BR112015027596B1 - PEPTIDE, SEQUENCE, DRUG, AND, USE OF A PEPTIDE - Google Patents

Abstract

PEPTIDE, SEQUENCE, DRUG, AND, USE OF A PEPTIDE. The present invention provides a novel peptide compound having an activating action on GLP-1 receptors and GIP receptors and use of the peptide compound as a medicine. Specifically, a peptide containing a partial sequence represented by formula (I) or a salt thereof and a medicine comprising the same are provided. P1 -Tyr-Aib-Glu-Gly-Thr-(Alpha) MePhe-Thr-Ser- Asp-Tyr-A11-A12-A13-Leu-Asp-A16-A17-Ala-Gln-A20-Glu-Phe-Val -Lys-Trp-Leu-Leu-Lys-A29 (I) wherein each symbol is of the form defined herein.

Description

Field Of Invention

[001] The present invention relates to a novel peptide compound having an activating action on GLP-1 receptors and GIP receptors and use of the peptide compound as a medicine.

Fundamentals of the Invention

[002] Both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are peptides called incretin. GLP-1 and GIP are secreted from small intestinal L cells and K cells, respectively.

[003] GLP-1 acts through GLP-1 receptors and is known to have a glucose-dependent insulinotropic action and a feeding suppression action. On the other hand, GIP is known to have a glucose-dependent insulinotropic action via GIP receptors, although its influence on feeding is unclear.

[004] Co-administration of a GLP-1 receptor agonist liraglutide and a GIP receptor agonist N-Ac-GIP has been reported to promote an action that improves glucose tolerance and an action that lowers body weight better than administration of liraglutide alone (Non-patent literature 1). Also, a GLP-1 receptor/GIP receptor coagonist peptide has been reported to show a stronger hypoglycemic and body weight lowering action than a GLP-1 receptor agonist alone (Patent Literature 1).

[005] Attempts have also been made to search for peptides with GLP-1 receptor/GIP receptor coagonist activity or glucagon receptor/GLP-1/GIP receptor triagonist activity and to develop these peptides as anti-obesity drugs or therapeutic drugs for diabetes, based on the structure of natural glucagon, GIP, or GLP-1 (Patent Literatures 1 to 8). None of the literature, however, describes the peptide compound of the present invention. Citation List Patent Literature Patent Literature 1 WO2010/011439 Patent Literature 2 WO2010/148089 Patent Literature 3 WO2011/119657 Patent Literature 4 WO2012/088379 Patent Literature 5 W02012/167744 Patent Literature 6 WO2013/164483 Literature patent 7 WO2013/192129 Literature patent 8 WO2013/192130 Non-patent literature Non-patent literature 1] Clinical Science 121, 107-117 (2011)

Summary of the Invention Technical problem

[006] The present invention claims to provide a novel peptide compound having high GLP-1 receptor/GIP receptor coagonist activity and used as an agent for the prophylaxis or treatment of obesity and the like.

Solution to the Problem

[007] Intensive studies were conducted on a novel peptide compound having higher GLP-1 receptor/GIP receptor coagonist activity and used as an agent for the prophylaxis or treatment of obesity and the like, and consequently it was observed that a compound of peptide containing a partial sequence represented by the formula (I) shown below and the like have superior GLP-1 receptor/GIP receptor coagonist activity, which resulted in completion of the present invention.

[008] Thus, the present invention relates to (1) a peptide comprising a partial sequence represented by formula (I):

[009] P1-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-A11-A12-A13-Leu-Asp-A16-A17-Ala-Gln-A20-Glu-Phe-Val -Lys-Trp-Leu-Leu-Lys-A29 (SEQ ID NO: 1) where P1 is a group represented by the formula: -RA1, -CO-RA1, -CO-ORA1, -CO-CORA1, -SO- RA1, -SO2-RA1, -SO2-ORA1, -CO-NRA2RA3, -SO2-NRA2RA3, or -C(=NRA1)-NRA2RA3 wherein RA1, RA2 and RA3 are each independently a hydrogen atom, optionally a hydrocarbon group substituted, or an optionally substituted heterocyclic group; A11 is Aib or Ala; A12 is Ala, Ile, Lys, Phe or Pya(4); A13 is Aib, Cha, Leu, αMePhe or α-MeTyr; A16 is Lys or Ser; A17 is Gln or Ile; A20 is Ala or Ser; and A29 is Gln or Gly, or a salt thereof (hereinafter sometimes abbreviated as compound (I)); (2) The peptide of the aforementioned (1) or a salt thereof, wherein P1 is a hydrogen atom; (3) The peptide of the aforementioned (1) or a salt thereof, wherein A11 is Aib; (4) The peptide of the aforementioned (1) or a salt thereof, wherein A12 is Ile; (5) The peptide of the aforementioned (1) or a salt thereof, wherein A13 is Aib; (6) The peptide of the aforementioned (1) or a salt thereof, wherein A16 is Lys; (7) The peptide of the aforementioned (1) or a salt thereof, wherein A17 is Gln; (8) The peptide of the aforementioned (1) or a salt thereof, wherein A20 is Ala; (9) The peptide of the aforementioned (1) or a salt thereof, wherein A29 is Gly; (10) The peptide of the above-mentioned (1) or a salt thereof, with an amino acid sequence represented by Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys- on the C-side terminus of A29; (11) The peptide of the aforementioned (1) or a salt thereof, wherein P1 is a hydrogen atom; A11 is Aib; A12 is Ile; A13 is Aib; A16 is Lys; A17 is Gln; A20 is Wing; A29 is Gly; and the peptide with an amino acid sequence represented by Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys- on the C-terminal side of A29; (12) H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val -Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 or a salt thereof; (13) H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe-Val -Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 or a salt thereof; (14) H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Gln-Glu-Phe-Val -Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 or a salt thereof; (15) H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Gln-Glu-Phe-Val -Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 or a salt thereof; (16) a medicine comprising the peptide of the aforementioned (1) or a salt thereof; (17) the medicine of the aforementioned (16), which is an activator of a GLP-1 receptor and a GIP receptor; (18) the medicament of the aforementioned (16), which is an agent for the prophylaxis or treatment of obesity or diabetes; (19) A method for the prophylaxis or treatment of obesity or diabetes in a mammal, comprising administering an effective amount of the peptide of the aforementioned (1) or a salt thereof to the mammal; (20) A method for activating a GLP-1 receptor and a GIP receptor in a mammal, comprising administering an effective amount of the peptide of the aforementioned (1) or a salt thereof to the mammal; (21) Use of the peptide of the aforementioned (1) or a salt thereof for the manufacture of an agent for the prophylaxis or treatment of obesity or diabetes; (22) The peptide of the aforementioned (1) or a salt thereof for use in the prophylaxis or treatment of obesity or diabetes.

Advantageous Effects of the Invention

[0010] Compound (I) has superior GLP-1 receptor/GIP receptor coagonist activity and shows significant feeding suppressive and body weight lowering effects IN VIVO. Furthermore, compound (I) has a low risk of hyperglycemic action and is also used in the treatment of obesity associated with diabetes and the like, by virtue of its low glucagon receptor agonist activity. Furthermore, compound (I) is excellent in solubility and also has the advantage that the compound can be easily formulated as a medicine.

Detailed Description of the Invention

[0011] The definition of each substituent used in the present patent application is described in detail below. Unless otherwise specified, each substituent has the following definition. In the present patent application, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine.

[0012] In the present patent application, examples of the "C16 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.

[0013] In the present patent application, examples of the "optionally halogenated C16 alkyl group" include a C1-6 alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 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.

[0014] In the present patent application, examples of the "C2-6 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.

[0015] In the present patent application, examples of the "C2-6 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.

[0016] In the present patent application, examples of the "C3-10 cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2 .1]octyl and adamantyl.

[0017] In the present patent application, examples of the "optionally halogenated C3-10 cycloalkyl group" include a C3-10 cycloalkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0018] In the present patent application, examples of the "C3-10 cycloalkenyl group" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.

[0019] In the present patent application, examples of the "C6-14 aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

[0020] In the present patent application, examples of the "C7-16 aralkyl group" include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

[0021] In the present patent application, examples of the "C16 alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

[0022] In the present patent application, examples of the "optionally halogenated C1-6 alkoxy group" include a C1-6 alkoxy group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 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.

[0023] In the present application, examples of the "C 3-10 cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

[0024] In the present application, examples of the "C1-6 alkylthio group" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.

[0025] In the present patent application, examples of the "optionally halogenated C1-6 alkylthio group" include a C1-6 alkylthio group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio.

[0026] In the present patent application, examples of the "C1-6 alkylcarbonyl group" include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl and heptanoyl.

[0027] In the present patent application, examples of the "optionally halogenated C1-6 alkylcarbonyl group" include a C1-6alkylcarbonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

[0028] In the present patent application, examples of the "C1-6 alkoxycarbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl.

[0029] In the present patent application, examples of the "C6-14 aryl carbonyl group" include benzoyl, 1-naphthoyl and 2-naphthoyl.

[0030] In the present patent application, examples of the "C7-16 aralkylcarbonyl group" include phenylacetyl and phenylpropionyl.

[0031] In the present patent application, examples of the "5- to 14-membered aromatic heterocyclylcarbonyl group" include nicotinoyl, isonicotinoyl, ethenoyl and furoyl.

[0032] In the present patent application, examples of the "non-aromatic 3- to 14-membered heterocyclylcarbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.

[0033] In the present patent application, examples of the "mono- or di-C1-6 alkyl carbamoyl group" include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

[0034] In the present patent application, examples of the "mono- or di-C7-16 alkyl-carbamoyl group" include benzylcarbamoyl and phenethylcarbamoyl.

[0035] In the present patent application, examples of the "C1-6 alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.

[0036] In the present patent application, examples of the "optionally halogenated C1-6 alkylsulfonyl group" include a C1-6 alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl.

[0037] In the present patent application, examples of the "C6-14 arylsulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

[0038] In the present patent application, 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 hydroxy group, an optionally substituted sulfanyl (SH) group and an optionally substituted silyl group.

[0039] In the present patent application, examples of the "hydrocarbon group" (including "hydrocarbon group" of "optionally substituted hydrocarbon group") include a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group , a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C6-14 aryl group and a C7-16 aralkyl group.

[0040] In the present patent application, examples of the “optionally substituted hydrocarbon group” include a hydrocarbon group optionally having substituent(s) selected from the following substituent group A. {substituent group A} (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) an optionally halogenated C1-6 alkoxy group, (7) a C6-14 aryloxy group (e.g., phenoxy, naphthoxy), (8) a C7-16 aralkyloxy group (for example, benzyloxy), (9) an aromatic 5- to 14-membered heterocyclyloxy group (for example, pyridyloxy), (10) a non-aromatic 3-membered heterocyclyloxy group to 14-membered (for example, morpholinyloxy, piperidinyloxy), (11) a C1-6 alkylcarbonyloxy group (for example, acetoxy, propanoyloxy), (12) a C6-14 arylcarbonyloxy group (for example, benzoyloxy, 1-naphthoyloxy , 2-naphthoyloxy), (13) a C1-6 alkoxycarbonyloxy group (for example, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (14) a mono- or di-C1-6 alkyl carbamoyloxy group (for example, methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy), (15) a C6-14 aryl carbamoyloxy group (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy), (16) an aromatic 5- to 14-membered heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), (17) a group 3- to 14-membered non-aromatic heterocyclylcarbonyloxy (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) an optionally halogenated C1-6 alkylsulfonyloxy group (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy), (19) a C6-14 arylsulfonyloxy group optionally substituted by a C1-6 alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy), (20) an optionally halogenated C1-6 alkylthio group, (21) a 5- to 14-membered aromatic heterocyclic group, (22) a 3- to 14-membered non-aromatic heterocyclic group 14-membered, (23) a formyl group, (24) a carboxy group, (25) an optionally halogenated C1-6 alkylcarbonyl group, (26) a C6-14 arylcarbonyl group, (27) an aromatic 5-membered heterocyclylcarbonyl group to 14-membered, (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, (29) a C1-6 alkoxycarbonyl group, (30) a C6-14 aryloxycarbonyl group (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2 -naphthyloxycarbonyl), (31) a C7-16 aralkyloxycarbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), (32) a carbamoyl group, (33) a thiocarbamoyl group, (34) a mono- or diC1-6 alkyl carbamoyl group , (35) a C6-14 aryl carbamoyl group (e.g., phenylcarbamoyl), (36) an aromatic 5- to 14-membered heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl, thienylcarbamoyl), (37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group 14-membered (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl), (38) an optionally halogenated C1-6 alkylsulfonyl group, (39) a C6-14 arylsulfonyl group, (40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g., pyridylsulfonyl , thienylsulfonyl), (41) an optionally halogenated C1-6 alkylsulfinyl group, (42) a C6-14 arylsulfinyl group (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl), (43) a 5- to 1-aromatic heterocyclylsulfinyl group 14-membered (e.g., pyridylsulfinyl, thienylsulfinyl), (44) an amino group, (45) a mono- or di-C1-6 alkyl amino group (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino , dipropylamino, dibutylamino, N-ethyl-N-methylamino), (46) a C6-14 mono- or di-aryl amino group (e.g., phenylamino), (47) a 5- to 14-membered aromatic heterocyclylamino group (e.g., (e.g., pyridylamino), (48) an aralkyl C7-16 amino group (e.g., benzylamino), (49) a formylamino group, (50) a C1-6 alkylcarbonylamino group (e.g., acetylamino, propanoylamino, butanoylamino), (51) a (C1-6 alkyl)(C1-6 alkylcarbonyl)amino group (e.g. N-acetyl-N-methylamino), (52) a C6-14 arylcarbonylamino group (e.g. phenylcarbonylamino, naphthylcarbonylamino ), (53) a C1-6 alkoxycarbonylamino group (for example, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino), (54) a C7-16 aralkyloxycarbonylamino group (for example, benzyloxycarbonylamino), (55) a C1-6 alkylsulfonylamino group (for example, methylsulfonylamino, ethylsulfonylamino), (56) a C6-14 arylsulfonyl amino group optionally substituted by a C1-6 alkyl group (for example, phenylsulfonylamino, toluenesulfonylamino), (57) a C1 alkyl group -6 optionally halogenated, (58) a C2-6 alkenyl group, (59) a C2-6 alkynyl group, (60) a C3-10 cycloalkyl group, (61) a C3-10 cycloalkenyl group, and (62) a aryl C6-14.

[0041] The number of the substituents mentioned above in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.

[0042] In the present patent application, examples of the "heterocyclic group" (including "heterocyclic group" of "optionally substituted heterocyclic group") include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group, and (iii) a bonded heterocyclic group of 7 to 10 members, each containing, as a ring-constituting atom in addition to the carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

[0043] In the present patent application, examples of the "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") include a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing, as a atom constituting the ring in addition to the carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

[0044] Preferable examples of the "aromatic heterocyclic group" include 5- or 6-membered monocyclic aromatic heterocyclic groups 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 8 to 14 tricyclic polycyclic aromatic heterocyclic groups, such as benzothiophenyl, benzoxazolyl, benzotriazolyl, pyrrolopyridinyl, imidazopyrazinyl, pyrrolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, iso indolyl, 1H- indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like.

[0045] In the present patent application, examples of the "non-aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group. containing, as an atom constituting the ring in addition to the carbon atom, from 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

[0046] Preferable examples of the "non-aromatic heterocyclic group" include 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as aziridinyl, oxiranyl, tyranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl , tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanil, diazepanil, azepinil, oxepanil, azocanyl, diazocanyl and the like; and fused 9- to 14-membered polycyclic non-aromatic heterocyclic groups (preferably bi- or tricyclic), such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b ]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenantridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetra hydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl , tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanentoyl, octahydroisoquinolyl and the like.

[0047] In the present patent application, preferable examples of the "linked 7- to 10-membered heterocyclic group" include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl.

[0048] In the present patent application, examples of the "nitrogen-containing heterocyclic group" include a "heterocyclic group" containing at least one nitrogen atom as an atom constituting the ring.

[0049] In the present patent application, examples of the "optionally substituted heterocyclic group" include a heterocyclic group optionally having substituent(s) selected from the aforementioned substituent group A.

[0050] The number of the substituents in the "optionally substituted heterocyclic group" is, for example, 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.

[0051] In the present patent application, examples of the "acyl group" include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulphine group, a sulfo group, a sulfamoyl group and a phosphono group, each optionally with “1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C6-14 aryl group, a C7-16 aralkyl group, a 5- to 14-membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from a halogen atom, an optionally halogenated C1-6 alkoxy group, a hydroxy group , a nitro group, a cyano group, an amino group and a carbamoyl group”.

