TWI770085B - Peptide compound - Google Patents

Abstract

The present invention relates to a peptide compound which is useful for treatment or prevention of obesity or diabetes or the like. More specifically, it relates to a peptide compound represented by the formula (I): P¹-Tyr-Aib-Glu-Gly-Thr-α-MePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-R^A10)-A11-A12-Aib-Leu-A15-Lys-Gln-A18-Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-A35-NH₂ (the symbols in the formula are as specified in the specification), and a treatment or prevention for obesity or diabetes or the like using the peptide compound.

Description

peptide compound

The present invention relates to a peptide compound useful in the treatment or prevention of obesity, diabetes and the like based on the activation of Y2 receptor, GLP-1 receptor and GIP receptor.

Peptide YY (PYY) is a peptide consisting of 36 amino acid residues isolated from the upper small intestine of pigs. PYY and neuropeptide Y (NPY) isolated from porcine brain belong to the same family of pancreatic polypeptides (PP) (Patent Documents 1 and 2).

It is known that PYY is secreted from digestive tract endocrine cells (L cells) in association with dietary intake, and exhibits a feeding inhibitory effect via the Y2 receptor. In terms of its action pathways, the gut/hypothalamic pathway mediated by Y2 receptors of NPY/AgRP expressing neurons in the hypothalamic arcuate nucleus, and the vagal afferent pathway mediated by Y2 receptors at vagal nerve terminals have been reported.

In addition, it has been reported that patients with anorexia nervosa (AN; Anorexia Nervosa) with abnormal eating behaviors have high PYY concentrations in the cerebrospinal cord, and patients with bulimia nervosa (BN; Bulimia Nervosa), compared with healthy people, have higher levels of PYY after eating. The increase in the concentration of PYY in the blood is extremely slow. Furthermore, it is known that The blood PYY concentration of obese patients is lower than that of healthy people.

Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulin secretion-stimulating polypeptide (GIP) are collectively referred to as incretin peptides. GLP-1 and GIP are secreted by L cells and K cells, respectively, in the small intestine. It is known that GLP-1 acts through the mediation of GLP-1 receptors, and has a glucose-dependent insulin secretion-promoting action and a feeding-inhibiting action. On the other hand, GIP is known to have a glucose-dependent insulin secretion-promoting action through the mediation of GIP receptors, but its effect on food intake is unclear.

It has been reported that a GLP-1 receptor/GIP receptor co-agonist peptide exhibits stronger blood sugar-lowering effects and body weight-lowering effects than GLP-1 receptor agonists alone (Patent Document 3). In addition, according to the structure of natural glucagon, GIP or GLP-1, it is also attempted to explore peptides with GLP-1 receptor/GIP receptor co-agonist activity, or to develop them as anti-obesity drugs and diabetes treatment drugs. (Patent Documents 3 to 6).

[Prior Art Literature] [Patent Literature]

[Patent Document 1] WO2006/049681

[Patent Document 2] WO2011/002066

[Patent Document 3] WO2010/011439

[Patent Document 4] WO2013/164483

[Patent Document 5] WO2014/192284

[Patent Document 6] WO2016/084826

An object of the present invention is to provide a peptide compound which has an activating action of Y2 receptor, GLP-1 receptor and GIP receptor and is useful as a preventive/therapeutic agent for obesity, diabetes and the like.

As a result of intensively examining peptide compounds useful as prophylactic/therapeutic agents for obesity, diabetes, etc. based on the activation of Y2 receptors, GLP-1 receptors and GIP receptors, the inventors found that they have the following formula ( The peptide compound of the sequence shown in I) is useful in the prevention/treatment of obesity or diabetes based on the activation of Y2 receptor, GLP-1 receptor and GIP receptor, and the present invention has been completed.

That is, the present invention relates to the following [1] to [17].

[1] A peptide or a salt thereof, wherein the peptide is represented by formula (I) (hereinafter, abbreviated as compound (I)): P ¹ -Tyr-Aib-Glu-Gly-Thr-α-MePhe-Thr -Ser-Asp-Lys(-Gly-Gly-Gly-Gly-R ^A10 )-A11-A12-Aib-Leu-A15-Lys-Gln-A18-Gln-Iva-Glu-Phe-Val-Arg-His- Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-A35-NH ₂ (SEQ ID NO: 1) [wherein, P ¹ represents a group represented by the following formula: -R ^A1 , -CO-R ^A1 , -CO-OR ^A1 , -CO-COR ^A1 , -SO-R ^A1 , -SO ₂ -R ^A1 , -SO ₂ -OR ^A1 , -CO-NR ^A2 R ^A3 , -SO ₂ -NR ^A2 R ^A3 , or -C(=NR ^A1 )-NR ^A2 R ^A3 (wherein, R ^A1 , R ^A2 and R ^A3 independently represent a hydrogen atom, a substituted hydrocarbon group, or a substituted heterocyclic group); R ^A10 Represents Pal or Oda; A11 represents Aib, Ala or Ser (A11 is preferably Aib, in other aspects, preferably Ala, in other aspects, preferably Ser); A12 represents Ile or Lys; A15 represents Asp or Glu; A18 represents Ala or Arg; A35 represents Tyr or Phe(2-F)].

[2] The peptide or salt thereof according to the above [1], wherein P ¹ is a hydrogen atom or a methyl group.

[3] The peptide or its salt according to the above [1], wherein R ^A10 is Pal.

[4] The peptide or salt thereof according to the above [1], wherein A12 is Ile.

[5] The peptide or its salt according to the above [1], wherein A15 is Glu.

[6] The peptide or salt thereof according to the above [1], wherein A18 is Arg.

[7] The peptide or salt thereof according to the above [1], wherein A35 is Tyr.

[8] A peptide or a salt thereof, which is H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib- Ile-Aib-Leu-Glu-Lys-Gln-Arg-Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ .

[9] A peptide or a salt thereof, which is H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Ala- Ile-Aib-Leu-Glu-Lys-Gln-Arg-Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ .

[10] A peptide or a salt thereof, which is Me-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Ser- Ile-Aib-Leu-Glu-Lys-Gln-Arg-Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ .

[11] A medicine comprising the peptide according to the above [1] or a salt thereof.

[12] The medicine according to the above [11], which is an activator of Y2 receptor, GLP-1 receptor and GIP receptor.

[13] The medicine according to the above [11], which is a preventive/therapeutic agent for obesity or diabetes.

[14] A method for preventing/treating obesity or diabetes in a mammal, comprising administering to the mammal an effective amount of the peptide according to the above [1] or a salt thereof.

[15] A method for activating Y2 receptors, GLP-1 receptors and GIP receptors in a mammal, comprising administering to the mammal an effective amount of the peptide according to the above [1] or a salt thereof.

[16] A use of the peptide or its salt according to the above [1], for the production of A preventive/therapeutic agent for obesity or diabetes.

[17] The peptide or its salt according to the above [1], which is used for the prevention/treatment of obesity or diabetes.

Compound (I) has a feeding inhibitory effect and a body weight reducing effect in vivo based on the activation of Y2 receptor, GLP-1 receptor and GIP receptor. Therefore, compound (I) is useful as a preventive and/or therapeutic agent for obesity or diabetes.

Figure 1 shows the anti-obesity effect of the compound of Example 41 (P41) in DIO mice. Each compound was administered subcutaneously to mice once a day for 4 weeks. (a) Day-to-day changes in body weight, (b) % hindrance rate of cumulative food intake, (c) body fat mass measured by EchoMRI, (d) body lean mass, (e) adipose tissue (fat pad) ) weight, (f) liver tissue weight, (g) TG content in liver, (h) Hematoxy-eosin staining of liver sections, (i) expression of each gene. *p<0.025, **p<0.005, ***p<0.0005 vs. vehicle (Shirley-Williams test), #p<0.025, ##p<0.005, ###p<0.0005 vs. vehicle (Williams' test), data represent mean ± SD (N=6).

Figure 2 shows the anti-obesity, anti-diabetic effects of P41 in ob/ob mice. Each compound was administered subcutaneously to mice once a day for 4 weeks. (a) GHb, (b) plasma glucose, (c) plasma insulin, (d) daily change in body weight, (e) % inhibition of cumulative food intake, (f) tissue weight amount, and (g) TG content in the liver. #p<0.025, ##p<0.005, ###p<0.0005 vs. vehicle (Shirley-Williams test), data represent mean ± SD (N=5-7). In addition, the vehicle-administered group was N=5, and the P41-administered group was N=7.

Figure 3 shows the anti-obesity, anti-diabetic effects of P41 in male KKA ^y mice. After subcutaneous administration of each compound to mice once a day for 4 weeks, (a) daily change in body weight, (b) % inhibition rate of cumulative food intake, (c) ΔGHb, (d) plasma Glucose, (e) plasma insulin, (f) liver tissue weight, (g) TG content in liver, and (h) white fat weight. *p<0.025, **p<0.005, ***p<0.0005 vs vehicle (Williams' test), #p<0.025, ##p<0.005, ### p<0.0005 vs vehicle (Shirley-Williams test) . Data represent mean ± SD (N=7).

Figure 4 shows the effect of P41 on the taste aversion test. Mice were dosed twice with compound and 0.1% saccharin during one week. On the second day after the second conditioning, both 0.1% sodium saccharin and tap water were supplied to the mice for 3 hours, the water intake of each liquid was measured, and the preference rate of saccharin was calculated. ***p<0.001 vs. vehicle (Dunnett's test). Data represent mean ± SD (N=7).

Figure 5 shows the feeding inhibitory effect of P41 in cynomolgus monkeys. About 8 hours after administration, the normal food was fed. During the 24 hours post-administration, no emesis was observed. N=2 (male: 1, female: 1).

Hereinafter, the definition of each substituent used in this specification will be described in detail. As long as it is not particularly limited, each substituent has the following definitions.

In this specification, "halogen atom" includes, for example, fluorine, Chlorine, Bromine, Iodine.

In this specification, "C _1-6 alkyl" includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl , pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethyl butyl, 2-ethylbutyl.

In the present specification, the "C _1-6 alkyl group which may be halogenated" includes, for example, a C _1-6 alkyl group which may have 1 to 7, preferably 1 to 5, halogen atoms. Specific examples 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 butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl.

In this specification, "C _2-6 alkenyl" includes, for example, vinyl, 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 yl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl.

In this specification, "C _2-6 alkynyl" includes, for example, 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 group, 5-hexynyl, 4-methyl-2-pentynyl.

In this specification, "C _3-10 cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1 ]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, adamantyl.

In the present specification, as "C _3-10 cycloalkyl which may be halogenated", for example, C _3-10 cycloalkyl which may have 1 to 7, preferably 1 to 5 halogen atoms can be exemplified . Specific examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl Heptyl, cyclooctyl.

In this specification, "C _3-10 cycloalkenyl" includes, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl .

In the present specification, the "C _6-14 aryl group" includes, for example, a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a 1-anthryl group, a 2-anthryl group, and a 9-anthryl group.

In the present specification, the "C _7-16 aralkyl group" includes, for example, a benzyl group, a phenethyl group, a naphthylmethyl group, and a phenylpropyl group.

In this specification, "C _1-6 alkoxy" includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, second Butoxy, tert-butoxy, pentyloxy, hexyloxy.

In the present specification, as "C _1-6 alkoxy which may be halogenated", for example, C _1-6 alkoxy which may have 1 to 7, preferably 1 to 5 halogen atoms can be exemplified . Specific examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, Butoxy, 4,4,4-trifluorobutoxy, isobutoxy, second butoxy, pentyloxy, hexyloxy.

In the present specification, "C _3-10 cycloalkoxy" includes, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy Oxygen.

In the present specification, the "C _1-6 alkylthio group" includes, for example, a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, the second butylthio group, the first Tributylthio, pentylthio, hexylthio.

In the present specification, the "C _1-6 alkylthio group which may be halogenated" includes, for example, a C _1-6 alkylthio group which may have 1 to 7, preferably 1 to 5 halogen atoms. . Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluoro Butylthio, pentylthio, hexylthio.

In the present specification, "C _1-6 alkyl-carbonyl" includes, for example, acetyl, propionyl, butyryl, 2-methylpropionyl, pentamyl, and 3-methylbutyryl , 2-methylbutyryl, 2,2-dimethylpropionyl, hexyl, and heptyl.

In the present specification, as "a C _1-6 alkyl-carbonyl group which may be halogenated", for example, a C _1-6 alkyl group which may have 1 to 7, preferably 1 to 5 halogen atoms can be exemplified - Carbonyl. As a specific example, an acetyl group, a chloroacetyl group, a trifluoroacetyl group, a trichloroacetyl group, a propionyl group, a butyryl group, a pentamyl group, and a hexyl group are mentioned.

In this specification, "C _1-6 alkoxy-carbonyl" includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, Isobutoxycarbonyl, second butoxycarbonyl, third butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl.

In this specification, as a "C _6-14 aryl-carbonyl group", for example, a benzyl group, a 1-naphthoyl group, and a 2-naphthoyl group are mentioned.

In the present specification, "C _7-16 aralkyl-carbonyl" includes, for example, a phenylacetyl group and a phenylpropionyl group.

In the present specification, the "5- to 14-membered aromatic heterocyclic carbonyl group" includes, for example, a nicotinyl group, an isonicotinoyl group, a thiophenecarboxyl group, and a furocarboxyl group.

In the present specification, the "3- to 14-membered non-aromatic heterocyclic carbonyl group" includes, for example, a morpholinylcarbonyl group, a piperidinylcarbonyl group, and a pyrrolidinylcarbonyl group.

In the present specification, "mono- or di-C _1-6 alkyl-aminocarboxy" includes, for example, methylaminocarboxy, ethylcarbamoyl, and dimethylcarbamoyl Carboxyl, diethylamine carboxyl, N-ethyl-N-methylamine carboxyl.

In the present specification, "mono- or di-C _7-16 aralkyl-aminocarboxy" includes, for example, benzylaminocarboxy and phenethylaminecarboxy.

In the present specification, "C _1-6 alkylsulfonyl" includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl Sulfonyl, second-butylsulfonyl, and third-butylsulfonyl.

In the present specification, as "a C _1-6 alkylsulfonyl group which may be halogenated", for example, a C _1-6 alkyl group which may have 1 to 7, preferably 1 to 5 halogen atoms can be exemplified Sulfonyl. Specific examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, and butylsulfonyl. Sulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, hexylsulfonyl.

In the present specification, the "C _6-14 arylsulfonyl group" includes, for example, a phenylsulfonyl group, a 1-naphthylsulfonyl group, and a 2-naphthylsulfonyl group.

