), genetic obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), drug-induced obesity (e.g., steroid, phenothiazine, insulin, sulfonylurea (SU) agent, beta-blocker induced obesity), and the like.

[1127] Examples of disease states or diseases associated with obesity include impaired glucose tolerance, diabetes (particularly type 2 diabetes, obese diabetes), abnormal lipid metabolism (synonymous with the hyperlipidemia mentioned above), hypertension, heart failure, hyperuricemia / gout, fatty liver (including non-alcoholic steatohepatitis), coronary heart disease (myocardial infarction, angina pectoris), cerebral infarction (cerebral thrombosis, transient ischemic attack), bone / joint diseases (knee osteoarthritis, hip osteoarthritis, deformed spondylitis, low back pain), sleep apnea syndrome / Pickwick syndrome, menstrual disorders (abnormal menstrual cycle, abnormal menstrual volume and cycle, amenorrhea, abnormal menstrual symptoms), metabolic syndrome, etc.

[1128] The Japanese Diabetes Society reported new diagnostic criteria for diabetes in 1999.

[1129] According to the report, diabetes refers to a state that satisfies any of the following: a fasting blood sugar level (glucose concentration in venous plasma) of 126 mg / dl or more, a 2-hour value (glucose concentration in venous plasma) in a 75 g oral glucose tolerance test (75 g OGTT) of 200 mg / d1 or more, and an occasional blood sugar level (glucose concentration in venous plasma) of 200 mg / dl or more. In addition, a state that does not apply to the above-mentioned diabetes and is not a state that shows "a fasting blood sugar level (glucose concentration in venous plasma) of less than 110 mg / dl or a 2-hour value (glucose concentration in venous plasma) in a 75 g oral glucose tolerance test (75 g OGTT) of less than 140 mg / dl" (normal type) is referred to as "borderline type".

[1130] In addition, the American Diabetes Association (ADA) in 1997 and the World Health Organization (WHO) in 1998 reported new diagnostic criteria for the diagnosis of diabetes.

[1131] According to these reports, diabetes refers to a state in which the fasting blood sugar level (glucose concentration in venous plasma) is 126 mg / dl or higher and the 2-hour value (glucose concentration in venous plasma) in a 75 g oral glucose tolerance test is 200 mg / dl or higher.

[1132] According to the above-mentioned report, impaired glucose tolerance refers to a state that satisfies the following conditions: the fasting blood glucose level (glucose concentration in venous plasma) is lower than 126 mg / dl, and the 2-hour value (glucose concentration in venous plasma) in the 75g oral glucose tolerance test is 140 mg / dl or higher and lower than 200 mg / dl. According to the report of ADA, the state showing a fasting blood glucose level (glucose concentration in venous plasma) of 110 mg / dl or higher and lower than 126 mg / dl is called IFG (Impaired Fasting Glucose). On the other hand, according to the report of WHO, the IFG (Impaired Fasting Glycemia) state showing a 2-hour value (glucose concentration in venous plasma) lower than 140 mg / dl in the 75g oral glucose tolerance test is called IFG (Impaired Fasting Glycemia).

[1133] The compound of the present invention is also used as an agent for preventing or treating diabetes determined according to the new diagnostic criteria mentioned above, borderline diabetes, impaired glucose tolerance, IFG (impaired fasting glucose) and IFG (abnormal fasting glucose). In addition, the compound of the present invention can prevent borderline, impaired glucose tolerance, IFG (impaired fasting glucose) or IFG (abnormal fasting glucose) from progressing to diabetes.

[1134] The compounds of the present invention can also be used as agents for preventing or treating metabolic syndrome. Compared with patients with single lifestyle-related diseases, the incidence of cardiovascular disease is significantly higher in patients with metabolic syndrome. Therefore, preventing or treating metabolic syndrome is extremely important for preventing cardiovascular disease.

[1135] The diagnostic criteria of metabolic syndrome were announced by WHO in 1999 and by NCEP in 2001. According to the diagnostic criteria of WHO, individuals with hyperinsulinemia or abnormal glucose tolerance (as requirements) and two or more of visceral obesity, dyslipidemia (high TG or low HDL) and hypertension are diagnosed as having metabolic syndrome (World Health Organization: Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications. Part I: Diagnosis and Classification of Diabetes Mellitus, World Health Organization, Geneva, 1999). According to the diagnostic criteria of the Adult Treatment Panel III of the National Cholesterol Education Program (Ischemic Heart Disease Guidelines), individuals with three or more of visceral obesity, hypertriglyceridemia, low HDL-cholesterolemia, hypertension, and abnormal glucose tolerance are diagnosed as having metabolic syndrome (National Cholesterol Education Program: Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). The Journal of the American Medical Association, Vol. 285, 2486-2497, 2001).

[1136] The compounds of the present invention can be used as a preventive / therapeutic agent for vomiting or nausea caused by, for example, the clinical pathological conditions or causes described in the following (1)-(6). In addition, the compounds of the present invention can be used as a preventive / therapeutic agent for chronic unexplained nausea and vomiting. Vomiting or nausea also includes an unpleasant feeling of an urgent need to discharge gastric contents through the mouth, such as feeling nauseous and retching, and may also be accompanied by autonomic symptoms, such as pale complexion, cold sweat, salivation, tachycardia and diarrhea. Vomiting also includes acute vomiting, prolonged vomiting and anticipatory vomiting.

[1137] (1) Diseases associated with vomiting or nausea, such as gastroparesis, hypomotility, peritonitis, abdominal tumors, constipation, gastrointestinal obstruction, cyclic vomiting syndrome, chronic unexplained nausea and vomiting, acute pancreatitis, chronic pancreatitis, hyperkalemia, cerebral edema, intracranial lesions, metabolic disorders, gastritis caused by infection, postoperative diseases, myocardial infarction, migraine, intracranial hypertension and intracranial hypotension (e.g., altitude sickness);

[1138] (2) Drug-induced vomiting or nausea, where the drugs are such as (i) alkylating agents (e.g., cyclophosphamide, carmustine, lomustine, chlorambucil, streptozotocin, dacarbazine, ifosfamide, temozolomide, busulfan, bendamustine, and melphalan), cytotoxic antibiotics (e.g., dactinomycin, doxorubicin, mitomycin-C, bleomycin, epirubicin, actinomycin D, amrubicin, idarubicin, daunorubicin, and pirarubicin), antimetabolites (e.g., cytarabine, methotrexate), (ii) opioid analgesics (e.g., morphine); (iii) dopamine receptor D1D2 agonists (e.g., apomorphine); (iv) cannabis and cannabinoid products, including cannabis hyperemesis gravis

[1139] (3) vomiting or nausea caused by radiation sickness or radiation therapy to the chest, abdomen, etc. for the treatment of cancer;

[1140] (4) vomiting or nausea caused by toxic substances or toxins;

[1141] (5) pregnancy-related vomiting and nausea, including hyperemesis gravidarum; and

[1142] (6) Vomiting and nausea caused by vestibular disorders (such as motion sickness or dizziness).

[1143] The compounds of the present invention can also be used for secondary prevention or inhibition of the progression of the various diseases mentioned above (e.g., cardiovascular events, such as myocardial infarction, etc.). In addition, the compounds of the present invention can also be used as food intake inhibitors and weight loss agents. The compounds of the present invention can also be used in combination with diet therapy (e.g., diet therapy for diabetes) and exercise therapy.

[1144] The drug containing the compound of the present invention shows low toxicity and is obtained according to a method known per se (e.g., a method described in the Japanese Pharmacopoeia) generally used as a production method for pharmaceutical preparations using the compound of the present invention alone or in admixture with a pharmacologically acceptable carrier, and is safely administered orally or parenterally (e.g., topical, rectal, intravenous administration) as a pharmaceutical preparation such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets), powders, granules, capsules (including soft capsules, microcapsules), liquids, lozenges, syrups, emulsions, suspensions, injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, etc.), external preparations (e.g., nasal preparations, skin preparations, ointments), suppositories (e.g., rectal suppositories, vaginal suppositories), pills, nasal preparations, pulmonary preparations (inhalants), blood transfusions, and the like.

[1145] These preparations may be controlled release preparations, such as rapid release preparations, sustained release preparations, and the like (eg, sustained release microcapsules).

[1146] The content of the compound of the present invention in the pharmaceutical preparation is about 0.01% to about 100% by weight of the entire preparation.

[1147] The pharmaceutically acceptable carriers mentioned above can be exemplified by various organic or inorganic carrier materials conventionally used as formulation materials, for example, excipients, lubricants, binders and disintegrants for solid preparations; or solvents, solubilizers, suspending agents, isotonic agents, buffers, soothing agents, etc. for liquid preparations. In addition, if necessary, general additives such as preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents, etc. can also be used appropriately in appropriate amounts.

[1148] Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.

[1149] Examples of lubricants include magnesium stearate, calcium stearate, talc, colloidal silicon dioxide and the like.

[1150] Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, starch, sucrose, gelatin, methyl cellulose, sodium carboxymethyl cellulose and the like.

[1151] Examples of disintegrants include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose and the like.

[1152] Examples of the solvent include water for injection, alcohol, propylene glycol, polyethylene glycol (Macrogol), sesame oil, corn oil, olive oil and the like.

[1153] Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.

[1154] Examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, etc.; hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.; and the like.

[1155] Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerol, D-mannitol and the like.

[1156] Examples of buffers include buffer solutions such as phosphate, acetate, carbonate, citrate, and the like.

[1157] Examples of soothing agents include benzyl alcohol and the like.

[1158] Examples of preservatives include parabens, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.

[1159] Examples of antioxidants include sulfites, ascorbic acid, α-tocopherol, and the like.

[1160] Examples of colorants include water-soluble edible coal tar dyes (e.g., food dyes such as Food Red No. 2 and No. 3, Food Yellow No. 4 and No. 5, Food Blue No. 1 and No. 2, etc.), water-insoluble lake dyes (such as the aluminum salts of the water-soluble edible coal tar dyes mentioned above), natural dyes (e.g., β-carotene, chlorophyll, red iron oxide), etc.

[1161] Examples of the sweetener include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.

[1162] Examples of the adsorbent include porous starch, calcium silicate (trade name: Florite RE), magnesium aluminum metasilicate (trade name: Neusilin), and light anhydrous silicic acid (trade name: Sylysia).

[1163] Examples of wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.

[1164] During the production of oral preparations, coatings may be applied if necessary for the purpose of taste masking, enteric solubility or persistence.

[1165] Examples of the coating base to be used for coating include a sugar coating base, an aqueous film coating base, an enteric film coating base, and a sustained-release film coating base.

[1166] As the sugar coating base, sucrose is used. In addition, one or more coating bases selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, etc. can be used in combination.

[1167] Examples of the aqueous film coating base include cellulose polymers such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, etc.; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name)], polyvinyl pyrrolidone, etc.; and polysaccharides such as pullulan, etc.

[1168] Examples of enteric film coating bases include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, etc.; acrylic acid polymers such as methacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit L-30D55 ​​(trade name)], methacrylic acid copolymer S [Eudragit S (trade name)], etc.; and naturally occurring substances such as shellac, etc.

[1169] Examples of the sustained-release film coating matrix include cellulose polymers such as ethylcellulose and the like; and acrylic polymers such as aminoalkyl methacrylate copolymer RS ​​[Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name)] and the like.

[1170] The coating base mentioned above may be used after being mixed with two or more coating bases thereof at an appropriate ratio. For coating, for example, a sunscreen such as titanium oxide, red iron oxide, etc. may be used.

[1171] The dosage of the compound of the present invention is appropriately determined according to the administration object, symptoms, administration method, etc. For example, when the compound of the present invention is orally administered to an obese or diabetic patient or gastroparesis (weight 60 kg), the daily dosage of the compound of the present invention is about 0.1 to 100 mg, preferably about 1.0 to 50 mg, more preferably about 1.0 to 20 mg. When the compound of the present invention is parenterally administered to an obese or diabetic patient or gastroparesis (weight 60 kg), the daily dosage of the compound of the present invention is about 0.001 to 30 mg, preferably about 0.01 to 20 mg, more preferably about 0.1 to 10 mg. These amounts can be administered in the form of about 1 portion to several portions per day.

[1172] The compounds of the invention can be administered, for example, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every week, twice a week, every other week, every 3 weeks, monthly, every 2 months, every 3 months, every 4 months, every 5 months, or every 6 months.

[1173] The compounds of the present invention can be used in combination with other drugs that have no adverse effects on the compounds of the present invention for the purpose of, for example, promoting the effects of the compounds of the present invention (therapeutic effects on obesity, diabetes, diseases accompanied by vomiting or nausea, and antiemetic effects), reducing the dosage of the compounds of the present invention, etc.

[1174] Examples of drugs that can be used in combination with the compound of the present invention (hereinafter sometimes abbreviated as concomitant drugs) include anti-obesity agents, therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents, diuretics, chemotherapeutic agents, immunotherapeutic agents, anti-inflammatory drugs, antithrombotic agents, osteoporosis therapeutic agents, vitamins, anti-dementia drugs, erectile dysfunction drugs, drugs for treating frequent urination or urinary incontinence, agents for treating dysuria, central D2 receptor antagonists, gastrointestinal prokinetic agents, antihistamines, muscarinic receptor antagonists, serotonin 5HT3 receptor antagonists, somatostatin analogs, corticosteroids, benzodiazepines, Anxiolytics, NK-1 receptor antagonists, hypercalcemia therapeutic drugs, etc. Specific examples of concomitant drugs include those mentioned below.