[0052] Examples of the "acyl group" also include a hydrocarbonsulfonyl group, a heterocyclylsulfonyl group, a hydrocarbonsulfinyl group and a heterocyclylsulfinyl group.

[0053] Here, hydrocarbonsulfonyl group means a sulfonyl group attached to the hydrocarbon group, heterocyclylsulfonyl group means a sulfonyl group attached to the heterocyclic group, hydrocarbonsulfinyl group means a sulfinyl group attached to the hydrocarbon group, and heterocyclylsulfinyl group means a sulfinyl group attached to the heterocyclic group.

[0054] Preferable examples of the "acyl group" include a formyl group, a carboxy group, a C1-6 alkyl carbonyl group, a C2-6 alkenyl carbonyl group (for example, crotonoyl), a C3-10 cycloalkyl carbonyl group (for example, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), a C3-10 cycloalkenylcarbonyl group (e.g., 2-cyclohexenecarbonyl), a C6-14 arylcarbonyl group, a C7-16 aralkylcarbonyl group, a 5- to 5-aromatic heterocyclylcarbonyl group 14-membered, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C1-6 alkoxycarbonyl group, a C6-14 aryloxycarbonyl group (e.g. phenyloxycarbonyl, naphthyloxycarbonyl), a C716 aralkyloxycarbonyl group (e.g. benzyloxycarbonyl, phenethyloxycarbonyl ), a carbamoyl group, a mono- or di-C1-6 alkyl carbamoyl group, a mono- or di- C2-6 alkenyl carbamoyl group (e.g. diallylcarbamoyl), a mono- or di-C3-10 cycloalkyl carbamoyl group (e.g. e.g., cyclopropylcarbamoyl), a C6-14 mono- or di-aryl carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C7-16 aralkyl carbamoyl group, an aromatic 5- to 14-membered heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-C16 alkyl thiocarbamoyl group (e.g. methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), a mono- or di-C2-6 alkenyl thiocarbamoyl group (e.g. diallylthiocarbamoyl) , a mono- or di-C3-10 cycloalkyl thiocarbamoyl group (for example, cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a mono- or dia-C6-14 aryl thiocarbamoyl group (for example, phenylthiocarbamoyl), a mono- or dia-C7 alkyl group -16 thiocarbamoyl (for example, benzylthiocarbamoyl, phenethylthiocarbamoyl), an aromatic 5- to 14-membered heterocyclylthiocarbamoyl group (for example, pyridylthiocarbamoyl), a sulphine group, a C1-6 alkylsulfinyl group (for example, methylsulfinyl, ethylsulfinyl), a sulfo group , a C1-6 alkylsulfonyl group, a C6-14 arylsulfonyl group, a phosphono group and a mono- or di-C1-6 alkylphosphono group (e.g. dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono).

[0055] In the present patent application, examples of the “optionally substituted amino group” include an amino group optionally having “1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group , a C6-14 aryl group, a C716 aralkyl group, a C1-6 alkylcarbonyl group, a C6-14 arylcarbonyl group, a C7-16 aralkylcarbonyl group, an aromatic 5- to 14-membered heterocyclylcarbonyl group, a heterocyclylcarbonyl group a 3- to 14-membered non-aromatic group, a C1-6 alkoxycarbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1-6 alkyl carbamoyl group, a mono- or dia- C7 alkyl group -16 carbamoyl group, a C16 alkylsulfonyl group and a C6-14 arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from substituent group A”.

[0056] Preferable examples of the optionally substituted amino group include an amino group, a mono- or di-(optionally halogenated C1-6 alkyl) amino group (for example, methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C2-6 alkenyl amino group (e.g. diallylamino), a mono- or di-C3-10 cycloalkyl amino group (e.g. cyclopropylamino, cyclohexylamino), a mono- or dia-C6-aryl group 14 amino (e.g. phenylamino), a mono- or di-aralkyl C7-16 amino group (e.g. benzylamino, dibenzylamino), a mono- or di-(optionally halogenated C1-6 alkyl)-carbonylamino group (e.g. , acetylamino, propionylamino), a C6-14 mono- or di-arylcarbonylamino group (for example, benzoylamino), a C7-16 mono- or diaralkylcarbonylamino group (for example, benzylcarbonylamino), a mono- or di- - a 5- to 14-membered aromatic heterocyclylcarbonyl amino group (for example, nicotinoylamino, isonicotinoylamino), a 3- to 14-membered non-aromatic mono- or di-heterocyclylcarbonylamino group (for example, piperidinylcarbonylamino), a mono- or di- C1 -alkoxy group -6 carbonylamino (e.g. tert-butoxycarbonylamino), an aromatic 5- to 14-membered heterocyclylamino group (e.g. pyridylamino), a carbamoylamino group, an amino (mono- or di-C 1-6 alkyl-carbamoyl) group (e.g. (e.g., methylcarbamoylamino), a (mono- or di-aralkyl C7-16 carbamoyl)amino group (e.g., benzylcarbamoylamino), a C1-6 alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), a C6-14 arylsulfonyl amino group ( for example, phenylsulfonylamino), a (C1-6 alkyl)(C1-6 alkylcarbonyl)amino group (for example, N-acetyl-N-methylamino) and a (C1-6 alkyl)(C6-14 aryl - carbonyl)amino (e.g. N-benzoyl-N-methylamino).

[0057] In the present patent application, examples of the “optionally substituted carbamoyl group” include a carbamoyl group optionally having “1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group , a C614 aryl group, a C7-16 aralkyl group, a C1-6 alkylcarbonyl group, a C614 arylcarbonyl group, a C7-16 aralkylcarbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a non-aromatic heterocyclylcarbonyl group a 3- to 14-membered alkoxy carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1-6 alkyl carbamoyl group, and a mono- or dia- C 7-16 alkyl group carbamoyl, each of which optionally has 1 to 3 substituents selected from substituent group A”.

[0058] Preferable examples of the optionally substituted carbamoyl group include a carbamoyl group, a mono- or diC1-6 alkyl carbamoyl group, a mono- or di-C2-6 alkenyl carbamoyl group (e.g., diallylcarbamoyl), a mono- or di-alkenyl carbamoyl group. di-C3-10 cycloalkyl carbamoyl (e.g. cyclopropylcarbamoyl, cyclohexylcarbamoyl), a C6-14 mono- or diaryl carbamoyl group (e.g. phenylcarbamoyl), a C7-16 mono- or diaralkyl carbamoyl group, a mono- or di-C1-6 alkylcarbonylcarbamoyl (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-aryl C6-14carbonylcarbamoyl group (e.g., benzoylcarbamoyl), and an aromatic 5- to 14-membered heterocyclylcarbamoyl group ( for example, pyridylcarbamoyl).

[0059] In the present patent application, examples of the “optionally substituted thiocarbamoyl group” include a thiocarbamoyl group optionally having “1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group , a C614 aryl group, a C7-16 aralkyl group, a C1-6 alkylcarbonyl group, a C614 arylcarbonyl group, a C7-16 aralkylcarbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a non-aromatic heterocyclylcarbonyl group a 3- to 14-membered alkoxy carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1-6 alkyl carbamoyl group, and a mono- or dia- C 7-16 alkyl group carbamoyl, each of which optionally has 1 to 3 substituents selected from substituent group A”.

[0060] Preferable examples of the optionally substituted thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-C1-6 alkyl thiocarbamoyl group (for example, methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), a mono- or di-C2-6 alkenyl thiocarbamoyl (e.g. diallylthiocarbamoyl), a mono- or di-C3-10 cycloalkyl thiocarbamoyl group (e.g. cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a C6-14 mono- or diaryl thiocarbamoyl group (e.g. phenylthiocarbamoyl), a mono- or di-C7-16 alkyl thiocarbamoyl group (e.g. benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- or di-C1-6 alkylcarbonyl thiocarbamoyl group (e.g. acetylthiocarbamoyl, propionylthiocarbamoyl), a C6-14 mono- or dia-arylcarbonylthiocarbamoyl group (for example, benzoylthiocarbamoyl); and a 5- to 14-membered aromatic heterocyclic thiocarbamoyl group (for example, pyridylthiocarbamoyl).

[0061] In the present patent application, examples of the “optionally substituted sulfamoyl group” include a sulfamoyl group optionally having “1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group , a C6-14 aryl group, a C7-16 aralkyl group, a C1-6 alkylcarbonyl group, a C6-14 arylcarbonyl group, a C7-16 aralkylcarbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C1-6 alkoxycarbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1-6 alkyl carbamoyl group, and a mono- or di- C7-16 aralkyl carbamoyl, each of which optionally has 1 to 3 substituents selected from substituent group A”.

[0062] Preferable examples of the optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di-C1-6 alkylsulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di- C2-6 alkenyl-sulfamoyl group (e.g. diallylsulfamoyl), a mono- or di-C3-10 cycloalkyl sulphamoyl group (e.g. cyclopropylsulfamoyl, cyclohexylsulfamoyl), a mono- or dia-C6-aryl group 14 sulfamoyl (e.g. phenylsulfamoyl), a mono- or di-aralkyl C7-16 alkyl sulphamoyl group (e.g. benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C1-6 alkylcarbonyl sulphamoyl group (e.g. acetylsulfamoyl, propionylsulfamoyl), a C6-14 mono- or dia-arylcarbonylsulfamoyl group (e.g. benzoylsulfamoyl), and a 5- to 14-membered aromatic heterocyclic sulfamoyl group (e.g. pyridylsulfamoyl).

[0063] In the present patent application, examples of the “optionally substituted hydroxy group” include a hydroxyl group optionally having “a substituent selected from a C1-6 alkyl group, a C26 alkenyl group, a C3-10 cycloalkyl group, an aryl group C6-14 aralkyl group, C7-16 aralkyl carbonyl group, C1-6 alkylcarbonyl group, C6-14 arylcarbonyl group, C7-16 aralkylcarbonyl group, aromatic 5- to 14-membered heterocyclylcarbonyl group, non-aromatic heterocyclylcarbonyl group a 3- to 14-membered alkoxy carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1-6 alkyl carbamoyl group, a mono- or dia- C 7-16 alkyl group carbamoyl, a C16 alkylsulfonyl group and a C6-14 arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from substituent group A”.

[0064] Preferable examples of the optionally substituted hydroxy group include a hydroxy group, a C1-6 alkoxy group, a C2-6 alkenyloxy group (for example, allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a cycloalkyloxy group C3-10 (e.g. cyclohexyloxy), a C6-14 aryloxy group (e.g. phenoxy, naphthyloxy), a C7-16 aralkyloxy group (e.g. benzyloxy, phenethyloxy), a C1-6 alkylcarbonyloxy group (e.g. acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C6-14 arylcarbonyloxy group (e.g. benzoyloxy), a C7-16 aralkylcarbonyloxy group (e.g. benzylcarbonyloxy), an aromatic 5- to 14-membered heterocyclylcarbonyloxy group (for example, nicotinoyloxy), a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (for example, piperidinylcarbonyloxy), a C 1-6 -alkoxycarbonyloxy group (for example, tert-butoxycarbonyloxy), an aromatic 5- to 14-membered heterocyclyloxy group (for example, pyridyloxy), a carbamoyloxy group, a C1-6 alkyl carbamoyloxy group (for example, methylcarbamoyloxy), a C7-16 aralkyl carbamoyloxy group (for example, benzylcarbamoyloxy), a C1-6 alkylsulfonyloxy group (for example, methylsulfonyloxy) , ethylsulfonyloxy) and a C6-14 arylsulfonyloxy group (e.g., phenylsulfonyloxy).

[0065] In the present patent application, examples of the “optionally substituted sulfanyl group” include a sulfanyl group optionally having “a substituent selected from a C1-6 alkyl group, a C26 alkenyl group, a C3-10 cycloalkyl group, an aryl group C6-14 aryl, a C7-16 aralkyl group, a C1-6 alkylcarbonyl group, a C6-14 arylcarbonyl group, and a 5- to 14-membered aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from the group substituent A” and a halogenated sulfanyl group.

[0066] Preferable examples of the optionally substituted sulfanyl group include a sulfanyl group (-SH), a C1-6 alkylthio group, a C2-6 alkenylthio group (for example, allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio) , a C3-10 cycloalkylthio group (e.g. cyclohexylthio), a C6-14 arylthio group (e.g. phenylthio, naphthylthio), a C7-16 aralkylthio group (e.g. benzylthio, phenethylthio), a C1-6 alkyl group -carbonylthio (e.g. acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), a C6-14 arylcarbonylthio group (e.g. benzoylthio), an aromatic 5- to 14-membered heterocyclylthio group (e.g. pyridylthio) and a halogenated type (e.g. pentafluorthio).

[0067] In the present patent application, examples of the "optionally substituted silyl group" include a silyl group optionally having "1 to 3 substituents selected from a C1-6 alkyl group, a C26 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group and a C7-16 aralkyl group, each of which optionally has 1 to 3 substituents selected from substituent group A”.

[0068] Preferable examples of the optionally substituted silyl group include a tri-C1-6 alkyl silyl group (for example, trimethylsilyl, tert-butyl(dimethyl)silyl).

[0069] The definition of each symbol in formula (I) is described in detail in the following. P1 is a group represented by the formula: - RA1, - CO-RA1, - CO-ORA1, - CO-CORA1, - SO-RA1, -SO2-RA1, -SO2-ORA1, -CO-NRA2RA3, -SO2-NRA2RA3 , or -C(=NRA1)-NRA2RA3 where RA1, RA2 and RA3 are each independently a hydrogen atom, an optionally substituted hydrocarbon group or optionally substituted heterocyclic group.

[0070] P1 is preferably a hydrogen atom. A11 is Aib or A1a.

[0071] A11 is preferably Aib.

[0072] A12 is Ala, Ile, Lys, Phe or Pya(4).

[0073] A12 is preferably IIe.

[0074] In an alternative embodiment, A12 is preferably Lys.

[0075] A13 is Aib, Cha, Leu, αMePhe or αMeTyr.

[0076] A13 is preferably Aib.

[0077] A16 is Lys or Ser.

[0078] A16 is preferably Lys.

[0079] A17 is Gln or Ile.

[0080] A17 is preferably Gln.

[0081] A20 is Ala or Ser.

[0082] A20 is preferably Wing.

[0083] A29 is Gln or Gly.

[0084] A29 is preferably Gly.

[0085] Compound (I) may have an additional peptide sequence on the C-terminal side (C-terminal sequence) of A29 in the partial sequence represented by formula (I).

[0086] Here, the length of the C-terminal sequence is not particularly limited and preferably has 1 to 11 amino acid residues, more preferably 6 to 11 amino acid residues.

[0087] Examples of the C-terminal sequence may include (i) an amino acid sequence represented by Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys (SEQ ID NO: 2), ( ii) an amino acid sequence derived from the sequence of (i) mentioned above by deletion, substitution (preferably conservative substitution), or addition of 1 to 11, preferably 1 to 5 amino acids, and (iii) a partial sequence comprising at least 1 (consecutive) amino acid residue, preferably 6 consecutive amino acid residues, from the N-terminal side of the sequence of (i) mentioned above or (ii). As the C-terminal sequence, (1) Gly-, (2) Gly-Pro-, (3) Gly-Pro-Ser-, (4) Gly-Pro-Ser-Ser- (SEQ ID NO: 3), (5) Gly-Pro-Ser-Ser-Gly- (SEQ ID NO: 4), (6) Gly-Pro-Ser-Ser-Gly-Ala- (SEQ ID NO: 5), (7) Gly-Pro -Ser-Ser-Gly-Ala-Pro- (SEQ ID NO: 6), (8) Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro- (SEQ ID NO: 7), (9) Gly -Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro- (SEQ ID NO: 8), (10) Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser- (SEQ ID NO: 9), (11) Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys- (SEQ ID NO: 2), or the like is specifically used.

[0088] The C-terminal sequence is preferably Gly-Pro-Ser-Ser- Gly-Ala-Pro-Pro-Pro-Ser- or Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser -Lys-.

[0089] The C-terminal sequence is particularly preferably Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-.

[0090] Compound (I) with the aforementioned C-terminal sequence has superior solubility.

[0091] Also, the compound (I) with the C-terminal sequence mentioned above has high activation action of GLP-1 receptor and GIP receptor IN VIVO.

[0092] Preferable examples of compound (I) include the following peptide or a salt thereof.

{Compound A}

[0093] Compound (I) in which P1 is a hydrogen atom; A11 is Aib; A12 is Ile; A13 is Aib; A16 is Lys; A17 is Gln; A20 is Wing; A29 is Gly; and the peptide with an amino acid sequence represented by Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys- on the C-terminal side of A29.