In this specification, the "substituent group" includes, for example, a halogen atom, a cyano group, a nitro group, a substituted hydrocarbon group, a substituted heterocyclic group, an acyl group, a substituted amino group, Can be substituted carbamoyl, can be substituted thiocarbamoyl, can be substituted sulfamoyl, can be substituted hydroxy, can be substituted mercapto (SH group), can be substituted silicon base.

In this specification, "hydrocarbon group" (including "hydrocarbon group" in "hydrocarbon group which may be substituted"), for example, C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkyne group can be exemplified group, C _3-10 cycloalkyl, C _3-10 cycloalkenyl, C _6-14 aryl, C _7-16 aralkyl.

In the present specification, "the hydrocarbon group which may be substituted" includes, for example, a hydrocarbon group which may have a substituent selected from the following substituent group A.

[Substituent Group A]

(1) halogen atom, (2) nitro group, (3) cyano group, (4) pendant oxy group, (5) hydroxyl group, (6) C _1-6 alkoxy group which may be halogenated, (7) C _{6 -14} Aryloxy (eg, phenoxy, naphthyloxy), (8) C _7-16 aralkoxy (eg, benzyloxy), (9) 5- to 14-membered aromatic heterocycleoxy ( For example, pyridyloxy), (10) 3- to 14-membered non-aromatic heterocyclyloxy (eg, morpholinyloxy, piperidinyloxy), (11) C _1-6 alkyl-carbonyloxy (eg, acetyloxy, propionyloxy), (12)C _6-14 aryl-carbonyloxy (eg, benzyloxy, 1-naphthyloxy, 2- naphthyloxy), (13)C _1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyl oxy), (14) mono- or di-C _1-6 alkyl-aminocarboxy (eg, methylaminocarboxy, ethylaminecarboxy, dimethylamine carboxyloxy, diethylamine carboxyloxy), (15)C _6-14 aryl-aminocarbamoyloxy (e.g., phenylamine carboxyloxy, naphthylamine carboxyloxy) (16) 5- to 14-membered aromatic heterocyclic carbonyloxy (eg, nicotinyloxy), (17) 3- to 14-membered non-aromatic heterocyclic carbonyloxy (eg, morpholine (18) C _1-6 alkylsulfonyloxy which may be halogenated (eg, methylsulfonyloxy, trifluoromethylsulfonyloxy) base), (19) C _6-14 arylsulfonyloxy (for example, phenylsulfonyloxy, tosylsulfonyloxy) which may be substituted by C _1-6 alkyl, (20) may be Halogenated C _1-6 alkylthio group, (21) 5- to 14-membered aromatic heterocyclic group, (22) 3- to 14-membered non-aromatic heterocyclic group, (23) carboxyl group, (24) carboxyl group, (25) C _1-6 alkyl-carbonyl, (26) C _6-14 aryl-carbonyl, (27) 5- to 14-membered aromatic heterocyclic carbonyl, (28) 3- to 14-membered non-aromatic which may be halogenated family of heterocyclic carbonyl, (29)C _1-6 alkoxy-carbonyl, (30) C _6-14 aryloxy-carbonyl (e.g., phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthyloxy carbonyl), (31) C _7-16 aralkoxy-carbonyl (for example, benzyloxycarbonyl, phenethoxycarbonyl), (32) aminocarboxy, (33) thiocarbamoyl, ( 34) Mono- or di-C _1-6 alkyl-aminocarbamoyl, (35) C _6-14 aryl-carbamoyl (eg, phenylamine carboxyl), (36) 5 to 14 Aromatic heterocyclic carbamoyl (for example, pyridylaminocarboxy, thienylcarbamoyl), (37) 3- to 14-membered non-aromatic heterocyclic carbamoyl (for example, morpholinylamine (38) C _1-6 alkylsulfonyl, (39) C _6-14 arylsulfonyl, (40) 5 to 14 members which may be halogenated Aromatic Heterocyclic Sulfonyl ( For example, pyridylsulfonyl, thienylsulfonyl), (41) C _1-6 alkylsulfinyl which may be halogenated, (42) C _6-14 arylsulfinyl (eg, benzene sulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl), (43) 5- to 14-membered aromatic heterocyclic sulfinyl (eg, pyridylsulfinyl, thienylsulfinyl), (44) amine, (45) mono- or di-C _1-6 alkylamino (eg, methylamino, ethylamino, propylamino, isopropyl amino, butylamine, dimethylamine, diethylamine, dipropylamine, dibutylamine, N-ethyl-N-methylamine), (46) mono - or di-C _6-14 arylamino (eg, phenylamino), (47) 5- to 14-membered aromatic heterocyclic amino (eg, pyridylamino), (48) C _7-16 Aralkylamino (eg, benzylamino), (49) carboxylamino, (50) C _1-6 alkyl-carbonylamino (eg, acetylamino, propionylamino) , butylamino), (51) (C _1-6 alkyl) (C _1-6 alkyl-carbonyl) amino (for example, N-acetyl-N-methylamino), (52) C _6-14 Aryl-carbonylamino (for example, phenylcarbonylamino, naphthylcarbonylamino), (53)C _1-6 alkoxy-carbonylamino (for example, methoxycarbonylamino, ethyl oxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino), (54)C _7-16 aralkoxy-carbonylamino (for example, benzyloxy carbonylamino), (55) C _1-6 alkylsulfonamido (for example, methylsulfonamido, ethylsulfonamido), (56) can be via C _1-6 alkyl C _6-14 arylsulfonylamino groups substituted with radicals (eg, phenylsulfonylamino, tosylamino), (57) C _1-6 alkyl which may be halogenated, (58) C _2-6 alkenyl, (59) C _2-6 alkynyl, (60) C _3-10 cycloalkyl, (61) C _3-10 cycloalkenyl, and (62) C _6-14 aryl.

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

In the present specification, "heterocyclic group" (including "heterocyclic group" in "heterocyclic group which may be substituted") includes, for example, ring constituent atoms other than carbon atoms, respectively (i) aromatic heterocyclic group, (ii) containing 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom Non-aromatic heterocyclyl and (iii) 7- to 10-membered hybrid bicyclyl.

In the present specification, "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") includes, for example, a group containing a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. A 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group having 1 to 4 heteroatoms as ring constituent atoms.

唑基、異

唑基、吡啶基、吡

基、嘧啶基、嗒

基、1,2,4-

二唑基、1,3,4-

二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、三唑基、四唑基、三

基等5至6員單環式芳香族雜環基； 苯并苯硫基、苯并呋喃基、苯并咪唑基、苯并

唑基、苯并異

唑基、苯并噻唑基、苯并異噻唑基、苯并三唑基、咪唑并吡啶基、噻吩并吡啶基、呋喃并吡啶基、吡咯并吡啶基、吡唑并吡啶基、

唑并吡啶基、噻唑并吡啶基、咪唑并吡

基、咪唑并嘧啶基、噻吩并嘧啶基、呋喃并嘧啶基、吡咯并嘧啶基、吡唑并嘧啶基、

唑并嘧啶基、噻唑并嘧啶基、吡唑并三

基、萘并[2,3-b]噻吩基、吩

噻基、吲哚基、異吲哚基、1H-吲唑基、嘌呤基、異喹啉基、喹啉基、呔

基、萘啶基、喹

啉基、喹唑啉基、

啉基、咔唑基、β-咔啉基、啡啶基、吖啶基、啡

基、啡噻

基、啡

基等8至14員稠合多環式(較佳為2或3環式)芳香族雜環基。 Preferred examples of the "aromatic heterocyclic group" include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,

azolyl, iso

azolyl, pyridyl, pyridine

base, pyrimidinyl, da

base, 1,2,4-

oxadiazolyl, 1,3,4-

oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazolyl

5- to 6-membered monocyclic aromatic heterocyclic groups such as radicals; benzothiophene, benzofuranyl, benzimidazolyl, benzoyl

azolyl, benziso

azolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridyl, thienopyridyl, furopyridyl, pyrrolopyridyl, pyrazolopyridyl,

azolopyridyl, thiazolopyridyl, imidazopyridyl

base, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl,

azolopyrimidyl, thiazolopyrimidyl, pyrazolotri

base, naphtho[2,3-b]thienyl, phene

Thiyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolinyl, quinolinyl, pyridine

base, naphthyridinyl, quinoline

olinyl, quinazolinyl,

Linoyl, carbazolyl, β-carboline, phenidyl, acridine, phenanthrene

base, phenothia

base, brown

8- to 14-membered condensed polycyclic (preferably 2- or 3-ring) aromatic heterocyclic group.

In this specification, "non-aromatic heterocyclic groups" (including "3- to 14-membered non-aromatic heterocyclic groups") include, for example, those containing carbon atoms, those selected from the group consisting of nitrogen atoms and sulfur atoms. A 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group having 1 to 4 heteroatoms of oxygen atoms as ring constituent atoms.

唑啉基、

唑啶基、吡唑啉基、吡唑啶基、噻唑啉基、噻唑啶基、四氫異噻唑基、四氫

唑基、四氫異

唑基、哌啶基、哌

基、四氫吡啶基、二氫吡啶基、二氫噻喃基、四氫嘧啶基、四氫嗒

基、二氫哌喃基、四氫哌喃基、四氫噻喃基、嗎啉基、硫代嗎啉基、氮雜環庚基、二氮雜環庚基、氮雜環庚三烯基、氧雜環庚基、氮雜環辛基、二氮雜環辛基等3至8員單環式非芳香族雜環基； 二氫苯并呋喃基、二氫苯并咪唑基、二氫苯并

唑基、二氫苯并噻唑基、二氫苯并異噻唑基、二氫萘并[2,3-b]噻吩基、四氫異喹啉基、四氫喹啉基、4H-喹

基、吲哚啉基、異吲哚啉基、四氫噻吩并[2,3-c]吡啶基、四氫苯并氮雜環庚三烯基、四氫喹

啉基、四氫啡啶基、六氫啡噻

基、六氫啡

基、四氫呔

基、四氫萘啶基、四氫喹唑啉基、四氫

啉基、四氫咔唑基、四氫-β-咔啉基、四氫吖啶基、四氫啡

基、四氫硫雜蒽基(tetrahydrothioxanthenyl)、 八氫異喹啉基等9至14員稠合多環式(較佳為2或3環式)非芳香族雜環基。 Preferred examples of the "non-aromatic heterocyclic group" include aziridinyl, epoxyethyl, epithioethyl, azetidinyl, oxetanyl, and thiane Butyl, tetrahydrothienyl, tetrahydrofuranyl, pyrroline, pyrrolidinyl, imidazolinyl, imidazolidinyl,

oxazoline,

oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydro

azolyl, tetrahydroiso

azolyl, piperidinyl, piper

base, tetrahydropyridyl, dihydropyridyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridine

base, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azacycloheptyl, diazepanyl, azacycloheptatrienyl , 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as oxeptyl, azacyclooctyl, diazepinyl, etc.; dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydro Benzo

azolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 4H-quinoline

base, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridyl, tetrahydrobenzazepine, tetrahydroquinoline

Linoyl, tetrahydrophenidyl, hexahydrophenothiline

base, hexahydrophenone

base, tetrahydropyridine

base, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydro

Linyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenone

9- to 14-membered condensed polycyclic (preferably 2- or 3-ring) non-aromatic heterocyclic groups such as tetrahydrothioxanthenyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl.

In the present specification, preferable examples of the "7- to 10-membered heterobridged ring group" include quinuclidinyl and 7-azabicyclo[2.2.1]heptyl.

In the present specification, the "nitrogen-containing heterocyclic group" includes at least one nitrogen atom as a ring constituent atom among the "heterocyclic group".

In this specification, the "heterocyclic group which may be substituted" includes, for example, a heterocyclic group which may have a substituent selected from the aforementioned substituent group A.

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

In the present specification, the "acyl group" includes, for example, "C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C 3-10 cycloalkyl group, C _3-10 ring 1 or 2 substituents of alkenyl, C _6-14 aryl, C _7-16 aralkyl, 5- to 14-membered aromatic heterocyclic group and 3- to 14-membered non-aromatic heterocyclic group" , carboxyl group, carboxyl group, thiocarbamoyl group, sulfinyl group, sulfonic acid group, sulfasulfonyl group, phosphine group, wherein the above-mentioned substituents can respectively have C selected from halogen atoms, halogenated C _1-6 1 to 3 substituents of alkoxy, hydroxyl, nitro, cyano, amine and amine carboxyl.

Moreover, as a "sulfonyl group", a hydrocarbon-sulfonyl group, a heterocyclic-sulfonyl group, a hydrocarbon-sulfinyl group, and a heterocyclic-sulfinyl group can also be mentioned.

Here, a hydrocarbon-sulfonyl group means a sulfonyl group bonded to a hydrocarbon group, a heterocycle-sulfonyl group means a sulfonyl group bonded to a heterocyclic group, and a hydrocarbon-sulfinyl group means a hydrocarbon group bonded The sulfinyl group, heterocycle-sulfinyl group means a sulfinyl group bonded to a heterocyclic group.

Preferable examples of the "acyl group" include a formyl group, a carboxyl group, a C _1-6 alkyl-carbonyl group, a C _2-6 alkenyl-carbonyl group (for example, a crotonyl group), a C _3-10 ring Alkyl-carbonyl (eg, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), _C3-10 cycloalkenyl-carbonyl (eg, 2-cyclohexenecarbonyl), _{C6 -14} Aryl-carbonyl, C _7-16 aralkyl-carbonyl, 5- to 14-membered aromatic heterocyclic carbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, C _1-6 alkoxy-carbonyl, C _{6 -14} Aryloxy-carbonyl (eg, phenoxycarbonyl, naphthoxycarbonyl), C _7-16 aralkoxy-carbonyl (eg, benzyloxycarbonyl, phenethoxycarbonyl), amine carboxyl , mono- or di-C _1-6 alkyl-amine carboxyl, mono- or di-C _2-6 alkenyl-amino carboxyl (eg, diallylamine carboxyl), mono- or Di-C _3-10 cycloalkyl-amine carboxyl (eg, cyclopropylamine carboxyl), mono- or di-C _6-14 aryl-amine carboxyl (eg, phenylamine carboxyl) base), mono- or di-C _7-16 aralkyl-carbamoyl, 5- to 14-membered aromatic heterocyclic carbamoyl (eg, pyridylcarbamoyl), thiocarbamoyl , mono- or di-C _1-6 alkyl-thiocarbamoyl (eg, methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C _2-6 alkenyl-thiocarbamyl (e.g., diallylthiocarbamyl), mono- or di-C _3-10 cycloalkyl-thiocarbamyl (eg, cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C _6-14 aryl-thiocarbamoyl (eg, phenylthiocarbamoyl) base), mono- or di-C _7-16 aralkyl-thiocarbamoyl (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), 5- to 14-membered aromatic family of heterocyclic thiocarbamyl (eg, pyridyl thiocarbamyl), sulfinyl, C _1-6 alkylsulfinyl (eg, methylsulfinyl, ethylsulfinyl) sulfonyl), sulfonic acid group, C _1-6 alkylsulfonyl group, C _6-14 arylsulfonyl group, phosphine group, mono- or di-C _1-6 alkyl phosphine group (for example, Dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono).