[1175] Examples of anti-obesity agents include monoamine uptake inhibitors (e.g., phentermine, sibutramine, mazindol, fluoxetine, tesofensine), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulators, GABA modulators (e.g., topiramate), neuropeptide Y antagonists (e.g., velibactam), cannabinoid receptor antagonists (e.g., rimonabant, tarenabant), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylase inhibitors, opioid receptor antagonists (e.g., GSK-1521498 ), orexin receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (e.g. AZD-4017), pancreatic lipase inhibitors (e.g. orlistat, sinostat), β3 agonists (e.g. N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetyl-CoA carboxylase (ACC) inhibitors, stearoyl-CoA desaturase inhibitors, microsomal triglyceride transfer protein inhibitors (e.g. R-256918), Na-glucose cotransporter inhibitors (e.g. such as JNJ-28431754, repagliflozin), NFκ inhibitors (such as HE-3286), PPAR agonists (such as GFT-505, DRF-11605), phosphotyrosine phosphatase inhibitors (such as sodium vanadate, Trodusquemin), GPR119 agonists (such as PSN-821, MBX-2982, APD597), glucokinase activators (such as AZD-1656), leptin, leptin derivatives (such as metreleptin), CNT F (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., pramlintide, AC-2307), neuropeptide Y agonists (e.g., PYY3-36, derivatives of PYY3-36, obineptide, TM-30339, TM-30335), oxyntomodulin preparations: FGF21 preparations (e.g., animal FGF21 preparations extracted from the pancreas of cows or pigs; human FGF21 preparations genetically synthesized using Escherichia coli or yeast; fragments or derivatives of FGF21), anorectics (e.g., P-57), GLP-1 receptor agonists, GLP-1 receptor / GIP receptor co-agonists, glucagon receptor / GLP-1 receptor / GIP receptor triple receptor agonists, and the like.

[1176] Here, as the therapeutic agent for diabetes, for example, there can be mentioned insulin preparations (for example, animal insulin preparations extracted from the pancreas of cattle or pigs; human insulin preparations genetically synthesized using Escherichia coli or yeast; zinc insulin; protamine zinc insulin; fragments or derivatives of insulin (for example, INS-1), oral insulin preparations), insulin sensitizers (for example, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate), Metaglidasen, AMG-131, baglitazone, MBX-2044, rivoglitazone, aleglitazar, cigliptin, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, Compounds described in WO007 / 013694, WO2007 / 018314, WO2008 / 093639 or WO2008 / 099794), α-glucosidase inhibitors (e.g. voglibose, acarbose, miglitol, emiglitate), biguanides (e.g. metformin, buformin or salts thereof (e.g. hydrochloride, fumarate, succinate)), insulin secretagogues (e.g. sulfonylureas (e.g. tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyburide, glimepiride, glipizide, glipizide), repaglinide, nateglinide, mitiglinide or calcium salt hydrates thereof), dipeptidyl peptidase IV inhibitors (e.g. alogliptin or salts thereof ( benzoate), vildagliptin, sitagliptin, saxagliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin or a salt thereof (preferably succinate)), β3 agonists (e.g. N-5984), GPR40 agonists (e.g. Fasiglifam or a hydrate thereof, disclosed in WO2004 / 041266, WO2004 / 106276, WO2005 / 063729, WO2005 / 063725, WO2005 / 087710, WO2005 / 095 338, compounds described in WO2007 / 013689 or WO2008 / 001931), SGLT2 (sodium-glucose co-transporter 2) inhibitors (e.g., dapagliflozin, AVE2268, TS-033, YM543, TA-7284, repagliflozin, ASP1941), SGLT1 inhibitors, 11β-hydroxysteroid dehydrogenase inhibitors (e.g., BVT-3498, INCB-13739), adiponectin or its agonist, IKK inhibitors (e.g., AS-2868), leptin resistance improving drugs, somatostatin receptor agonists, glucokinase activators (e.g., pioglitazone, AZD1656, AZD6370, TTP-355,Compounds described in WO006 / 112549, WO007 / 028135, WO008 / 047821, WO008 / 050821, WO008 / 136428 or WO008 / 156757), GPR119 agonists (e.g., PSN821, MBX-2982, APD597), FGF21, FGF analogs, ACC2 inhibitors, GLP-1 receptor agonists, GLP-1 receptor / GIP receptor co-agonists, glucagon receptor / GLP-1 receptor / GIP receptor triple receptor agonists, etc. ,

[1177] As therapeutic agents for diabetic complications, aldose reductase inhibitors (e.g., torestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat (AS-3201), lidostat), neurotrophic factors and their increasing agents (e.g., NGF, NT-3, BDNF, neurotrophic production / secretion promoters described in WO01 / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole), compounds described in WO2004 / 039365), PKC inhibitors (e.g., rubusta mesylate), AGE inhibitors (e.g., ALT946, N-benzoylmethyl The invention relates to the following drugs: (a) thiazolium bromide (ALT766), EXO-226, pyridorin, pyridoxamine), GABA receptor agonists (e.g. gabapentin, pregabalin), serotonin and norepinephrine reuptake inhibitors (e.g. duloxetine), sodium channel inhibitors (e.g. lacosamide), reactive oxygen species scavengers (e.g. lipoic acid), cerebral vasodilators (e.g. tiapuride, mexiletine), somatostatin receptor agonists (e.g. BIM23190), apoptosis signal regulating kinase-1 (ASK-1) inhibitors, GLP-1 receptor agonists, GLP-1 receptor / GIP receptor co-agonists, glucagon receptor / GLP-1 receptor / GIP receptor triple receptor agonists, etc.

[1178] As therapeutic agents for hyperlipidemia, there can be mentioned HMG-CoA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or salts thereof (e.g., sodium salt, calcium salt)), squalene synthetase inhibitors (e.g., compounds described in WO97 / 10224, such as N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine -3-yl] acetyl] piperidine-4-acetic acid), fibrate compounds (e.g., bezafibrate, clofibrate, bisfibrate, clinofibrate), anion exchange resins (e.g., cholestyramine), probucol, niacin drugs (e.g., nicotinic acid drugs (e.g., nicotinamide, niceritrol, niaspan), eicosapentaenoic acid ethyl ester, plant sterols (e.g., stigmasterol, gamma-oryzanol), cholesterol absorption inhibitors (e.g., zechia), CETP inhibitors (e.g., dalcetrapib, anacetrapib), ω-3 fatty acid preparations (e.g., ω-3-fatty acid ethyl ester 90 (ω-3-acid ethyl ester 90)), etc.

[1179] Examples of antihypertensive agents include angiotensin converting enzyme inhibitors (e.g., captopril, enalapril, delapril, etc.), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil, etc.), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonipine, nicardipine, cilnidipine, etc.), beta blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol, etc.), clonidine, etc.

[1180] As the diuretic, for example, xanthine derivatives (e.g., theobromine sodium salicylate, theobromine calcium salicylate, etc.), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, pentoflumethiazide, polythiazide, methylchlorothiazide, etc.), anti-aldosterone preparations (e.g., spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (e.g., acetazolamide, etc.), chlorobenzenesulfonamide agents (e.g., chlorthalidone, mefruside, indapamide, etc.), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide, etc., etc. can be mentioned.

[1181] Examples of chemotherapeutic agents include alkylating agents (e.g., cyclophosphamide, ifosfamide), antimetabolites (e.g., methotrexate, 5-fluorouracil), anticancer antibiotics (e.g., mitomycin, doxorubicin), plant-derived anticancer agents (e.g., vincristine, vindesine, paclitaxel), cisplatin, carboplatin, etoposide, etc. Among them, 5-fluorouracil derivatives such as Furtulon or Neofurtulon are preferred.

[1182] Examples of immunotherapeutic agents include microbial or bacterial components (e.g., muramyl dipeptide derivatives, Picibanil), polysaccharides with immunopotentiating activity (e.g., Lentinan, Sizoran, Krestin), cytokines obtained by genetic engineering methods (e.g., interferon, interleukin (IL)), colony stimulating factors (e.g., granulocyte colony stimulating factor, erythropoietin), etc. Among them, interleukins such as IL-1, IL-2, IL-12, etc. are preferred.

[1183] Examples of anti-inflammatory drugs include nonsteroidal anti-inflammatory drugs such as aspirin, acetaminophen, indomethacin, and the like.

[1184] As the antithrombotic agent, for example, heparin (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (e.g., warfarin potassium), antithrombin drugs (e.g., argatroban, dabigatran), FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, YM150, described in WO02 / 06234, WO2004 / 048363, WO2005 / 03 0740, compounds described in WO2005 / 058823 or WO2005 / 113504), thrombolytic agents (e.g., urokinase, thiokinase, alteplase, natplase, monteplase, pamiplase), platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, eicosapentaenoic acid ethyl ester, beraprost sodium, sarpogrelate hydrochloride), and the like.

[1185] Examples of therapeutic agents for osteoporosis include alfacalcidol, calcitriol, elcatonin, salmon calcitonin, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, risedronate disodium and the like.

[1186] Examples of vitamins include vitamin B1, vitamin B 12 wait.

[1187] Examples of anti-dementia drugs include tacrine, donepezil, rivastigmine, galantamine, etc.

[1188] Examples of erectile dysfunction drugs include apomorphine, sildenafil citrate, etc.

[1189] Examples of the drug for treating frequent urination or urinary incontinence include flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like.

[1190] Examples of the therapeutic agent for dysuria include acetylcholinesterase inhibitors (eg, destigmine) and the like.

[1191] Examples of central D2 receptor antagonists include typical psychotherapeutic drugs (prochlorperazine, haloperidol, chlorpromazine, etc.), serotonin dopamine antagonists (perospirone, risperidone, etc.) and multifunctional receptor-targeted antipsychotic drugs (olanzapine, etc.).

[1192] Examples of gastrointestinal prokinetic agents include peripheral D2 receptor antagonists (metoclopramide, domperidone, etc.) and 5HT4 receptor agonists (mosapride, etc.).

[1193] Examples of antihistamines include hydroxyzine, diphenhydramine, and chlorpheniramine.

[1194] Examples of the muscarinic receptor antagonist include central muscarinic receptor antagonists (scopolamine, etc.) and peripheral muscarinic receptor antagonists (butylscopolamine, etc.).

[1195] Examples of serotonin 5HT3 receptor antagonists include granisetron, ondansetron, azasetron, indesisetron, palonosetron, and ramosetron.

[1196] Examples of somatostatin analogs include octreotide.

[1197] Examples of corticosteroids include dexamethasone, betamethasone, and methylprednisolone.

[1198] Benzodiazepines Examples of anxiolytics include lorazepam and alprazolam, examples of NK-1 receptor antagonists include aprepitant and fosaprepitant, and examples of hypercalcemia therapeutic drugs include bisphosphonates.

[1199] In addition, drugs that have been confirmed to have cachexia-improving effects in animal models or clinically, i.e., cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide drugs, tetrahydrocannabinol drugs, agents for improving fat metabolism (e.g., eicosapentaenoic acid), growth hormone, IGF-1, or antibodies against cachexia-inducing factors such as TNF-α, LIF, IL-6, or oncostatin M, can also be used in combination with the compounds of the present invention.

[1200] Alternatively, glycation inhibitors (e.g. ALT-711), drugs promoting nerve regeneration (e.g. Y-128, VX853, neurotrophic peptides), antidepressants (e.g. desipramine, amitriptyline, imipramine), antiepileptic drugs (e.g. lamotrigine, Trileptal, Keppra, Zonegran, pregabalin, Harkoseride, carbamazepine), antiarrhythmic drugs (e.g. mexiletine), acetylcholine receptor ligands (e.g. ABT-594), endothelin receptor antagonists (e.g. ABT-627), monoamine uptake inhibitors (e.g. tramadol), narcotic analgesics (e.g. morphine), GABA receptor agonists (e.g. gabapentin, MR preparations of gabapentin), α2 receptor agonists (e.g. clonidine), local analgesics (e.g. capsaicin), antianxiety drugs (e.g. benzothiazepines ), phosphodiesterase inhibitors (such as sildenafil), dopamine receptor agonists (such as apomorphine), midazolam, ketoconazole, etc. can be used in combination with the compounds of the present invention.

[1201] The time for administering the compound of the present invention and the concomitant drug is not limited, and they may be administered to the administration subject simultaneously or in a staggered manner.

[1202] Examples of such modes of administration include the following:

[1203] (1) administering a single preparation obtained by simultaneously processing the compound of the present invention and a concomitant drug, (2) administering two preparations of the compound of the present invention and a concomitant drug that have been separately produced simultaneously through the same administration route, (3) administering two preparations of the compound of the present invention and a concomitant drug that have been separately produced through the same administration route in a staggered manner, (4) administering two preparations of the compound of the present invention and a concomitant drug that have been separately produced simultaneously through different administration routes, (5) administering two preparations of the compound of the present invention and a concomitant drug that have been separately produced through different administration routes in a staggered manner (for example, administering in the order of the compound of the present invention and the concomitant drug or in the reverse order), and the like.

[1204] The dosage of the concomitant drug can be appropriately determined based on the dosage adopted in the clinical situation. The mixing ratio of the compound of the present invention and the concomitant drug can be appropriately determined according to the administration object, symptoms, administration method, target disease, combination, etc. When the administration object is a human, for example, 0.01 to 100 parts by weight of the concomitant drug can be used relative to 1 part by weight of the compound of the present invention.

[1205] By combining the compounds of the present invention with concomitant drugs, it is possible to achieve:

[1206] (1) compared with the single administration of the compound of the present invention or the concomitant drug, the dose of the compound of the present invention or the concomitant drug can be reduced,

[1207] (2) The drug to be used in combination with the compound of the present invention can be selected according to the patient's condition (mild, severe, etc.),

[1208] (3) Longer treatment cycles can be set by selecting a concomitant drug having an action and mechanism different from that of the compound of the present invention,

[1209] (4) Sustained therapeutic effects can be designed by selecting a concomitant drug having an action and mechanism different from that of the compound of the present invention,

[1210] (5) A synergistic effect, etc. can be provided by using the compound of the present invention and a concomitant drug in combination.