[0094] Compound (I) can be produced according to a peptide synthesis method known per se. The peptide synthesis method can be any one of, for example, a solid phase synthesis process and a liquid phase synthesis process. That is, the peptide in question can be produced by repeating the condensation of a partial peptide or amino acid capable of constituting compound (I) and the remaining portion (which can be constituted by two or more amino acids) according to a desired sequence. When a product with the desired sequence has a protecting group, the peptide in question can be produced by removing a protecting group. Examples of the known condensation method and method of eliminating a protecting group include methods described in the following (1) to (5). (1) M. Bodanszky and M.A. Ondetti: Peptide Synthesis, Interscience Publishers, New York (1966) (2) Schroeder and Luebke: The Peptide, Academic Press, New York (1965) (3) Nobuo Izumiya, et al.: Peptide Gosei-no-Kiso from Jikken (Basics and experiments of peptide synthesis), published by Maruzen Co. (1975) (4) Haruaki Yajima and Shunpei Sakakibara: Seikagaku Jikken Koza (Biochemical Experiment) 1, Tanpakushitsu no Kagaku (Chemistry of Proteins) IV, 205 (1977) (5) Haruaki Yajima, ed.: Zoku Iyakuhin no Kaihatsu (A sequel to Development of Pharmaceuticals), Vol. 14, Peptide Synthesis, published by Hirokawa Shoten

[0095] After the reaction, compound (I) can be purified and isolated using conventional purification methods such as solvent extraction, distillation, column chromatography, liquid chromatography, recrystallization, etc., in combination thereof. When the peptide obtained by the aforementioned method is in a free form, it can be converted to a suitable salt by a known method; conversely, when the peptide is obtained in the form of a salt, the salt can be converted to a free form or another salt by a known method.

[0096] The starting compound can also be a salt. Examples of such a salt include those exemplified as salts of compound (I) mentioned below.

[0097] For condensation of amino acid or protected peptide, various activation reagents used for peptide synthesis can be used, which are particularly preferably triphosphonium salts, tetramethyluronium salts, carbodiimides and the like. Examples of the trisphosphonium salt include benzotriazol-1-yloxytris(pyrrolizino)phosphoniumexafluorophosphate (PyBOP), bromotris(pyrrolizino)phosphoniumexafluorophosphate (PyBroP), 7-azabenzotriazol-1-yloxytris(pyrrolizino)phosphoniumhexafluorophosphate (PyAOP), examples of the tetramethyluronium salt include 2 -(1H-benzotriazol-1-yl)-1,1,3,3-hexafluorophosphate (HBTU), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-hexafluorophosphate (HATU), 2 -(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TBTU), 2-(5-norbornane-2,3-dicarboxyimide)-1,1,3,3-tetramethyluroniumtetrafluoroborate ( TNTU), O-(N-succimidyl)-1,1,3,3-tetramethyluroniotetrafluoroborate (TSTU) and examples of the carbodiimide include DCC, N,N'-diisopropylcarbodiimide (DIPCDI), N-ethyl-N' -(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HCl) and the like. For condensation using these, addition of a racemization inhibitor (eg HONB, HOBt, HOAt, HOOBt etc.) is preferable. A solvent to be used for the condensation can be appropriately selected from those known to be used for the peptide condensation reaction. For example, acid amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and the like anhydrous or water-containing, halogenated hydrocarbons such as methylene chloride, chloroform and the like, alcohols such as trifluoroethanol, phenol and the like, sulfoxides such as dimethylsulfoxide and the like, tertiary amines such as pyridine and the like, ethers such as dioxane, tetrahydrofuran and the like, nitriles such as acetonitrile, propionitrile and the like, esters such as methyl acetate, ethyl acetate and the like similar, an appropriate mixture of the same and the like can be used. Reaction temperature is appropriately selected from the range known to be used for peptide binding reactions and is normally selected from the range of about -20°C to 50°C. An activated amino acid derivative is typically used 1.5 to 6 times in excess. In the synthesis phase, when a test using the ninhydrin reaction reveals that the condensation is insufficient, sufficient condensation can be carried out by repeating the condensation reaction without removing the protecting groups. If condensation is still insufficient even after repeating the reaction, unreacted amino acids can be acylated with acetic anhydride, acetylimidazole or the like, in such a way that an influence on subsequent reactions can be avoided.

[0098] Examples of the protecting groups for the amino groups of the starting amino acid include Z, Boc, tert-pentyloxycarbonyl, isobornyloxycarbonyl, 4-methoxybenzyloxycarbonyl, Cl-Z, Br-Z, adamantyloxycarbonyl, trifluoroacetyl, phthaloyl, formyl, 2-nitrophenylsulfenyl, diphenylphosphinothioyl, Fmoc, trityl and the like.

[0099] Examples of the carboxyl protecting group for the starting amino acid include allyl, 2-adamantyl, 4-nitrobenzyl, 4-methoxybenzyl, 4-chlorobenzyl, phenacyl and benzyloxycarbonylhydrazine, tert-butoxycarbonylhydrazide, tritylhydrazide and the like, in addition to the C1-6 alkyl group, C3-10 cycloalkyl group, C7-14 aralkyl group mentioned above.

[00100] The hydroxyl group of serine or threonine can be protected, for example, by esterification or etherification. Examples of the group suitable for esterification include lower (2-4C)alkanoyl groups such as an acetyl group and the like, aroyl groups such as a benzoyl group and the like and the like, and a group derived from an organic acid and the like. Furthermore, examples of the group suitable for etherification include benzyl, tetrahydropyranyl, tert-butyl(But), trityl(Trt) and the like.

[00101] 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.

[00102] Examples of the protecting group for histidine imidazole include Tos, 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), DNP, Bom, Bum, Boc, Trt, Fmoc and the like.

[00103] Examples of the protecting group for the guanidino group of arginine include Tos, Z, 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), p-methoxybenzenesulfonyl (MBS), 2,2,5,7,8- pentamethylchromane-6-sulfonyl (Pmc), mesitylene-2-sulfonyl (Mts), 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), Boc, Z, NO2 and the like.

[00104] Examples of the protecting group for a lysine side chain amino group include Z, Cl-Z, trifluoroacetyl, Boc, Fmoc, Trt, Mtr, 4,4-dimethyl-2,6-dioxocyclohexylideneyl (Dde) and the like.

[00105] Examples of the indolyl protecting group of tryptophan include formyl (For), Z, Boc, Mts, Mtr and the like.

[00106] Examples of the protective group for asparagine and glutamine include Trt, xanthyl (Xan), 4,4'-dimethoxybenzhydryl (Mbh), 2,4,6-trimethoxybenzyl (Tmob) and the like.

[00107] Examples of activated carboxyl groups in the starting material include acid anhydride, azide, active esters [ester with alcohol (eg, pentachlorophenol, 2,4,5-trichlorophenol, 2,4-dinitrophenol, cyanomethylalcohol, paranitrophenol, HONB, N-hydroxysuccimide, 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole(HOAt)] and the like. Examples of the activated amino group in the starting material include corresponding phosphorus amide.

[00108] Examples of the method for removing (removing) a protecting group include a catalytic reduction in a stream of hydrogen in the presence of a catalyst such as Pd-black or carbon-on-Pd; an acid treatment using anhydrous hydrogen fluoride, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetate, trimethylsilyl bromide (TMSBr), trimethylsilyl trifluoromethanesulfonate, tetrafluoroboric acid, tris(trifluor)boric acid, boron tribromide, or a solution mixture thereof; a base treatment using diisopropylethylamine, triethylamine, piperidine, piperazine or the like; and reduction with sodium in liquid ammonia and the like. The elimination reaction by acid treatment described above is generally carried out at a temperature of -20 °C to 40 °C; the acid treatment is efficiently carried out by adding a cation scavenger such as anisole, phenol, thioanisole, metacresol and paracresol; dimethylsulfite, 1,4-butanedithiol, 1,2-ethanedithiol and the like. Also, a 2,4-dinitrophenyl group used as an imidazole protecting group of histidine is removed by thiophenol treatment; a formyl group used as an indole protecting group of tryptophan is removed by deprotection by acid treatment in the presence of 1,2-ethanedithiol, 1,4-butanedithiol, or the like, as well as by alkali treatment with dilute sodium hydroxide, ammonia diluted or similar.

[00109] Protection of a functional group that should not be involved in the reaction of a starting material and a protecting group, elimination of the protecting group, activation of a functional group involved in the reaction and the like can be appropriately selected from known protecting groups and known means.

[00110] In one method of preparing a peptide amide, it is formed by a solid phase synthesis using an amide synthesis resin or the α-carboxyl group of the carboxy terminal amino acid is amidated and a peptide chain is elongated to a desired chain length towards the amino group side, thereafter a peptide in which the protecting group for the N-terminal α-amino group of the peptide chain is only removed and a peptide in which the protecting group for the C carboxyl group - terminal just removed from the peptide chain are prepared and both peptides are condensed in a mixed solvent described earlier. For details regarding the condensation reaction, the same above applies. After the condensation-protected peptide is purified, all protecting groups can be removed by the previously described method to yield a desired crude polypeptide. By purifying this crude peptide using various publicly known means of purification and lyophilizing the main fraction, a desired amide of the peptide can be prepared.

[00111] When compound (I) is present in the form of a configurational isomer, such as enantiomer, diastereomer etc., a conformer or the like, they are also encompassed in compound (I) and each can be isolated by known means per se or by on-demand separation and purification methods. Furthermore, when compound (I) is in the form of a racemate, it can be separated into S and R forms by conventional optical resolution.

[00112] When compound (I) includes stereoisomers, both isomers alone and mixtures of each isomer are also encompassed in compound (I).

[00113] Compound (I) can be chemically modified according to a method known per se and using polyethylene glycol. For example, chemically modified compound (I) can be conjugally produced by attaching polyethylene glycol to Cys residue, Asp residue, Glu residue, Lys residue and the like of compound (I).

[00114] Compound (I) modified by polyethylene glycol (PEG) produces, for example, the effects of promoting biological activity, prolonging blood circulation time, reducing immunogenicity, improving solubility and improving resistance to metabolism, of a therapeutically and diagnostically important peptide.

[00115] The molecular weight of PEG is not particularly limited and is usually about 1 K to about 1000 K daltons, preferably about 10 K to about 100 K daltons, more preferably about 20 K to about 60 K daltons .

[00116] A method well known in the art can be used as a method to modify compound (I) by PEG, and for example, the methods described below can be used. (1) A PEGylation reagent with an active ester (eg, SUNBRIGHT MEGC-30TS (trade name), NOF Corp.) is attached to the amino group of compound (I). (2) A PEGylation reagent with an aldehyde (eg, SUNBRIGHT ME-300AL (trade name), NOF Corp.) is attached to the amino group of compound (I). (3) A divalent cross-linking reagent (e.g. GMBS (Dojindo Laboratories), EMCS (Dojindo Laboratories), KMUS (Dojindo Laboratories), SMCC (Pierce)) is attached to compound (I), to which a PEGylation reagent with a thiol group (eg, SUNBRIGHT ME-300-SH (trade name), NOF Corp.) is then attached. (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 this thiol group reacted with a reagent of PEGylation with a maleimide group (e.g., SUNBRIGHT ME-300MA (trade name), NOF Corp.). (5) 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 this thiol group reacted with a reagent of PEGylation with an iodoacetamide group (e.g., SUNBRIGHT ME-300IA (trade name), NOF Corp.). (6) A w-aminocarboxylic acid or an a-amino acid is introduced as a linker to the N-terminal amino group of compound (I) and an amino group derived from this linker is reacted with a PEGylation reagent with an active ester (e.g., SUNBRIGHT MEGC-30TS (trade name), NOF Corp.). (7) A w-aminocarboxylic acid or an a-amino acid is introduced as a linker at the N-terminal amino group of compound (I), and an amino group derived from this linker is reacted with a PEGylation reagent with an aldehyde group (e.g., SUNBRIGHT ME-300AL (trade name), NOF Corp.).

[00117] Furthermore, compound (I) may be a solvate (eg, hydrate) or a non-solvate (eg, non-hydrate).

[00118] Compound (I) may be labeled with an isotope (for example, 3H, 14C, 35S, 125I) or the like.

[00119] Furthermore, compound (I) can be a conversion form of deuterium in which 1H is converted to 2H(D).

[00120] Compound (I) labeled or substituted with an isotope can be used as, for example, a marker (PET marker) for use in Positron Emission Tomography (PET) and is used in the fields of medical diagnosis and the like.

[00121] For the peptides mentioned herein, the left end is the N-terminus (amino terminus) and the right end is the C-terminus (carboxyl terminus) according to conventional peptide tagging. The C-terminus of the peptide can be any one of an amide (-CONH2), a carboxyl group (-COOH), a carboxylate (-COO-), an alkylamide (-CONHRa), and an ester (-COORa). Particularly, amide (-CONH2) is preferable.

[00122] Compound (I) may be in a salt form. Examples of such a salt include metal salts, ammonium salts, salts with organic base, salts with inorganic acid, salts with organic acid, salts with basic or acidic amino acids and the like.

[00123] 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.

[00124] Preferable examples of the salt with organic base include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylenediamine and the like.

[00125] Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

[00126] Preferable examples of the salt with 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, acid benzenesulfonic acid, p-toluenesulfonic acid and the like.

[00127] Preferable examples of the basic amino acid salt include salts with arginine, lysine, ornithine and the like. Preferable examples of the acidic amino acid salt include salts with aspartic acid, glutamic acid and the like.

[00128] Among the salts mentioned above, a pharmaceutically acceptable salt is preferable. For example, when a compound has an acidic functional group, an inorganic salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.), alkaline earth metal salt (e.g. calcium salt, magnesium salt, barium salt etc.) and the like, ammonium salt etc. and when a compound has a basic functional group, for example, a salt with inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, or a salt with organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like are preferable.

[00129] Compound (I) may be in a prodrug form.

[00130] A prodrug means a compound that is converted to compound (I) with a reaction due to an enzyme, gastric acid, etc. in physiological condition in the human body, i.e. a compound which is converted to compound (I) by oxidation, reduction, hydrolysis, etc. according to an enzyme; a compound which is converted to compound (I) by hydrolysis etc. due to gastric acid, etc.

[00131] Examples of a prodrug of compound (I) include a compound in which an amino of compound (I) is acylated, alkylated or phosphorylated (for example, compound in which amino of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranoylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated and the like); a compound in which a hydroxy of compound (I) is acylated, alkylated, phosphorylated or borated (e.g. a compound in which a hydroxy of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated ); a compound in which a carboxy of compound (I) is esterified or amidated (e.g. a compound in which a carboxy of compound (I) is esterified C1-6 alkyl, esterified phenyl, esterified carboxymethyl, esterified dimethylaminomethyl, esterified pivaloyloxymethyl, esterified ethoxycarbonyloxyethyl esterified, esterified phthalidyl, esterified or methylamidated (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, esterified or methylamidated cyclohexyloxycarbonylethyl) and the like. Among others, a compound in which the carboxy of compound (I) is esterified with C1-6 alkyl such as methyl, ethyl, tert-butyl or the like is preferably used. These compounds can be produced from compound (I) by a method known per se.

[00132] A prodrug of compound (I) may also be one that is converted to compound (I) 'under a physiological condition, such as those described in IYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol.7, Design of Molecules, p.163-198, Published by HIROKAWA SHOTEN (1990).

[00133] In the present patent application, the prodrug can form a salt. Examples of such a salt include those exemplified as the salt of compound (I).

[00134] Compound (I) can be a crystal. Crystals having a single crystal form or a mixture of several crystal forms are also included in compound (I). Crystals can be produced by crystallizing compound (I) according to a crystallization method known per se.

[00135] Furthermore, compound (I) may be a cocrystal or pharmaceutically acceptable cocrystal salt. Here, cocrystal or cocrystal salt means a crystalline substance of two or more particular substances that are solid at room temperature, each having different physical properties (e.g. structure, melting point, heat of fusion, hygroscopicity, solubility, stability etc.). The cocrystal and cocrystal salt can be produced by per se known cocrystallization.

[00136] The crystal of compound (I) is superior in physicochemical properties (eg, melting point, solubility, stability) and biological properties (eg, pharmacokinetics (absorption, distribution, metabolism, excretion), expression of efficacy ) and thus it is extremely used as a medicine.

[00137] Compound (I) and a prodrug thereof (hereinafter sometimes abbreviated as the compound of the present invention) have an activating action on GLP-1 receptors and GIP receptors.

[00138] The compound of the present invention has a high activating action on GLP-1 receptors and GIP receptors, particularly, IN VIVO.