In the present specification, the "amino group that may be substituted" may include, for example, "a group selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _3-10 cycloalkyl, C _{6 -14} aryl, C _7-16 aralkyl, C _1-6 alkyl-carbonyl, C _6-14 aryl-carbonyl, C _7-16 aralkyl-carbonyl, 5- to 14-membered aromatic heterocyclic carbonyl , 3- to 14-membered non-aromatic heterocyclic carbonyl, C _1-6 alkoxy-carbonyl, 5- to 14-membered aromatic heterocyclyl, amine carboxyl, mono- or di-C _1-6 alkyl-amine 1 or 2 substituents among carboxyl, mono- or di-C _7-16 aralkyl-carbamoyl, C _1-6 alkylsulfonyl and C _6-14 arylsulfonyl, wherein the substituents may respectively have 1 to 3 substituents selected from the group A of substituents".

As preferred examples of the substituted amine group, an amine group, mono- or di-(C _1-6 alkyl which may be halogenated) amine group (eg, methylamino group, trifluoromethyl group) can be listed. amine, dimethylamine, ethylamine, diethylamine, propylamine, dibutylamine), mono- or di-C _2-6 alkenylamine (eg, diene propylamino), mono- or di- _C3-10 cycloalkylamino (eg, cyclopropylamino, cyclohexylamino), mono- or di- _C6-14 arylamino (eg , phenylamino), mono- or di-C _7-16 aralkylamino (eg, benzylamino, dibenzylamino), mono- or di- (C _1-6 which may be halogenated alkyl)-carbonylamino (eg, acetylamino, propionylamino), mono- or di-C _6-14 aryl-carbonylamino (eg, benzylamino), mono- or di-C _7-16 aralkyl-carbonylamino (for example, benzylcarbonylamino), mono- or di-5 to 14 membered aromatic heterocyclic carbonylamino (for example, nicotinylamino, isonicotinoylamino), mono- or di-3- to 14-membered non-aromatic heterocyclic carbonylamino (eg, piperidinylcarbonylamino), mono- or di-C _1-6 alkoxy- Carbonylamino (eg, 3-butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino (eg, pyridylamino), carbamoylamino, (mono- or di-C _{1 -6} alkyl-aminocarbamoyl)amino (eg, methylaminocarbamoyl), (mono- or di-C _7-16 aralkyl-aminocarbamoyl)amine (eg, benzyl aminocarbamoylamino), C _1-6 alkylsulfonamido (eg, methylsulfonamido, ethylsulfonamido), C _6-14 arylsulfonamido (for example, phenylsulfonylamino), (C _1-6 alkyl) (C _1-6 alkyl-carbonyl)amino (for example, N-acetyl-N-methylamino), (C _1-6 alkyl)(C _6-14 aryl-carbonyl)amino (eg, N-benzyl-N-methylamino).

In the present specification, "a substituted amine carboxyl group" may include, for example, "a C _1-6 alkyl group, a C _2-6 alkenyl group, a C 3-10 cycloalkyl group, a C 2-6 alkenyl group, a C _3-10 cycloalkyl group, C _6-14 aryl, C _7-16 aralkyl, C _1-6 alkyl-carbonyl, C _6-14 aryl-carbonyl, C _7-16 aralkyl-carbonyl, 5- to 14-membered aromatic hetero Cyclocarbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, C _1-6 alkoxy-carbonyl, 5- to 14-membered aromatic heterocyclyl, amine carboxyl, mono- or di-C _1-6 alkyl - 1 or 2 substituents of carbamoyl and mono- or di-C _7-16 aralkyl-carbamoyl, wherein these substituents may respectively have 1 to 3 selected from substituent group A Substituent" of the carbamoyl group.

In terms of preferred examples of the substituted carbamoyl, carbamoyl, mono- or di-C _1-6 alkyl-carbamoyl, mono- or di-C _2-6 Alkenyl-aminocarboxy (eg, diallylaminecarboxy), mono- or di-C _3-10 cycloalkyl-carbamoyl (eg, cyclopropylaminecarboxy, cyclohexyl carbamoyl), mono- or di-C _6-14 aryl-carbamoyl (e.g., phenylaminecarbamoyl), mono- or di-C _7-16 aralkyl-carbamoyl , mono- or di-C _1-6 alkyl-carbonyl-aminocarboxy (e.g., acetylaminocarboxy, propanoyl carboxy), mono- or di-C _6-14 aryl -Carbonyl-aminocarbamoyl (eg, benzylaminocarboxy), 5- to 14-membered aromatic heterocyclic carbamoyl (eg, pyridylaminocarboxy).

In the present specification, "a thiocarbamoyl group that may be substituted" includes, for example, "a group selected from the group consisting of C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkane group". base, C _6-14 aryl, C _7-16 aralkyl, C _1-6 alkyl-carbonyl, C _6-14 aryl-carbonyl, C _7-16 aralkyl-carbonyl, 5- to 14-membered aromatic Aromatic heterocyclic carbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, C _1-6 alkoxy-carbonyl, 5- to 14-membered aromatic heterocyclic, carbamoyl, mono- or di-C _1-6 1 or 2 substituents of alkyl-aminocarbonyl and mono- or di-C _7-16 aralkyl-aminocarbonyl, wherein these substituents may have 1 to 1 selected from substituent group A, respectively 3 substituents" of the thiocarbamoyl group.

In terms of preferred examples of the thiocarbamoyl group that may be substituted, thiocarbamoyl, mono- or di-C _1-6 alkyl-thiocarbamyl (for example, methyl thiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl base), mono- or di-C _2-6 alkenyl-thiocarbamyl (eg, diallylthiocarbamyl), mono- or di-C _3-10 cycloalkyl-thio carbamoyl (eg, cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C _aryl -carbamoyl (eg, benzene thiocarbamoyl), mono- or di-C _7-16 aralkyl-thiocarbamoyl (eg, benzylthiocarbamoyl, phenethylthiocarbamoyl) , mono- or di-C _1-6 alkyl-carbonyl-thiocarbamoyl (eg, acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or di- C _6-14 Aryl-carbonyl-thiocarbamoyl (eg, benzylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl (eg, pyridylthiocarbamyl) carbamoyl).

In the present specification, "a sulfasulfonyl group that may be substituted" includes, for example, "a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _3-10 cycloalkyl group, a C 1-6 alkyl group, a C 2-6 alkenyl group, C _6-14 aryl, C _7-16 aralkyl, C _1-6 alkyl-carbonyl, C _6-14 aryl-carbonyl, C _7-16 aralkyl-carbonyl, 5- to 14-membered aromatic hetero Cyclocarbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, C _1-6 alkoxy-carbonyl, 5- to 14-membered aromatic heterocyclyl, amine carboxyl, mono- or di-C _1-6 alkyl - 1 or 2 substituents of carbamoyl and mono- or di-C _7-16 aralkyl-carbamoyl, wherein these substituents may respectively have 1 to 3 selected from substituent group A Substituent" of the sulfamoyl group.

Preferred examples of the sulfasulfonyl group that can be substituted include: sulfasulfonyl group, mono- or di-C _1-6 alkyl-sulfasulfonyl group (for example, methylsulfamoyl group, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C _2-6 alkenyl- sulfamoyl (eg, diallyl sulfamoyl), mono- or di-C _3-10 cycloalkyl-sulfamoyl (eg, cyclopropyl sulfamoyl, cyclohexyl sulfamoyl) base), mono- or di-C _6-14 aryl-sulfamoyl (eg, phenyl sulfamoyl), mono- or di-C _7-16 aralkyl-sulfamoyl (eg, benzyl sulfamoyl, phenethyl sulfamoyl), mono- or di-C _1-6 alkyl-carbonyl-sulfamoyl (e.g., acetylsulfamoyl, propionyl sulfamoyl) sulfamoyl), mono- or di-C _6-14 aryl-carbonyl-sulfamoyl (eg, benzyl sulfamoyl), 5- to 14-membered aromatic heterocyclic sulfamoyl (eg, pyridine sulfamoyl group).

In the present specification, the "hydroxyl group that may be substituted" may include, for example, "a group selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _3-10 cycloalkyl, C _{6- 14} aryl, C _7-16 aralkyl, C _1-6 alkyl-carbonyl, C _6-14 aryl-carbonyl, C _7-16 aralkyl-carbonyl, 5- to 14-membered aromatic heterocyclic carbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, C _1-6 alkoxy-carbonyl, 5- to 14-membered aromatic heterocyclic, carbamoyl, mono- or di-C _1-6 alkyl-carbamoyl Substituents of yl, mono- or di-C _7-16 aralkyl-carbamoyl, C _1-6 alkylsulfonyl and C _6-14 arylsulfonyl, wherein these substituents can be Each has a hydroxyl group selected from 1 to 3 substituents selected from the substituent group A".

Preferred examples of the substituted hydroxyl group include hydroxyl, C _1-6 alkoxy, C _2-6 alkenyloxy (for example, allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), C _3-10 cycloalkoxy (eg, cyclohexyloxy), C _6-14 aryloxy (eg, phenoxy, naphthyloxy) base), C _7-16 aralkoxy (eg, benzyloxy, phenethoxy), C _1-6 alkyl-carbonyloxy (eg, acetyloxy, propionyloxy, butyryloxy) _{( _} For example, benzylcarbonyloxy), 5- to 14-membered aromatic heterocyclic carbonyloxy (eg, nicotinyloxy), 3- to 14-membered non-aromatic heterocyclic carbonyloxy (eg, piperidinylcarbonyl oxy), C _1-6 alkoxy-carbonyloxy (eg, tert-butoxycarbonyloxy), 5- to 14-membered aromatic heterocycleoxy (eg, pyridyloxy), carboxamide Alkyloxy, C _1-6 alkyl-aminocarboxy (eg, methylaminocarboxy), C _7-16 aralkyl-aminocarboxy (eg, benzylamine carboxyloxy), C _1-6 alkylsulfonyloxy (for example, methylsulfonyloxy, ethylsulfonyloxy), C _6-14 arylsulfonyloxy ( For example, phenylsulfonyloxy).

In the present specification, the "mercapto group that may be substituted" includes, for example, "a mercapto group selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _3-10 cycloalkyl, C _6- Substituents of ₁₄ aryl, C _7-16 aralkyl, C _1-6 alkyl-carbonyl, C _6-14 aryl-carbonyl and 5- to 14-membered aromatic heterocyclic groups, wherein these substituents can be respectively A mercapto group, halogenated mercapto group having 1 to 3 substituents selected from Substituent Group A".

Preferred examples of the mercapto group that can be substituted include: a mercapto (-SH) group, a C _1-6 alkylthio group, a C _2-6 alkenylthio group (for example, allylthio, 2-butane) alkenylthio, 2-pentenylthio, 3-hexenylthio), C _3-10 cycloalkylthio (eg, cyclohexylthio), C _6-14 arylthio (eg, benzene thio, naphthylthio), C _7-16 aralkylthio (for example, benzylthio, phenethylthio), C _1-6 alkyl-carbonylthio (for example, acetylthio, propionyl sulfanyl, butyrylthio, isobutyrylthio, trimethylacetylsulfanyl), C _6-14 aryl-carbonylsulfanyl (eg, benzylsulfanyl), 5- to 14-membered aromatic heterocycles Epithio (eg, pyridylthio), halogenated thio (eg, pentafluorothio).

In this specification, with regard to the "silicon group that may be substituted", for example, it may have "a group selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _3-10 cycloalkyl, C ₆ 1 to 3 substituents of _-14 aryl group and C _7-16 aralkyl group, wherein these substituent groups may respectively have 1 to 3 substituent groups selected from the group A of substituents "silyl group".

Preferred examples of the substituted silicon group include tri-C _1-6 alkylsilyl (eg, trimethylsilyl, tert-butyl(dimethyl)silyl).

Hereinafter, the definition of each symbol in the formula (I) will be described in detail.

P ¹ represents a group represented by the following formula: -R ^A1 , -CO-R ^A1 , -CO-OR ^A1 , -CO-COR ^A1 , -SO-R ^A1 , -SO ₂ -R ^A1 , -SO ₂ - OR ^A1 , -CO-NR ^A2 R ^A3 , -SO ₂ -NR ^A2 R ^A3 , or -C(=NR ^A1 )-NR ^A2 R ^A3 (wherein R ^A1 , R ^A2 and R ^A3 independently represent a hydrogen atom , which may be substituted hydrocarbyl, or which may be substituted heterocyclyl).

P ¹ is preferably a hydrogen atom or a methyl group.

In Lys No. 10, the linker/alkyl chain moiety represented by (-Gly-Gly-Gly-Gly-R ^A10 ) is bonded to the ε-amino group of Lys to form the following structure.

The persistence of the action of compound (I) can be achieved by the presence of this linker/alkyl chain.

R ^A10 means Pal or Oda.

R ^A10 is preferably Pal.

A11 represents Aib, Ala or Ser.

A11 is preferably Aib.

In other aspects, A11 is preferably Ala.

In other aspects, A11 is preferably Ser.

A12 means Ile or Lys.

A12 is preferably Ile.

A15 represents Asp or Glu.

A15 is preferably Glu.

A18 represents Ala or Arg.

A18 is preferably Arg.

A35 represents Tyr or Phe(2-F).

A35 is preferably Tyr.

Preferred examples of compound (I) include the following peptides or salts thereof.

[Compound A] is [P ¹ is methyl, R ^A10 represents Pal or Oda; A11 represents Aib, Ala or Ser (preferably Aib, in other aspects, preferably Ala, in other aspects, preferably A12 represents Ile; A15 represents Glu; A18 represents Arg; A35 represents the peptide represented by Tyr] or its salt (I).

[Compound B] is the compound (I) of the peptide (SEQ ID NO: 40) described in Example 31 or a salt thereof.

Compound (I) of the peptide described in Example 35 (SEQ ID NO: 44) or a salt thereof.

Compound (I) of the peptide (SEQ ID NO: 50) described in Example 41 or a salt thereof.

Compound (I) can be produced according to a known peptide synthesis method. The peptide synthesis method may be, for example, either a solid-phase synthesis method or a liquid-phase synthesis method. That is, enabling the formation of compound (I) can be performed repeatedly Part of the peptide or amino acid and the residual part (which can be composed of two or more amino acids) are condensed into the desired sequence to produce the desired peptide. When the product having the desired sequence has a protecting group, the desired peptide can be produced by removing the protecting group. As a well-known condensation method or a protecting group removal method, the method described in following (1)-(5) is mentioned, for example.