[1211] Example

[1212] The abbreviations used in the present specification represent the following (Table 1). Hyphens in terms such as α-MePhe and the like as described herein may be omitted and represent the same meaning.

[1213] In the amino acid sequence used in the present specification, the left side represents the N-terminus, and the right side represents the C-terminus.

[1214] [Table 1]

[1215]

[1216]

[1217]

[1218] In this specification, where bases, amino acids, etc. are represented by their codes, they are based on the conventional codes according to the IUPAC-IUB Biochemical Nomenclature Committee or the common codes in the art, examples of which are shown below. For amino acids that may have optical isomers, unless otherwise indicated, the L-form is presented (e.g., "Ala" is the L-form of Ala). In addition, "D-" refers to the D-form (e.g., "D-Ala" is the D-form of Ala), and "DL-" refers to the racemate of the D-form and the L-form (e.g., "DL-Ala" is the DL racemate of Ala).

[1219] TFA: trifluoroacetic acid

[1220] Gly or G: Glycine

[1221] Ala or A: Alanine

[1222] Val or V: Valine

[1223] Leu or L: Leucine

[1224] Ile or I: Isoleucine

[1225] Ser or S: serine

[1226] Thr or T: threonine

[1227] Cys or C: Cysteine

[1228] Met or M: Methionine

[1229] Glu or E: Glutamic acid

[1230] Asp or D: Aspartic acid

[1231] Lys or K: lysine

[1232] Arg or R: Arginine

[1233] His or H: Histidine

[1234] Phe or F: Phenylalanine

[1235] Tyr or Y: tyrosine

[1236] Trp or W: Tryptophan

[1237] Pro or P: Proline

[1238] Asn or N: Asparagine

[1239] Gln or Q: Glutamine

[1240] The present invention is explained in detail below by referring to the following reference examples, examples, test examples and formulation examples, which are only some embodiments and thus should not be construed as limiting. In addition, the present invention can be modified without departing from the scope of the present invention.

[1241] The term "room temperature" in the following examples means generally ranging from about 10° C. to about 35° C. As for "%", the yield is by mole %, the solvent used for chromatography is by volume %, and other "%" are by weight %.

[1242] NMP: Methylpyrrolidone

[1243] THF: Tetrahydrofuran

[1244] DMF: N, N-dimethylformamide

[1245] WSC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[1246] DCC: N, N'-dicyclohexylcarbodiimide

[1247] DIPCDI: N,N'-diisopropylcarbodiimide

[1248] HOBt: 1-Hydroxybenzotriazole monohydrate

[1249] Oxyma: ethyl 2-cyano-2-(hydroxyimino)acetate

[1250] Reference Example 1

[1251] Synthesis of H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber amide resin (SEQ ID NO: 4)

[1252] Sieber amide resin (0.61meq / g, 410mg) is added to the reaction tube, and then the reaction tube is loaded into the peptide synthesizer (ABI 433A). According to the Fmoc / DCC / HOBt scheme, amino acids are condensed continuously. In the last step, the N-terminal Fmoc group is removed. After the condensation is terminated, the resin is washed with MeOH and dried under reduced pressure. As a result, 1137mg (0.220meq / g) of protected peptide resin of interest is obtained.

[1253] Reference Example 2

[1254] Synthesis of H-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Aib-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Aib-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber amide resin (SEQ ID NO: 5)

[1255] Sieber amide resin (0.71meq / g, 71mg) was added to the reaction tube, which was then placed in a peptide synthesizer. The amino acids were condensed sequentially according to the following protocol: the protocol used 20% piperidine / NMP [50°C, 5 minutes] to deprotect the Fmoc group, and 5 equivalents of Fmoc-amino acid / DIPCDI / Oxyma [50°C, 15 minutes] to condense the Fmoc-amino acid. The condensation of Gln (Trt) at position 19 and Ala at position 18 was performed by double coupling. The Fmoc group at the N-terminus was removed in the last step. After the condensation was completed, the resin was washed with MeOH and dried under reduced pressure. As a result, 264mg (0.189meq / g) of the protected peptide resin of interest was obtained.

[1256] Reference Example 3

[1257] Synthesis of H-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Arg(Pbf)-Sieber amide resin (SEQ ID NO: 6)

[1258] Sieber amide resin (0.71mmol / g, 141mg) was added to 5 reaction tubes, which were then placed in a peptide synthesizer. Amino acids were sequentially condensed according to the following protocol: the protocol used 20% piperidine / NMP [50°C, 5 minutes] to deprotect the Fmoc group, and 5 equivalents of Fmoc-amino acid / DIPCDI / Oxyma [50°C, 15 minutes] to condense the Fmoc-amino acid. After extension, the resins in each reaction tube were mixed, washed with MeOH, and dried under reduced pressure to obtain 1282mg of the protected peptide resin H-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Arg(Pbf)-Sieber amide resin (0.394mmol / g).

[1259] Reference Example A

[1260] Synthesis of H-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber amide resin (SEQ ID NO: 481)

[1261] Sieber amide resin (0.71meq / g, 1.40g, 1.0mmol) was added to the reaction tube, which was then placed in a peptide synthesizer to extend the amino acids sequentially according to the following protocol: 20% piperidine / NMP [reacted at room temperature for 15 minutes] was used to deprotect the Fmoc group, and 8 equivalents of Fmoc-amino acid / DIPCDI / Oxyma [reacted at room temperature for 150 minutes] were used to condense the Fmoc-amino acid. After extension, the obtained resin was washed with MeOH and dried under reduced pressure to obtain 5.2064g of the protected peptide resin of interest.

[1262] Reference Example B

[1263] Synthesis of Boc-MeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Lys-Asp(OtBu)-Arg(Pbf)-Aib-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Sieber amide resin (SEQ ID NO: 482)

[1264] Sieber amide resin (0.71 meq / g, 140.8 mg, 0.1 mmol) was added to the reaction tube, which was then placed in a peptide synthesizer, and the amino acids were sequentially extended according to the following protocol: the Fmoc group was deprotected using 20% ​​piperidine / NMP [reacted at 50° C. for 5 minutes], and the Fmoc-amino acid was condensed using 5 equivalents of Fmoc-amino acid / DIPCDI / Oxyma [reacted at 50° C. for 15 minutes]. In this case, the condensation reaction of Boc-Me Tyr (tBu) at position 1, Thr (tBu) at position 5, Ile at position 12, Arg (Pbf) at position 16, Gln (Trt) at position 19, and Trp (Boc) at position 25 was performed at 50° C. for 30 minutes. The obtained Boc-MeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Lys-Asp(OtBu)-Arg(Pbf)-Aib-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Sieber amide resin was suspended in 2% hydrazine / NMP solution, and the resulting suspension was stirred at 50°C for 10 minutes, then the solution was removed by filtration, and the above operation was repeated 8 times to deprotect the ivDde group of Lys at position 14. The obtained resin was washed with MeOH and dried under reduced pressure to obtain 762.1 mg of Boc-MeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Lys-Asp(OtBu)-Arg(Pbf)-Aib-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Sieber amide resin.

[1265] Reference Example C

[1266] Synthesis of Boc-MeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Lys-Asp(OtBu)-Arg(Pbf)-Aib-Ala-Gln(T rt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Alko resin (SEQ ID NO:483)

[1267] Fmoc-Ser(tBu)-Alko resin (0.68meq / g, 147.1mg, 0.1mmol) was added to the reaction tube, and then the reaction tube was placed in a peptide synthesizer to sequentially extend the amino acids according to the following protocol: 20% piperidine / NMP [reacted at room temperature for 15 minutes] was used to deprotect the Fmoc group, and 5 equivalents of Fmoc-amino acid / DIPCDI / Oxyma [reacted at 50°C for 15 minutes] was used to condense the Fmoc-amino acid. The obtained Boc-MeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser( tBu)-Ile-Aib-Lys(ivDde)-Asp(OtBu)-Arg(Pbf)-Aib-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Tr t)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Alko resin was suspended in a 2% hydrazine / NMP solution, the resulting suspension was stirred at 50°C for 10 minutes, and then the solution was removed by filtration, and the aforementioned operation was repeated 8 times to deprotect the ivDde group of Lys at position 14. Subsequently, the resin was washed with MeOH and dried under reduced pressure to obtain 664.0 mg of the protected peptide resin of interest.

[1268] Example 1

[1269] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Aib-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 12) (Compound 6)

[1270] The H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber amide resin (0.220 meq / g, 46 mg) prepared in Reference Example 1 was weighed and placed in a reaction tube and swollen with DMF. After filtering and removing DMF, Fmoc-Aib-OH (32.5 mg), a 0.5 M Oxyma solution in DMF (200 μL) and diisopropylcarbodiimide (15.9 μL) were successively added to the resin, and the mixture was shaken for 2 hours. The reaction solution was filtered out, and the resin was washed 6 times with DMF. After confirming the negative in the ninhydrin test, a 20% piperidine DMF solution was added thereto and the mixture was shaken for 1 minute. The solution was filtered out, and then a 20% piperidine DMF solution was added thereto again, and the mixture was shaken for 20 minutes. The solution was filtered out, and then the resin was washed 10 times with DMF. The Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to continuously condense Gln(Trt), Ala, Gln(Trt), Lys(Boc), Asp(OtBu), Leu, Aib, Ile*, Ser(tBu), Tyr(tBu), Leu, Ser(tBu), Val, Val, Thr(tBu), Gly, Glu(OtBu), Aib and Tyr(tBu) (*: overnight reaction). The resin was washed with MeOH and then dried under reduced pressure to give 64 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Val-Val-Ser(tBu)-Leu-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Aib-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber amide resin.

[1271] To 64 mg of the obtained resin, 1 mL of TFA: meta-cresol: anisole thioether: ethanedithiol: H2O: triisopropylsilane (80: 5: 5: 5: 2.5: 2.5) was added, and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate, and the supernatant was removed after centrifugation, and the aforementioned operation was repeated three times, thereby washing the precipitate. The residue was extracted with a 50% acetic acid aqueous solution, the resin was filtered off, and then a Daisopak SP-100-5-ODS-P column (250×20 mm inner diameter) was used for preparative HPLC. [Solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, flow rate 8 mL / min, A / B: 63 / 37 to 53 / 47 linear concentration gradient elution (60 min)] The fractions containing the target product were collected and freeze-dried to obtain 16.0 mg of white powder.

[1272] Mass spectrometry, (M+H) + 4231.2 (calculated value: 4231.3)

[1273] HPLC elution time: 7.4min

[1274] Elution conditions:

[1275] Column: Merck Chromolith Performance RP-18e (100×4.6mm inner diameter)

[1276] Eluent: Solution A: 0.1% TFA-water, Solution B: acetonitrile containing 0.1% TFA, A / B: 95 / 5 to 35 / 65 linear concentration gradient elution (10 min)

[1277] Flow rate: 3.0mL / min

[1278] Example 2

[1279] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Aib-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (acetate of compound 6)

[1280] The powder (1084.2 mg) prepared in the same manner as in Example 1 was dissolved in a small amount of acetonitrile-water, an ion exchange resin (AG1 X8 resin (acetate form), 1.2 meq / mL, 2.1 mL) was added thereto, and the resulting mixture was allowed to stand for 1 hour while occasionally shaking. After filtering off the resin, the filtrate was freeze-dried to obtain 929.6 mg of a white powder.

[1281] Mass spectrometry results: (M+H) + 4231.3 (calculated value 4231.3)

[1282] HPLC elution time: 7.5 minutes

[1283] Elution conditions:

[1284] Column Chromolith Performance RP-18e (100x 4.6mm i.d.)

[1285] Elution: Solution A: 0.1% TFA-water, and solution B: 0.1% TFA-acetonitrile, A / B: 95 / 5 to 35 / 65. Linear concentration gradient elution (10 minutes).

[1286] Flow rate: 3.0mL / min

[1287] Example 3

[1288] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Aib-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (hydrochloride salt of compound 6)

[1289] The powder prepared in Example 2 (73.0 mg) was dissolved in a small amount of acetonitrile-water, and 1N hydrochloric acid (172 μL) was added thereto while cooling with ice. After stirring at 0° C. for 2 hours, the resulting mixture was allowed to stand overnight at 4° C. The obtained solution was freeze-dried to obtain 71 mg of a white powder.

[1290] Mass spectrometry results: (M+H) + 4231.6 (calculated value 4231.3)

[1291] HPLC elution time: 7.4 minutes

[1292] Elution conditions:

[1293] Column Chromolith Performance RP-18e (100x4.6mm inner diameter)

[1294] Elution: Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-acetonitrile, A / B: 95 / 5 to 35 / 65. Linear concentration gradient elution (10 minutes).

[1295] Flow rate: 3.0mL / min

[1296] Example 4

[1297] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Phe-Tyr-Ser-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Aib-G lu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 13) (compound 7)

[1298] The H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber amide resin (0.220 meq / g, 46 mg) prepared in Reference Example 1 was weighed and placed in a reaction tube and swollen with DMF. After filtering and removing DMF, Fmoc-Aib-OH (32.5 mg), a 0.5 M Oxyma solution in DMF (200 μL) and diisopropylcarbodiimide (15.9 μL) were successively added to the resin, and the mixture was shaken for 2 hours. The reaction solution was filtered out, and the resin was washed 6 times with DMF. After confirming the negative in the ninhydrin test, a 20% piperidine DMF solution was added thereto and the mixture was shaken for 1 minute. The solution was filtered out, and then a 20% piperidine DMF solution was added thereto again, and the mixture was shaken for 20 minutes. The solution was filtered out, and then the resin was washed 10 times with DMF. The Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to continuously condense Gln(Trt), Ala, Gln(Trt), Lys(Boc), Asp(OtBu), Leu, Aib, Ile*, Ser(tBu), Tyr(tBu), Phe, Ser(tBu), Val, Val, Thr(tBu), Gly, Glu(OtBu), Aib and Tyr(tBu) (*: overnight reaction). The resin was washed with MeOH and then dried under reduced pressure to give 74 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Val-Val-Ser(tBu)-Phe-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Aib-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber amide resin.