[00139] GLP-1 and GIP are hormones of the intestine called incretin and have the action of promoting insulin secretion from the pancreas. Since incretin is closely related to glucose metabolism, the compound with an activating action on GLP-1 receptors and GIP receptors is used in the prophylaxis or treatment of symptoms associated with glucose metabolism disorder, including obesity.

[00140] Thus, the compound of the present invention has a feeding suppression action, weight gain inhibitory action and the like.

[00141] Furthermore, the compound of the present invention has superior solubility. The solubility of the compound of the present invention in water is preferably 1 mg/ml or higher, more preferably 10 mg/ml or higher.

[00142] The compound of the present invention can be used as an activator of a GLP-1 receptor and a GIP receptor (GLP-1 receptor/GIP receptor coagonist).

[00143] In the present invention, the activator of a GLP-1 receptor and a GIP receptor (GLP-1 receptor/GIP receptor coagonist) means an agent with both GLP-1 receptor activating action ( GLP-1 receptor agonist action) and a GIP receptor activating action (GIP receptor agonist action). Specifically, activator of a GLP-1 receptor and a GIP receptor (GLP-1 receptor/GIP receptor coagonist) means an agent in which EC50 against GLP-1 receptor and EC50 against GIP receptor are 1:20 to 20:1, preferably 1:5 to 5:1.

[00144] The compound of the present invention has a low glucagon receptor activating action (glucagon receptor agonist) and thus has a low hyperglycemic action attributed to it. EC50 of the compound of the present invention against glucagon receptor is 1/1000 or less, preferably 1/10000 or less, compared with EC50 of the compound of the present invention against GLP-1 receptor or GIP receptor.

[00145] The compound of the present invention is low in its toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiac toxicity, carcinogenicity), has few side effects, and can be safely administered to a mammal (e.g. , human, bovine, horse, dog, cat, monkey, mouse, rat) as an agent for the prophylaxis or treatment of various diseases mentioned below and the like.

[00146] The compound of the present invention can be used as an agent for the treatment or prophylaxis of various diseases including obesity, by virtue of the above-mentioned activating action on GLP-1 receptors and GIP receptors. The compound of the present invention can be used as an agent for the prophylaxis or treatment of, for example, symptomatic obesity, obesity based on simple obesity, disease state or disease associated with obesity, eating disorder, diabetes (for example, type 1, type 2 diabetes, gestational diabetes, obese diabetes), hyperlipidemia (e.g. hypertriglyceridemia, hypercholesterolaemia, high LDL-cholesterolaemia, low HDL-cholesterolaemia, postprandial hyperlipaemia), hypertension, heart failure, diabetic complications (e.g. neuropathy, nephropathy, retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious disease (eg, respiratory infection, urinary tract infection, gastrointestinal infection, dermal soft tissue infections, lower limb infection), diabetic gangrene, dry mouth , hypacusis, cerebrovascular disorder, peripheral blood circulation disorder], metabolic syndrome (disease status with 3 or more selected hypertriglycerid(TG)emia, low HDL cholesterol (HDL-C), hypertension, abdominal obesity, and impaired glucose tolerance ), sarcopenia, and the like.

[00147] Examples of symptomatic obesity include endocrine obesity (eg, Cushing's syndrome, hypothyroidism, insulinoma, obese type II diabetes, pseudohypoparathyroidism, hypogonadism), central obesity (eg, hypothalamic obesity, frontal lobe syndrome, Kleine- Levin), hereditary obesity (eg, Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), drug-induced obesity (eg, steroid, phenothiazine, insulin, sulfonylurea agent (SU), β-blocker-induced obesity ) and the like.

[00148] Examples of the disease state or disease associated with obesity include glucose tolerance disorders, diabetes (particularly type 2 diabetes, obese diabetes), abnormality of lipid metabolism (synonymous with the aforementioned hyperlipidemia), hypertension, heart failure, gout hyperuricemia, fatty liver (including non-alcoholic steatohepatitis), coronary heart disease (myocardial infarction, angina pectoris), cerebral infarction (cerebral thrombosis, transient cerebral ischemic attack), bone/joint disease (knee osteoarthritis, rib osteoarthritis , spondylitis deformans, low back pain), sleep apnea syndrome/Pickwick syndrome, menstrual disorder (abnormal menstrual cycle, abnormal flow and menstrual cycle, amenorrhea, abnormal catamenial symptom), metabolic syndrome and the like.

[00149] New diagnostic criteria were reported by The Japan Diabetes Society in 1999 on the diagnostic criteria for diabetes.

[00150] According to this report, diabetes refers to a state that meets any fasting blood glucose level (venous plasma glucose concentration) of 126 mg/dl or more, a 2-hour value (glucose concentration in venous plasma) of 200 mg/dl or more on the 75 g oral glucose tolerance test (75 g OGTT) and a casual blood glucose level (venous plasma glucose concentration) of 200 mg/dl or more. Also, a condition that does not apply to the aforementioned diabetes and is not a condition that has “a fasting blood glucose level (venous plasma glucose concentration) of less than 110 mg/dl or a 2-hour value (concentration of venous plasma glucose) less than 140 mg/dl on the 75 g oral glucose tolerance test (75 g OGTT)” (normal type) is called the “borderline type”.

[00151] In addition, new diagnostic criteria were reported by the American Diabetes Association (ADA) in 1997 and by the World Health Organization (WHO) in 1998 on the diagnostic criteria for diabetes.

[00152] According to these reports, diabetes refers to a state that meets a fasting blood glucose level (venous plasma glucose concentration) of 126 mg/dl or more and a 2-hour value (glucose concentration in venous plasma) of 200 mg/dl or more on the 75 g oral glucose tolerance test.

[00153] According to the aforementioned reports, impaired glucose tolerance refers to a state that meets a fasting blood glucose level (venous plasma glucose concentration) less than 126 mg/dl and a 2-hour value (venous plasma glucose concentration) of 140 mg/dl or more and less than 200 mg/dl on the 75 g oral glucose tolerance test. According to the ADA report, a condition that has a fasting blood glucose level (venous plasma glucose concentration) of 110 mg/dl or more and less than 126 mg/dl is called FGA (fasting glucose anomaly). . On the other hand, according to the WHO report, a state of AGJ (fasting blood glucose abnormality) that shows a 2-hour value (venous plasma glucose concentration) less than 140 mg/dl in the oral glucose tolerance test than 75 g is called FGA (fasting glucose abnormality).

[00154] The compound of the present invention is also used as an agent for the prophylaxis or treatment of diabetes determined according to the aforementioned new diagnostic criteria, borderline type diabetes, impaired glucose tolerance, AGJ (fasting glycemic abnormality) and FGA (fasting glucose abnormality). Furthermore, the compound of the present invention can prevent the progression of borderline type, impaired glucose tolerance, FGA (fasting blood glucose abnormality) or FGA (fasting blood glucose abnormality) in diabetes.

[00155] The compound of the present invention has the action of inhibiting weight gain, and as such, it can be used as a weight gain inhibitor for mammals. A mammal that undergoes application of the compound of the present invention may be a mammal desired to prevent weight gain. The mammal may be a mammal with a genetic risk of weight gain, or it may be a mammal affected by lifestyle-related disease, such as diabetes, hypertension and/or hyperlipidemia. The weight gain may be attributable to excessive food intake or unbalanced diets, or it may be weight gain from a concomitant drug (e.g., insulin sensitizers with a PPARY agonist-like action, such as troglitazone, rosiglitazone, englitazone , ciglitazone, pioglitazone and the like). Alternatively, the weight gain may be weight gain before reaching obesity, or it may be weight gain in patients with obesity. Here, obesity is defined as a body mass index (BMI: body weight (kg) H [height (m)]2) of 25 or more (according to the criteria of the Japan Society for the Study of Obesity) for Japanese and such as a BMI of 30 or more (according to WHO criteria) for Western people.

[00156] The compound of the present invention is also used as an agent for the prophylaxis or treatment of metabolic syndrome. The incidence of cardiovascular disease is significantly higher in patients with the metabolic syndrome compared with patients with a single lifestyle-related disease. Thus prophylaxis or treatment of metabolic syndrome is very important to prevent cardiovascular disease.

[00157] The diagnostic criteria for metabolic syndrome were announced by WHO in 1999 and by NCEP in 2001. According to WHO diagnostic criteria, an individual with hyperinsulinemia or abnormal glucose tolerance as a requirement and two or more obesity visceral dyslipidemia (high TG or low HDL) and hypertension is diagnosed as with 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 Adult Treatment Panel III diagnostic criteria of the National Cholesterol Education Program (ischemic heart disease guide) in the USA, an individual with three or more of visceral obesity, hypertriglyceridemia, low HDL-cholesterolemia, hypertension, and abnormal glucose tolerance is diagnosed with 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 (Adults Treatment Panel III). The Journal of the American Medical Association, Vol. 285, 2486-2497, 2001).

[00158] The compound of the present invention can also be used as an agent for the prophylaxis or treatment of, for example, osteoporosis, cachexia (for example, cancerous cachexia, tuberculous cachexia, diabetic cachexia, cachexia associated with blood disease, cachexia associated with endocrine disease, cachexia associated with infectious disease, or cachexia caused by acquired immunodeficiency syndrome), fatty liver, polycystic ovary syndrome, kidney disease (eg, chronic renal failure, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease), muscular dystrophy, myocardial infarction, angina pectoris, cerebrovascular disorder (eg, cerebral infarction, stroke), Alzheimer's disease, Parkinson's disease, anxiety, dementia, insulin resistant syndrome, X syndrome, hyperinsulinemia, paresthesia caused by hyperinsulinemia, acute or chronic diarrhoea, inflammatory disease (e.g. chronic rheumatoid arthritis, spondylitis deformans, arthritis deformans, low back pain, gout, post-operative or post-traumatic inflammation, swelling, neuralgia, laryngopharyngitis, cystitis, hepatitis (including non-alcoholic steatohepatitis), pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory large bowel disease), ulcerative colitis, gastric mucosal damage (including gastric mucosal damage caused by aspirin)), intestinal mucosal damage thin stomach, malabsorption, testicular dysfunction, visceral obesity syndrome and sarcopenia.

[00159] In addition, the compound of the present invention can also be used as an agent for the prophylaxis or treatment of various cancers (in particular, breast cancer (e.g., ductal invasive breast cancer, ductal non-invasive breast cancer, ductal cancer) inflammatory breast cancer, etc.), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer, etc.), pancreatic cancer (e.g., pancreatic ductal cancer, etc.), gastric cancer ( e.g., papillary adenocarcinoma, mucosal adenocarcinoma, adenosquamous carcinoma, etc.), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, etc.), colon cancer (e.g., e.g., gastrointestinal stromal tumor, etc.), rectal cancer (e.g., gastrointestinal stromal tumor, etc.), colorectal cancer (e.g., familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumor, etc.), colon cancer small bowel (e.g. non-Hodgki lymphoma, gastrointestinal stromal tumor, etc.), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (e.g., nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, etc.), throat cancer salivary gland, brain tumor (eg, pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, etc.), neurilemmoma, liver cancer (eg, primary liver cancer, extrahepatic bile duct cancer, etc.), cancer renal (e.g. renal cell cancer, transitional cell cancer of renal pelvis and uterus, etc.), bile duct cancer, endometrial cancer, uterine cervical cancer, ovarian cancer (e.g. epithelial ovarian cancer, extragonadal germ cell, ovarian germ cell tumor, low malignant potential ovarian tumor, etc.), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (ocular) melanoma, Merkel cell carcinoma, etc. .), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g. medullary thyroid cancer, etc.), parathyroid cancer, nasal cavity cancer, sinus cancer, bone tumor (e.g. osteosarcoma, Ewing's tumor, uterine sarcoma, soft tissue sarcoma, etc.), angiofibroma, retinal sarcoma, penile cancer, testicular tumor, pediatric solid tumor (eg, Wilms' tumor, childhood renal tumor, etc.), Kaposi's sarcoma , Kaposi's sarcoma caused by AIDS, maxillary sinus tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, leukemia (eg, acute myelogenous leukemia, acute lymphoblastic leukemia, etc.), etc.).

[00160] The compound of the present invention can also be used for prevention or secondary suppression of the progression of various diseases mentioned above (for example, cardiovascular events such as myocardial infarction and the like). Furthermore, the compound of the present invention is also used as a feeding suppressant and weight gain inhibitor. The compound of the present invention can also be used in combination with a diet therapy (eg diet therapy for diabetes) and an exercise therapy.

[00161] A medicine containing the compound of the present invention has low toxicity and is obtained using the compound of the present invention alone or in admixture with a pharmaceutically acceptable carrier according to a method known per se (for example, the method described in the Japanese Pharmacopoeia ) commonly used as methods of manufacturing pharmaceutical preparations and safely administered orally or parenterally (e.g., topically, rectally, administered intravenously) as a pharmaceutical preparation, e.g., tablets (including sugar-coated tablets, film-coated tablets, tablets sublingually, orally disintegrating tablets), powders, granules, capsules (including softgels, microcapsules), liquids, troches, syrups, emulsions, suspensions, injections (e.g. subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, etc. ), external preparations (e.g., transnasal preparations, dermal preparations, ointments), suppository (e.g., rectal suppositories, vaginal suppositories), precipitates, nasal preparations, lung preparations (inhalants), transfusions, and the like.

[00162] These preparations may be controlled-release preparations, such as a rapid-release preparation, an extended-release preparation, and the like (for example, an extended-release microcapsule).

[00163] The content of the compound of the present invention in a pharmaceutical preparation is about 0.01 - about 100% by weight of the total preparation.

[00164] The aforementioned pharmaceutically acceptable carrier can be exemplified by various organic or inorganic carrier materials which are conventionally used as preparation materials, for example, excipient, lubricant, glidant and disintegrant for solid preparations; or solvent, solubilizing agent, suspending agent, isotonic agent, buffering agent, soothing agent and the like for liquid preparations. Additionally, if necessary, general additives such as preservative, antioxidant, colorant, sweetening agent, adsorbing agent, wetting agent and the like can also be used appropriately in a suitable amount.

[00165] Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.

[00166] Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.

[00167] Examples of the glidant include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like.

[00168] Examples of the disintegrant include starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium starch carboxymethylcellulose, L-hydroxypropylcellulose and the like.

[00169] Examples of the solvent include water for injection, alcohol, propylene glycol, Macrogol, sesame oil, corn oil, olive oil and the like.

[00170] 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.

[00171] Examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like; and the like.

[00172] Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.

[00173] Examples of the buffering agent include buffer solutions such as phosphates, acetates, carbonates, citrates and the like.

[00174] Examples of the soothing agent include benzyl alcohol and the like.

[00175] Examples of the preservative include esters of parahydroxybenzoic acid, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.

[00176] Examples of the antioxidant include sulfites, ascorbic acid, α-tocopherol and the like.

[00177] Examples of the dye include water-soluble food mineral tar dyes (for example, 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 and the like), water-insoluble lacquer dyes (eg, aluminum salts of the previously mentioned water-soluble food mineral tar dyes), natural dyes (eg, β-carotene, chlorophyll, ferric oxide red) and the like.

[00178] Examples of the sweetening agent include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia and the like.

[00179] 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: Silysia).

[00180] Examples of the wetting agent include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.

[00181] During the production of an oral preparation, coating can be applied as needed for the purpose of masking the taste, enteric property or durability.

[00182] Examples of the base coat to be used for coating include sugar base coat, aqueous film base coat, enteric film base coat and extended release film base coat.

[00183] As the sugar base coating, sucrose is used. Furthermore, one or more selected types of talc, precipitated calcium carbonate, gelatin, acacia, pullulan, carnauba wax and the like can be used in combination.

[00184] Examples of the aqueous film-based coating include cellulose polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methylhydroxyethyl cellulose etc.; synthetic polymers such as polyvinylacetal diethylaminoacetate, copolymer E aminoalkyl methacrylate [Eudragit E (trade name)], polyvinylpyrrolidone etc.; and polysaccharides such as pullulan etc.

[00185] Examples of the enteric film base coat include cellulose polymers such as hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, carboxymethylethyl cellulose, cellulose acetate phthalate etc.; acrylic 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.

[00186] Examples of the extended release film base coat include cellulose polymers such as ethyl cellulose etc.; and acrylic polymers such as aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acetyl methacrylate-ethyl methacrylate copolymer suspension [Eudragit NE (trade name)] and the like.

[00187] The above-mentioned basecoats can be used after mixing with two or more types thereof in appropriate ratios. For coating, for example, a light shielding agent such as titanium oxide, red ferric oxide and the like can be used.

[00188] The dosage of the compound of the present invention is appropriately determined according to the administration subject, symptom, administration method and the like. For example, when the compound of the present invention is orally administered to a patient with obesity or diabetes (body 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 a patient with obesity or diabetes (body weight 60 kg), the daily dosage of the compound of the present invention is about 0.01 to 30 mg, preferably about 0.1 to 20 mg , more preferably about 0.5 to 10 mg. These amounts can be administered in about 1 to several servings per day.