(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) "Basics and Experiments of Peptide Synthesis" by Nobuo Izumiya, Maruzen Co., Ltd. (1975)

(4) Jimei Yajima and Shunhei Sakakihara, Lectures on Biochemical Experiments 1, Chemistry of Proteins IV, 205 (1977)

(5) Supervised by Harumi Yajima, Continued Development of Pharmaceutical Products, Volume 14, Peptide Synthesis, Hirokawa Shoten

After the reaction, compound (I) can be isolated and purified by a conventional purification method, for example, by combining solvent extraction, distillation, column chromatography, liquid chromatography, recrystallization, and the like. When the peptide obtained by the above method is a free form, it can be converted into an appropriate salt by a well-known method. Conversely, when a salt is obtained, it can be converted into a free form by a well-known method.

In addition, the raw material compound may be a salt, and such a salt may be exemplified as the salt of the compound (I) described later.

烷、四氫呋喃等醚類；乙腈、丙腈等腈類；乙酸甲酯、乙酸乙酯等酯類或此等之適當混合物等。反應溫度係從可使用於形成胜肽鍵之反應之已知範圍適當地選擇，通常可從約-20℃至50℃之範圍適當地選擇。通常使用1.5至6倍過量之經活化之胺基酸衍生物。在固相合成之情況，於 使用茚三酮反應(ninhydrin reaction)測試之結果，縮合不充分的情況，可不進行保護基之脫離，藉由重覆進行縮合反應，而可進行充分之縮合。即使重覆進行反應仍無法得到充分之縮合，可使用乙酸酐或乙醯基咪唑等將未反應之胺基酸醯化，從而避免後續反應被影響。 Regarding the condensation of the protected amino acid or peptide, various activation reagents that can be used in peptide synthesis can be used, especially ginsenoside salts, tetramethyluronium salts, carbodiimides, etc. . Examples of phosphonium salts include benzotriazol-1-yloxy phosphonium hexafluorophosphate (pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP), bis(pyrrolidinyl)phosphonium bromide hexafluorophosphate (PyBroP) , 7-azabenzotriazol-1-yl hexafluorophosphate (pyrrolidinyl) phosphonium (PyAOP), tetramethyluronium salts include: 2-(1H hexafluorophosphate) -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (HBTU), 2-(7-azabenzotriazol-1-yl)-1, hexafluorophosphate 1,3,3-Tetramethyluronium (HATU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(5-norbornene-2,3-dicarboxyimide)-1,1,3,3-tetramethyluronium tetrafluoroborate (TNTU), O-(N-succinic acid tetrafluoroborate) imino)-1,1,3,3-tetramethyluronium (TSTU), DCC, N,N'-diisopropylcarbodiimide (DIPCDI ), N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI·HCl), etc. When the condensation is carried out by this, it is preferable to add a racemization inhibitor (for example, HONB, HOBt, HOAt, HOOBt, etc.). As the solvent used for the condensation, it can be appropriately selected from solvents known to be used in the condensation reaction of peptides. For example, amides such as anhydrous or water-containing N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane and chloroform can be used ; alcohols such as trifluoroethanol and phenol; sulfites such as dimethyl sulfoxide; tertiary amines such as pyridine;

ethers such as alkane and tetrahydrofuran; nitriles such as acetonitrile and propionitrile; esters such as methyl acetate and ethyl acetate or suitable mixtures of these, etc. The reaction temperature is appropriately selected from a known range that can be used for the reaction to form a peptide bond, and usually can be appropriately selected from a range of about -20°C to 50°C. Typically a 1.5 to 6-fold excess of the activated amino acid derivative is used. In the case of solid-phase synthesis, in the case of insufficient condensation, the detachment of the protecting group may not be carried out, and sufficient condensation may be carried out by repeating the condensation reaction. Even if the reaction is repeated, sufficient condensation cannot be obtained, and the unreacted amino acid can be acylated with acetic anhydride or acetylimidazole, so as to avoid the subsequent reaction being affected.

As the protecting group of the amino group of the raw amino acid, for example, Z, Boc, tertiary pentyloxycarbonyl, isobornyloxycarbonyl, 4-methoxybenzyloxycarbonyl, Cl-Z, Br-Z, adamantyloxycarbonyl, trifluoroacetyl, phthaloyl, carboxyl, 2-nitrophenylsulphenyl, diphenylthiophosphino, Fmoc, Trityl, etc.

In addition to the above-mentioned C _1-6 alkyl group, C _3-10 cycloalkyl group, and C _7-14 aralkyl group, the protecting group for the carboxyl group of the raw amino acid includes, for example, aryl group, 2-adamantine Alkyl, 4-nitrobenzyl, 4-methoxybenzyl, 4-chlorobenzyl, benzylmethyl and benzyloxycarbonylhydrazine, tert-butoxycarbonylhydrazine, tritylhydrazine Hydrazine etc.

The hydroxyl groups of serine and threonine can be protected by, for example, esterification or etherification. Examples of groups suitable for this esterification include lower (C _2-4 ) alkyl acetyl groups such as acetyl groups, aryl groups such as benzyl groups, and groups derived from organic acids. Moreover, as a group suitable for etherification, for example, a benzyl group, a tetrahydropyranyl group, a tertiary butyl group (But), a trityl group ( ^Trt ), etc. are mentioned.

As a protective group of the phenolic hydroxyl group of tyrosine, Bzl, 2, 6- dichlorobenzyl, 2-nitrobenzyl, Br-Z, tert-butyl etc. are mentioned, for example.

Examples of protecting groups for imidazole of histidine include Tos, 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), DNP, Bom, Bum, Boc, Trt , Fmoc, etc.

烷-6-磺醯基(Pmc)、均三甲苯-2-磺醯基(Mts)、2,2,4,6,7-五甲基二氫苯并呋喃-5-磺醯基(Pbf)、Boc、Z、NO₂等。 Examples of the protecting group for the guanidino group of arginine include Tos, Z, 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), p-methoxybenzene Sulfonyl (MBS), 2,2,5,7,8-pentamethyl

Alkyl-6-sulfonyl (Pmc), mesitylene-2-sulfonyl (Mts), 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf ), Boc, Z, NO ₂ , etc.

As the protecting group of the side chain amine group of lysine, for example, Z, Cl-Z, trifluoroacetone, Boc, Fmoc, Trt, Mtr, 4,4-dimethyl-2,6 - Two-sided oxycyclohexylene ethyl (Dde), etc.

As for the indolyl protecting group of tryptophan, for example, a forma group (For), Z, Boc, Mts, Mtr, etc. are mentioned.

As the protecting group of aspartic acid and glutamic acid, for example, Trt, xanthyl (Xan), 4,4'-dimethoxydiphenylmethyl (Mbh), 2,4, 6-trimethoxybenzyl (Tmob) and the like.

As far as the carboxyl group of the raw material is activated, for example, the corresponding acid anhydride, azide, active ester [and alcohol (for example, pentachlorophenol, 2,4,5-trichlorophenol, 2,4-dinitro) of phenol, cyano-methanol, p-nitrophenol, HONB, N-hydroxysuccinimide, 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt)) ester] etc. As the amine group of the raw material is activated, for example, the corresponding phosphamide can be mentioned.

等之鹼處理；或在氨水中藉由鈉還原等。藉由上述酸處理之脫離反應一般於-20℃至40℃之溫度進行，惟，藉由添加如苯甲醚、酚、苯基甲硫醚、間甲酚、對甲酚之陽離子捕捉劑、或二甲基硫化物、1,4-丁二硫醇、1,2-乙二硫醇等有效地進行酸處理。又，作為組胺酸之咪唑保護基所使用的2,4-二硝基苯基，藉由硫酚處理而除去，作為色胺酸之吲哚保護基所使用的甲醯基，除上述之1,2-乙二硫醇、1,4-丁二硫醇等存在下藉由酸處理之脫保護以外，亦可藉由稀氫氧化鈉、稀釋之氨水等之鹼處理而除去。 For the method of removing (leaving) the protecting group, for example, contact reduction in a hydrogen stream in the presence of a catalyst such as Pd black or Pd carbon, and anhydrous hydrogen fluoride, methanesulfonic acid, trifluoromethanesulfonic acid, etc. can also be mentioned. Acid, trifluoroacetic acid, trimethylsilane bromide (TMSBr), trimethylsilyl trifluoromethanesulfonate, tetrafluoroboric acid, gins (trifluoro)boron, boron tribromide or a mixture of these, etc. acid treatment; or by diisopropylethylamine, triethylamine, piperidine, piperidine

Alkali treatment, etc.; or reduction by sodium in ammonia water, etc. The detachment reaction by the above acid treatment is generally carried out at a temperature of -20°C to 40°C, but by adding cation scavengers such as anisole, phenol, phenylmethyl sulfide, m-cresol, p-cresol, Or dimethyl sulfide, 1,4-butanedithiol, 1,2-ethanedithiol, etc. are effectively acid-treated. In addition, the 2,4-dinitrophenyl group used as the imidazole protecting group of histidine was removed by thiophenol treatment, and the carboxyl group used as the indole protecting group of tryptophan, except for the above In addition to deprotection by acid treatment in the presence of 1,2-ethanedithiol, 1,4-butanedithiol, etc., it can also be removed by alkali treatment such as dilute sodium hydroxide, diluted ammonia water, or the like.

The protection of the functional group that does not participate in the reaction of the raw material, the protective group, the detachment of the protective group, the activation of the functional group that participates in the reaction, and the like can be appropriately selected from well-known protective groups or well-known means.

As for the method of obtaining the amide body of the peptide, solid-phase synthesis is carried out using a resin for amide body synthesis, or the α-carboxyamide of the carboxyl terminal amino acid is aminated, and the peptide chain is extended on the amino group side. After reaching the desired chain length, a peptide with only the α-amino protecting group at the N-terminus of the peptide chain removed, and a peptide (or amino acid) with only the carboxyl protecting group at the C-terminus removed, and then the two The peptides are condensed in a mixed solvent as described above. The details of the condensation reaction are the same as those described above. After the protected peptide obtained by condensation is purified, all the protecting groups can be removed by the above method to obtain the desired crude polypeptide. the rough The peptide is purified by various known purification means, and the main part is lyophilized to obtain the amide body of the desired peptide.

Compound (I) can be produced, for example, by the following method. First, compound (II) in which the Lys (-Gly-Gly-Gly-Gly-R ^A10 ) moiety of compound (I) is Lys is produced by a well-known peptide synthesis method. Compound (II) may also be supported on resin. Among them, the amino acid and P ¹ constituting the compound (II) are preferably protected by an appropriate protecting group so as not to adversely affect the production of the compound (I). Moreover, as a protective group, the protective group used in the reference example and an Example mentioned later can be mentioned. In addition, in Lys of the aforementioned compound (II), the side chain amine group is protected by an orthogonal protecting group (eg ivDde; in this specification, (1-(4,4-dimethyl-2,6-di-side oxy) Cyclohex-1-yl)-3-methylbutyl) is abbreviated as ivDde) for protection. Then, the orthogonal protecting group of Lys of compound (II) is removed under selective conditions, and the amino acids corresponding to (-Gly-Gly-Gly-Gly-H) are sequentially condensed according to their own well-known methods. , and compound (III) is obtained. Compound (III) may also be supported on resin.

P ¹ -Tyr-Aib-Glu-Gly-Thr-α-MePhe-Thr-Ser-Asp-Tyr-Aib-Lys-Aib-Leu-Asp-A16-A17-Ala-A19-Ala-Glu-Phe-Val -A24-Trp-Leu-Leu-A28-Gly(II) (SEQ ID NO: 1) [the symbols in the formula have the same meanings as above]

P ¹ -Tyr-Aib-Glu-Gly-Thr-α-MePhe-Thr-Ser-Asp-Tyr-Aib-Lys(-Gly-Gly-Gly-Gly-H)-Aib-Leu-Asp-A16-A17 -Ala-A19-Ala-Glu-Phe-Val-A24-Trp-Leu-Leu-A28-Gly(III) (SEQ ID NO: 1) [the symbols in the formula have the same meanings as above].

The amino acid and P ¹ constituting the compound (III) are preferably protected with an appropriate protecting group as in the case of the compound (II).

Compound (I) can be obtained by condensing compound (IV) with compound (III) according to a method known per se, then removing all protecting groups, and optionally cleaved from the resin. R ^A10 constituting the compound (IV) is preferably protected by an appropriate protecting group (hereinafter, abbreviated as P in some cases) as in the case of the compounds (II) and (III).

HO-R ^A10 (IV)

[wherein, R ^A10 represents Oda or Pal].

The protective group represented by P includes, for example, the above-mentioned protective group for the carboxyl group (preferably tertiary butyl group). As compound (IV), for example, a commercially available product can be used.

Compound (I) can also be produced by sequentially condensing fragmented peptides produced in the same manner as the above-mentioned method by a method known per se.

The amino acid and P ¹ constituting the fragmented peptide can be protected with an appropriate protecting group as in the case of compound (II). Moreover, you may carry on resin.

When compound (I) exists as configurational isomers such as enantiomers, diastereoisomers, conformers, etc., these are also included in compound (I), and If desired, they can be isolated by means known per se, by the aforementioned separation and purification means, respectively. In addition, when the compound (I) is a racemate, it can be separated into an S form and an R form by ordinary optical separation means.

In the case where a stereoisomer exists in the compound (I), the case where the isomer is a single one and the case where it is a mixture thereof are included in the compound (I).

Compound (I) can be chemically modified using polyethylene glycol according to a method known per se. For example, a chemically modified body of compound (I) can be produced by conjugated-bonding Cys residue, Asp residue, Glu residue, Lys residue, etc. of compound (I) with polyethylene glycol. Furthermore, a linker structure may be present between compound (I) and polyethylene glycol.

By modifying compound (I) with polyethylene glycol (PEG), it is possible to enhance the biological activity of therapeutically and diagnostically important peptides, prolong blood circulation time, reduce immunity, improve solubility, and improve metabolic resistance effect, etc.

The molecular weight of PEG is not particularly limited, but is usually about 1K to about 1000K Dalton, preferably about 10K to about 100K Dalton, more preferably about 20K to about 60K Dalton.

As the method for modifying compound (I) with PEG, a method known in the art can be used, for example, the following method can be used.

(1) The amine group of the compound (I) is bound to a PEGylation reagent having an active ester (for example, SUNBRIGHT MEGC-30TS (trade name), NOF).