[1299] To 74 mg of the obtained resin, 1 mL of TFA: meta-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80: 5: 5: 5: 2.5: 2.5) was added, and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate, and the supernatant was removed after centrifugation, and the aforementioned operation was repeated three times, thereby washing the precipitate. The residue was extracted with a 50% acetic acid aqueous solution, the resin was filtered off, and then a Daisopak SP-100-5-ODS-P column (250×20 mm inner diameter) was used for preparative HPLC. [Solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, flow rate 8 mL / min, A / B: 63 / 37 to 53 / 47 linear concentration gradient elution (60 min)] The fractions containing the target product were collected and freeze-dried to obtain 17.0 mg of a white powder.

[1300] Mass spectrometry, (M+H) + 4265.1 (calculated value: 4265.3)

[1301] HPLC elution time: 7.3min

[1302] Elution conditions:

[1303] Column: Merck Chromolith Performance RP-18e (100×4.6mm inner diameter)

[1304] Eluent: Solution A: 0.1% TFA-water, Solution B: acetonitrile containing 0.1% TFA, A / B: 95 / 5 to 35 / 65 linear concentration gradient elution (10 min)

[1305] Flow rate: 3.0mL / min

[1306] Example 5

[1307] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-Val-Lys-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Aib-G lu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 14) (compound 8)

[1308] H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber amide resin (0.220 meq / g, 46.0 mg) prepared in Reference Example 1 was weighed into a reaction tube and swollen with DMF. After filtering to remove DMF, Fmoc-Aib-OH (32.5 mg), a 0.5 M Oxyma solution in DMF (200 μL) and diisopropylcarbodiimide (15.9 μL) were successively added to the resin, and the mixture was shaken for 2 hours. The reaction solution was filtered out, and the resin was washed 6 times with DMF. After confirming the negative in the ninhydrin test, a 20% piperidine DMF solution was added thereto and the mixture was shaken for 1 minute. The solution was filtered out, and then a 20% piperidine DMF solution was added thereto again, and the mixture was shaken for 20 minutes. The solution was filtered out, and then the resin was washed 10 times with DMF. The Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to continuously condense Gln(Trt), Ala, Gln(Trt), Lys(Boc), Asp(OtBu), Leu, Aib, Ile*, Ser(tBu), Tyr(tBu), Asp(OtBu), Ser(tBu), Lys(Boc), Val, Thr(tBu), Gly, Glu(OtBu), Aib and Tyr(tBu) (*: overnight reaction). The resin was washed with MeOH and then dried under reduced pressure to give 73 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Val-Lys(Boc)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Aib-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber amide resin.

[1309] To 73 mg of the obtained resin, 1 mL of TFA: meta-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80: 5: 5: 5: 2.5: 2.5) was added, and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate, and the supernatant was removed after centrifugation, and the aforementioned operation was repeated three times, thereby washing the precipitate. The residue was extracted with a 50% acetic acid aqueous solution, the resin was filtered off, and then a Daisopak SP-100-5-ODS-P column (250×20 mm inner diameter) was used for preparative HPLC. [Solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, flow rate 8 mL / min, A / B: 68 / 32 to 58 / 42 linear concentration gradient elution (60 min)] The fractions containing the target product were collected and freeze-dried to obtain 15.7 mg of white powder.

[1310] Mass spectrometry, (M+H) + 4262.3 (Calculated value: 4262.3)

[1311] HPLC elution time: 6.6min

[1312] Elution conditions:

[1313] Column: Merck Chromolith Performance RP-18e (100×4.6mm inner diameter)

[1314] Eluent: Solution A: 0.1% TFA-water, Solution B: acetonitrile containing 0.1% TFA, A / B: 95 / 5 to 35 / 65 linear concentration gradient elution (10 min)

[1315] Flow rate: 3.0mI / min

[1316] Example 6

[1317] H-Tyr-Aib-Glu-Gly-Thr-Val-Lys-Ser-Asp-Tyr-Ser-Ile-Leu-Leu-Asp-Lys-Gln-Ala-Gln-Aib-Gl u-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2(SEQ ID NO: 15) (compound 10)

[1318] The H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber amide resin (0.220 meq / g, 46 mg) prepared in Reference Example 1 was weighed and placed in a reaction tube and swollen with DMF. After filtering and removing DMF, Fmoc-Aib-OH (32.5 mg), a 0.5 M Oxyma solution in DMF (200 μL) and diisopropylcarbodiimide (15.9 μL) were successively added to the resin, and the mixture was shaken for 2 hours. The reaction solution was filtered out, and the resin was washed 6 times with DMF. After confirming the negative in the ninhydrin test, a 20% piperidine DMF solution was added thereto and the mixture was shaken for 1 minute. The solution was filtered out, and then a 20% piperidine DMF solution was added thereto again, and the mixture was shaken for 20 minutes. The solution was filtered out, and then the resin was washed 10 times with DMF. The Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to continuously condense Gln(Trt), Ala, Gln(Trt), Lys(Boc), Asp(OtBu), Leu, Leu, Ile*, Ser(tBu), Tyr(tBu), Asp(OtBu), Ser(tBu), Lys(Boc), Val, Thr(tBu), Gly, Glu(OtBu), Aib and Tyr(tBu) (*: overnight reaction). The resin was washed with MeOH and then dried under reduced pressure to give 85 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Val-Lys(Boc)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Leu-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Aib-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber amide resin.

[1319] To 85 mg of the obtained resin, 1 mL of TFA: meta-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80: 5: 5: 5: 2.5: 2.5) was added, and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate, and the supernatant was removed after centrifugation, and the aforementioned operation was repeated three times, thereby washing the precipitate. The residue was extracted with a 50% acetic acid aqueous solution, the resin was filtered off, and then a Daisopak SP-100-5-ODS-P column (250×20 mm inner diameter) was used for preparative HPLC. [Solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, flow rate 8 mL / min, A / B: 67 / 33 to 57 / 43 linear concentration gradient elution (60 min)] The fractions containing the target product were collected and freeze-dried to obtain 19.0 mg of a white powder.

[1320] Mass spectrometry, (M+H) + 4290.5 (calculated value: 4290.3)

[1321] HPLC elution time: 6.7min

[1322] Elution conditions:

[1323] Column: Merck Chromolith Performance RP-18e (100×4.6mim inner diameter)

[1324] Eluent: Solution A: 0.1% TFA-water, Solution B: acetonitrile containing 0.1% TFA, A / B: 95 / 5 to 35 / 65 linear concentration gradient elution (10 min)

[1325] Flow rate: 3.0mL / min

[1326] Example 7

[1327] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Aib-G lu-Phe-Val-Lys-Trp-Aib-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 50) (compound 42)

[1328] H-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Aib-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Aib-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber amide resin (0.189 meq / g, 132 mg) prepared in Reference Example 2 was weighed into a reaction tube, and then the reaction tube was placed in a peptide synthesizer. The amino acids were sequentially condensed according to the following protocol: the protocol used 20% piperidine / NMP [50°C, 5 minutes] to deprotect the Fmoc group and 5 equivalents of Fmoc-amino acid / DIPCDI / Oxyma [50°C, 15 minutes] to condense the Fmoc-amino acid. After completing the condensation, the resin was washed with MeOH and dried under reduced pressure to obtain 171 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Val-Val-Ser(tBu)-Leu-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Aib-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Aib-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber amide resin.

[1329] To 171 mg of the obtained resin, 1 mL of TFA: meta-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80: 5: 5: 5: 2.5: 2.5) was added, and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate, and the supernatant was removed after centrifugation, and the aforementioned operation was repeated three times, thereby washing the precipitate. The residue was extracted with a 50% acetic acid aqueous solution, the resin was filtered off, and then a Daisopak SP-100-5-ODS-P column (250×20 mm inner diameter) was used for preparative HPLC. [Solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, flow rate 8 mL / min, A / B: 65 / 35 to 55 / 45 linear concentration gradient elution (60 min)] The fractions containing the target product were collected and freeze-dried to obtain 29.1 mg of a white powder.

[1330] Mass spectrometry, (M+H)+ 4202.4 (calculated value: 4203.3)

[1331] HPLC elution time: 7.3min

[1332] Elution conditions:

[1333] Column: Merck Chromolith Performance RP-18e (100×4.6mm inner diameter)

[1334] Eluent: Solution A: 0.1% TFA-water, Solution B: acetonitrile containing 0.1% TFA, A / B: 95 / 5 to 35 / 65 linear concentration gradient elution (10 min)

[1335] Flow rate: 3.0mL / min

[1336] Example 8

[1337] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Gin-Ala-Gln-Aib-G lu-Phe-Val-Arg-Trp-Leu-Leu-Arg-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2 (SEQ ID NO: 36) (compound 30)

[1338] Sieber amide resin (0.7mmol / g, 149mg) was added to 2 reaction tubes, which were then placed in a peptide synthesizer. Amino acids were sequentially condensed according to the following protocol: the protocol used 20% piperidine / NMP [50°C, 5 minutes] to deprotect the Fmoc group, and 5 equivalents of Fmoc-amino acid / DIPCDI / Oxyma [50°C, 15 minutes] to condense the Fmoc-amino acid. After extension, the resin was washed with MeOH and dried under reduced pressure to obtain 1308 mg of the protected peptide resin of interest, H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Val-Val-Ser(tBu)-Leu-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Arg(Pbf)-Gln(Trt)-Ala-Gln(Trt)-Aib-Glu(OtBu)-Phe-Val-Arg(Pbf)-Trp(Boc)-Leu-Leu-Arg(Pbf)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Arg(Pbf)-sieber amide resin. 15mL TFA: meta-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80: 5: 5: 5: 2.5: 2.5) was added to the total amount of the resin obtained, and the resulting mixture was then stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate, and the supernatant was removed after centrifugation, and the aforementioned operation was repeated twice, thereby washing the precipitate. The residue was extracted with 50% acetic acid aqueous solution, and after filtering to remove the resin, several purifications were performed by preparative HPLC using a daisopak SP-100-5-ODS-P column (250x 20mm inner diameter), which used a linear concentration gradient elution (60 minutes), solution A: 0.1% TFA-water, and solution B: acetonitrile containing 0.1% TFA, A / B from 62 / 38 to 52 / 48, flow rate 8mL / minute, and the fraction containing the product of interest was collected and freeze-dried to obtain 190.1mg white powder.

[1339] The obtained powder (190.1 mg) was dissolved in a small amount of acetonitrile aqueous solution. An ion exchange resin (AG1 X8 resin (acetate form), 1.2 meq / mL, 365 μL) was added to the solution, and then allowed to stand for 1 hour with occasional shaking. After filtering to remove the resin, the filtrate was freeze-dried to obtain 159.2 mg of white powder.

[1340] Mass spectrometry results: (M+H) + 4343.3 (calculated value 4343.3)

[1341] HPLC elution time: 7.5 minutes

[1342] Elution conditions:

[1343] Column Merck Chromolith Performance RP-18e (4.6x 100mm i.d.)

[1344] Elution: Solution A: 0.1% TFA-water, and solution B: 0.1% TFA-acetonitrile, A / B: 95 / 5 to 35 / 65. Linear concentration gradient elution (10 minutes).

[1345] Flow rate: 3.0mL / min

[1346] Example 9

[1347] Synthesis of Methyl-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Ile-Ala-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2 (SEQ ID NO: 65) (Compound 59)

[1348] H-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Arg(Pbf)-Sieber amide resin (0.394 mmol / g, 127 mg) prepared in Reference Example 3 was added to a reaction tube, which was then placed in a peptide synthesizer. Amino acids were sequentially condensed according to a protocol that used 20% piperidine / NMP [50° C., 5 minutes] to deprotect the Fmoc group and 5 equivalents of Fmoc-amino acid / DIPCDI / Oxyma [50° C., 15 minutes] to condense the Fmoc-amino acid. After extension, the resin was washed with MeOH and dried under reduced pressure to obtain the protected peptide resin of interest, Boc-Me-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Ala-Leu-Asp(OtBu)-Arg(Pbf)-Ile-Ala-Gln(Trt)-Gln(Trt)-Asp(OtBu)-Phe-Val-Asn(Trt)-Trp(Boc)-Leu-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Arg(Pbf)-Sieber amide resin. 3.5mL TFA: meta-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80: 5: 5: 5: 2.5: 2.5) was added to the total amount of the resin obtained, and the resulting mixture was then stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate, and the supernatant was removed after centrifugation, and the aforementioned operation was repeated twice, thereby washing the precipitate. The residue was extracted with 50% acetic acid aqueous solution, and after filtering to remove the resin, it was purified by the preparative HPLC using a daisopak SP-100-5-ODS-P column (250x20mm inner diameter), which used a linear concentration gradient elution (60 minutes), solution A: 0.1% TFA-water, and solution B: acetonitrile containing 0.1% TFA, A / B from 60 / 40 to 50 / 50, flow rate 8mL / minute, and the fraction containing the product of interest was collected and freeze-dried, thereby obtaining 71.4mg white powder.

[1349] The total amount of the obtained powder was dissolved in a small amount of acetonitrile aqueous solution. An ion exchange resin (AG1X8 resin (acetate form), 1.2 meq / mL, 67 μL) was added to the solution, which was then allowed to stand for 1 hour with occasional shaking. After filtering to remove the resin, the filtrate was freeze-dried to obtain 59.0 mg of white powder.

[1350] Mass spectrometry results: (M+H) + 4464.8 (calculated value 4464.3)

[1351] HPLC elution time: 7.8 minutes

[1352] Elution conditions:

[1353] Column Merck Chromolith Performance RP-18e (4.6x 100mm i.d.)