[00189] The compound of the present invention can be administered, for example, every day (once a day, twice a day, 3 times a day, 4 times a day, 5 times a day, 6 times a day), at every 2nd day, every 3rd day, every 4th day, every 5th day, every 6th day, every week, twice a week, every other week, every 3 weeks, every month, every 2 months, every 3 months, every 4 months, every 5 months or every 6 months.

[00190] The compound of the present invention can be used in combination with other drugs that do not adversely influence the compound of the present invention, for the purpose, for example, of promoting the action (effect treatment for obesity, diabetes and the like) of the compound of the present invention, reducing the dose of the compound of the present invention, and the like.

[00191] Examples of a drug that can be used in combination with the compound of the present invention (hereinafter sometimes abbreviated as a concomitant drug) include anti-obesity agents, therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia , antihypertensive agents, diuretics, chemotherapeutics, immunotherapeutics, anti-inflammatory drugs, antithrombotic agents, therapeutic agents for osteoporosis, vitamins, antidementia drugs, drugs for erectile dysfunction, therapeutic drugs for urinary frequency or urinary incontinence, therapeutic agents for dysuria and the like . Specific examples of the concomitant drug include those mentioned below.

[00192] Examples of the anti-obesity agent include monoamine uptake inhibitors (for example, phentermine, sibutramine, mazindol, fluoxetine, tesofensine), serotonin 2C receptor agonists (for example, lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor, GABA modulator (e.g. topiramate), neuropeptide Y antagonists (e.g. velneperit), cannabinoid receptor antagonists (e.g. rimonabant, taranabant), ghrelin antagonists, ghrelin receptor antagonists, ghrelinacylation enzyme, opioid receptor antagonists (eg, GSK-1521498), orexin receptor antagonists, melanocortin 4 receptor agonists, 11-e-hydroxysteroid dehydrogenase inhibitors (eg, AZD-4017), pancreatic lipase inhibitors (e.g. orlistat, cetilistat), β3 agonists (e.g. N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetylCoA carboxylase (ACC) inhibitors, desaturated stearoyl-CoA enzyme inhibitors, microsomal triglyceride (eg, R-256918), Na-glucose cotransporter inhibitors (eg, JNJ-28431754, remogliflozin), inhibitory NFK (eg, HE-3286), PPAR agonists (eg, GFT-505 , DRF-11605), phosphotyrosine phosphatase inhibitors (e.g. sodium vanadate, Trodusquemin), GPR119 agonists (e.g. PSN-821, MBX-2982, APD597), glucokinase activators (e.g. AZD-1656) , leptin, leptin derivatives (eg, metreleptin), CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (eg, pramlintide, AC-2307), neuropeptide agonists Y (e.g., PYY3-36, PYY3-36 derivatives, obineptide, TM-30339, TM-30335), oxyntomodulin preparations: FGF21 preparations (e.g., animal FGF21 preparations extracted from bovine or porcine pancreas; human FGF21 preparations genetically synthesized using ESCHERICHIA COLI or yeast; FGF21 fragments or derivatives), anorectic agents (e.g., P-57), and the like.

[00193] Here, as the therapeutic agent for diabetes, for example, insulin preparations (for example, animal insulin preparations extracted from bovine or porcine pancreas; human insulin preparations genetically synthesized using ESCHERICHIA COLI or yeast; zinc insulin; zinc protamine insulin; insulin fragment or derivative (e.g. INS-1), oral insulin preparation), insulin sensitizers (e.g. pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate), Metaglidasen, AMG-131, Balaglitazone, MBX-2044, Rivoglitazone, Aleglitazar, Chiglitazar, Lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, compound 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 a salt thereof (e.g. hydrochloride, fumarate , succinate)), insulin-secreting (e.g., sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glibuzol), repaglinide, nateglinide, mitiglinide or hydrated calcium salt thereof ), dipeptidyl peptidase IV inhibitors (e.g. Alogliptin or a salt thereof (preferably 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, compound described in WO2004/041266, WO2004/106276, WO2005/063729, WO2005/063725, WO2005/087710, WO2005/095338, WO2007/013689 or WO2008/001931), SGLT2 inhibitors (sodium-glucose cotransporter 2) (e.g. Depagliflozin , AVE2268, TS-033, YM543, TA-7284, Remogliflozin, ASP1941), SGLT1 inhibitors, 11β-hydroxysteroid dehydrogenase inhibitors (e.g. BVT-3498, INCB-13739), adiponectin or agonist thereof, IKK inhibitors (e.g. AS-2868), drugs that improve leptin resistance, somatostatin receptor agonists, glucokinase activators (e.g. Piragliatin, AZD1656, AZD6370, TTP-355, compound described in WO006/112549, WO007/028135 , WO008/047821, WO008/050821, WO008/136428 or WO008/156757), GPR119 agonists (for example, PSN821, MBX-2982, APD597), FGF21, FGF analogue, ACC2 inhibitors and the like can be mentioned.

[00194] As the therapeutic agent for diabetic complications, aldose reductase inhibitors (eg, tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat (AS-3201), lidorestat), neurotrophic factor, and agents that increase the same ( eg NGF, NT-3, BDNF, agent promoting neurotrophic production/secretion described in WO01/14372 (e.g. 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5- [3-(2-methylphenoxy)propyl]oxazole), compound described in WO2004/039365), PKC inhibitors (e.g. ruboxistaurin mesylate), AGE inhibitors (e.g. ALT946, N-phenacylthiazolium bromide (ALT766) , EXO-226, Pyridorin, pyridoxamine), GABA receptor agonists (eg, gabapentin, pregabalin), serotonin and norepinephrine reuptake inhibitors (eg, duloxetine), sodium channel inhibitors (eg, lacosamide), scavengers active oxygen (e.g., thioctic acid), cerebral vasodilators (e.g., tiapuride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), inhibitors of apoptosis signal-regulating kinase-1 (ASK-1) and similar can be mentioned.

[00195] As the therapeutic agent for hyperlipidemia, HMG-COA reductase inhibitors (for example, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or a salt thereof (for example, sodium salt, calcium salt) ), squalene synthase inhibitors (e.g. compound described in WO97/10224, e.g. N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-acid) -(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidin-4-acetic acid), fibrate compounds (e.g. bezafibrate , clofibrate, simfibrate, clinofibrate), anion exchange resin (eg, cholestyramine), probucol, nicotinic acid drugs (eg, nicomol, niceritrol, niaspan), ethyl eicosapentate, phytosterol (eg, soisterol, gamma oryzanol (y-oryzanol)), cholesterol absorption inhibitors (eg, zechia), CETP inhibitors (eg, dalcetrapib, anacetrapib), w-3 fatty acid preparations (eg, w-3 fatty acid ethyl esters 90 (w-3 90 acid ethyl esters)) and the like may be mentioned.

[00196] Examples of the antihypertensive agent include angiotensin converting enzyme inhibitors (for example, captopril, enalapril, delapril, etc.), angiotensin II antagonists (for example, 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, efonidipine, nicardipine, cilnidipine, etc.), β-blockers (e.g. , metoprolol, atenolol, propranolol, carvedilol, pindolol, etc.), clonidine and the like.

[00197] As the diuretic, for example, xanthine derivatives (for example, theobromine sodiumicylate salt and the like), thiazide preparations (for example, ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, poly5thiazide, methylothiazide and antialdosterone preparations (e.g., spironolactone, triamterene and the like), carbonic anhydrase inhibitors (e.g., acetazolamide and the like), chlorobenzenesulfonamide agents (e.g., chlorthalidone, mefruside, indapamide and the like), azosemide, isosorbide, Ethacrynic acid, piretanide, bumetanide, furosemide and the like may be mentioned.

[00198] Examples of the chemotherapeutics include alkylating agents (eg, cyclophosphamide, ifosfamide), antimetabolites (eg, methotrexate, 5-fluorouracil), anticancer antibiotics (eg, mitomycin, adriamycin), plant-derived anticancer agents (eg, vincristine, vindesine, Taxol), cisplatin, carboplatin, etoposide and the like. Among others, a 5-fluorouracil derivative Furtulon or Neofurtulon or the like is preferable.

[00199] Examples of the immunotherapy include microbial or bacterial components (for example, muramyl dipeptide derivative, Picibanil), polysaccharides with immunoenhancing activity (for example, lentinan, sizofiran, Krestin), cytokines obtained by genetic engineering approaches (for example, interferon , interleukin (IL)), colony-stimulating factors (eg, granulocyte colony-stimulating factor, erythropoietin), and the like. Among others, interleukins such as IL-1, IL-2, IL-12 and the like are preferable.

[00200] Examples of the anti-inflammatory drug include non-steroidal anti-inflammatory drugs such as aspirin, acetaminophen, indomethacin and the like.

[00201] As the antithrombotic agent, for example, heparin (for example, heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (for example, warfarin potassium), antithrombin drugs (for example, aragatroban , dabigatran), FXa inhibitors (e.g. rivaroxaban, apixaban, edoxaban, YM150, compound described in WO02/06234, WO2004/048363, WO2005/030740, WO2005/058823 or WO2005/113504), thrombolytic agents (e.g. urokinase , thisokinase, alteplase, nateplase, monteplase, pamiteplase), platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride) and the like may be mentioned.

[00202] Examples of the therapeutic agent for osteoporosis include alfacalcidol, calcitriol, elcatonin, salmon calcitonin, estriol, ipriflavone, disodium pamidronate, alendronate sodium hydrate, disodium incadronate, disodium risedronate and the like.

[00203] Examples of the vitamin include vitamin B1, vitamin B12 and the like.

[00204] Examples of the antidementia drug include tacrine, donepezil, rivastigmine, galantamine and the like.

[00205] Examples of the erectile dysfunction drug include apomorphine, sildenafil citrate and the like.

[00206] Examples of the therapeutic drug for urinary frequency or urinary incontinence include flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like.

[00207] Examples of the therapeutic agent for dysuria include acetylcholine esterase inhibitors (eg, distigmine) and the like.

[00208] In addition, a drug confirmed to have an action that improves cachexia both in animal models and clinically, i.e., a cyclooxygenase inhibitor (eg, indomethacin), a progesterone derivative (eg, megestrol), a glucocorticoid (eg, dexamethasone), a metoclopramide drug, a tetrahydrocannabinol drug, an agent for improving fat metabolism (eg, eicosapentaenoic acid), growth hormone, IGF-1, or an antibody against a cachexia-inducing factor TNF-α, LIF, IL-6 or oncostatin M or the like can also be used in combination with the compound of the present invention.

[00209] Alternatively, a glycation inhibitor (eg, ALT-711), a drug that promotes nerve regeneration (eg, Y-128, VX853, prosapteide), an antidepressant (eg, desipramine, amitriptyline, imipramine ), an antiepileptic drug (eg, lamotrigine, Trileptal, Keppra, Zonegran, Pregabalin, Harkoseride, carbamazepine), an antiarrhythmic drug (eg, mexiletine), an acetylcholine receptor ligand (eg, ABT-594), an endothelin receptor antagonist (eg, ABT-627), a monoamine uptake inhibitor (eg, tramadol), a narcotic analgesic (eg, morphine), a GABA receptor agonist (eg, gabapentin, MR preparation of gabapentin), an α2-receptor agonist (eg, clonidine), a local analgesic (eg, capsaicin), an anti-anxiety drug (eg, benzothiazepine), a phosphodiesterase inhibitor (eg, sildenafil), an agonist of the dopamine receptor (e.g. apomorphine), midazolam, ketoconazole or the like can be used in combination with the compound of the present invention.

[00210] The administration time of the compound of the present invention and that of the concomitant drug are not limited, and they can be administered simultaneously or in an alternate manner to the administration subject.

[00211] Examples of such a mode of administration include the following: (1) administration of a single preparation obtained by simultaneously processing the compound of the present invention and the concomitant drug, (2) simultaneous administration of two types of preparations of the compound of the present invention, and the concomitant drug, which were separately produced, by the same route of administration, (3) administration of two types of preparations of the compound of the present invention and the concomitant drug, which were separately produced, by the same route of administration in an alternate manner, ( 4) Simultaneous administration of two types of preparations of the compound of the present invention and the concomitant drug, which were separately produced, by different administration routes, (5) Administration of two types of preparations of the compound of the present invention and the concomitant drug, which were separately produced, by different routes of administration in an alternating manner (for example, administration in the order of the compound of the present invention and the concomitant drug, or in the reverse order), and the like.

[00212] The dose of the concomitant drug can be appropriately determined based on the dose employed in clinical situations. The mixing ratio of the compound of the present invention and a concomitant drug can be appropriately determined depending on the administration subject, symptom, administration method, target disease, combination and the like. When the administration subject is human, for example, a concomitant drug can be used in 0.01 to 100 parts by weight with respect to 1 part by weight of the compound of the present invention.

[00213] Combining the compound of the present invention and concomitant drug: (1) the dose of the compound of the present invention or a concomitant drug can be reduced as compared to single administration of the compound of the present invention or a concomitant drug, (2) the drug to be used in combination with the compound of the present invention can be selected depending on the condition of the patients (mild, severe and the like), (3) the treatment period can be made longer by selecting a concomitant drug with action and mechanism different from those of the compound of the present invention, (4) a prolonged treatment effect can be designed by selecting a concomitant drug with different action and mechanism than the compound of the present invention, (5) a synergistic effect can be provided by a combined use of the compound of the present invention and a concomitant drug and the like can be achieved.

Examples

[00214] The abbreviations used in the present patent application mean the following (Table 1-1 and Table 1-2). A hyphen in terms such as α-MePhe and the like as described herein may be omitted and the omission event also represents the same meaning. [Table 1-1] [Table 1-2]

[00215] In the patent application, where bases, amino acids, etc. are denoted by their codes, they are based on the conventional codes according to the IUPAC-IUB Commission on Biochemical Nomenclature or by the common codes in the technology, examples of which are shown below. For amino acids that may have an optical isomer, the L-form is shown unless otherwise indicated (eg, "Ala" is the L-form of Ala). Furthermore, "D-" means a D-form (e.g., "D-Ala" is the D-form of Ala) and "DL-" means a racemate of a D-form and an L-form (e.g. , "DL-Ala" is DL racemate of Ala). TFA : : trifluoroacetic acid Gly or G : : glycine Ala or A : : alanine Val or V : : valine Leu or L : : leucine Ile or I : : isoleucine Ser or S : : serine Thr or T : : threonine Cys or C : : cysteine Met or M : : methionine Glu or E : : glutamic acid Asp or D : : aspartic acid Lys or K : : lysine Arg or R : : arginine His or H : : histidine Phe or F : : phenylalanine Tyr or Y : : tyrosine Trp or W : : tryptophan Pro or P : : proline Asn or N : : asparagine Gln or Q : : glutamine pGlu : : pyroglutamic acid α-MeTyr : : α-methyltyrosine

[00216] The present invention is explained in detail below by referring to the following Reference Examples, Examples, Test Examples and Formulation Examples, which are mere embodiments and should not be considered as limiting. Furthermore, the present invention can be modified without departing from the scope of the invention.

[00217] The term “ambient temperature” in the following Examples indicates the range of generally from about 10 °C to about 35 °C. As for “%”, the yield is in mol/mol%, the solvent used for chromatography is in % by volume and the other “%” is in % by weight. THF: tetrahydrofuran DMF: N,N-dimethylformamide WSC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HOBt: 1-hydroxybenzotriazole monohydrate

Reference example 1

[00218] 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)-amide resin Sieber (SEQ ID NO: 10)

[00219] Sieber amide resin (0.69 meq/g, 362 mg) was added to a reaction tube, which was then loaded into a peptide synthesizer. Amino acids were successively condensed according to the Fmoc/DCC/HOBt Protocol. In the final step, the N-terminal Fmoc group was removed. After the end of condensation, the resin was washed with MeOH and dried under reduced pressure. As a result, 1025 mg (0.244 meq/g) of the protected peptide resin of interest was obtained.

Reference example 2

[00220] 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)-Sieber amide resin (SEQ ID NO: 11)

[00221] Sieber amide resin (0.69 meq/g, 362 mg) was added to a reaction tube, which was then loaded into a peptide synthesizer. Amino acids were successively condensed according to the Fmoc/DCC/HOBt Protocol. In the final step, the N-terminal Fmoc group was removed. After the end of condensation, the resin was washed with MeOH and dried under reduced pressure. As a result, 1331 mg (0.188 meq/g) of the protected peptide resin of interest was obtained.