(2) The amine group of the compound (I) is bonded to a PEGylation reagent having an aldehyde (eg, SUNBRIGHT ME-300AL (trade name), NOF).

(3) The compound (I) is bonded to a divalent cross-linking reagent (eg, GMBS (Tongjin Chemical), EMCS (Tongjin Chemical), KMUS (Tongjin Chemical), SMCC (Pierce)), and then with PEG having a thiol group Chemical reagents (eg, SUNBRIGHT ME-300-SH (trade name), NOF) bond.

(4) A sulfhydryl group is introduced into compound (I) with an SH-introducing agent (for example, D-cysteine residue, L-cysteine residue, Traut's reagent), and the sulfhydryl group is combined with maleic acid Amine group PEGylation reagent (for example, SUNBRIGHT ME-300MA (trade name), NOF) reacts.

(5) In compound (I), a sulfhydryl group is introduced with an SH-introducing agent (for example, D-cysteine residue, L-cysteine residue, Traut's reagent), and the sulfhydryl group is combined with iodoacetyl group Amine group PEGylation reagent (eg, SUNBRIGHT ME-300IA (trade name), NOF) reacts.

(6) Introducing ω-amino carboxylic acid, α-amino acid, etc. as a linker at the N-terminal amino group of compound (I), and making the amino group derived from the linker and the PEGylation reagent having an active ester (such as , SUNBRIGHT MEGC-30TS (trade name), Japan Oil) reaction.

(7) Introducing ω-amino carboxylic acid, α-amino acid, etc. as a linker into the N-terminal amino group of compound (I), and then combining the amine group derived from the linker with a PEGylation reagent having an aldehyde group ( For example, SUNBRIGHT ME-300AL (trade name), NOF) reacts.

Also, Compound (I) may be a solvate (eg, a hydrate) or an unsolvate (eg, a non-hydrate).

Compound (I) can be identified by isotopes (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I) and the like.

In addition, the compound (I) may be a deuterium transformant which converts ¹ H into ² H (D).

Isotopically labeled or substituted compound (I) can be used For example, it is a tracking agent (PET tracking agent) used in positron emission tomography (Positron Emission Tomography: PET), and is suitable for fields such as medical diagnosis.

The peptides in this specification, according to the convention of peptide labeling, have the N-terminus (amino-terminus) at the left end and the C-terminus (carboxy-terminus) at the right end. The C-terminus of the peptide can be amide (-CONH ₂ ), carboxyl (-COOH), carboxylate (-COO ^- ), alkyl amide (-CONHR ^a ) or ester (-COOR ^a ), particularly preferably amide Amine ( _-CONH2 ).

Compound (I) may be in the form of a salt. The salts include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.

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

Preferred examples of salts with organic bases include trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, Salts of cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc.

Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.

Preferred examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methyl alcohol Salts of sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.

In terms of preferred examples of salts with basic amino acids, there can be listed: salts with arginine, lysine, ornithine, etc., in terms of preferred examples of salts with acidic amino acids, Examples include salts with aspartic acid, glutamic acid, and the like.

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

Compound (I) may also be a prodrug.

Prodrug means a compound that is converted into compound (I) by reaction with enzymes or gastric acid under physiological conditions in vivo, that is, a compound that is converted into compound (I) by enzymatic oxidation, reduction, hydrolysis, etc. , or converted into a compound of compound (I) by hydrolysis or the like caused by gastric acid or the like.

As the prodrug of compound (I), compounds in which the amine group of compound (I) is acylated, alkylated or phosphorylated (for example, the amine group of compound (I) is eicosylated, propylamidoylation, amylaminocarbonylation, (5-methyl-2-oxy-1,3-dioxol-4-yl)methoxycarbonylation, tetrahydrofurylation, pyrrole pyridylmethylated, trimethylacetoxymethylated or tertiary butylated compounds); compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated or boroxidated (e.g. , the hydroxyl group of compound (I) is acetylated, palmitylated, propylated, trimethyl acetylated, succinylated, fumaricated, propylamidated or dimethylaminoated Methylcarbonylated compounds); compounds in which the carboxyl group of compound (I) is esterified or amidated (for example, the carboxyl group of compound (I) is esterified with C _1-6 alkyl, phenyl esterified, carboxymethyl ester methylation, dimethylamino methyl esterification, trimethylacetoxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalate esterification, (5-methyl-2-oxygen-1 , 3-dioxol-4-yl) methyl esterification, cyclohexyloxycarbonyl ethyl esterification or methyl amination compound), etc., wherein the carboxyl group of compound (I) is preferably methylated C _1-6 alkyl esterified compounds such as base, ethyl, tert-butyl, etc. These compounds can be produced from compound (I) according to a method known per se.

In addition, the prodrug of compound (I) can also be converted into compound (I) under the physiological conditions as described on pages 163 to 198 of Molecular Design, Vol.

In the present specification, the prodrug may form a salt, and the salt may be exemplified as the salt of the compound (I).

Compound (I) may also be a crystal, and the crystal form may be single or a mixture of crystal forms, all of which are contained in compound (I). The crystal can be produced by crystallization by applying a crystallization method known per se.

Furthermore, Compound (I) may be a pharmaceutically acceptable co-crystal or a co-crystal salt. Wherein, co-crystal or co-crystal salt means that two or more kinds have different physical properties (for example, structure, melting point, heat of fusion, hygroscopicity, solubility and stability, etc.), and are at room temperature A crystalline substance composed of a unique substance of a solid. Co-crystals or co-crystal salts can be produced according to co-crystallisation methods known per se.

Crystals of compound (I) have excellent physicochemical properties (eg, melting point, solubility, stability) and biological properties (eg, pharmacokinetics (absorption, distribution, metabolism, excretion), pharmacodynamic performance), and are therefore very suitable for medicine.

Compound (I) and its prodrugs (hereinafter, simply referred to as compounds of the present invention) may have activation effects on Y2 receptors, GLP-1 receptors and GIP receptors.

The compounds of the present invention are particularly capable of high activation of Y2 receptors, GLP-1 receptors and GIP receptors in the body.

Since the Y2 receptor has a feeding inhibitory effect, a peptide having a Y2 receptor activating effect is useful for the prevention or treatment of obesity, diabetes, and symptoms related to eating disorders. In addition, GLP-1 and GIP are digestive tract hormones called incretin, and have the action of promoting insulin secretion from the pancreas. Since incretin is closely related to glucose metabolism, the compound having GLP-1 receptor and GIP receptor activation effects can be useful in the prevention or treatment of diabetes, obesity, and symptoms related to abnormal glucose metabolism.

Therefore, the compound of the present invention may have a feeding inhibitory effect, a body weight reducing effect, and the like.

The compounds of the present invention have high biological and chemical stability, and can be expected to have sustained effects in the body.

It is known that GLP-1 receptor agonists have clinical side effects of nausea and emesis. However, compared with GLP-1 receptor agonists, the compounds of the present invention can alleviate such emetic effects.

The compounds of the present invention can be used as activators of Y2 receptors, GLP-1 receptors and GIP receptors.

In the present invention, the activator of Y2 receptor, GLP-1 receptor and GIP receptor means that it has Y2 receptor activation (Y2 receptor agonist), GLP-1 receptor activation (GLP- 1 receptor agonist action) and GIP receptor activation (GIP receptor agonist action).

The compounds of the present invention have low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and few side effects, and can be used as prophylactic/therapeutic agents for various diseases described later, etc. to mammals (eg, humans, cattle, horses, dogs, cats, monkeys, mice, rats) are safely administered.

By activating the above-mentioned GLP-1 receptor and GIP receptor, the compound of the present invention can be used as a therapeutic or preventive agent for diabetes, obesity, and various diseases. The compounds of the present invention can be used, for example, for symptomatic obesity, obesity based on simple obesity, conditions or diseases associated with obesity, eating disorders, diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, obesity-type diabetes), Hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, hyperLDL cholesterolemia, hypoHDL cholesterolemia, postprandial hyperlipidemia), hypertension, heart failure, diabetic complications [eg, Neuropathy, nephropathy, retinopathy, diabetic cardiomyopathy, cataract, macrovascular disorder, osteopenia, diabetic hyperosmolar coma, infectious diseases (eg, respiratory infections, urinary tract infections, digestive infections, skin Soft tissue infection, lower extremity infection), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disease, peripheral vascular circulation disease], metabolic syndrome (with hypertriglyceride (TG) hyperemia, low HDL cholesterol ( 3 of HDL-C) hyperemia, hypertension, abdominal obesity and impaired glucose tolerance more than one disorder), sarcopenia, etc. prophylactic or therapeutic agent.

、胰島素、磺醯基脲(SU)劑、β-阻斷劑所造成之肥胖)等。 Symptomatic obesity includes endocrine obesity (eg, Cushing's syndrome, hypothyroidism, insulinoma, obese type 2 diabetes, pseudohypoparathyroidism, hypogonadism) , Central obesity (eg, hypothalamic obesity, frontal lobe syndrome, Kleine-Levin syndrome), genetic obesity (eg, Prader-Willi syndrome, sexual immaturity Finger deformities (Laurence-Moon-Biedl syndrome), drug-induced obesity (eg, via steroids, phenothi

, obesity caused by insulin, sulfonylurea (SU) agents, β-blockers) and so on.

Examples of pathologies or diseases associated with obesity include glucose intolerance disorder, diabetes (especially type 2 diabetes and obesity-type diabetes), abnormal lipid metabolism (similar to the above-mentioned hyperlipidemia), hypertension, heart failure, Hyperuricemia/gout, fatty liver (including non-alchoholic steato-hepatitis), coronary artery disease (myocardial infarction, stenosis), cerebral infarction (cerebral thrombosis, transient ischemic attack) ), bone/joint disease (disease knee, hip deformity, spondylosis, low back pain), sleep apnea syndrome/Pickwick syndrome, menstrual abnormalities (abnormal menstrual cycle , abnormal menstrual flow and cycle, amenorrhea, abnormal menstrual symptoms), metabolic syndrome, etc.

The criteria for determining diabetes can refer to the new criteria reported by the Japan Diabetes Association in 1999.

For the purposes of this report, diabetes means a condition that complies with any of the following: Fasting blood glucose (glucose concentration in venous plasma) is 126mg/dl or more, 2-hour value (glucose concentration in venous plasma) of 75g oral glucose load test (75g OGTT) is more than 200mg/dl, random blood glucose value (glucose concentration in venous plasma) is more than 200mg/dl. In addition, will not meet the above-mentioned diabetes, but not "fasting blood glucose value (glucose concentration in venous plasma) less than 110mg/dl or 75g oral glucose load test (75g OGTT) 2 hours value (glucose concentration in venous plasma) less than The state of 140mg/dl" (normal type) is called "borderline type".

In addition, regarding the criteria for determination of diabetes, ADA (American Diabetes Association) in 1997, WHO (World Health Organization) in 1998 proposed new criteria for determination.

According to these reports, diabetes means a condition that meets the following symptoms: shows a fasting blood glucose value (glucose concentration in venous plasma) of 126 mg/dl or more, and a 2-hour value of a 75 g oral glucose load test (a glucose concentration in venous plasma) Glucose concentration) is the state of 200 mg/dl or more.

Also, according to the above report, impaired glucose tolerance means that the fasting blood glucose value (glucose concentration in venous plasma) is less than 126 mg/dl, and the 2-hour value (glucose concentration in venous plasma) of the 75 g oral glucose load test is Above 140mg/dl and less than 200mg/dl. Furthermore, according to the ADA report, the state of fasting blood glucose (glucose concentration in venous plasma) of 110 mg/dl or more and less than 126 mg/dl is called fasting glucose intolerance (IFG (Impaired Fasting Glucose)). On the other hand, according to the WHO report, among the IFG (Impaired Fasting Glucose), the state where the 2-hour value (glucose concentration in venous plasma) of 75 g of oral glucose load test is less than 140 mg/dl is called fasting blood glucose Abnormal (IFG (Impaired Fasting Glycemia)).

The compound of the present invention can also be used for the prevention of diabetes mellitus, borderline type, impaired glucose tolerance, fasting glucose intolerance (IFG (Impaired Fasting Glucose)), and fasting glucose abnormality IFG (Impaired Fasting Glycemia) determined in accordance with the above-mentioned new criteria /Therapeutic agent. Furthermore, the compound of the present invention can prevent the development of diabetes from borderline type, impaired glucose tolerance, fasting glucose intolerance (IFG (Impaired Fasting Glucose)) and fasting abnormal glucose (Impaired Fasting Glycemia).

The compounds of the present invention can be used as a weight-reducing agent for mammals based on their weight-reducing effect. The applicable mammals may be mammals that are intended to lose weight, and may be mammals at risk of hereditary overweight, or may be lactating mammals suffering from lifestyle diseases such as diabetes, hypertension, and/or hyperlipidemia. animal. Excessive body weight can be caused by excessive dietary intake or nutritional imbalance, and can also be caused by concomitant drugs (eg, troglitazone, rosiglitazone, englitazone) , ciglitazone (ciglitazone), pioglitazone (pioglitazone) and other insulin resistance improvers with similar PPARγ agonist effect, etc.) overweight. In addition, the overweight may be the overweight before attaining obesity, or may be the overweight of an obese patient. Among them, obesity is defined as a BMI (body mass index: weight (kg) ÷ [length (m)] ² ) of 25 or more (based on the Japanese Society of Obesity) for Japanese, and a BMI of 30 for Europeans and Americans above (according to WHO standards).

The compounds of the present invention are also suitable for metabolic syndrome (metabolic syndrome) preventive / therapeutic agent. Compared with patients with a single lifestyle disease, patients with metabolic syndrome have a significantly higher rate of cardiovascular diseases, so prevention/treatment of metabolic syndrome is extremely important in preventing cardiovascular diseases.

The criteria for determining metabolic syndrome were published by WHO in 1999 and published by NCEP in 2001. According to the criteria of the WHO, with hyperinsulinemia or abnormal glucose tolerance as the basic conditions, and two or more of visceral obesity, abnormal lipidemia (high TG or low HDL), and hypertension, the diagnosis is made as 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). If it is based on the management indicators of ischemic heart disease in the United States, that is, the criteria for the Adult Treatment Panel III (Adult Treatment Panel III) of the National Cholesterol Education Program, patients with visceral obesity, hyperlipidemia, Metabolic syndrome (National Cholesterol Education Program: Executive Summary of the Third Report of 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).