[1354] Elution: Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-acetonitrile, A / B: 95 / 5 to 35 / 65. Linear concentration gradient elution (10 minutes).

[1355] Flow rate: 3.0mL / min

[1356] Example 10

[1357] Synthesis of Methyl-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2 (SEQ ID NO: 110) (Compound 104)

[1358] H-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Arg(Pbf)-Sieber amide resin (0.394 mmol / g, 127 mg) prepared in Reference Example 3 was added to a reaction tube, which was then placed in a peptide synthesizer. Amino acids were sequentially condensed according to a protocol that used 20% piperidine / NMP [50° C., 5 minutes] to deprotect the Fmoc group and 5 equivalents of Fmoc-amino acid / DIPCDI / Oxyma [50° C., 15 minutes] to condense the Fmoc-amino acid. After extension, the resin was washed with MeOH and dried under reduced pressure to obtain the protected peptide resin of interest Boc-Me-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Ala-Leu-Asp(OtBu)-Arg(Pbf)-Aib-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Leu-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Arg(Pbf)-Sieber amide resin. 4mL TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80: 5: 5: 5: 2.5: 2.5) was added to the total amount of the obtained resin, and the resulting mixture was then stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate, and the supernatant was removed after centrifugation, and the aforementioned operation was repeated twice, thereby washing the precipitate. The residue was extracted with a 50% aqueous acetic acid solution, and after filtering to remove the resin, it was purified by preparative HPLC using a daisopak SP-100-5-ODS-P column (250 x 20mm inner diameter), which used a linear concentration gradient elution (60 minutes), solution A: 0.1% TFA-water, and solution B: acetonitrile containing 0.1% TFA, A / B from 62 / 38 to 52 / 48, flow rate 8mL / minute, and the fractions containing the product of interest were collected and freeze-dried to obtain 81mg of a white powder.

[1359] The total amount of the obtained powder was dissolved in a small amount of acetonitrile aqueous solution. An ion exchange resin (AG1X8 resin (acetate form), 1.2 meq / mL, 78 μL) was added to the solution, which was then allowed to stand for 1 hour with occasional shaking. After filtering to remove the resin, the filtrate was freeze-dried to obtain 53.2 mg of white powder.

[1360] Mass spectrometry results: (M+H) + 4345.1 (calculated value 4344.3)

[1361] HPLC elution time: 7.7 minutes

[1362] Elution conditions:

[1363] Column Merck Chromolith Performance RP-18e (4.6x 100mm i.d.)

[1364] Elution: Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-acetonitrile, A / B: 95 / 5 to 35 / 65. Linear concentration gradient elution (10 minutes).

[1365] Flow rate: 3.0mL / min

[1366] Embodiment 11

[1367] Synthesis of Methyl-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2 (SEQ ID NO: 119) (Compound 113)

[1368] H-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Arg(Pbf)-Sieber amide resin (0.394 mmol / g, 127 mg) prepared in Reference Example 3 was added to a reaction tube, which was then placed in a peptide synthesizer. Amino acids were sequentially condensed according to a protocol that used 20% piperidine / NMP [50° C., 5 minutes] to deprotect the Fmoc group and 5 equivalents of Fmoc-amino acid / DIPCDI / Oxyma [50° C., 15 minutes] to condense the Fmoc-amino acid. After extension, the resin was washed with MeOH and dried under reduced pressure to obtain the protected peptide resin of interest Boc-Me-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Arg(Pbf)-Aib-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Arg(Pbf)-Sieber amide resin. 4mL TFA: meta-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80: 5: 5: 5: 2.5: 2.5) was added to the total amount of the resin obtained, and the resulting mixture was then stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate, and the supernatant was removed after centrifugation, and the aforementioned operation was repeated twice, thereby washing the precipitate. The residue was extracted with a 50% aqueous acetic acid solution, and after filtering to remove the resin, it was purified by preparative HPLC using a daisopak SP-100-5-ODS-P column (250x 20mm inner diameter), which used a linear concentration gradient elution (60 minutes), solution A: 0.1% TFA-water, and solution B: acetonitrile containing 0.1% TFA, A / B from 61 / 39 to 51 / 49, flow rate 8mL / minute, and the fraction containing the product of interest was collected and freeze-dried to obtain 71.1mg white powder.

[1369] The total amount of the obtained powder was dissolved in a small amount of acetonitrile aqueous solution. An ion exchange resin (AG1X8 resin (acetate form), 1.2 meq / mL, 68 μL) was added to the solution, which was then allowed to stand for 1 hour with occasional shaking. After filtering to remove the resin, the filtrate was freeze-dried to obtain 62.8 mg of white powder.

[1370] Mass spectrometry results: (M+H) + 4345.0 (calculated value 4344.3)

[1371] HPLC elution time: 7.6 minutes

[1372] Elution conditions:

[1373] Column Merck Chromolith Performance RP-18e (4.6x 100mm i.d.)

[1374] Elution: Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-acetonitrile, A / B: 95 / 5 to 35 / 65. Linear concentration gradient elution (10 minutes).

[1375] Flow rate: 3.0mL / min

[1376] Example 12

[1377] Synthesis of Methyl-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2 (SEQ ID NO: 123) (Compound 117)

[1378] Sieber amide resin (0.71mmol / g, 352mg) was added to the reaction tube, which was then placed in a peptide synthesizer. Amino acids were sequentially condensed according to the following protocol: the protocol used 20% piperidine / NMP [50°C, 5 minutes] to deprotect the Fmoc group, and 5 equivalents of Fmoc-amino acid / DIPCDI / Oxyma [50°C, 15 minutes] to condense the Fmoc-amino acid. After extension, the resin was washed with MeOH and dried under reduced pressure to obtain the protected peptide resin of interest Boc-Me-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Ala-Leu-Asp(OtBu)-Arg(Pbf)-Aib-His(Trt)-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Arg(Pbf)-Sieber amide resin. 4 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80: 5: 5: 5: 2.5: 2.5) was added to the total amount of the obtained resin, and the resulting mixture was then stirred at room temperature for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate, and the supernatant was removed after centrifugation, and the aforementioned operation was repeated twice, thereby washing the precipitate. The residue was extracted with a 50% aqueous acetic acid solution, and after filtering to remove the resin, it was purified by preparative HPLC using a daisopak SP-100-5-ODS-P column (250 x 20 mm inner diameter), which used a linear concentration gradient elution (60 minutes), solution A: 0.1% TFA-water, and solution B: acetonitrile containing 0.1% TFA, A / B from 69 / 31 to 59 / 41, flow rate 8 mL / min, and the fraction containing the product of interest was collected and freeze-dried to obtain 190.8 mg of a white powder.

[1379] The total amount of the obtained powder was dissolved in a small amount of acetonitrile aqueous solution. An ion exchange resin (AG1X8 resin (acetate form), 1.2 meq / mL, 179 μL) was added to the solution, and then allowed to stand for 1 hour with occasional shaking. After filtering to remove the resin, the filtrate was freeze-dried to obtain 170.0 mg of white powder.

[1380] Mass spectrometry results: (M+H) +4443.3 (calculated value 4444.3)

[1381] HPLC elution time: 6.5 minutes

[1382] Elution conditions:

[1383] Column Merck Chromolith Performance RP-18e (4.6x 100mm i.d.)

[1384] Elution: Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-acetonitrile, A / B: 95 / 5 to 35 / 65. Linear concentration gradient elution (10 minutes).

[1385] Flow rate: 3.0mL / min

[1386] Embodiment 13

[1387] Synthesis of H-MeTyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Eda-GGGGG-)-Asp-Arg-Aib-Ala- Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 (SEQ ID NO: 354) (compound 341)

[1388] H-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber amide resin (SEQ ID NO: 481) (260.4 mg, 0.05 mmol) synthesized in Reference Example A was weighed into a reaction tube, and then the reaction tube was placed in a peptide synthesizer. Amino acids were sequentially extended according to the following protocol: the Fmoc group was deprotected using 20% ​​piperidine / NMP [reacted at 50° C. for 5 minutes], and the Fmoc-amino acid was condensed using 5 equivalents of Fmoc-amino acid / DIPCDI / Oxyma [reacted at 50° C. for 15 minutes]. In this case, the condensation reaction of Boc-MeTyr(tBu) at position 1, Thr(tBu) at position 5, Ile at position 12, Arg(Pbf) at position 16, Gln(Trt) at position 19, and Trp(Boc) at position 25 was carried out at 50°C for 30 minutes. The obtained Boc-MeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Lys(ivDde)-Asp(OtBu)-Arg(Pbf)-Aib-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt) -Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber amide resin was suspended in a 2% hydrazine / NMP solution, the resulting suspension was stirred at 50°C for 10 minutes, and then the solution was removed by filtration, and the aforementioned operation was repeated 8 times to deprotect the ivDde group of Lys at position 14. Subsequently, Fmoc-Gly-Glv-Gly-OH was introduced using a peptide synthesizer, and then Gly, Gly and eicosandioic acid were introduced successively. In this case, 20% piperidine / NMP [reacted at 50°C for 5 minutes] was used to deprotect the Fmoc group, and a condensation reaction was performed using a double coupling method, wherein all reactions were performed at 50°C for 15 minutes, the solution was removed by filtration, and then the same condensation reaction was repeated.After completing the solid phase synthesis, the resin was washed with MeOH and dried under reduced pressure to obtain 421.5 mg of the protected peptide resin of interest Boc-MeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Lys(Eda-GGGGG-)-Asp(OtBu)-Arg(Pbf)-Aib-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber amide resin. 4.6mL TFA: meta-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80: 5: 5: 5: 2.5: 2.5) was added to the total amount of the obtained resin, and the resulting mixture was then stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate, and the supernatant was removed after centrifugation. This operation was repeated twice to wash the precipitate. The residue was extracted with 90% acetic acid aqueous solution and the resin was removed by filtration, and then purified by preparative HPLC using Phenomenex Kinetex 5μm XB-C18 (250×30.0mm inner diameter), which used a linear concentration gradient elution (60 minutes), solution A: 0.1% TFA-water, and solution B: acetonitrile containing 0.1% TFA, A / B from 40 / 60 to 50 / 50, flow rate 15mL / minute, and the fractions containing the product of interest were collected and freeze-dried to obtain 70.1mg white powder.

[1389] Subsequently, the total amount of the obtained powder was dissolved in 50% acetonitrile-water, an ion exchange resin [AG1X8 resin (acetate form), 1.2 meq / mL, 182 μL] was added to the solution, and the resulting mixture was shaken for 1 hour. After filtering off the resin, the filtrate was freeze-dried to obtain 58.8 mg of the acetate of the product of interest.

[1390] Mass spectrometry results: (M+H) + 4811.57 (calculated value 4812.54)

[1391] HPLC elution time: 6.19 minutes

[1392] Elution conditions:

[1393] Column: Kinetex 1.7μm C8 100A, (100×2.1mm inner diameter)

[1394] Elution: Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-acetonitrile, A / B: 80 / 20 to 30 / 70. Linear concentration gradient elution (10 minutes).

[1395] Flow rate: 0.5mL / min

[1396] Temperature: 40℃

[1397] Embodiment 14

[1398] Synthesis of H-MeTyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Oda-GGGGG-)-Ala- Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 (SEQ ID NO: 362) (compound 349)

[1399] H-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber amide resin (SEQ ID NO: 481) (520.0 mg, 0.1 mmol) synthesized in Reference Example A was weighed into a reaction tube, and then the reaction tube was placed in a peptide synthesizer. Amino acids were sequentially extended according to the following protocol: the Fmoc group was deprotected using 20% ​​piperidine / NMP [reacted at 50° C. for 5 minutes], and the Fmoc-amino acid was condensed using 5 equivalents of Fmoc-amino acid / DIPCDI / Oxyma [reacted at 50° C. for 15 minutes]. In this case, the condensation reaction of Boc-MeTyr(tBu) at position 1, Thr(tBu) at position 5, Ile at position 12, Gln(Trt) at position 19, and Trp(Boc) at position 25 was carried out at 50°C for 30 minutes. The obtained Boc-MeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Arg(Pbf)-Lys(ivDde)-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt) -Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Glv-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber amide resin was suspended in a 2% hydrazine / NMP solution, the resulting suspension was stirred at 50°C for 10 minutes, and then the solution was removed by filtration, and the aforementioned operation was repeated 8 times to deprotect the ivDde group of Lys at position 17. Subsequently, Fmoc-Gly-Gly-Gly-OH was introduced using a peptide synthesizer, and then Gly, Gly, and octadecane dioic acid were introduced successively. In this case, 20% piperidine / NMP [reacted at 50°C for 5 minutes] was used to deprotect the Fmoc group, and a condensation reaction was performed using a double coupling method, wherein all reactions were performed at 50°C for 15 minutes, the solution was removed by filtration, and then the same condensation reaction was repeated.After completing the solid phase synthesis, the resin was washed with MeOH and dried under reduced pressure to obtain 817.0 mg of the protected peptide resin of interest Boc-MeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Arg(Pbf)-Lys(Oda-GGGGG-)-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber amide resin. 8mL TFA: meta-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80: 5: 5: 5: 2.5: 2.5) was added to the total amount of the obtained resin, and the resulting mixture was then stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate, and the supernatant was removed after centrifugation. This operation was repeated twice, and the precipitate was then washed. The residue was extracted with 90% acetic acid aqueous solution and the resin was removed by filtration, and then purified by preparative HPLC using Phenomenex Kinetex 5μm XB-C18 (250×30.0mm inner diameter), which used a linear concentration gradient elution (60 minutes), solution A: 0.1% TFA-water, and solution B: acetonitrile containing 0.1% TFA, A / B from 40 / 60 to 50 / 50, flow rate 15mL / minute, and the fractions containing the product of interest were collected and freeze-dried to obtain 109.2mg of white powder.