Reference example 3

[00222] Synthesis of H-Ala-Gln(Trt)-Ala-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: 12)

[00223] Sieber amide resin (0.61 meq/g, 410 mg) was added to a reaction tube, which was then loaded into a peptide synthesizer. Amino acids were successively condensed according to the Fmoc/DCC/HOBt Protocol. Double coupling was performed to introduce 18-position and 20-position Ala and 19-position Gln(Trt). In the final step, the N-terminal Fmoc group was removed. After the end of condensation, the resin was washed with MeOH and dried under reduced pressure. As a result, 1110 mg (0.225 meq/g) of the protected peptide resin of interest was obtained.

Example 1

[00224] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Ala-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 13) 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 Sieber -Ser(tBu)-Lys(Boc)-amide resin (0.244 meq/g, 41.0 mg) prepared in Reference Example 1 was weighed into a reaction tube and swelled with DMF. After removal of DMF by filtration, Fmoc-Ala-OH (31.1 mg), 0.5 M OxymaPure in DMF (200 μL) and diisopropylcarbodiimide (15.9 μL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Gln(Trt), Ala, Gln(Trt), Lys(Boc), Asp(OtBu), Leu, Aib, Ile*, Ala, Tyr(tBu ), Asp(OtBu), Ser(tBu), Thr(tBu), αMePhe, 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 83 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)- Asp(OtBu)-Tyr(tBu)-Ala-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-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)-amide resin Sieber.

[00225] To 83 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1.5 hours . Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 65/35-55/45 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 22.5 mg of a white powder.

[00226] Mass spectrometry, (M+H)+ 4267.4 (Calculated: 4267.2) HPLC elution time: 7.1 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4.6 mm I.D.) eluent: using solution A: 0.1% TFA-water, solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution (10 min) flow rate : 3.0 mL/min Example 2 Synthesis of H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln -Ala-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 14 ) H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala Sieber -Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-amide resin (0.244 meq/g, 41.0 mg) prepared in Reference Example 1 was weighed into a reaction tube and swelled with DMF. After removal of DMF by filtration, Fmoc-Ala-OH (31.1 mg), 0.5 M Oxymapure in DMF (200 μL) and diisopropylcarbodiimide (15.9 μL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Gln(Trt), Ala, Gln(Trt), Lys(Boc), Asp(OtBu), Leu, Aib, Ile*, Aib, Tyr(tBu ), Asp(OtBu), Ser(tBu), Thr(tBu), αMePhe, 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 84.5 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)- Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-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)-amide resin Sieber.

[00227] To 84.5 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1, 5 hours. Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 65/35-55/45 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 21.5 mg of a white powder.

[00228] Mass spectrometry, (M+H)+ 4281.5 (Calculated: 4281.2) HPLC elution time: 7.2 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4.6 mm I.D.) eluent: using solution A: 0.1% TFA-water, solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution (10 min) flow rate : 3.0 mL/min

Example 3

[00229] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Ala-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ser-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 15) 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 Sieber -Ser(tBu)-Lys(Boc)-amide resin (0.244 meq/g, 41.0 mg) prepared in Reference Example 1 was weighed into a reaction tube and swelled with DMF. After removal of DMF by filtration, Fmoc-Ser(tBu)-OH (38.3 mg), 0.5 M Oxymapure in DMF (200 μL) and diisopropylcarbodiimide (15.9 μL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Gln(Trt), Ala, Gln(Trt), Lys(Boc), Asp(OtBu), Leu, Aib, Ile*, Ala, Tyr(tBu ), Asp(OtBu), Ser(tBu), Thr(tBu), αMePhe, 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 73.3 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)- Asp(OtBu)-Tyr(tBu)-Ala-Ile-Aib-Leu-Asp(OtBu)- Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ser(tBu)-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 Sieber (tBu)-Lys(Boc)-amide resin.

[00230] To 73.3 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1, 5 hours. Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 65/35-55/45 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 17.1 mg of a white powder.

[00231] Mass spectrometry, (M+H)+ 4283.6 (Calculated: 4283.2) HPLC elution time: 7.1 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4.6 mm I.D.) eluent: using solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution (10 min ) flow rate: 3.0 mL/min

Example 4

[00232] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ser-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 16) 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 Sieber -Ser(tBu)-Lys(Boc)-amide resin (0.244 meq/g, 41.0 mg) prepared in Reference Example 1 was weighed into a reaction tube and swelled with DMF. After removal of DMF by filtration, Fmoc-Ser(tBu)-OH (38.3 mg), 0.5 M Oxymapure in DMF (200 μL) and diisopropylcarbodiimide (15.9 μL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Gln(Trt), Ala, Gln(Trt), Lys(Boc), Asp(OtBu), Leu, Aib, Ile*, Aib, Tyr(tBu ), Asp(OtBu), Ser(tBu), Thr(tBu), αMePhe, 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 63 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)- Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)- Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ser(tBu)-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 Sieber (tBu)-Lys(Boc)-amide resin.

[00233] To 63 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1.5 hours . Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 64/36-54/46 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 14.7 mg of a white powder.

[00234] Mass spectrometry, (M+H)+ 4297.8 (Calculated: 4297.2) HPLC elution time: 7.2 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4.6 mm I.D.) eluent: using solution A: 0.1% TFA-water, solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution (10 min) flow rate : 3.0 mL/min

Example 5

[00235] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Ala-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 (SEQ ID NO: 17) 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)-Sieber amide resin (0.188 meq/g, 53.2 mg) prepared in Reference Example 2 was weighed into a reaction tube and swelled with DMF. After removal of DMF by filtration, Fmoc-Ala-OH (31.1 mg), 0.5 M Oxymapure in DMF (200 μL) and diisopropylcarbodiimide (15.9 μL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Gln(Trt), Ala, Gln(Trt), Lys(Boc), Asp(OtBu), Leu, Aib, Ile*, Ala, Tyr(tBu ), Asp(OtBu), Ser(tBu), Thr(tBu), αMePhe, 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 97 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)- Asp(OtBu)-Tyr(tBu)-Ala-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-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) -Sieber amide resin.

[00236] To 97 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1.5 hours . Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 63/37-53/47 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 25.2 mg of a white powder.

[00237] Mass spectrometry, (M+H)+ 4139.2 (Calculated: 4139.1) HPLC elution time: 7.3 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4.6 mm I.D.) eluent: using solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution (10 min ) flow rate: 3.0 mL/min

Example 6

[00238] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 (SEQ ID NO: 18) 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)-Sieber amide resin (0.188 meq/g, 53.2 mg) prepared in Reference Example 2 was weighed into a reaction tube and swelled with DMF. After removal of DMF by filtration, Fmoc-Ala-OH (31.1 mg), 0.5 M Oxymapure in DMF (200 μL) and diisopropylcarbodiimide (15.9 μL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Gln(Trt), Ala, Gln(Trt), Lys(Boc), Asp(OtBu), Leu, Aib, Ile*, Aib, Tyr(tBu ), Asp(OtBu), Ser(tBu), Thr(tBu), αMePhe, 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 78.1 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)- Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-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) -Sieber amide resin.

[00239] To 78.1 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1, 5 hours. Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 63/37-53/47 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 18.4 mg of a white powder.

[00240] Mass spectrometry, (M+H)+ 4152.9 (Calculated: 4153.1) HPLC elution time: 7.4 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4.6 mm I.D.) eluent: using solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution (10 min ) flow rate: 3.0 mL/min

Example 7

[00241] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Ala-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ser-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 (SEQ ID NO: 19) 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)-Sieber amide resin (0.188 meq/g, 53.2 mg) prepared in Reference Example 2 was weighed into a reaction tube and swelled with DMF. After removal of DMF by filtration, Fmoc-Ser(tBu)-OH (38.3 mg), 0.5 M Oxymapure in DMF (200 μL) and diisopropylcarbodiimide (15.9 μL, 0.1 mmol) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Gln(Trt), Ala, Gln(Trt), Lys(Boc), Asp(OtBu), Leu, Aib, Ile*, Ala, Tyr(tBu ), Asp(OtBu), Ser(tBu), Thr(tBu), αMePhe, 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 87 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)- Asp(OtBu)-Tyr(tBu)-Ala-Ile-Aib-Leu- Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ser(tBu)-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)-Sieber amide resin.

[00242] To 87 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1.5 hours . Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 65/35-55/45 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 17 mg of a white powder.

[00243] Mass spectrometry, (M+H)+ 4154.8 (Calculated: 4155.1) HPLC elution time: 7.3 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4, 6 mm I.D.) eluent: using Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution ( 10 min) flow rate: 3.0 mL/min

Example 8

[00244] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ser-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 (SEQ ID NO: 20) 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)-Sieber amide resin (0.188 meq/g, 53.2 mg) prepared in Reference Example 2 was weighed into a reaction tube and swelled with DMF. After removal of DMF by filtration, Fmoc-Ser(tBu)-OH (38.3 mg), 0.5 M Oxymapure in DMF (200 μL) and diisopropylcarbodiimide (15.9 μL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Gln(Trt), Ala, Gln(Trt), Lys(Boc), Asp(OtBu), Leu, Aib, Ile*, Aib, Tyr(tBu ), Asp(OtBu), Ser(tBu), Thr(tBu), αMePhe, 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 76.8 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu) )- Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala- Gln(Trt)-Ser(tBu)-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)-Sieber amide resin.

[00245] To 76.8 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1, 5 hours. Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 63/37-53/47 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 16.6 mg of a white powder.

[00246] Mass spectrometry, (M+H)+ 4169.2 (Calculated: 4169.1) HPLC elution time: 7.4 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4, 6 mm I.D.) eluent: using Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution ( 10 min) flow rate: 3.0 mL/min

Example 9

[00247] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 21)

[00248] H-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser( tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Ser(tBu)-Lys(Boc)-Sieber amide resin (0.225 meq/g, 44.4 mg) prepared in Reference Example 3 was weighed into a reaction tube and swollen with DMF. After removal of DMF by filtration, Fmoc-Gln(Trt)-OH (61.1 mg), 0.5 M Oxymapure in DMF (200 μL) and diisopropylcarbodiimide (15.9 μL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Lys(Boc), Asp(OtBu), Leu, Aib, Lys(Boc), Aib, Tyr(tBu), Asp(OtBu), Ser(tBu ), Thr(tBu), αMePhe, 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 72.4 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu) )- Asp(OtBu)-Tyr(tBu)-Aib-Lys(Boc)-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)- Ala-Gln(Trt)-Ala-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.

[00249] To 72.4 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 67/33-57/43 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 13.9 mg of a white powder.

[00250] Mass spectrometry, (M+H)+ 4295.8 (Calculated: 4296.2) HPLC elution time: 6.9 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4, 6 mm I.D.) eluent: using Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution ( 10 min) flow rate: 3.0 mL/min

Example 10

[00251] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ala-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 22) H-Ala-Gln (Trt)-Ala-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 (0.225 meq/g, 44.4 mg) prepared in Reference Example 3 was weighed into a reaction tube and swollen with DMF. After removal of DMF by filtration, Fmoc-Gln(Trt)-OH (61.1 mg), 0.5 M Oxymapure in DMF (200 µL) and diisopropylcarbodiimide (15.9 µL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Lys(Boc), Asp(OtBu), Leu, Aib, Ala, Aib, Tyr(tBu), Asp(OtBu), Ser(tBu), Thr (tBu), αMePhe, 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 86.1 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu) )- Asp(OtBu)-Tyr(tBu)-Aib-Ala-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-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.

[00252] To 86.1 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 66/34-56/44 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 16.2 mg of a white powder.

[00253] Mass spectrometry, (M+H)+ 4238.6 (Calculated: 4239.2) HPLC elution time: 7.1 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4, 6 mm I.D.) eluent: using Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution ( 10 min) flow rate: 3.0 mL/min

Example 11

[00254] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Phe-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 23) H-Ala-Gln (Trt)-Ala-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 (0.225 meq/g, 44.4 mg) prepared in Reference Example 3 was weighed into a reaction tube and swollen with DMF. After removal of DMF by filtration, Fmoc-Gln(Trt)-OH (61.1 mg), 0.5 M Oxymapure in DMF (200 µL) and diisopropylcarbodiimide (15.9 µL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Lys(Boc), Asp(OtBu), Leu, Aib, Phe, Aib, Tyr(tBu), Asp(OtBu), Ser(tBu), Thr (tBu), αMePhe, 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 76.4 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu) )- Asp(OtBu)-Tyr(tBu)-Aib-Phe-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-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.

[00255] To 76.4 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 65/35-55/45 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 4.7 mg of a white powder.

[00256] Mass spectrometry, (M+H)+ 4315.1 (Calculated: 4315.2) HPLC elution time: 7.2 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4, 6 mm I.D.) eluent: using Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution ( 10 min) flow rate: 3.0 mL/min

Example 12

[00257] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Pya(4)-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala- Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 24) H- Ala-Gln(Trt)-Ala-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 (0.225 meq/g, 44.4 mg) prepared in Reference Example 3 was weighed into a glass tube. reaction and swollen with DMF. After removal of DMF by filtration, Fmoc-Gln(Trt)-OH (61.1 mg), 0.5 M Oxymapure in DMF (200 µL) and diisopropylcarbodiimide (15.9 µL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Lys(Boc), Asp(OtBu), Leu, Aib, Pya(4)*, Aib, Tyr(tBu), Asp(OtBu), Ser( tBu), Thr(tBu), αMePhe, Thr(tBu)**, Gly, Glu(OtBu), Aib and Tyr(tBu) (*: 17.4 μL of DIPEA was added during condensation; **: reaction during all night). The resin was washed with MeOH and then dried under reduced pressure to give 78.4 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu) )- Asp(OtBu)-Tyr(tBu)-Aib-Pya(4)-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-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.

[00258] To 78.4 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 67/33-57/43 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 15.2 mg of a white powder.

[00259] Mass spectrometry, (M+H)+ 4316.2 (Calculated: 4316.2) HPLC elution time: 6.9 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4, 6 mm I.D.) eluent: using Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution ( 10 min) flow rate: 3.0 mL/min

Example 13

[00260] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-αMePhe-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 25) H-Ala-Gln (Trt)-Ala-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 (0.225 meq/g, 44.4 mg) prepared in Reference Example 3 was weighed into a reaction tube and swollen with DMF. After removal of DMF by filtration, Fmoc-Gln(Trt)-OH (61.1 mg), 0.5 M Oxymapure in DMF (200 µL) and diisopropylcarbodiimide (15.9 µL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Lys(Boc), Asp(OtBu), Leu, αMePhe, Ile, Aib, Tyr(tBu), Asp(OtBu), Ser(tBu), Thr (tBu), αMePhe, 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 69.1 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu) )- Asp(OtBu)-Tyr(tBu)-Aib-Ile-αMePhe-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-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.

[00261] To 69.1 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 64/36-54/46 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 14.4 mg of a white powder.

[00262] Mass spectrometry, (M+H)+ 4356.9 (Calculated: 4357.3) HPLC elution time: 7.4 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4, 6 mm I.D.) eluent: using Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution ( 10 min) flow rate: 3.0 mL/min

Example 14

[00263] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Cha-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 26) H-Ala-Gln (Trt)-Ala-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 (0.225 meq/g, 44.4 mg) prepared in Reference Example 3 was weighed into a reaction tube and swollen with DMF. After removal of DMF by filtration, Fmoc-Gln(Trt)-OH (61.1 mg), 0.5 M Oxymapure in DMF (200 µL) and diisopropylcarbodiimide (15.9 µL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Lys(Boc), Asp(OtBu), Leu, Cha, Ile, Aib, Tyr(tBu), Asp(OtBu), Ser(tBu), Thr (tBu), αMePhe, 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 71.5 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu) )- Asp(OtBu)-Tyr(tBu)-Aib-Ile-Cha-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-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.

[00264] To 71.5 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 63/37-53/47 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 16 mg of a white powder.

[00265] Mass spectrometry, (M+H)+ 4348.7 (Calculated: 4349.3) HPLC elution time: 7.5 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4, 6 mm I.D.) eluent: using Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution ( 10 min) flow rate: 3.0 mL/min

Example 15

[00266] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-αMePhe-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 27) H-Ala-Gln (Trt)-Ala-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 (0.225 meq/g, 44.4 mg) prepared in Reference Example 3 was weighed into a reaction tube and swollen with DMF. After removal of DMF by filtration, Fmoc-Gln(Trt)-OH (61.1 mg), 0.5 M Oxymapure in DMF (200 µL) and diisopropylcarbodiimide (15.9 µL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Lys(Boc), Asp(OtBu), Leu, αMePhe, Lys(Boc), Aib, Tyr(tBu), Asp(OtBu), Ser(tBu ), Thr(tBu), αMePhe, 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 77.9 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu) )-Asp(OtBu)-Tyr(tBu)-Aib-Lys(Boc)-αMePhe-Leu- Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-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)-amide resin Sieber.