The compounds of the present invention can also be used, for example, in osteoporosis, cachexia (eg, cancer cachexia, tuberculosis cachexia, diabetic cachexia, blood disease cachexia, endocrine disease cachexia, Infectious disease cachexia or cachexia caused by acquired immune deficiency syndrome), fatty liver, polycystic ovarian syndrome, kidney disease (for example, chronic renal failure, diabetic nephropathy, glomerulonephritis, glomerulosclerosis disease, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease), muscle atrophy, myocardial infarction, stenosis, cerebrovascular disease (eg, cerebral infarction, stroke), Alzheimer's disease, Parkinson's disease , Anxiety, Dementia, Insulin Resistance Syndrome, Syndrome X, Hyperinsulinemia, Perception Disorders of Hyperinsulinemia, Acute or Chronic Diarrhea, Inflammatory Diseases Degeneration arthritis, low back pain, gout, inflammation after surgery or trauma, swelling, neuralgia, sore throat, cystitis, hepatitis (including nonalcoholic steatohepatitis), pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory colorectal disease), ulcerative colitis, gastric mucosal damage (including aspirin-induced gastric mucosal damage), small intestinal mucosal damage, malabsorption, testicular dysfunction, visceral obesity syndrome, sarcopenia Prophylactic/Therapeutic Agents.

Furthermore, the compounds of the present invention can also be used as various cancers (including breast cancer (eg, invasive ductal breast cancer, non-invasive ductal breast cancer, inflammatory breast cancer, etc.), prostate cancer (eg, hormone-dependent prostate cancer, non-hormonal-dependent breast cancer, etc.) prostate cancer, etc.), pancreatic cancer (for example, pancreatic duct cancer, etc.), gastric cancer (for example, papillary adenocarcinoma, mucinous adenocarcinoma, adenocarcinoma, etc.), lung cancer (for example, non-small cell lung cancer, small cell lung cancer, etc.) , malignant mesothelioma, etc.), colon cancer (eg, gastrointestinal stromal tumor, etc.), rectal cancer (eg, gastrointestinal stromal tumor, etc.), colorectal cancer (eg, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, digestive stromal tumor, etc.), small bowel cancer (eg, non-Hodgkin lymphoma, gastrointestinal stromal tumor, etc.), esophagus cancer, duodenal cancer, tongue cancer, pharyngeal cancer (eg, upper pharyngeal cancer, mesopharyngeal cancer, lower pharyngeal cancer, etc.) pharyngeal cancer, etc.), salivary gland cancer, brain tumors (for example, pineal astrocytoma, follicular astrocytoma, diffuse astrocytoma, degenerative astrocytoma, etc.), schwannoma, liver cancer (For example, primary liver cancer, extrahepatic cholangiocarcinoma, etc.), kidney cancer (for example, renal cell carcinoma, renal pelvis and urinary duct transitional epithelial cancer, etc.), cholangiocarcinoma, endometrial cancer, cervical cancer, ovarian cancer ( For example, epithelial ovarian cancer, extragonadal cell tumor, ovarian germ cell tumor, ovarian low-grade tumor, etc.), bladder cancer, urethral cancer, skin cancer (for example, intraocular (eye) melanoma, Merkel cell carcinoma (Merkel cell carcinoma, etc.), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (eg, medullary thyroid cancer, etc.), parathyroid cancer, nasal cancer, paranasal cancer, bone tumors (eg, osteosarcoma, Ewing tumor, uterine sarcoma, soft tissue sarcoma, etc.), angiofibroma, omental sarcoma, penile cancer, testicular tumor, pediatric solid cancer (eg, Wilms' tumor, pediatric kidney tumor etc.), Kaposi's sarcoma, Kaposi's sarcoma arising from AIDS, palate cavity tumor, glomus fibrosus, leiomyosarcoma, rhabdomyosarcoma, leukemia (e.g., acute myeloid leukemia, acute prophylactic/therapeutic agent for lymphoblastic leukemia, etc.), etc.).

The compounds of the present invention can also be used for secondary prevention and progression inhibition of the above-mentioned various diseases (eg, cardiovascular conditions such as myocardial infarction). again, The compounds of the present invention are also suitable for use as food intake inhibitors, weight loss agents. The compounds of the present invention can be used in combination with dietary therapy (eg, dietary therapy for diabetes) and exercise therapy.

Medicines containing the compounds of the present invention are low in toxicity, and in terms of the production methods of pharmaceutical preparations, the compounds of the present invention are prepared as they are or according to commonly used methods known per se (for example, methods described in the Japanese Pharmacopoeia). Mixed with a pharmacologically acceptable carrier to form, for example, lozenges (including sugar-coated lozenges, film-coated lozenges, sublingual lozenges, orally disintegrating lozenges), powders, granules, capsules (including soft capsules, microcapsules), Liquids, tablets, syrups, emulsions, suspensions, injections (for example, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, etc.), external preparations (for example, nasal administration preparations, transdermal preparations, ointments) suppositories (for example, rectal suppositories, vaginal suppositories), pellets, nasal, pulmonary (inhalation), drops and other pharmaceutical preparations, administered orally or parenterally (for example, topical, rectal , intravenous administration, etc.) safely administered.

Such formulations may be release-controlled formulations such as immediate-release formulations or sustained-release formulations (eg, sustained-release microcapsules).

Furthermore, the content of the compound of the present invention in the pharmaceutical preparation is about 0.01 to about 100% by weight of the entire preparation.

In terms of the above-mentioned pharmacologically acceptable carriers, in terms of preparation materials, various conventional organic or inorganic carrier substances can be cited, for example, excipients, lubricants, binders and disintegrating agents in solid preparations can be cited. Solvents, dissolving aids, suspending agents, isotonic agents, buffers and pain relievers in powder or liquid formulations. Furthermore, it can be appropriate and appropriate as needed Additives such as usual preservatives, antioxidants, colorants, sweeteners, adsorbents, humectants, etc. are used.

Examples of excipients include lactose, white sugar, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, and the like.

As a lubricant, magnesium stearate, calcium stearate, talc, colloidal silica, etc. are mentioned, for example.

Examples of the binder include crystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, and gelatin. , methyl cellulose, sodium carboxymethyl cellulose, etc.

Examples of disintegrating agents include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium methyl starch, and L-hydroxypropyl cellulose.

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

Examples of dissolution aids include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate.

Examples of suspending agents include stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, and benzethonium chloride. chloride), glycerol monostearate and other surfactants; such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl Hydrophilic polymers such as cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose.

Examples of isotonic agents include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, and the like.

As a buffer, a buffer solution, such as phosphate, acetate, carbonate, citrate, etc. are mentioned, for example.

As a pain reliever, benzyl alcohol etc. are mentioned, for example.

As a preservative, parabens, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc. are mentioned, for example.

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

Examples of colorants include water-soluble edible tar dyes (for example, edible red No. 2 and 3, edible yellow No. 4 and 5, edible blue No. 1 and 2, etc.), water-insoluble deep Red pigments (eg, aluminum salts of the aforementioned water-soluble edible tar pigments), natural pigments (eg, β-carotene, chlorophyll, red iron oxide), and the like.

Examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, and the like.

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

As the wetting agent, for example: propylene glycol monohard Fatty acid ester, sorbitan monooleate, diethylene glycol monolaurate, polyoxyethylene lauryl ether.

In the manufacture of oral dosage forms, coating may be carried out for the purpose of taste masking, or enteric solubility or persistence, if necessary.

The coating base used for coating includes, for example, a sugar coating base, a water-soluble film coating base, an enteric film coating base, and a sustained-release film coating base.

White sugar can be used as a sugar-coating base, and one or more selected from the group consisting of talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, and the like can be used in combination.

Examples of water-soluble film coating bases include cellulose-based polymers such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, and methyl hydroxyethyl cellulose; Synthetic polymers such as vinyl acetal diethyl amino acetate, amino alkyl methacrylate copolymer E [Eudragit E (trade name)], polyvinyl pyrrolidone; polysaccharides such as pullulan carbohydrate.

Examples of enteric film coating bases include hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and acetate phthalate. Cellulose-based polymers such as cellulose; 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)] and other acrylic polymers; natural products such as shellac.

Examples of sustained-release film coating bases include Such as: cellulose-based polymers such as ethyl cellulose; amino alkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE ( trade name)] and other acrylic polymers.

The above-mentioned coating bases can be used by mixing two or more kinds thereof in an appropriate ratio. Moreover, at the time of coating, a light-shielding agent, such as titanium oxide and ferric oxide, can also be used, for example.

The dose of the compound of the present invention can be appropriately selected depending on the subject to be administered, the symptoms, the method of administration, and the like. For example, when the compound of the present invention is orally administered to obese or diabetic patients (body weight 60 kg), the dosage of the compound of the present invention per day 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 administered parenterally to obese or diabetic patients (body weight 60kg), the dosage of the compound of the present invention is about 0.001 to 30 mg per day, preferably about 0.01 to 20 mg, more preferably About 0.1 to 10 mg. This equal amount can be divided into 1 to several times a day for administration.

The compound of the present invention can be taken, for example, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, twice a week, once every other week, Administration was performed once every 3 weeks, once a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months or once every 6 months.

For example, for the purpose of enhancing the effect of the compound of the present invention (the therapeutic effect of obesity, diabetes, etc.), reducing the amount of the compound of the present invention, etc., the compound of the present invention can also be combined with the compound of the present invention without causing adverse effects on the compound of the present invention. Concomitant use of other medicines.

Examples of agents that can be used in combination with the compound of the present invention (hereinafter, may be simply referred to as a combination agent) include, for example, anti-obesity agents, therapeutic agents for diabetes, agents for treating diabetic complications, agents for treating hyperlipidemia, and agents for lowering blood pressure. , Diuretics, Chemotherapy agents, Immunotherapy agents, Anti-inflammatory drugs, Antithrombotic agents, Osteoporosis therapeutic agents, Vitamin drugs, Antidementia drugs, Erectile dysfunction improving drugs, Frequent urination/urinary incontinence treatment drugs, Dysuria treatment agent, etc. Specifically, the following can be mentioned.

Examples of the anti-obesity agent include monoamine uptake inhibitors (for example, phentermine, sibutramine, mazindol, fluroxetine, somexa) tesofensine), serotonin 2C receptor agonists (eg, lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulators, GABA modulators (eg, topinmate) (topiramate), neuropeptide Y antagonists (eg, velneperit, cannabinoid receptor antagonists (eg, rimonabant, taranavan), growth hormone antagonists, somatotropin receptor antagonists, ghrelin agonists, opioid receptor antagonists (e.g., GSK-1521498), orexin receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (eg, AZD-4017), pancreatic lipase inhibitors (eg, orlistat, cetilistat), β3 agonists (eg, N-5984), diacylglycerol transferase 1 (DGAT1) inhibitor, acetyl CoA carboxylase (ACC) inhibitor, stearate CoA desaturase inhibitor, microsomal triglyceride transfer protein Inhibitors (eg, R-256918), Na-glucose co-delivery carrier inhibitors (eg, JNJ-28431754, remogliflozin, NFκ inhibitors (eg, HE-3286), PPAR agonists (eg, GFT-505, DRF-11605) , phosphotyrosine phosphatase inhibitors (eg, sodium vanadate, Trodusquemin), GPR119 agonists (eg, PSN821, MBX-2982, APD597), glucokinase activators (eg, AZD) -1656), leptin, leptin derivatives (eg, metreleptin), CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonists , amylin preparations (eg, prmlintide, AC-2307), neuropeptide Y agonists (eg, PYY3-36, derivatives of PYY3-36, obineptide, TM -30339, TM-30335), oxyntomodulin preparations: FGF21 preparations (for example, animal FGF21 preparations extracted from bovine, porcine pancreas; human FGF21 preparations synthesized by genetic engineering using Escherichia coli, yeast; FGF21 preparations fragments or derivatives), feeding inhibitors (eg, P-57), and the like.

(glipizide)、格列丁唑(glybuzole))、瑞格列奈(repaglinide)、那格列奈(nateglinide)、米格列奈(mitiglinide)或其鈣鹽水合物)、二肽基肽酶IV抑制劑(例如，阿格列汀(Alogliptin)或其鹽(較佳為苯甲酸鹽)、維格列汀(Vildagliptin)、西他列汀(Sitagliptin)、沙格列汀(Saxagliptin)、BI1356、GRC8200、MP-513、PF-00734200、PHX1149、SK-0403、ALS2-0426、TA-6666、TS-021、KRP-104、曲格列汀(Trelagliptin)或其鹽(較佳為琥珀酸鹽))、β3促效劑(例如，N-5984)、GPR40促效劑(例如，法西格列泛(Fasiglifam)或其水合物、WO2004/041266、WO2004/106276、WO2005/063729、WO2005/063725、WO2005/087710、WO2005/095338、 WO2007/013689或WO2008/001931記載之化合物)、鈉-葡萄糖協同轉運蛋白(SGLT2(sodium-glucose cotransporter 2))抑制劑(例如，達格列

(Dapagliflozin)、AVE2268、TS-033、YM543、TA-7284、瑞格列

(remogliflozin)、ASP1941)、SGLT1抑制藥、11β-羥基類固醇脫氫酶抑制藥(例如，BVT-3498、INCB-13739)、脂聯素(adiponectin)或其促效藥、IKK抑制藥(例如，AS-2868)、瘦體素抗性改善藥、生長抑素(somatostatin)受體促效藥、葡萄糖激酶活化藥(例如，皮拉格利他汀(Piragliatin)、AZD1656、AZD6370、TTP-355、WO2006/112549、WO2007/028135、WO2008/047821、WO2008/050821、WO2008/136428或WO2008/156757記載之化合物)、GPR119促效劑(例如，PSN821、MBX-2982、APD597)、FGF21、FGF類似物、ACC2抑制劑等。 Examples of the therapeutic agent for diabetes include insulin preparations (for example, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations synthesized by genetic engineering using Escherichia coli and yeast; zinc insulin; protamine zinc insulin Fragments or derivatives of insulin (eg, INS-1), oral insulin preparations), insulin resistance improving agents (eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof ( Maleate is preferred), Metaglidasen, AMG-131, Balaglitazone, MBX-2044, Rivoglitazone, Aleglitazar ), Chiglitazar, Lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, WO2007/013694, WO2007/018314, WO2008/093639 or WO2008/099794 compounds described), alpha-glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate), biguanides stimulants (eg, metformin, buformin, or salts thereof (eg, hydrochloride, fumarate, succinate)), insulin secretion enhancers (eg, sulfonylureas) agents (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetaminophen ( acetohexamide), glyclopyramide, glimepiride, glipizide

(glipizide, glybuzole), repaglinide, nateglinide, mitiglinide or its calcium salt hydrate), dipeptidyl peptidase IV Inhibitors (eg, 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 its salt (preferably succinate) )), beta3 agonists (eg, N-5984), GPR40 agonists (eg, Fasiglifam or a hydrate thereof, WO2004/041266, WO2004/106276, WO2005/063729, WO2005/063725 , WO2005/087710, WO2005/095338, WO2007/013689 or the compounds described in WO2008/001931), sodium-glucose cotransporter (SGLT2 (sodium-glucose cotransporter 2)) inhibitors (for example, dapagliflozin

(Dapagliflozin), AVE2268, TS-033, YM543, TA-7284, Regoli

(remogliflozin, ASP1941), SGLT1 inhibitors, 11β-hydroxysteroid dehydrogenase inhibitors (eg, BVT-3498, INCB-13739), adiponectin or its agonists, IKK inhibitors (eg, AS-2868), leptin resistance improving drugs, somatostatin receptor agonists, glucokinase activators (eg, Piragliatin, AZD1656, AZD6370, TTP-355, WO2006 /112549, WO2007/028135, WO2008/047821, WO2008/050821, WO2008/136428 or compounds described in WO2008/156757), GPR119 agonists (eg PSN821, MBX-2982, APD597), FGF21, FGF analogs, ACC2 inhibitors, etc.