[1400] Subsequently, the total amount of the obtained powder was dissolved in 50% acetonitrile-water, an ion exchange resin [AG1X8 resin (acetate form), 1.2 meq / mL, 285 μL] was added to the solution, and the resulting mixture was shaken for 1 hour. After filtering off the resin, the filtrate was freeze-dried to obtain 93.1 mg of the acetate of the product of interest.

[1401] Mass spectrometry results: (M+H) + 4810.655 (calculated value 4812.54)

[1402] HPLC elution time: 6.09 minutes

[1403] Elution conditions:

[1404] Column: Kinetex1.7μm C8100A, (100×2.1mm inner diameter)

[1405] Elution: Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-acetonitrile, A / B: 80 / 20 to 30 / 70. Linear concentration gradient elution (10 minutes).

[1406] Flow rate: 0.5mL / min

[1407] Temperature: 40℃

[1408] Embodiment 15

[1409] Synthesis of Ac-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Eda-GGGGG-)-Asp-Arg-Aib-Ala-G ln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO: 448) (compound 435)

[1410] Sieber amide resin (0.71 meq / g, 70.4 mg, 0.05 mmol) was added to the reaction tube, and then the amino acids were sequentially extended to the N-terminus according to the following scheme: 20% piperidine / NMP [reacted at 50 ° C for 5 minutes] was used to deprotect the Fmoc group, and 5 equivalents of Fmoc-amino acid / DIPCDI / Oxyma [reacted at 50 ° C for 15 minutes] was used to condense the Fmoc-amino acid. In this case, the condensation reaction of Boc-MeTyr (tBu) at position 1, Thr (tBu) at position 5, Ile at position 12, Arg (Pbf) at position 16, Gln (Trt) at position 19, and Trp (Boc) at position 25 was carried out at 50 ° C for 30 minutes. To the obtained H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Lys(ivDde)-Asp(OtBu)-Arg(Pbf)-Aib-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber amide resin was added 0.625 ml of the mixed solution. In the mixed solution, 0.5 M acetic anhydride, 0.5 M pyridine and 0.05 M Oxyma was dissolved in NMP, and the resulting mixture was reacted at 50°C for 2 minutes. After washing the resin with NMP, the resin was suspended in a 2% hydrazine / NMP solution, the resulting suspension was stirred at 50°C for 10 minutes, and then the solution was removed by filtration, and the aforementioned operation was repeated 8 times to deprotect the ivDde group of Lys at position 14. Subsequently, Gly, Gly, Fmoc-Gly-Gly-Gly-OH and eicosandioic acid were successively introduced using a peptide synthesizer. In this case, 20% piperidine / NMP [reacted at 50°C for 5 minutes] was used to deprotect the Fmoc group, and a double coupling method was used for the condensation reaction, wherein all reactions were carried out at 50°C for 15 minutes, the solution was removed by filtration, and then the same condensation reaction was repeated.After completing the solid phase synthesis, the resin was washed with MeOH and dried under reduced pressure to obtain 470.7 mg of the protected peptide resin of interest Ac-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Lys(Eda-GGGGG-)Asp(OtBu)-Arg(Pbf)-Aib-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber amide resin. 4.8mL TFA: meta-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80: 5: 5: 5: 2.5: 2.5) is added to the total amount of the resin obtained, and the resulting mixture is then stirred for 1.5 hours. Diethyl ether is added to the reaction solution to obtain a precipitate, and the supernatant is removed after centrifugation. This operation is repeated twice, and the precipitate is washed. The residue is extracted with 90% acetic acid aqueous solution and filtered to remove the resin, and then purified by the preparative HPLC using Phenomenex Kinetex 5μm XB-C18 (250×30.0mm inner diameter), which uses a linear concentration gradient elution (60 minutes), solution A: 0.1% TFA-water, and solution B: acetonitrile containing 0.1% TFA, A / B from 57 / 43 to 47 / 53, flow rate 15mL / minute, and the fraction containing the product of interest is collected and freeze-dried to obtain 58.8mg white powder.

[1411] Subsequently, the total amount of the obtained powder was dissolved in 50% acetonitrile-water, an ion exchange resin [AG1X8 resin (acetate form), 1.2 meq / mL, 152 μL] was added to the solution, and the resulting mixture was shaken for 1 hour. After filtering off the resin, the filtrate was freeze-dried to obtain 53.6 mg of the acetate of the product of interest.

[1412] Mass spectrum results: (M+H)+4841.26 (calculated value 4840.53)

[1413] HPLC elution time: 7.12 minutes

[1414] Elution conditions:

[1415] Column: Kinetex 1.7μm C8 100A, (100×2.1mm inner diameter)

[1416] Elution: Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-acetonitrile, A / B: 80 / 20 to 30 / 70. Linear concentration gradient elution (10 minutes).

[1417] Flow rate: 0.5mL / min

[1418] Temperature: 40℃

[1419] Example 16

[1420] Synthesis of H-MeTyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Oda-GGGGG-)-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-NH2 (SEQ ID NO: 428) (compound 415)

[1421] Boc-MeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Lys-Asp(OtBu)-Arg(Pbf)-Aib-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Sieber amide resin (SEQ ID NO: 482) (38.1 mg, 0.005 mmol) synthesized in Reference Example B was weighed into a reaction tube, and the reaction tube was then placed in a peptide synthesizer. Gly, Gly, Fmoc-Gly-Gly-Gly-OH and octadecane dioic acid were introduced according to the following scheme: the Fmoc group was deprotected using 20% ​​piperidine / NMP [reacted at 50°C for 5 minutes], and the Fmoc-amino acid was condensed using 5 equivalents of Fmoc-amino acid / DIPCDI / Oxyma [reacted at 50°C for 15 minutes]. In this case, the Fmoc group was deprotected using 20% ​​piperidine / NMP [reacted at 50°C for 5 minutes], and the condensation reaction was performed using a double coupling method, wherein after the reaction was performed at 50°C for 15 minutes, the solution was filtered off, and then the same condensation reaction was repeated. After completing the solid phase synthesis, the resin was washed with MeOH and dried under reduced pressure to obtain 45.3 mg of the protected peptide resin of interest Boc-MeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Lys(Oda-GGGGG-)Asp(OtBu)-Arg(Pbf)-Aib-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Sieber amide resin. To the total amount of the obtained resin, 0.5 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80: 5: 5: 5: 2.5: 2.5) was added, and the resulting mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate, and the supernatant was removed after centrifugation. This operation was repeated, and the precipitate was then washed.The residue was extracted with 90% aqueous acetic acid and the resin was removed by filtration, and then purified by preparative HPLC using Phenomenex Kinetex 5μm XB-C18 (250×20.0mm inner diameter) using linear concentration gradient elution (60 minutes), solution A: 0.1% TFA-water, and solution B: acetonitrile containing 0.1% TFA, A / B from 59 / 41 to 49 / 51, flow rate 8mL / min, and fractions containing the product of interest were collected and freeze-dried to obtain 3.7mg of white powder.

[1422] Mass spectrum results: (M+H)+4006.32 (calculated value 4007.14)

[1423] HPLC elution time: 5.97 minutes

[1424] Elution conditions:

[1425] Column: Kinetex 1.7μm C8 100A, (100×2.1mm inner diameter)

[1426] Elution: Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-acetonitrile, A / B: 80 / 20 to 30 / 70. Linear concentration gradient elution (10 minutes).

[1427] Flow rate: 0.5mL / min

[1428] Temperature: 40℃

[1429] Embodiment 17

[1430] Synthesis of H-MeTyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Oda-GGGGG-)-Asp-Arg-Aib-Ala- Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-OH(SEQ ID NO: 454) (compound 441)

[1431] Weigh the Boc-MeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Lys-Asp(OtBu)-Arg(Pbf)-Aib-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Alko resin (SEQ ID NO: 483) (166.0 mg, 0.025 mmol) was placed in a reaction tube, and then the reaction tube was placed in a peptide synthesizer. The Fmoc group was deprotected using 20% ​​piperidine / NMP [reacted at 50° C. for 5 minutes], and then Fmoc-Gly-Gly-Gly-OH was introduced using a peptide synthesizer, and then Gly, Gly and octadecane dioic acid were introduced successively. In this case, the Fmoc group was deprotected using 20% ​​piperidine / NMP [reacted at 50° C. for 5 minutes], and a condensation reaction was performed using a double coupling method, wherein the reaction was performed at 50° C. for 15 minutes, the solution was filtered off, and then the same condensation reaction was repeated. After completion of the solid phase synthesis, the resin was washed with MeOH and dried under reduced pressure to obtain the protected peptide resin of interest, Boc-MeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Lys(Oda-GGGGG-)-Asp(OtBu)-Arg(Pbf)-Aib-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Alko resin. Subsequently, 2.5 mL of TFA: meta-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80: 5: 5: 5: 2.5: 2.5) was added to the total amount of the obtained resin, and the resulting mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate, and the supernatant was removed after centrifugation. This operation was repeated twice, and the precipitate was then washed.The residue was extracted with 50% aqueous acetic acid and filtered to remove the resin, and then purified by preparative HPLC using a YMC-TriartC8-S-10 μm, 20 nm column (250 x 30 mm inner diameter) using a linear concentration gradient elution (60 minutes), solution A: 0.1% TFA-water, and solution B: acetonitrile containing 0.1% TFA, A / B from 40 / 60 to 50 / 50, flow rate 15 mL / min, and fractions containing the product of interest were collected and freeze-dried to obtain 3.4 mg of white powder.

[1432] Mass spectrum results: (M+H)+4784.51 (calculated value 4785.49)

[1433] HPLC elution time: 5.88 minutes

[1434] Elution conditions:

[1435] Column: Kinetex 1.7μm C8 100A, (100×2.1mm inner diameter)

[1436] Elution: Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-acetonitrile, A / B: 80 / 20 to 30 / 70. Linear concentration gradient elution (10 minutes).

[1437] Flow rate: 0.5mL / min

[1438] Temperature: 40℃

[1439] Embodiment 18

[1440] Synthesis of H-MeTyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Eda-PEG(3)-PEG(3)-)- Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 (SEQ ID NO: 320) (compound 307)

[1441] Sieber amide resin (0.71 meq / g, 70.4 mg, 0.05 mmol) was added to the reaction tube, which was then placed in a peptide synthesizer to sequentially extend the amino acids according to the following protocol: the Fmoc group was deprotected using 20% ​​piperidine / NMP [reacted at 50°C for 5 minutes], and the Fmoc-amino acid was condensed using 5 equivalents of Fmoc-amino acid / DIPCDI / Oxyma [reacted at 50°C for 15 minutes]. The subsequent operation is carried out: the obtained Boc-MeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Arg(Pbf)-Lys(ivDde)-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber amide resin is suspended in a 2% hydrazine / NMP solution, the resulting suspension is stirred at room temperature for 3 hours, and then the solution is filtered to remove. After filtration, the resin was suspended in a 2% hydrazine / NMP solution and reacted at room temperature overnight to deprotect the ivDde group of Lys at position 14. Subsequently, the resin was washed with MeOH and dried under reduced pressure to obtain 388.8 mg of Boc-MeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Arg(Pbf)-Lys-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber amide resin.

[1442] 38.9 mg (0.01 mmol) of the obtained resin was weighed and placed in a reaction tube, which was then placed in a peptide synthesizer. According to the scheme of using 20% ​​piperidine / NMP [reacting at 50°C for 5 minutes] to deprotect the Fmoc group, and using 5 equivalents of an acid reagent (Fmoc-amino acid or mono-tert-butyl eicosandioate) and DIPCDI / Oxyma for condensation, PEG (3), PEG (3), and mono-tert-butyl eicosandioate were introduced successively using a peptide synthesizer. The condensation reaction was carried out using a double coupling method, wherein the reaction was carried out at 50°C for 15 minutes, the solution was filtered to remove, and then the same condensation reaction was repeated. After the solid phase synthesis was completed, the resin was washed with MeOH and dried under reduced pressure to obtain 39.3 mg of the protected peptide resin of interest Boc-MeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Arg(Pbf)-Lys(19-tert-butox ycarbonyl-nonadedanoyl-PEG(3)-PEG(3)-)-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber amide resin.

[1443] Subsequently, 0.5 mL of TFA: meta-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80: 5: 5: 5: 2.5: 2.5) was added to the total amount of the obtained resin, and the resulting mixture was then stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate, and the supernatant was removed after centrifugation. This operation was repeated twice, and the precipitate was then washed. The residue was extracted with 90% acetic acid aqueous solution and the resin was removed by filtration, and then purified by preparative HPLC using a YMC-Triart C8-S-10 μm, 20 nm column (250 x 20 mm inner diameter), which used a linear concentration gradient elution (60 minutes), solution A: 0.1% TFA-water, and solution B: acetonitrile containing 0.1% TFA, A / B from 52 / 48 to 42 / 58, flow rate 8 mL / min, and the fraction containing the product of interest was collected and freeze-dried to obtain 7.5 mg of a white powder.

[1444] Mass spectrum results: (M+H)+4846.10 (calculated value 4845.61)

[1445] HPLC elution time: 7.11 minutes

[1446] Elution conditions:

[1447] Column: Kinetex1.7μm C8100A, (100×2.1mm inner diameter)

[1448] Elution: Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-acetonitrile, A / B: 80 / 20 to 30 / 70. Linear concentration gradient elution (10 minutes).

[1449] Flow rate: 0.5mL / min

[1450] Temperature: 40℃

[1451] Embodiment 19

[1452] Synthesis of Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Hda-GGGGG-)-Asp-Arg-Aib-Ala-G ln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO: 472) (compound 459)

[1453] Sieber amide resin (0.71 meq / g, 352 mg, 0.25 mmol) was added to the reaction tube, which was then placed in a peptide synthesizer to sequentially extend the amino acids according to the following protocol: the Fmoc group was deprotected using 20% ​​piperidine / NMP [reacted at room temperature for 15 minutes], and the Fmoc-amino acid was condensed using 5 equivalents of Fmoc-amino acid / DIPCDI / Oxyma [reacted at room temperature for 150 minutes].