[00267] To 77.9 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 65/35-55/45 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 13.4 mg of a white powder.

[00268] Mass spectrometry, (M+H)+ 4371.7 (Calculated: 4372.3) HPLC elution time: 7.1 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4, 6 mm I.D.) eluent: using Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution ( 10 min) flow rate: 3.0 mL/min

Example 16

[00269] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Cha-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 28) H-Ala-Gln (Trt)-Ala-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 (0.225 meq/g, 44.4 mg) prepared in Reference Example 3 was weighed into a reaction tube and swollen with DMF. After removal of DMF by filtration, Fmoc-Gln(Trt)-OH (61.1 mg), 0.5 M Oxymapure in DMF (200 µL) and diisopropylcarbodiimide (15.9 µL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Lys(Boc), Asp(OtBu), Leu, Cha, Lys(Boc), Aib, Tyr(tBu), Asp(OtBu), Ser(tBu ), Thr(tBu), αMePhe, 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 75.1 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu) )- Asp(OtBu)-Tyr(tBu)-Aib-Lys(Boc)-Cha-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)- Ala-Gln(Trt)-Ala-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.

[00270] To 75.1 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 65/35-55/45 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 14.7 mg of a white powder.

[00271] Mass spectrometry, (M+H)+ 4364.7 (Calculated: 4364.3) HPLC elution time: 7.1 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4, 6 mm I.D.) eluent: using Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution ( 10 min) flow rate: 3.0 mL/min

Example 17

[00272] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-αMeTyr-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 29) H-Ala-Gln (Trt)-Ala-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 (0.225 meq/g, 44.4 mg) prepared in Reference Example 3 was weighed into a reaction tube and swollen with DMF. After removal of DMF by filtration, Fmoc-Gln(Trt)-OH (61.1 mg), 0.5 M Oxymapure in DMF (200 µL) and diisopropylcarbodiimide (15.9 µL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Lys(Boc), Asp(OtBu), Leu, αMeTyr, Ile, Aib, Tyr(tBu), Asp(OtBu), Ser(tBu), Thr (tBu), αMePhe, 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 56.2 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu) )- Asp(OtBu)-Tyr(tBu)-Aib-Ile-αMeTyr-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-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.

[00273] To 56.2 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 65/35-55/45 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 1.4 mg of a white powder.

[00274] Mass spectrometry, (M+H)+ 4373.8 (Calculated: 4373.2) HPLC elution time: 7.2 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4, 6 mm I.D.) eluent: using Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution ( 10 min) flow rate: 3.0 mL/min

Example 18

[00275] Synthesis of Ac-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 30) 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 Sieber -Ser(tBu)-Lys(Boc)-amide resin (0.253 meq/g, 39.5 mg) prepared by a similar approach to Reference Example 1 was weighed into a reaction tube and swelled with DMF. After removal of DMF by filtration, Fmoc-Ala-OH (31.1 mg), 0.5 M Oxymapure in DMF (200 µL) and diisopropylcarbodiimide (15.9 µL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Gln(Trt), Ala, Gln(Trt), Lys(Boc), Asp(OtBu), Leu, Aib, Ile*, Aib, Tyr(tBu ), Asp(OtBu), Ser(tBu), Thr(tBu), αMePhe, Thr(tBu)*, Gly, Glu(OtBu), Aib and Tyr(tBu) (*: overnight reaction). Then the N-terminal Fmoc group was removed by treatment with piperidine and then DMF (200 μL), DIPEA (17.4 μL) and AC2O (9.4 μL) were successively added to the resin and the mixture was shaken for 90 minutes. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, the resin was washed with MeOH and dried under reduced pressure to give 43 mg of Ac-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr( tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu- Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala- Glu(OtBu)-Phe-Val- Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly- Ala-Pro- Sieber Pro-Pro-Ser(tBu)-Lys(Boc)-amide resin.

[00276] To 43 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 62/38-52/48 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 7.8 mg of a white powder.

[00277] Mass spectrometry, (M+H)+ 4323.4 (Calculated: 4323.2) HPLC elution time: 7.5 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4, 6 mm I.D.) eluent: using Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution ( 10 min) flow rate: 3.0 mL/min

Example 19

[00278] Synthesis of Benzoyl-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser- Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 31) 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 Sieber -Ser(tBu)-Lys(Boc)-amide resin (0.253 meq/g, 39.5 mg) prepared in Reference Example 1 was weighed into a reaction tube and swelled with DMF. After removal of DMF by filtration, Fmoc-Ala-OH (31.1 mg), 0.5 M Oxymapure in DMF (200 µL) and diisopropylcarbodiimide (15.9 µL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Gln(Trt), Ala, Gln(Trt), Lys(Boc), Asp(OtBu), Leu, Aib, Ile*, Aib, Tyr(tBu ), Asp(OtBu), Ser(tBu), Thr(tBu), αMePhe, Thr(tBu)*, Gly, Glu(OtBu), Aib and Tyr(tBu) (*: overnight reaction). Then the N-terminal Fmoc group was removed by treatment with piperidine and then benzoic acid (12.2 mg), 0.5 M Oxymapure in DMF (200 μL) and diisopropylcarbodiimide (15.9 μL) were successively added to the resin and the mixture stirred overnight. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, the resin was washed with MeOH and then dried under reduced pressure to give 54.8 mg of Benzoyl-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe -Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)- Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt) -Ala- Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala Sieber -Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-amide resin.

[00279] To 54.8 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 60/40-50/50 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 10.1 mg of a white powder.

[00280] Mass spectrometry, (M+H)+ 4385.2 (Calculated: 4385.2) HPLC elution time: 7.7 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4, 6 mm I.D.) eluent: using Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution ( 10 min) flow rate: 3.0 mL/min

Example 20

[00281] Synthesis of 4PyCO-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser- Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 32) 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 Sieber -Ser(tBu)-Lys(Boc)-amide resin (0.253 meq/g, 39.5 mg) prepared in Reference Example 1 was weighed into a reaction tube and swelled with DMF. After removal of DMF by filtration, Fmoc-Ala-OH (31.1 mg), 0.5 M Oxymapure in DMF (200 µL) and diisopropylcarbodiimide (15.9 µL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Gln(Trt), Ala, Gln(Trt), Lys(Boc), Asp(OtBu), Leu, Aib, Ile*, Aib, Tyr(tBu ), Asp(OtBu), Ser(tBu), Thr(tBu), αMePhe, Thr(tBu)*, Gly, Glu(OtBu), Aib and Tyr(tBu) (*: overnight reaction). Then the N-terminal Fmoc group was removed by treatment with piperidine and then 4-pyridinecarboxylic acid (12.3 mg), 0.5 M Oxymapure in DMF (200 μL) and diisopropylcarbodiimide (15.9 μL) were successively added to the resin and the mixture was stirred overnight. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, the resin was washed with MeOH and then dried under reduced pressure to give 62.9 mg of 4PyCO-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe -Thr(tBu)-Ser(tBu)- Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala- Gln(Trt) -Ala-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.

[00282] To 62.9 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 62/38-52/48 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 13.3 mg of a white powder.

[00283] Mass spectrometry, (M+H)+ 4386.2 (Calculated: 4386.2) HPLC elution time: 7.3 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4, 6 mm I.D.) eluent: using Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution ( 10 min) flow rate: 3.0 mL/min

Example 21

[00284] Synthesis of cPrCO-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser- Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 33) 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 Sieber -Ser(tBu)-Lys(Boc)-amide resin (0.253 meq/g, 39.5 mg) prepared in Reference Example 1 was weighed into a reaction tube and swelled with DMF. After removal of DMF by filtration, Fmoc-Ala-OH (31.1 mg), 0.5 M Oxymapure in DMF (200 µL) and diisopropylcarbodiimide (15.9 µL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Gln(Trt), Ala, Gln(Trt), Lys(Boc), Asp(OtBu), Leu, Aib, Ile*, Aib, Tyr(tBu ), Asp(OtBu), Ser(tBu), Thr(tBu), αMePhe, Thr(tBu)*, Gly, Glu(OtBu), Aib and Tyr(tBu) (*: overnight reaction). Then the N-terminal Fmoc group was removed by treatment with piperidine and then cyclopropanecarboxylic acid (8.6 mg), 0.5 M Oxymapure in DMF (200 μL) and diisopropylcarbodiimide (15.9 μL) were successively added to the resin and the mixture stirred overnight. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, the resin was washed with MeOH and then dried under reduced pressure to give 61.8 mg of cPrCO-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe -Thr(tBu)-Ser(tBu)- Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala- Gln(Trt) -Ala-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.

[00285] To 61.8 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 61/39-51/49 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 11.7 mg of a white powder.

[00286] Mass spectrometry, (M+H)+ 4349.2 (Calculated: 4349.2) HPLC elution time: 7.6 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4, 6 mm I.D.) eluent: using Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution ( 10 min) flow rate: 3.0 mL/min

Example 22

[00287] Synthesis of amidino-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 34) 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 Sieber -Ser(tBu)-Lys(Boc)-amide resin (0.253 meq/g, 39.5 mg) prepared in Reference Example 1 was weighed into a reaction tube and swelled with DMF. After removal of DMF by filtration, Fmoc-Ala-OH (31.1 mg), 0.5 M Oxymapure in DMF (200 µL) and diisopropylcarbodiimide (15.9 µL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Gln(Trt), Ala, Gln(Trt), Lys(Boc), Asp(OtBu), Leu, Aib, Ile*, Aib, Tyr(tBu ), Asp(OtBu), Ser(tBu), Thr(tBu), αMePhe, Thr(tBu)*, Gly, Glu(OtBu), Aib and Tyr(tBu) (*: overnight reaction). Then the N-terminal Fmoc group was removed by treatment with piperidine and then DMF (200 µL), N,N'-Bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (31 mg) and DIPEA (17 .4 µL) were successively added to the resin and the mixture was stirred overnight. The reaction solution was filtered and then DMF (200 μL), N,N' -Bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (31 mg) and DIPEA (17.4 μL) were successively added to the resin and the mixture was stirred overnight again. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, the resin was washed with MeOH and then dried under reduced pressure to give 54.7 mg of BocNHC(=NBoc)-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr( tBu)-αMePhe- Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala- Gln(Trt)-Ala-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)-amide resin Sieber.

[00288] To 54.7 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 62/38-52/48 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 10.7 mg of a white powder.

[00289] Mass spectrometry, (M+H)+ 4323.2 (Calculated: 4323.2) HPLC elution time: 7.3 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4, 6 mm I.D.) eluent: using Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution ( 10 min) flow rate: 3.0 mL/min

Example 23

[00290] Synthesis of H-NMeTyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser- Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 35) 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 Sieber -Ser(tBu)-Lys(Boc)-amide resin (0.253 meq/g, 39.5 mg) prepared in Reference Example 1 was weighed into a reaction tube and swelled with DMF. After removal of DMF by filtration, Fmoc-Ala-OH (31.1 mg), 0.5 M Oxymapure in DMF (200 µL) and diisopropylcarbodiimide (15.9 µL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Gln(Trt), Ala, Gln(Trt), Lys(Boc), Asp(OtBu), Leu, Aib, Ile*, Aib, Tyr(tBu ), Asp(OtBu), Ser(tBu), Thr(tBu), αMePhe, Thr(tBu)*, Gly, Glu(OtBu), Aib and NMeTyr(tBu) (*: overnight reaction). The resin was washed with MeOH and then dried under reduced pressure to give 66.2 mg of H-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu) )-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu- Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-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)-amide resin Sieber.

[00291] To 66.2 mg of the resin obtained was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H2O: triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain precipitation, and the precipitation was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 63/37-53/47 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 9 mg of a white powder.

[00292] Mass spectrometry, (M+H)+ 4295.1 (Calculated: 4295.2) HPLC elution time: 7.2 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4, 6 mm I.D.) eluent: using Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution ( 10 min) flow rate: 3.0 mL/min

Example 24

[00293] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Ala-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 36)

[00294] A H-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)- Sieber's Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-amide resin (0.244 meq/g, 41.0 mg) prepared in Reference Example 1 was weighed into a reaction tube and swollen with DMF. After removal of DMF by filtration, Fmoc-Ala-OH (31.1 mg), 0.5 M Oxymapure in DMF (200 µL) and diisopropylcarbodiimide (15.9 µL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Gln(Trt), Ala, Gln(Trt), Lys(Boc), Asp(OtBu), Leu, Tyr(tBu), Lys(Boc)* , Aib, Tyr(tBu), Asp(OtBu), Ser(tBu), Thr(tBu), αMePhe, Thr(tBu)*, Gly, Glu(OtBu), Aib and Tyr(tBu) (*: reaction throughout at night). The resin was washed with MeOH and then dried under reduced pressure to give 66.8 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu) )-Asp(OtBu)-Tyr(tBu)-Aib-Lys(Boc)-Tyr(tBu)- Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala- Glu(OtBu)-Phe-Val- Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly- Ala-Pro- Sieber Pro-Pro-Ser(tBu)-Lys(Boc)-amide resin.

[00295] To 66.8 mg of the resin obtained was added 1 ml of TFA:m-cresol:thioanisole:ethanedithiol:H2O:triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain precipitate, and the precipitate was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 66/34-56/44 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 16.1 mg of a white powder.

[00296] Mass spectrometry, (M+H)+ 4374.6 (Calculated: 4374.2) HPLC elution time: 6.9 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4, 6 mm I.D.) eluent: using Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution ( 10 min) flow rate: 3.0 mL/min

Example 25

[00297] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Gln-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH2 (SEQ ID NO: 37) A H-Glu( OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro- Sieber's Pro-Ser(tBu)-Lys(Boc)-amide resin (0.244 meq/g, 41.0 mg) prepared in Reference Example 1 was weighed into a reaction tube and swelled with DMF. After removal of DMF by filtration, Fmoc-Gln(Trt)-OH (61.1 mg), 0.5 M Oxymapure in DMF (200 µL) and diisopropylcarbodiimide (15.9 µL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Gln(Trt), Ala, Gln(Trt), Lys(Boc), Asp(OtBu), Leu, Tyr(tBu), Lys(Boc)* , Aib, Tyr(tBu), Asp(OtBu), Ser(tBu), Thr(tBu), αMePhe, Thr(tBu)*, Gly, Glu(OtBu), Aib and Tyr(tBu) (*: reaction throughout at night). The resin was washed with MeOH and then dried under reduced pressure to give 55.0 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu) )-Asp(OtBu)-Tyr(tBu)-Aib-Lys(Boc)-Tyr(tBu)- Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Gln( Trt)-Glu(OtBu)-Phe- Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala Sieber -Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-amide resin.

[00298] To 55.0 mg of the resin obtained was added 1 mL of TFA:m-cresol:thioanisole:ethanedithiol:H2O:triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain precipitate, and the precipitate was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 66/34-56/44 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 13.7 mg of a white powder.

[00299] Mass spectrometry, (M+H)+ 4431.5 (Calculated: 4431.3) HPLC elution time: 6.9 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4, 6 mm I.D.) eluent: using Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution ( 10 min) flow rate: 3.0 mL/min

Example 26

[00300] Synthesis of H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Gln-Glu-Phe -Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 (SEQ ID NO: 38) A 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)-Sieber amide resin (0.188 meq/g, 53.2 mg) prepared in Reference Example 2 was weighed into a reaction tube and swelled with DMF. After removal of DMF by filtration, Fmoc-Gln(Trt)-OH (61.1 mg), 0.5 M Oxymapure in DMF (200 µL) and diisopropylcarbodiimide (15.9 µL) were successively added to the resin and then the mixture was stirred for 1.5 hours. The reaction solution was filtered and the resin was then washed with DMF 6 times. After confirmation of negativity in the Kaiser test, a DMF solution of 20% piperidine was added thereto and the mixture was stirred for 1 minute. The solution was filtered and a 20% piperidine DMF solution was added to it again and the mixture was stirred for 20 minutes. The solution was filtered and the resin was then washed with DMF 10 times. This Fmoc amino acid condensation-Fmoc deprotection cycle was repeated to successively condense Gln(Trt), Ala, Gln(Trt), Lys(Boc), Asp(OtBu), Leu, Tyr(tBu), Lys(Boc)* , Aib, Tyr(tBu), Asp(OtBu), Ser(tBu), Thr(tBu), αMePhe, Thr(tBu)*, Gly, Glu(OtBu), Aib and Tyr(tBu) (*: reaction throughout at night). The resin was washed with MeOH and then dried under reduced pressure to give 95.4 mg of H-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu) )-Asp(OtBu)-Tyr(tBu)-Aib-Lys(Boc)-Tyr(tBu)-Leu- Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Gln( Trt)-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala Sieber -Pro-Pro-Pro-Ser(tBu)-amide resin.