唑)、WO2004/039365記載之化合物)、PKC抑制劑(例如，魯伯斯塔甲磺酸鹽(ruboxistaurin mesylate))、AGE抑制劑(例如，ALT946、 N-苄醯甲基噻唑鎓溴化物(ALT766)、EXO-226、吡多胺二鹽酸鹽(Pyridorin)、吡多胺(pyridoxamine))、GABA受體促效藥(例如，加巴噴丁(gabapentin)、普加巴林(pregabalin))、血清素/正腎上腺素再吸收抑制藥(例如，度洛西汀(duloxetine))、鈉通道抑制藥(例如，拉科胺(lacosamide))、活性氧消去藥(例如，硫辛酸)、腦血管擴張劑(例如，泰必利(tiapride)、美西律(mexiletine))、生長抑素(somatostatin)受體促效藥(例如，BIM23190)、細胞凋亡信號調節激酶-1(ASK-1)抑制藥等。 Examples of therapeutic agents for diabetic complications include aldose reductase inhibitors (eg, tolrestat, epalrestat, zopolrestat, fidarestat ( fidarestat), CT-112, ranirestat (AS-3201), lidorestat), neurotrophic factors and their promoting drugs (eg, NGF, NT-3, BDNF, WO01/14372 Neurotrophic factor production/secretion promoters described (eg, 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy) )propyl]

azole), compounds described in WO 2004/039365), PKC inhibitors (eg, ruboxistaurin mesylate), AGE inhibitors (eg, ALT946, N-benzylmethylthiazolium bromide ( ALT766), EXO-226, Pyridorin, pyridoxamine), GABA receptor agonists (eg, gabapentin, pregabalin), serotonin /Norepinephrine reuptake inhibitors (eg, duloxetine), sodium channel inhibitors (eg, lacosamide), reactive oxygen species scavengers (eg, lipoic acid), cerebral vasodilators (eg, tiapride, mexiletine), somatostatin receptor agonists (eg, BIM23190), apoptosis signal-regulated kinase-1 (ASK-1) inhibitors Wait.

吖呯-3-基]乙醯基]哌啶-4-乙酸)、纖維酸酯(fibrate)系化合物(例如，苯纖維酸酯(bezafibrate)、克洛纖維酸酯(clofibrate)、辛弗纖維酸酯(simfibrate)、克諾纖維酸酯(clinofibrate))、陰離子交換樹脂(例如，消膽鹼(cholestyramine))、普羅布考(probucol)、菸酸系藥劑(例如，尼可莫爾(nicomol)、菸酸戊四醇酯(niceritrol)、菸酸緩釋片(niaspan))、二十碳五烯酸乙酯、 植物固醇(例如，大豆固醇(soysterol)、γ-谷維素(γ-oryzanol))、膽固醇吸收抑制劑(例如，依澤替米貝片(zetia))、CETP抑制劑(例如，達塞曲匹(dalcetrapib)、安塞曲匹(anacetrapib))、ω-3脂肪酸製劑(例如，ω-3-脂肪酸乙酯90(ω-3-acid ethyl esters 90))等。 Hyperlipidemia therapeutic agents include HMG-CoA reductase inhibitors (for example, pravastatin, simvastatin, lovastatin, atorvastatin, Fluvastatin (fluvastatin), rosuvastatin (rosuvastatin), pitavastatin (pitavastatin) or their salts (eg, sodium salt, calcium salt)), squalene synthesis enzyme inhibitor (eg, WO97/10224 Compounds described in pamphlet No. , for example, N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3 -Dimethoxyphenyl)-2-oxy-1,2,3,5-tetrahydro-4,1-benzo

acridine-3-yl]acetoxy]piperidine-4-acetic acid), fibrate-based compounds (eg, bezafibrate, clofibrate, sinfer simfibrate, clinofibrate), anion exchange resins (eg, cholestyramine), probucol, niacin-based agents (eg, nicomol) ), niceritrol (niceritrol, niaspan), ethyl eicosapentaenoate, phytosterols (eg, soysterol, γ-oryzanol (γ- oryzanol), cholesterol absorption inhibitors (eg, zetia), CETP inhibitors (eg, dalcetrapib, anacetrapib), omega-3 fatty acid formulations (For example, ω-3-fatty acid ethyl esters 90 (ω-3-acid ethyl esters 90)) and the like.

Examples of hypotensive agents include angiotensin-converting enzyme inhibitors (for example, captopril, enalapril, derapril, etc.), angiotensin II antagonists (eg, candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan ), telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil, etc.), calcium antagonists (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine ), cilnidipine, etc.), beta blockers (eg, metoprolol, atenolol, propranolol, carvedilol, Pindolol (pindolol, etc.), clonidine (clonidine), etc.

(thiazide)系製劑(例如，乙噻

(ethiazide)、環戊噻

、三氯甲噻

、氫氯噻

、氫氟噻

、苄氫氯噻

、戊氟噻

、聚噻

(polythiazide)、甲氯噻

等)、抗醛固酮製劑(例如，螺旋內酯固醇(spironolactone)、三胺蝶啶(triamterene)等)、碳酸脫水酵素抑制劑(例如，乙醯唑胺(acetazolamide)等)、氯苯磺醯胺系製劑(例如，氯噻酮(chlorthalidone)、美呋西特(mefruside)、吲達帕胺(indapamide)等)、唑噻醯胺(azosemide)、異色普(isosorbide)、依他尼酸(ethacrynic acid)、吡咯他尼(piretanide)、布美他尼(bumetanide)、呋塞米(furosemide)等。 Examples of diuretics include xanthine derivatives (for example, sodium salicylate theobromine, calcium salicylate theobromine, etc.),

(thiazide) preparations (eg, thiazide)

(ethiazide), cyclopentathioate

, Trichlorothiazide

, Hydrochlorothiazide

, hydrofluorothiazide

, benzyl hydrochlorothiazide

, penfluthiazine

, Polythio

(polythiazide), methylchlorothiazide

etc.), antialdosterone preparations (for example, spironolactone, triamterene, etc.), carbonic dehydratase inhibitors (for example, acetazolamide, etc.), chlorobenzene sulfonic acid Amine-based preparations (for example, chlorthalidone, mefruside, indapamide, etc.), azosemide, isosorbide, etacrine ( ethacrynic acid), piretanide, bumetanide, furosemide, etc.

Examples of chemotherapeutic agents include alkylating agents (eg, cyclophosphamide, ifosfamide), metabolic antagonists (eg, methotrexate, 5-fluorouracil) ), anticancer antibiotics (eg, mitomycin, adriamycin), plant-derived anticancer agents (eg, vincristine, vindesine, paclitaxel) ), cisplatin, carboplatin, etoposide and the like. Among them, 5-fluorouracil derivatives such as flutulon or neofurtulon are preferred.

Examples of immunotherapeutic agents include microorganisms or bacterial components (for example, muramyl dipeptide derivatives, picibanir), polysaccharides having immune-enhancing activity (for example, lentinan). (lentinan), schizophyllan (schizophyllan), Yunzhi polysaccharide (krestin), cytokines obtained by genetic engineering technology (eg, interferon, interleukin (IL)), colony stimulating factor (eg , granulococcus colony-stimulating factor, erythropoietin) etc., among which interleukins such as IL-1, IL-2, and IL-12 are preferred.

Examples of anti-inflammatory drugs include non-steroidal anti-inflammatory drugs such as aspirin, acetaminophen, and indomethacin.

As the antithrombotic agent, heparin (for example, heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), acetone warfarin (for example, acetobenzyl hydroxycoumarin potassium), antithrombin drugs (eg, aragatroban, dabigatran), FXa inhibitors (eg, rivaroxaban, apixa Compounds described in apixaban, edoxaban, YM150, WO02/06234, WO2004/048363, WO2005/030740, WO2005/058823 or WO2005/113504, thrombolytics (eg, urokinase) ), tisokinase, alteplase, nateplase, monteplase, pamiteplase), platelet aggregation inhibitors (eg, thiophene ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl eicosapentaenoate, beraprost sodium (beraprost sodium), sarpogrelate hydrochloride) and the like.

As an osteoporosis therapeutic agent, for example, α -calcidol (alfacalcidol), calcitriol (calcitriol), elcatonin (elcatonin), calcitonin salmon (calcitonin salmon), estriol Alcohol (estriol), ipriflavone (ipriflavone), pamidronate disodium (pamidronate disodium), alendronate sodium hydrate (alendronate sodium hydrate), ibandronate disodium (incadronate disodium), risedronate Disodium acid (risedronate disodium) and so on.

As _a vitamin drug, vitamin B1, vitamin _B12 , etc. are mentioned, for example.

As an antidementia drug, tacrine, donepezil, rivastigmine, galanthamine, etc. are mentioned, for example.

Examples of the erectile dysfunction improving drug include apomorphine, sildenafil citrate, and the like.

Examples of drugs for the treatment of urinary frequency/urinary incontinence include flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride, and the like.

As a dysuria therapeutic agent, an acetylcholinesterase inhibitor (for example, distigmine) etc. are mentioned.

Furthermore, agents that have been confirmed to improve cachexia in animal models or clinically, namely, cyclooxygenase inhibitors (for example, indomethacin), progesterone derivatives (for example, megestrol acetate) Megestrol acetate), saccharide steroids (eg, dexamethasone), metoclopramide-based agents, tetrahydrocannabinol-based agents, fat metabolism improving agents (eg, eicosapentaenoic acid) ), growth hormones, IGF-1, or any of the factors that target cachexia Antibodies to TNF-α, LIF, IL-6, oncostatin M and the like can also be used in combination with the compound of the present invention.

(imipramine))、抗癲癇藥(例如，拉莫三

(lamotrigine)、除癲達(Trileptal)、優閒錠(Keppra)、佐能安(Zonegran)、普瑞巴林(Pregabalin)、拉考醯胺(Harkoseride)、卡馬西平(carbamazepine))、抗心律不整藥(例如，美西律(mexiletine))、乙醯基膽鹼受體配位子(例如，ABT-594)、內皮素受體拮抗藥(例如，ABT-627)、單胺攝取抑制藥(例如，曲馬多(tramadol))、麻藥性鎮痛藥(例如，嗎啡)、GABA受體促效藥(例如，加巴噴丁(gabapentin)、加巴噴丁MR劑)、α2受體促效藥(例如，可樂定(clonidine))、局部鎮痛藥(例如，辣椒素)、抗焦慮藥(例如，苯并硫氮呯(benzothiazepine))、磷酸二酯酶抑制藥(例如，西地那非(sildenafil))、多巴胺受體促效藥(例如，阿樸嗎啡(apomorphine))、咪達唑侖(midazolam)、酮康唑(ketoconazole)等，亦可與本發明化合物併用。 Furthermore, glycation inhibitors (for example, ALT-711), nerve regeneration promoting drugs (for example, Y-128, VX853, prosaptide), antidepressants (for example, desipramine), acetaminophen amitriptyline, imipramine

(imipramine), antiepileptic drugs (eg, lamotrigine

(lamotrigine), Trileptal, Keppra, Zonegran, Pregabalin, Harkoseride, carbamazepine), antiarrhythmic Drugs (eg, mexiletine), acetylcholine receptor ligands (eg, ABT-594), endothelin receptor antagonists (eg, ABT-627), monoamine uptake inhibitors ( For example, tramadol), narcotic analgesics (eg, morphine), GABA receptor agonists (eg, gabapentin, gabapentin MR agents), alpha2 receptor agonists (eg, clonidine ( clonidine), topical analgesics (eg, capsaicin), anxiolytics (eg, benzothiazepine), phosphodiesterase inhibitors (eg, sildenafil), dopamine receptors Body agonists (eg, apomorphine), midazolam, ketoconazole and the like can also be used in combination with the compounds of the present invention.

The timing of administration of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the subject at the same time, or may be administered at different times.

The administration form includes, for example: (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, (2) Two preparations obtained by separately formulating the compound of the present invention and the concomitant drug are administered simultaneously by the same administration route, (3) Two preparations obtained by separately formulating the compound of the present invention and the concomitant drug are administered in the same administration (4) Two preparations obtained by separately formulating the compound of the present invention and the concomitant drug are administered simultaneously by different administration routes, (5) The compound of the present invention and the concomitant drug are separately formulated The obtained two preparations are administered by different administration routes and time-staggered (for example, the compound of the present invention and the concomitant drug are administered in sequence, or in reverse order).

The dose of the concomitant drug can be appropriately selected based on the clinically used dose. In addition, the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected according to the administration target, symptoms, administration method, target disease, combination, and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug can be used with respect to 1 part by weight of the compound of the present invention.

By combining the compound of the present invention with a concomitant drug, (1) the dose of the present invention can be reduced compared to the case where the compound of the present invention or the concomitant drug is administered alone, and (2) the dose can be reduced according to the symptoms (mild symptoms) of the patient. , severe disease, etc.), select the medicament that can be used in combination with the compound of the present invention, (3) by selecting the concomitant medicament with a different mechanism of action from the compound of the present invention, a longer treatment period can be set, (4) by selecting the compound of the present invention. Concomitant drugs with different mechanisms of action can achieve continuation of the therapeutic effect. Multiply effect, etc.

[Example]

The abbreviations used in this specification represent the meanings of the following (Table 1-1, Table 1-2, and Table 1-3). The hyphens included in α-MePhe and the like in this specification may be omitted, and the same meaning is indicated when omitted.

In the amino acid sequence used in this specification, the left terminus represents the N terminus, and the right terminus represents the C terminus.