[1454] The obtained Boc-Me-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Lys(ivDde)-Asp(OtBu)-Arg(Pbf)-Aib-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt) t)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber amide resin was suspended in 2% hydrazine / NMP solution, and the resulting suspension was stirred at room temperature for 3 hours, then the solution was removed by filtration, and the above operation was repeated twice to deprotect the ivDde group of Lys at position 14.

[1455] Subsequently, the resin was washed with MeOH and dried under reduced pressure to obtain 1.87 g of Boc-Me-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Lys-Asp(OtBu)-Arg(Pbf)-Aib-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber amide resin.

[1456] 37.3 mg (0.005 mmol) of the obtained resin was weighed and placed in a reaction tube, and then the reaction tube was placed in a peptide synthesizer. Subsequently, Fmoc-Gly-Gly-OH and Fmoc-Gly-Gly-Gly-OH were introduced using a peptide synthesizer according to the following scheme: 20% piperidine / NMP [reacted at 50°C for 5 minutes] was used to deprotect the Fmoc group, and 5 equivalents of Fmoc-amino acid / DIPCDI / Oxyma [50°C, 15 minutes] were used to condense the Fmoc-amino acid; then Boc-Me-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr (tBu)-Ser(tBu)-Ile-Aib-Lys(H-Gly-Gly-Gly-Gly-Gly-)-Asp(OtBu)-Arg(Pbf)-Aib-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber amide resin. In this case, the condensation reaction was carried out using a double coupling method, wherein all reactions were carried out at 50° C. for 15 minutes, the solution was filtered off, and then the same condensation reaction was repeated. 6.4 mg of adipic anhydride, 6.4 mg of DIPEA and NMP (0.1 ml) were added to the obtained resin, and the solution was stirred at room temperature for 2 hours. After filtering off the reaction solution, the resin was washed with MeOH and dried under reduced pressure to obtain 36.9 mg of the protected peptide resin of interest, Boc-Me-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Iva-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Lys(Hda-GGGGG-)-Asp(tBu)-Arg(Pbf)-Aib-Ala-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Sieber amide resin.

[1457] Subsequently, 0.5mL TFA: meta-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80: 5: 5: 5: 2.5: 2.5) was added to the total amount of the obtained resin, and the resulting mixture was then stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate, and the supernatant was removed after centrifugation. This operation was repeated twice, and the precipitate was then washed. The residue was extracted with 90% acetic acid aqueous solution and filtered to remove the resin, and then purified by preparative HPLC using Phenomenex Kinetex 5μm XB-C18 (250x20.0mm inner diameter), which used a linear concentration gradient elution (60 minutes), solution A: 0.1% TFA-water, and solution B: acetonitrile containing 0.1% TFA, A / B from 66 / 34 to 56 / 44, flow rate 8mL / minute, and the fractions containing the product of interest were collected and freeze-dried to obtain 2.9mg white powder.

[1458] Mass spectrum results: (M+H)+4616.573 (calculated value 4616.32)

[1459] HPLC elution time: 4.09 minutes

[1460] Elution conditions:

[1461] Column: Kinetex1.7μm C8100A, (100×2.1mm inner diameter)

[1462] Elution: Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-acetonitrile, A / B: 80 / 20 to 30 / 70. Linear concentration gradient elution (10 minutes).

[1463] Flow rate: 0.5mL / min

[1464] Temperature: 40℃

[1465] According to Examples 1 to 19, compounds not described in the Examples disclosed in FIGS. 8A to 8D and 9-1A, 9-1B, 9-1C to 9-5A, 9-5B, 9-5C were synthesized.

[1466] Test Example 1

[1467] (A) Evaluation of agonist activity against human GIPR and human GLP-1R using the increase in intracellular cAMP concentration as an indicator

[1468] (1) Construction of expression plasmid of human GIPR gene

[1469] The human GIPR gene having the same sequence as that of Genebank Accession No. U39231 was cloned into the pMSRα-neo vector to prepare hGIPR / pMSRα-neo.

[1470] (2) Construction of cells expressing reporter gene plasmids

[1471] The luciferase reporter gene with a cAMP response sequence located upstream was transferred to CHO-K1 cells to construct CRE-LUC / CHO-K1 cells.

[1472] (3) Construction of reporter gene plasmid

[1473] The cAMP response sequence and four copies of the Zeocin resistance gene were transferred to the pGL3(R2.2)-Basic vector (Promega) to construct the Cre-luc(Zeo) reporter gene plasmid.

[1474] (4) Transferring the human GIPR gene into CRE-LUC / CHO-K1 cells and obtaining expression cells

[1475] The plasmid hGIPR / pMSRα-neo obtained in (1) was transferred to the CRE-LUC / CHO-K1 cells obtained in (2) to obtain transformants. Subsequently, the cell line hGIPR / CRE-LUC / CHO-K1 cells in which luciferase expression was induced were selected from the obtained transformants by adding GIP.

[1476] (5) Construction of human GLP-1R gene expression plasmid

[1477] The human GLP-1R gene having the same sequence as that of Genebank Accession No. NM_002062 was cloned into the pIRESneo3 vector to prepare hGLP-1 / pIRESneo3.

[1478] (6) Transferring the human GLP-1R gene and reporter gene plasmid into CHO-K1 cells and obtaining expression cells

[1479] Cre-luc (Zeo) obtained in (3) and plasmid hGLP-1 / pIRESneo3 obtained in (5) were transferred to CHO-K1 cells to obtain transformants. Subsequently, a cell line hGLP-1R / CRE-luc / CHO-K1 cell in which luciferase expression is induced was selected from the obtained transformants by adding GLP-1.

[1480] (7) Reporter gene assay

[1481] Take 25 μL of hGIPR / CRE-LUC / CHO-K1 cells per aliquot to provide 5 x 10 3 Cells were inoculated in 384-well white plates (Corning) in the form of 10 cells / well, and then cultured overnight in HamF12 medium containing 10% fetal bovine serum, 100U / mL penicillin and 100μg / mL streptomycin in a CO2 incubator at 37°C. 5μL of the culture medium containing the test compound was added to the cells, and then incubated for 4 hours at a specified concentration in a CO2 incubator at 37°C. Steady-Glo (Promega) was added in an amount of 30μL and shaken in the dark. After 20 minutes, luciferase activity was measured using an ELISA reader Envision (PerkinElmer). When the luciferase activity was 100% in the presence of 10nM GIP and 0% in the presence of DMSO instead of the test compound, the increase in intracellular cAMP concentration was used as an indicator to calculate the GIPR agonist activity.

[1482] Using hGLP-1R / CRE-luc / CHO-K1 cells, GLP-1R agonist activity was determined in the same manner as above. When the luciferase activity in the presence of 10 nM GLP-1 was 100%, and the luciferase activity in the case of adding DMSO instead of the test compound was 0%, the GLP-1R agonist activity was calculated using the increase in intracellular cAMP concentration as an indicator.

[1483] As shown in Table 2-1, the compounds of the present invention have excellent GIP receptor selective activation effect.

[1484] [Table 2-1]

[1485]

[1486]

[1487]

[1488]

[1489]

[1490]

[1491]

[1492]

[1493]

[1494]

[1495]

[1496]

[1497] (B) Use [ 125 I]-GIP to assess binding activity to human GIPR

[1498] (1) Construction of expression plasmid of human GIPR gene

[1499] The human GIPR gene having the same sequence as that of Genebank Accession No. U39231 was cloned into the pcDNA3.3 vector to prepare hGIPR / pcDNA3.3.

[1500] (2) Preparation of human GIPR virus-like particles (VLPs) using Expi293F cells

[1501] One day before transfection, plate 850 mL of Expi293F cells at 1.8 x 10 6 The cells were inoculated in a 3-L flask (Corning Incorporated) at a concentration of 1 cell / mL and then cultured for 24 hours at 37°C, 8% CO2, 85rpm. The Expi293 expression system kit (Thermo Fisher Scientific) was used for transfection. More specifically, 0.67mg pcDNA3.3 / hGIPR and 0.33mg pcDNA3.3 / GAG plasmids for VLP preparation were added to 50mL opti-MEM (Thermo Fisher Scientific) to prepare a DNA mixture. Subsequently, 2.7mL Expifectamine was added to 50mL opti-MEM and allowed to stand for 5 minutes, and then the DNA mixture was mixed therein and the resulting mixture was allowed to stand for 20 minutes, and then further added to the culture medium. 20 hours after transfection, 5mL Enhancer 1 and 50mL Enhancer 2 were added thereto. 96 hours after transfection, the culture medium was centrifuged at 850xg for 15 minutes to obtain a supernatant. The obtained supernatant was ultracentrifuged at 54000xg for 1 hour to obtain the GIPR_VLP fraction. The precipitate was washed once with PBS and then suspended in a small amount of PBS to obtain GIPR_VLP. The obtained GIPR_VLP was stored at -80°C until use. Protein quantification was performed using GelCode Blue Safe Protein Stain (GelCode Blue Safe Protein Stain, Thermo Fisher Scientific) with BSA as the standard.

[1502] (3) Measurement of the binding activity of test compounds to human GIPR

[1503] To measure the binding activity to GIPR, [ 125 I]GIP (PerkinElmer, Inc.) and the test compound at the specified concentration were mixed into GIPR_VLP in the assay buffer (50 mM HEPES (pH 7.4, WAKO 342-01375), 5 mM EGTA (WAKO 346-01312), 5 mM MgCl2 (WAKO 136-03995), 0.1% BSA (Merck millipore 81-066-04) and 0.005% Tween 20 (BioRad 170-6531)) and reacted at room temperature for 2 hours. The cells were harvested using a cell harvester. 125 I] The VLPs bound by GIP were captured in GF / C glass fiber filter 96-well plates (PerkinElmer 6005274) and washed with assay buffer. The GF / C glass fiber filter 96-well plates in which VLPs were captured were dried overnight at 42°C. Thereafter, MicroScint-O (PerkinElmer 6013611) was added to the GF / C glass fiber filter 96-well plates sealed with a back seal, and the plates were sealed with a top seal. The radioactivity of each well was finally measured using a Topcount (PerkinElmer), and when in the presence of GIP at a final concentration of 1 μM [ 125 I] GIP binding activity was 100%, and the wells to which DMSO was added [ 125 When the I]GIP binding activity was 0%, the binding activity of the test compound to GIPR was calculated.

[1504] As shown in Table 2-2, the compounds of the present invention have excellent binding activity to the GIP receptor.

[1505] [Table 2-2]

[1506]

[1507]

[1508]

[1509]

[1510]

[1511]

[1512]

[1513]

[1514]

[1515]

[1516] Test Example 2

[1517] Oral glucose tolerance test (1)

[1518] Use glucose load to be 0.03nmol / kg C57BL / 6J mice to carry out oral glucose tolerance test (OGTT).Subcutaneously administer each peptide or solvent (control group) before increasing glucose load for 30 minutes, and measure the glucose level of 30 minutes and 60 minutes after oral administration of glucose, to assess the effect of compound.Calculate the effect of compound by following calculation formula, and it is expressed as the rate of increase (%) of blood sugar level.

[1519] Increase rate of blood glucose level (%) = (blood glucose level after glucose loading in the group administered with the compound - blood glucose level before glucose loading) / (blood glucose level after glucose loading in the control group - blood glucose level before glucose loading) x 100

[1520] The results are shown in Table 3-1. As shown in Table 3-1, it was confirmed that the compound of the present invention inhibited the increase in blood sugar level caused by oral administration of increased glucose load.

[1521] [Table 3-1]

[1522]

[1523]

[1524] Oral glucose tolerance test (2)

[1525] Use glucose load to be 3nmol / kg C57BL / 6J mice to carry out oral glucose tolerance test (OGTT).Every peptide or solvent (control group) were subcutaneously administered 72 hours before increasing glucose load, and the blood glucose level of 30 minutes after oral administration of glucose was measured to assess the effect of the compound.The effect of the compound was calculated by the following calculation formula, and it was expressed as the rate of increase (%) of blood glucose level.

[1526] Increase rate of blood glucose level (%) = (blood glucose level after glucose loading in the group administered with the compound - blood glucose level before glucose loading) / (blood glucose level after glucose loading in the control group - blood glucose level before glucose loading) x 100

[1527] The results are shown in Table 3-2. As shown in Table 3-2, it was confirmed that the compound of the present invention inhibited the increase in blood sugar level caused by oral administration of increased glucose load.

[1528] [Table 3-2]

[1529]

[1530] Test Example 3: Conditioned taste aversion test in mice

[1531] (Figure 1-1, Figure 1-2)

[1532] 0.1% saccharin water and the 14-residue Y2R agonist PYY-1119 (4-imidazolecarbonyl-Ser-D-Hyp-Iva-Pya(4)-Cha-Leu(Me)-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Cha-NH2 (SEQ ID NO: 164) were administered to male C57BL / 6J mice to induce conditioned taste aversion (CTA) to saccharin water, and the effects of the compounds of the present invention on the taste aversion induced by PYY-1119 were evaluated. The general procedure of the CTA experiment is as follows.

[1533] Conditioning was performed in the following manner: On days 1 and 3, mice were provided with saccharin water, and PYY-1119 (10 nmol / kg, subcutaneously) was administered 10 minutes later. In addition, the test compound or solvent was administered subcutaneously simultaneously with PYY-1119.

[1534] On day 2, only the solvent was administered 10 minutes after tap water was provided.

[1535] On day 4, only tap water was provided.

[1536] On day 5, a test of choosing between a saccharine water bottle and a tap water bottle was performed, and the preference for saccharine water was assessed.