[00301] To 95.4 mg of the resin obtained was added 1 mL of TFA:m-cresol:thioanisole:ethanedithiol:H2O:triisopropylsilane (80:5:5:5:2.5:2.5) and the mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain precipitate, and the precipitate was washed by repeating an operation three times to remove the supernatant after centrifugation. The residue was extracted with 50% aqueous acetic acid solution and the resin was removed by filtration, followed by preparative HPLC using Daisopak SP-100-5-ODS-P column (250 x 20 mm I.D.) [solution A: 0. 1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, flow rate 8 mL/min, A/B: 61/39-51/49 linear concentration gradient elution (60 min)]. Fractions containing the product in question were collected and lyophilized to give 20.0 mg of a white powder.

[00302] Mass spectrometry, (M+H)+ 4303.0 (Calculated: 4303.2) HPLC elution time: 7.1 min elution condition: column: Merck Chromolith Performance RP-18e (100 x 4, 6 mm I.D.) eluent: using Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A/B: 95/5 - 35/65 linear concentration gradient elution ( 10 min) flow rate: 3.0 mL/min

Test example 1

[00303] Evaluation of agonist activity against human GIPR, human GLP-1R and human glucagon R using increase in intracellular cAMP concentration as index

(1) Construction of expression plasmid for the human GIPR gene

[00304] The human GIPR gene a sequence identical to the sequence of GenBank Accession No. U39231 was cloned into the pMSRα-neo vector to prepare hGIPR/pMSRα-neo.

(2) Construction of cell expressing reporter plasmid

[00305] The luciferase reporter gene with an upstream cAMP response sequence was introduced into CO-K1 cells to construct CRE-LUC/CO-K1 cells.

(3) Construction of reporter plasmid

[00306] Four copies of the cAMP response sequence and the Zeocin resistance gene were introduced into the pGL3(R2,2)-basic vector (Promega) to construct the Cre-luc(Zeo) reporter plasmid.

(4) Introduction of the human GIPR gene into the CRE-LUC/CO-K1 cell and obtaining the expression cell

[00307] The hGIPR/pMSRα-neo plasmid obtained in (1) was introduced into the CRE-LUC/CO-K1 cells obtained (2) to obtain transformers. Next, a cell line induced to express luciferase, i.e., hGIPR/CRE-LUC/CO-K1 cells, was selected from the transformers obtained by adding GIP.

(5) Construction of expression plasmid for human GLP-1R gene

[00308] The human GLP-1R gene a sequence identical to the sequence of GenBank Accession No. NM_002062 was cloned into the pIRESneo3 vector to prepare hGLP-1/pIRESneo3.

(6) Introduction of the human GLP-1R gene and the reporter plasmid into the CO-K1 cell and obtaining the expression cell

[00309] The Cre-luc(Zeo) obtained in (3) and the hGLP-1/pIRESneo3 plasmid obtained in (5) were introduced into CO-K1 cells to obtain transformers. Next, a cell line induced to express luciferase, ie, hGLP-1R/CRE-luc/CO-K1 cells, was selected from transformers obtained by adding GLP-1.

(7) Construction of expression plasmid for human R glucagon gene

[00310] The human glucagon gene R a sequence identical to the sequence of GenBank Accession No. NM_000160 was cloned into the pMSRα-neo vector to prepare hGlucagonR/pMSRα-neo.

(8) Introduction of the human R glucagon gene into the CRE-LUC/CO-K1 cell and obtaining the expression cell

[00311] The hGlucagonR/pMSRα-neo plasmid obtained in (7) was introduced into the CRE-LUC/CO-K1 cells obtained in (2) to obtain transformers. Next, a cell line induced to express luciferase, i.e., hGlucagonR/CRE-LUC/CO-K1 cells, was selected from transformers obtained by adding glucagon.

(9) Reporter essay

[00312] hGIPR/CRE-LUC/CO-K1 cells were inoculated at a cell density of 25 μL/well (5 x 104 cells/well) to a 384-well white plate (Corning) and grown overnight in Ham F12 medium containing 10% fetal bovine serum, 100 U/mL penicillin and 100 µg/mL streptomycin in a 37°C CO2 incubator. A medium containing a test compound was added at a concentration of 5 µL/well to the cells and the resulting cells were incubated for 4 hours in a 37°C CO2 incubator to give the final concentration of 1 µM. PicaGene LT7.5 (Toyo Ink Co., Ltd.) was added thereto at a concentration of 30 µL/well and the mixture was stirred under shielded light. After 30 minutes, luciferase activity was measured using an Envision plate reader (PerkinElmer). The luciferase activity in the presence of 10 nM GIP was defined as 100% and the luciferase activity of adding DMSO instead of the test compound was defined as 0%. GIPR agonist activity was calculated with an increase in intracellular cAMP concentration as an index. The results are shown in table 2.

[00313] GLP-1R agonist activity was assayed in the same manner as before using hGLP-1R/CRE-luc/CO-K1 cells. Luciferase activity in the presence of 10 nM GLP-1 was defined as 100% and the luciferase activity of addition of DMSO instead of test compound was defined as 0%. GLP-1R agonist activity was calculated with an increase in intracellular cAMP concentration as an index. The results are shown in table 2.

[00314] Glucagon R agonist activity was assayed in the same manner as before using hGlucagonR/CRE-LUC/CO-K1 cells. Luciferase activity in the presence of 10 nM glucagon was defined as 100% and the luciferase activity of addition of DMSO instead of test compound was defined as 0%. Glucagon agonist activity was calculated with an increase in intracellular cAMP concentration as an index. The results are shown in table 2.

[00315] As shown in Table 2, the compound of the present invention has a superior activating action on GLP-1 receptors and GIP receptors. Furthermore, the compound of the present invention has a low glucagon receptor activating action. [Table 2]

Test example 2

[00316] 2-day continuous subcutaneous administration trial

[00317] The feed suppressing activity of a test compound was examined by the method described below.

[00318] The test compound was dissolved in a solvent (50% DMSO) in such a way that sustained release could occur at 10 nmol/kg/day and the solution was filled into the Alzet pump (DURECT Corporation, model: 1003D). The pump thus filled with the solution to be administered was submerged in physiological saline to start and then used. The pump was incorporated by the following method. Each 8- to 9-week-old male C57BL/6J mouse (20-26°C, with food and water available ad libitum; 12-hour light-12-hour dark cycle) was anesthetized; the skin on the upper back was incised and the aforementioned pump was embedded subcutaneously; the incision was saturated. After weighing, this mouse was returned to the rearing cage (raised alone) and previously given heavy food; Food consumption as of 2 days after administration was measured. Feed consumption was calculated by subtracting the amount of feed remaining from the feed weight given on the day of initiation of dosing. When the food consumption of a control group receiving administration of the solvent alone was related to a suppression rate of 0%, the food suppressive activity of each test compound was evaluated based on the cumulative food consumption 2 days later. from the beginning of the administration. The food intake suppression rate (%) of the test compound was defined as (Control group food consumption - Test compound food consumption - administered group) / Control group food consumption x 100.

[00319] As shown in Table 3, the compound of the present invention has a superior food intake suppressive action. [Table 3]

Test example 3

[00320] 2-week continuous subcutaneous administration study in DIO mice

[00321] The antiobesity activity of a test compound was examined by the method described below.

[00322] Diet-induced obesity (DIO) mice were prepared by feeding male C57BL/6J mice a high-fat diet (D12451: Research Diets, Inc.). The test compound was dissolved in a solvent (50% DMSO) such that sustained release could occur at 1 nmol/kg/day and the solution was filled into the Alzet Pump (DURECT Corporation, model: 1002). The pump thus filled with the solution to be administered was submerged in physiological saline to start and was then used. The pump was introduced by the following method. Each 35-37 week old male DIO-C57BL/6J mouse (20-26°C, with food and water available ad libitum; 12 hour light-12 hour dark cycle) was anesthetized; the skin on the upper back was incised and the aforementioned pump was embedded subcutaneously; the incision was saturated. After weighing, this mouse was returned to the rearing cage (raised alone) and previously given heavy food; body weight was measured every 1 to 3 days after initiation of administration. The anti-obesity activity of each test compound was evaluated based on the rate of weight loss 2 weeks after initiation of administration, with the rate of weight loss in a control group receiving administration of the solvent alone related to 0%.

[00323] As shown in Table 4, the compound of the present invention has superior anti-obesity activity. [Table 4]

Test example 4 solubility test

[00324] The solubility of a test compound was examined by the method described below.

[00325] The test compound of approximately 2 mg was measured precisely. Solvents (10 μL, 20 μL or 40 μL) with different pHs (Britton-Robinson buffer (pH 3, 5, 7, 9)) were added to each test compound at 25 °C and the solubility was observed visually.

[00326] As shown in Table 5, all test compounds showed good solubility at each pH. [Table 5] Formulation Example 1 (1) Compound of Example 1 10.0 mg (2) Lactose 70.0 mg (3) Corn Starch 50.0 mg (4) Soluble Starch 7.0 mg (5) Magnesium Stearate 3. 0mg

[00327] Compound of example 1 (10.0 mg) and magnesium stearate (3.0 mg) are granulated with an aqueous soluble starch solution (0.07 ml) (7.0 mg as soluble starch), dried and mixed with lactose (70.0 mg) and corn starch (50.0 mg). The mixture is compressed to give a tablet.

[00328] Formulation example 2 (1) Compound of example 1 5.0 mg (2) Sodium chloride 20.0 mg (3) Distilled water for a total amount of 2 mL

[00329] The compound of example 1 (5.0 mg) and sodium chloride (20.0 mg) are dissolved in distilled water and water is added to a total amount of 2.0 ml. The solution is filtered and filled into a 2 mL ampoule under aseptic conditions. The ampoule is sterilized and tightly sealed to give a solution for injection.

Industrial Applicability

[00330] The compound of the present invention has superior GLP-1 receptor/GIP receptor coagonist activity and is used as a drug for the prophylaxis or treatment of various diseases associated with GLP-1 receptor/GIP receptor, for example , obesity.

[00331] All publications, patents and patent applications cited herein are incorporated herein by reference in full. Free Text Sequence Listing SEQ ID NO: 1: Artificial Sequence (Synthetic Peptide (Formula (I))) SEQ ID NO: 2: Artificial Sequence (Synthetic Peptide (C-terminal Sequence)) SEQ ID NO: 3: Artificial Sequence (Synthetic peptide (C-terminal sequence)) SEQ ID NO: 4: Artificial sequence (Synthetic peptide (C-terminal sequence)) SEQ ID NO: 5: Artificial sequence (Synthetic peptide (C-terminal sequence)) SEQ ID NO: 6: Artificial sequence (Synthetic peptide (C-terminal sequence)) SEQ ID NO: 7: Artificial sequence (Synthetic peptide (C-terminal sequence)) SEQ ID NO: 8: Artificial sequence (Synthetic peptide (C-terminal sequence)) SEQ ID NO: 9: Artificial Sequence (Synthetic Peptide ( C-terminal Sequence)) SEQ ID NO: 10: Artificial Sequence (Synthetic Peptide (Reference Example 1)) SEQ ID NO: 11: Artificial Sequence (Synthetic Peptide (Reference Example 1) reference 2)) SEQ ID NO: 12: Artificial sequence (Synthetic peptide (Reference example 3)) SEQ ID NO: 13: Artificial sequence (Synthetic peptide (Example 1)) SEQ ID NO: 14: Artificial sequence (Synthetic peptide ( Example 2)) SEQ ID NO: 15: Artificial Sequence (Synthetic Peptide (Example 3)) SEQ ID NO: 16: Artificial Sequence (Synthetic Peptide (Example 4)) SEQ ID NO: 17: Artificial Sequence (Synthetic Peptide (Example 5) )) SEQ ID NO: 18: Artificial Sequence (Synthetic Peptide (Example 6)) SEQ ID NO: 19: Artificial Sequence (Synthetic Peptide (Example 7)) SEQ ID NO: 20: Artificial Sequence (Synthetic Peptide (Example 8)) SEQ ID NO: 21: Artificial Sequence (Synthetic Peptide (Example 9)) SEQ ID NO: 22: Artificial Sequence (Synthetic Peptide (Example 10)) SEQ ID NO: 23: Artificial Sequence (Synthetic Peptide (Example 11)) SEQ ID NO: 24: Artificial Sequence (Synthetic Peptide (Example 12)) SEQ ID NO: 25: Artificial Sequence (Synthetic Peptide (Example 13)) SEQ ID NO: 26: Artificial Sequence (Synthetic Peptide (Example 14)) SEQ ID NO: 27: Artificial Sequence (Synthetic Peptide (Example 15)) SEQ ID NO: 28: Artificial Sequence (Synthetic Peptide (Example 16)) SEQ ID NO: 29: Artificial Sequence (Synthetic Peptide (Example 17)) SEQ ID NO: 30: Artificial Sequence (Synthetic Peptide (Example 18)) SEQ ID NO: 31: Artificial Sequence (Synthetic Peptide (Example 19)) SEQ ID NO: 32: Artificial Sequence (Peptide (Example 20)) SEQ ID NO: 33: Artificial Sequence ( Peptide (Example 21)) SEQ ID NO: 34: Artificial Sequence (Peptide (Example 22)) SEQ ID NO: 35: Artificial Sequence (Peptide (Example 23)) SEQ ID NO: 36: Artificial Sequence (Peptide (Example 24)) ) SEQ ID NO: 37: Artificial Sequence (Peptide (Example 25)) SEQ ID NO: 38: Artificial Sequence (Peptide (Example 26))

Claims (20)

1. Peptide, characterized by the fact that it has the formula (I): P1-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-A11-A12-A13-Leu-Asp-A16-A17 -Ala-Gln-A20-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-A29 where P1 is selected from the group consisting of a hydrogen atom, methyl group, acetyl group, benzoyl group, 4- group pyridylcarbonyl (4-PyCO), cyclopropanecarbonyl group (CPrCO), and amidino group; A11 is Aib or Ala; A12 is Ala, Ile, Lys, Phe or Pya(4); A13 is Aib, Cha, Leu, αMePhe or αMeTyr; A16 is Lys or Ser; A17 is Gln or Ile; A20 is Ala or Ser; A29 is Gln or Gly, and an amino acid sequence represented by Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser- or Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro- Pro-Ser-Lys- on the C-terminal side of A29, or a salt thereof. 2. Peptide according to claim 1 or a salt thereof, characterized in that P1 is a hydrogen atom. 3. Peptide according to claim 1 or a salt thereof, characterized in that A11 is Aib. 4. Peptide according to claim 1 or a salt thereof, characterized in that A12 is Ile. 5. Peptide according to claim 1 or a salt thereof, characterized in that A13 is Aib. 6. Peptide according to the same claim, characterized by the fact that A16 is Lys. 7. Peptide according to claim 1 or a salt thereof, characterized in that A17 is Gln. 8. Peptide according to claim 1 or a salt thereof, characterized in that A20 is Ala. 9. Peptide according to claim 1 or a salt thereof, characterized in that A29 is Gly. 10. Peptide according to claim 1 or a salt thereof, characterized in that it is with an amino acid sequence represented by Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys- on the C-terminal side of the A29. 11. Peptide according to claim 1 or a salt thereof, characterized in that P1 is a hydrogen atom; A11 is Aib; A12 is Ile; A13 is Aib; A16 is Lys; A17 is Gln; A20 is Wing; A29 is Gly; and the peptide with an amino acid sequence represented by Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys- on the C-terminal side of A29. 12. Sequence, characterized by the fact that it comprises H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Ala -Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH 2 , or a salt thereof. 13. Sequence, characterized by the fact that it comprises H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Ala -Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH 2 , or a salt thereof. 14. Sequence, characterized by the fact that it comprises H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Gln -Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH 2 , or a salt thereof. 15. Sequence, characterized by the fact that it comprises H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Tyr-Leu-Asp-Lys-Gln-Ala-Gln-Gln -Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 , or a salt thereof. 16. Medication, characterized in that it comprises the peptide as defined in claim 1 or a salt thereof. 17. Medication according to claim 16, characterized in that it is an activator of a GLP-1 receptor and a GIP receptor. 18. Medicine according to claim 16, characterized in that it is an agent for the prophylaxis or treatment of obesity or diabetes. 19. Use of a peptide as defined in claim 1 or a salt thereof, characterized in that it is for the manufacture of an agent for the prophylaxis or treatment of obesity or diabetes. 20. Peptide according to claim 1 or a salt thereof, characterized in that it is for use in the prophylaxis or treatment of obesity or diabetes.