[1537] Compound 6 was dissolved in 10% DMSO / saline and administered simultaneously with pYY-1119 at a dose of 1 mol / kg, 3 mol / kg, 10 nmol / kg, 30 nmol / kg or 100 mol / kg. As a result, compound 6 inhibited the taste aversion induced by pYY-1119 in a dose-dependent manner ( FIG1-1 ).

[1538] Compound 117 was dissolved in 0.1% Tween 80 / 10% DMSO / saline and administered simultaneously with PYY-1119 at a dose of 0.003 nmol / kg, 0.01 nmol / kg, 0.03 nmol / kg, 0.1 nmol / kg, 0.3 nmol / kg or 1 mol / kg. As a result, compound 117 inhibited the taste aversion induced by PYY-1119 in a dose-dependent manner (Figures 1-2).

[1539] Test Example 4: Vomiting Inhibition Test in Ferrets

[1540] 1. Effect of subcutaneous injection of compound 6 on cisplatin-induced acute vomiting model

[1541] Ferret testing was performed by Nissei Bilis Co., Ltd. (Shiga prefecture, Japan). Cisplatin (10 mg / kg, intraperitoneal injection) was administered to male ferrets (10 weeks old, n=6) to induce acute vomiting. Vehicle (10% DMSO / saline, subcutaneous), compound 6 (subcutaneous injection of 16.7 or 167 nmol / kg / h (corresponding to approximately 70.7 and 707 μg / kg / h, respectively), started 1 hour before cisplatin administration) and aprepitant (NK1R antagonist, 3 mg / kg, oral, administered 1 hour before cisplatin administration) were evaluated using the above ferrets. The frequency of nausea and vomiting (feeling nausea, vomiting) was monitored over a period of 8 hours after cisplatin administration. When administered at 167 nmol / kg / h, compound 6 completely eliminated acute nausea and vomiting, at least to the same extent as the effect achieved by aprepitant (Figure 2-1). Plasma levels of Compound 6 assessed at the completion of the test were 133.4 nmol / L and 392.7 nmol / L when administered at 16.7 or 167 nmol / kg / h, respectively.

[1542] 2. Effect of subcutaneous injection of compound 117 on cisplatin-induced acute nausea and vomiting model

[1543] 24 ferrets were divided into 6 groups of 4 in each group, and the vehicle (0.09 weight / volume% Tween 80 / 10% DMSO / saline) and 0.15, 0.5, 1.5, 5 and 15 μg / kg (0.03, 0.1, 0.3, 1 and 3 nmol / kg) of compound 117 were subcutaneously injected into each group, and 1 hour later, 10 mg / kg cisplatin was intraperitoneally administered to each group. The condition of the ferrets was monitored until 6 hours after the administration of cisplatin to record the frequency and time point of abdominal contraction movements and vomiting behavior. As a result, in the group to which compound 117 was administered, it was noted that the inhibition of vomiting symptoms was carried out in a dose-dependent manner (Figure 2-2).

[1544] 3. Effects of Compound 117 and Compound 341 in Cisplatin-Induced Delayed Emesis Model

[1545] 28 ferrets were divided into 4 groups, 7 in each group, and 5 mg / kg cisplatin was injected intraperitoneally. After 34 hours, the vehicle (0.09 weight / volume% Tween 80 / 10% DMSO / saline), 1.5 μg / kg and 15 μg / kg of compound 117 and 144 μg / kg of compound 341 were subcutaneously injected into each group. The condition of the ferrets was monitored until 72 hours after the administration of cisplatin to record the frequency and time point of abdominal contraction movements and vomiting behavior. As a result, when 1.5 μg / kg (0.3 nmol / kg) or 15 μg / kg (3 nmol / kg) of compound 117 was administered, the latency of vomiting symptoms (the time from the administration of cisplatin to the initial appearance of vomiting symptoms) was delayed (Figure 2-3), and when 144 μg / kg (30 nmol / kg) of compound 341 was administered, it was noted that the vomiting symptoms were suppressed.

[1546] 4. Effects of subcutaneously administered GIP agonist analogs in the morphine-induced acute nausea and vomiting model

[1547] Male ferrets (4 months old) were used repeatedly until 8 months old. To evaluate the antiemetic effect, GIP agonist analogs other than natural human GIP were administered subcutaneously 30 minutes before morphine administration. Natural human GIP was administered subcutaneously 5 minutes before morphine administration. Compound 6 at a dose of 4.2 μg / kg (1 nmol / kg) completely attenuated morphine (0.6 mg / kg, subcutaneous) induced nausea and vomiting in ferrets (Figure 3). Compound 59 (0.45 μg / kg, 0.1 nmol / kg; 4.47 μg / kg, 1 nmol / kg; 13.4 μg / kg, 3 mol / kg), compound 75 (4.44 μg / kg, 1 nmol / kg), compound 104 (4.35 μg / kg, 1 nmol / kg), compound 113 (0.43 μg / kg, 0.1 nmol / kg; 4.35 μg / kg, 1 nmol / kg) and compound 117 (4.45 μg / kg, 1 nmol / kg) also inhibited morphine-induced nausea and vomiting in ferrets ( Figure 4 , Figure 5 ).

[1548] 5. Effects of subcutaneously administered compounds 341, 349, 253, 268, 284, 292 and 314 in the morphine-induced acute nausea and vomiting model

[1549] 144 μg / kg (30 nmol / kg) of compound 341, 144 μg / kg (30 nmol / kg) of compound 349, 144 μg / kg (30 nmol / kg) of compound 253, 145 μg / kg (30 nmol / kg) of compound 268, 144 μg / kg (30 nmol / kg) of compound 284, 145 μg / kg (30 nmol / kg) of compound 292 and 145 μg / kg (30 nmol / kg) of compound 314 were dissolved in vehicle (0.09 weight / volume % Tween 80 / 10% DMSO / saline) to prepare test solutions. 0.5 mg / kg of test solution and vehicle were subcutaneously administered to ferrets (4 in each group). 0.6 mg / kg of morphine was subcutaneously administered at each time of 4 hours or 120 hours after administration. Ferrets were monitored up to 60 minutes after morphine administration to record the frequency and timing of abdominal contraction movements, gagging behavior, licking, and irritability behavior.

[1550] As a result, in the experiment in which morphine was administered 4 hours after administration, vomiting behavior was noted in all 4 ferrets in the vehicle group, but no vomiting symptoms were observed in the 4 ferrets in each of the groups receiving 144 μg / kg of compound 341, the group receiving 144 μg / kg of compound 349, the group receiving 144 μg / kg of compound 253, the group receiving 145 μg / kg of compound 268, the group receiving 144 μg / kg of compound 284, the group receiving 145 μg / kg of compound 292, and the group receiving 145 μg / kg of compound 314 ( FIG. 6-1 ). In addition, the plasma levels of compound 341, compound 349, compound 253, compound 268, compound 284, compound 292 and compound 314 were 154.0nmol / L, 143.4nmol / L, 108.4nmol / L, 104.9nmol / L, 163.3nmol / L, 96.7nmol / L and 172.7nmol / L, respectively, 4 hours after administration. In addition, in the experiment of morphine administration 120 hours after administration, vomiting behavior was noted in all 4 ferrets in the vehicle group, but no vomiting symptoms were observed in the 4 ferrets in the group receiving 144μg / kg compound 341, and vomiting symptoms were noted to be suppressed in the group receiving 144μg / kg compound 349 (Figure 6-2). In addition, the plasma levels of compound 341 and compound 349 were 82.3nmol / L and 43.3nmol / L, respectively, 120 hours after administration.

[1551] 6. PYY-1119-induced vomiting in dogs

[1552] The effects of a single subcutaneous administration of Compound 6 and Compound 117 on PYY-1119 (10 μg / kg [approximately 5 nmol / kg], subcutaneous)-induced nausea and vomiting were evaluated in beagle dogs.

[1553] For compound 6, combined use and single administration of PYY-1119 were tested in 2 female and 2 male cases (24 to 32 months old) at 7-day intervals, and compound 6 was administered 10 minutes before the administration of PYY-1119. During the 2-hour observation period after the administration of PYY-1119, compound 6 (150 nmol / kg) significantly suppressed the frequency of vomiting to 0 to 1 / 3, while for PYY-1119 alone, the observed frequency of vomiting was 6 to 28 times (Figure 7-1).

[1554] For compound 117, the test was performed as a crossover test using 4 female cases (36 months old) at intervals of 7 days, and compound 117 and its culture medium were administered 1 hour before the administration of PYY-1119. During the 2-hour observation period after the administration of PYY-1119, compound 117 (10 nmol / kg) significantly suppressed the vomiting frequency to 0 to 1 / 3, while in the culture medium group, the observed vomiting frequency was 8 to 30 times, and the average suppression rate of vomiting frequency was 93% (Figure 7-2).

[1555] Preparation Example 1

[1556] (1) 10.0 mg of the compound of Example 1

[1557] (2) Lactose 70.0 mg

[1558] (3) Corn starch 50.0 mg

[1559] (4) Soluble starch 7.0 mg

[1560] (5) Magnesium stearate 3.0 mg

[1561] The compound of Example 1 (10.0 mg) and magnesium stearate (3.0 mg) were granulated with a water-soluble starch solution (0.07 ml) (7.0 mg in the form of soluble starch), dried and mixed with lactose (70.0 mg) and corn starch (50.0 mg). The mixture was compressed to obtain tablets.

[1562] Preparation Example 2

[1563] (1) 5.0 mg of the compound of Example 1

[1564] (2) Sodium chloride 20.0 mg

[1565] (3) Distilled water to a total volume of 2 ml

[1566] The compound of Example 1 (5.0 mg) and sodium chloride (20.0 mg) were dissolved in distilled water, and then water was added to a total of 2.0 ml. The solution was filtered and aseptically filled into a 2 ml ampoule. The ampoule was sterilized and tightly sealed to obtain a solution for injection.

[1567] Industrial Applicability

[1568] The compound of the present invention has excellent GIP receptor selective agonist activity and is useful as a drug for preventing or treating various diseases associated with the GIP receptor (eg, diabetes, obesity, diseases associated with vomiting or nausea, etc.).

[1569] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

[1570] Free text for sequence listings

[1571] SEQ ID NO: 1: Synthetic peptide

[1572] SEQ ID NO: 2: Synthetic peptide

[1573] SEQ ID NO: 3: Synthetic peptide

[1574] SEQ ID NO: 4: Synthetic peptide (reference example 1)

[1575] SEQ ID NO: 5: Synthetic peptide (reference example 2)

[1576] SEQ ID NO: 6: Synthetic peptide (reference example 3)

[1577] SEQ ID NO: 7 to 163: Synthetic peptides (compounds 1 to 157, respectively))

[1578] SEQ ID NO: 164: Synthetic peptide (PYY-1119)

[1579] SEQ ID NO: 165: Synthetic peptide (Formula (I))

[1580] SEQ ID NO: 166: Synthetic peptide (Formula (II))

[1581] SEQ ID NO: 167: Synthetic peptide (Formula (III))

[1582] SEQ ID NO: 168: Synthetic peptide (Formula (IV))

[1583] SEQ ID NO: 169: Synthetic peptide (Formula (V))

[1584] SEQ ID NO: 170: Synthetic peptide (Formula (VI))

[1585] SEQ ID NO: 171 to 480: Synthetic peptides (compounds 158 to 467, respectively)

[1586] SEQ ID NO: 481: Synthetic peptide (Reference Example A: Compound 468)

[1587] SEQ ID NO: 482: Synthetic peptide (Reference Example B: Compound 469)

[1588] SEQ ID NO: 483: Synthetic peptide (Reference Example C: Compound 470)

[1589] SEQ ID NO: 484 to 535: Synthetic peptides (compounds 471 to 522, respectively)

[1590] SEQ ID NO: 536 to 565: Synthetic peptide

[1591] SEQ ID NO: 566: Synthetic peptide (Formula (X)

[1592] SEQ ID NO: 567 to 569: Synthetic peptides (Formula (VII) to (IX))

Claims

1. A peptide represented by one of the following: (SEQ ID NO: 12), (SEQ ID NO: 36), Me-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Ile-Ala-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2 (SEQ ID NO: 65); Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2 (SEQ ID NO: 110); Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2 (SEQ ID NO: 119); Me-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-His-Gln-Aib-As n-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2(SEQ ID NO: 123), Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Eda-GGGGG-)-Asp-Arg-Aib-Ala-Gl n-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2(SEQ ID NO: 354), or Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Oda-GGGGG-)-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 (SEQ ID NO: 362), or a salt thereof.

2. The peptide represented by the following formula according to claim 1: H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Aib-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 12), or a salt thereof.

3. The peptide represented by the following formula according to claim 1: H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Gln-Ala-Gln-Aib-Glu-Phe-Val-Arg-Trp-Leu-Leu-Arg-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2 (SEQ ID NO: 36), or a salt thereof.

4. The peptide represented by the following formula according to claim 1: Me-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Ile-Ala-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2 (SEQ ID NO: 65), or a salt thereof.

5. The peptide represented by the following formula according to claim 1: Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2 (SEQ ID NO: 110), or a salt thereof.

6. The peptide represented by the following formula according to claim 1: Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2 (SEQ ID NO: 119), or a salt thereof.

7. The peptide represented by the following formula according to claim 1: Me-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH2 (SEQ ID NO: 123), or a salt thereof.

8. The peptide represented by the following formula according to claim 1: Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Eda-GGGGG-)-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 (SEQ ID NO: 354), or a salt thereof.

9. The peptide represented by the following formula according to claim 1: Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Oda-GGGGG-)-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 (SEQ ID NO: 362), or a salt thereof.

10. A medicament comprising the peptide according to claim 1 or a salt thereof.

11. Use of the peptide or a salt thereof according to claim 1 for the manufacture of a medicament for activating a GIP receptor in a mammal.

12. Use of the peptide or a salt thereof according to claim 1 for the manufacture of an inhibitor of vomiting or nausea.

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