In this specification, bases or amino acids are represented by abbreviations, which are based on the abbreviations of the IUPAC-IUB Committee on Biochemical Nomenclature (Commision on Biochemical Nomenclature) or those commonly used in the field, and are exemplified in the following illustrate. In addition, regarding the case where an amino acid may have an optical isomer, unless otherwise specified or otherwise clearly stated, it represents the L-form (for example, "Ala" is Ala of the L-form). In addition, in the case of "D-", it means D type (for example, "D-Ala" is Ala of D type), and in the case of "DL-", it means the elimination of D type and L type. The isomers (eg, "DL-Ala" refers to the racemates of D-form Ala and L-form 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: Glutamate

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: aspartic acid

Gln or Q: Glutamate

pGlu: pyroglutamate

α-MeTyr: α-Methyltyrosine

The present invention is further described in detail by the following reference examples, examples, test examples and formulation examples. However, these examples are only simple implementations and are not intended to limit the present invention. Moreover, without exceeding the scope of the present invention, Different variations are possible.

The "room temperature" in the following examples generally means about 10°C to about 35°C. % in yield means mole/mol %, solvent used in chromatography means volume %, others means weight %.

THF: Tetrahydrofuran

DMF: N,N-Dimethylformamide

WSC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

HOBt: 1-Hydroxybenzotriazole monohydrate

Reference Example 1

H-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln Synthesis of (Trt)-Arg(Pbf)-Phe(2-F)-Sieber Amide Resin (SEQ ID NO: 2)

Sieber amide resin (0.71 meq/g, 352 mg) was added to the reaction tube and mounted to the peptide synthesizer. The amino acids were condensed sequentially according to the Fmoc/DCC/HOBt procedure. Double coupling was performed when Lys (Boc) at position 29 was introduced. The N-terminal Fmoc group was removed in the final step. After the condensation was completed, the resin was washed with MeOH and dried under reduced pressure. 1384 mg (0.181 meq/g) of the intended protected peptide resin was obtained.

Reference example 2

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)-Aib-Ile-Aib-Leu-Asp(OtBu) -Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys( Synthesis of Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Phe(2-F)-Sieber Amide Resin (SEQ ID NO: 3)

H-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu) prepared in Reference Example 1 -Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Phe(2-F)-Sieberamide resin (0.181 meq/g, 276 mg) was added to the reaction tube and installed into the peptide synthesizer. Sequentially condensed amino acids by Fmoc/DIPCDI/OxymaPure process combine. Double coupling was performed upon introduction of Gln (Trt) at position 19, Ala at position 18, Ile at position 12, and Thr (tBu) at position 5. The N-terminal Fmoc group was removed in the final step. After the condensation was completed, the resin was washed with MeOH and dried under reduced pressure. 389 mg (0.129 meq/g) of the intended protected peptide resin was obtained.

Reference Example 3

H-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln Synthesis of (Trt)-Arg(Pbf)-Phe(2-F)-Rink Amide AM Resin (SEQ ID NO: 4)

Rink amide AM resin (0.29 meq/g, 862 mg) was added to the reaction tube and installed into the peptide synthesizer. The amino acids are sequentially condensed by the Fmoc/DCC/HOBt process. Double coupling was performed when Lys (Mtt) at position 29 was introduced. The N-terminal Fmoc group was removed in the final step. After the condensation was completed, the resin was washed with MeOH and dried under reduced pressure. 1788 mg (0.140 meq/g) of the intended protected peptide resin was obtained.

Reference Example 4

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)-Aib-Ile-Aib-Leu-Asp(OtBu) -Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt) Synthesis of -Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Phe(2-F)-Rink Amide AM Resin (SEQ ID NO: 5)

H-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu) prepared in Reference Example 3 -Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Phe(2-F)-Rink amide AM resin (0.140 meq/g, 357 mg) was added to the reaction tube and installed into the peptide synthesizer. The amino acids are sequentially condensed by the Fmoc/DIPCDI/OxymaPure process. Double coupling was performed upon introduction of Gln (Trt) at position 19, Arg (Pbf) at position 18, Ile at position 12 and Thr (tBu) at position 5. The N-terminal Fmoc group was removed in the final step. After the condensation was completed, the resin was washed with MeOH and dried under reduced pressure. 452 mg (0.111 meq/g) of the intended protected peptide resin was obtained.

Reference Example 5

H-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln Synthesis of (Trt)-Arg(Pbf)-Tyr(tBu)-Rink Amide AM Resin (SEQ ID NO: 6)

Rink Amide AM resin (0.29 meq/g, 690 mg) was added to the reaction tube and installed into the peptide synthesizer. The amino acids are sequentially condensed by the Fmoc/DCC/HOBt process. Double coupling was performed when Lys (Mtt) at position 29 was introduced. The N-terminal Fmoc group was removed in the final step. After the condensation was completed, the resin was washed with MeOH and dried under reduced pressure. 1449 mg (0.138 meq/g) of the intended protected peptide resin was obtained.

Reference Example 6

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)-Aib-Ile-Aib-Leu-Asp(OtBu) -Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt) Synthesis of -Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink amide AM resin (SEQ ID NO: 7)

H-Iva-Glu(OtBu)-Phe-Val-Arg prepared in Reference Example 5 (Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)- Rink amide AM resin (0.138 meq/g, 290 mg) was added to the reaction tube and installed into the peptide synthesizer. The amino acids were condensed sequentially by the Fmoc/DIPCDI/OxymaPure procedure. Double coupling was performed upon introduction of Gln (Trt) at position 19, Arg (Pbf) at position 18, Ile at position 12 and Thr (tBu) at position 5. The N-terminal Fmoc group was removed in the final step. After the condensation was completed, the resin was washed with MeOH and dried under reduced pressure. 417 mg (0.096 meq/g) of the intended protected peptide resin was obtained.

Reference Example 7

H-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln Synthesis of (Trt)-Arg(Pbf)-Tyr(tBu)-Sieberamide resin (SEQ ID NO: 8)

Sieber amide resin (0.71 meq/g, 352 mg) was added to the reaction tube and installed into the peptide synthesizer. The amino acids are sequentially condensed by the Fmoc/DCC/HOBt process. Double coupling was performed when Lys (Boc) at position 29 was introduced. The N-terminal Fmoc group was removed in the final step. After the condensation was completed, the resin was washed with MeOH and dried under reduced pressure. 1373 mg (0.182 meq/g) of the intended protected peptide resin was obtained.

Reference Example 8

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)-Aib-Ile-Aib-Leu-Asp(OtBu) -Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys( Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieberamide resin (SEQ ID NO: 9) Synthesis

H-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu) prepared in Reference Example 7 -Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieberamide resin (0.182 meq/g, 275 mg) was added to the reaction tube and installed into the peptide synthesizer. The amino acids are sequentially condensed by the Fmoc/DIPCDI/OxymaPure process. Double coupling was performed upon introduction of Gln (Trt) at position 19, Ala at position 18, Ile at position 12, and Thr (tBu) at position 5. The N-terminal Fmoc group was removed in the final step. After the condensation was completed, the resin was washed with MeOH and dried under reduced pressure. 409 mg (0.122 meq/g) of the intended protected peptide resin was obtained.

Example 1

H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Phe(2-F) _-NH2 (SEQ ID NO: 10)

Measure the H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)-Aib-Ile- prepared in Reference Example 2 Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu -Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Phe(2-F)-Sieber amide resin (0.129meq/g, 97 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-Tyr(tBu)-OH (33.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. Pass After removing the reaction liquid by filtration, the resin was washed with NMP 6 times. After confirming that the Kaiser test was negative, a 2% hydrazine-NMP solution was added to the obtained resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Fmoc-Gly-Gly-Gly-OH (41.1 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, an NMP solution (200 μL) of Pal-OSu (35.4 mg) and DIPEA (17.4 μL) was added, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, the resin was washed with MeOH and dried under reduced pressure to obtain Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser (tBu)-Asp(OtBu)-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln( Trt )-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln (Trt)-Arg(Pbf)-Phe(2-F)-Sieber amide resin 101.3 mg.

To 101.3 mg of the obtained resin, 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added, and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removal of the resin by filtration, linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). 60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA; flow rate: 8 mL/min, A/B: 56/44-46/54), collect the part containing the object, and Freeze drying gave 23.1 mg of white powder.

(M+H) ⁺ 4606.1 (calculated 4605.5) by mass analysis

HPLC dissolution time: 17.4 minutes

Dissolution Conditions:

Column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 2

H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Oda)-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Phe(2-F)-NH ₂ (SEQ ID NO: 11)

Measure the H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)-Aib-Ile- prepared in Reference Example 2 Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu -Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Phe(2-F)-Sieber amide resin (0.129meq/g, 97 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-Tyr(tBu)-OH (33.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. The cycle of condensation of this Fmoc amino acid-Fmoc deprotection is repeated, and the Gly-Gly-Gly, Oda(OtBu) condenses sequentially. The resin was washed with MeOH and dried under reduced pressure to obtain Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Lys(-Gly-Gly-Gly-Gly-Oda(tBu))-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Iva- Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)- Arg(Pbf)-Phe(2-F)-Sieber amide resin 94.6 mg.

To 94.6 mg of the obtained resin, 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added, and stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 60/40-50/50), collect the part containing the target substance, And freeze-dried to obtain 21.4 mg of white powder.

(M+H) ⁺ 4664.4 (calculated 4663.6) by mass analysis

HPLC dissolution time: 15.4 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, with A/B: 80/20 to 30/70 for linear concentration gradient dissolution (25 minutes).

Flow rate: 1.0mL/min

Example 3

H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Phe(2-F) _-NH2 (SEQ ID NO: 12)

Measure the H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)-Aib-Ile- prepared in Reference Example 4 Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)- Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Phe(2-F)-Rink amide AM resin (0.111 meq/g, 89.3 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-Tyr(tBu)-OH (33.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Add 20% after confirming that the Kather test is negative Piperidine in NMP and shaken for 1 min. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Fmoc-Gly-Gly-Gly-OH (41.1 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, an NMP solution (200 μL) of Pal-OSu (35.4 mg) and DIPEA (17.4 μL) was added, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, the resin was washed with MeOH and dried under reduced pressure to obtain Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser (tBu)-Asp(OtBu)-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf) -Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg( Pbf)-Gln(Trt)-Arg(Pbf)-Phe(2-F)-Rink amide AM resin 110.2 mg.

To 110.2 mg of the obtained resin was added 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5), and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removal of the resin by filtration, linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). 60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 58/42-48/52), collect the part containing the object, and Freeze drying gave 9.3 mg of white powder.

(M+H) ⁺ 4691.1 by mass analysis (calculated 4690.6)

HPLC dissolution time: 16.9 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 4

H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Oda)-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Phe(2-F) _-NH2 (SEQ ID NO: 13)

Measure the H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)-Aib-Ile- prepared in Reference Example 4 Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)- Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf) -Phe(2-F)-Rink amide AM resin (0.111 meq/g, 89.3 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-Tyr(tBu)-OH (33.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Repeat the cycle of condensation of Fmoc amino acid-Fmoc deprotection) to condense Gly-Gly-Gly and Oda(OtBu) sequentially. The resin was washed with MeOH and dried under reduced pressure to obtain Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)- Lys(-Gly-Gly-Gly-Gly-Oda(OtBu))-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)- Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt) )-Arg(Pbf)-Phe(2-F)-Rink amide AM resin 109.6 mg.

To 109.6 mg of the obtained resin, 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added, and stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate, and after centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removal of the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 61/39-51/49), collect the part containing the target substance, And freeze-dried to obtain 9.5 mg of white powder.

(M+H) ⁺ 4749.1 (calculated 4748.6) by mass analysis

HPLC dissolution time: 14.9 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 5

Me-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Phe(2-F) _-NH2 (SEQ ID NO: 14)

Measure the H-Aib-Glu(OtBu)-Gly-Thr prepared in Reference Example 4 (tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg (Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu) -Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Phe(2-F)-Rink Amide AM resin (0.111 meq/g, 89.3 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-NMeTyr(tBu)-OH (35.1 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Fmoc-Gly-Gly-Gly-OH (41.1 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After removing the solution by filtration, add 20% piperidine in NMP again, And shake for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, an NMP solution (200 μL) of Pal-OSu (35.4 mg) and DIPEA (17.4 μL) was added, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, the resin was washed with MeOH and dried under reduced pressure to obtain Boc-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser (tBu)-Asp(OtBu)-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf) -Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg( Pbf)-Gln(Trt)-Arg(Pbf)-Phe(2-F)-Rink amide AM resin 135.1 mg.

To 135.1 mg of the obtained resin was added 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5), and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, liquid A: 0.1% was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250×20 mm ID). TFA-water, liquid B: acetonitrile containing 0.1% TFA flow rate: 8 mL/min, A/B: 57/43-47/53 linear concentration gradient dissolution (60 minutes), collect the fraction containing the target substance, And freeze-dried to obtain 10.8 mg of white powder.

(M+H) ⁺ 4705.1 (calculated 4704.6) by mass analysis

HPLC dissolution time: 16.9 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 6

Me-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Oda)-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Phe(2-F) _-NH2 (SEQ ID NO: 15)

Measure the H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)-Aib-Ile- prepared in Reference Example 4 Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)- Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Phe(2-F)-Rink amide AM resin (0.111 meq/g, 89.3 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-NMeTyr(tBu)-OH (35.1 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was Washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Gly-Gly-Gly, Oda(OtBu) were condensed sequentially by repeating the cycle of condensation of Fmoc amino acid-Fmoc deprotection. The resin was washed with MeOH and dried under reduced pressure to obtain Boc-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Lys(-Gly-Gly-Gly-Gly-Oda(OtBu))-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt) -Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln( Trt)-Arg(Pbf)-Phe(2-F)-Rink amide AM resin 121.2 mg.

To 121.2 mg of the obtained resin, 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added, and stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 61/39-51/49), collect the part containing the target substance, And freeze-dried to obtain 9.1 mg of white powder.

(M+H) ⁺ 4763.3 (calculated 4762.6) by mass analysis

HPLC dissolution time: 14.9 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 7

H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 16)

Measure the H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)-Aib-Ile- prepared in Reference Example 6 Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)- Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink Amide AM resin (0.096meq/ g, 104 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-Tyr(tBu)-OH (33.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. Pass After removing the reaction liquid by filtration, the resin was washed with NMP 6 times. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Fmoc-Gly-Gly-Gly-OH (41.1 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, an NMP solution (200 μL) of Pal-OSu (35.4 mg) and DIPEA (17.4 μL) was added, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, the resin was washed with MeOH and dried under reduced pressure to obtain Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser (tBu)-Asp(OtBu)-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf) -Gln(Trt)-Iva-Glu (OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg (Pbf)-Tyr(tBu)-Rink amide AM resin 109.1 mg.

To 109.1 mg of the obtained resin was added 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5), and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 57/43-47/53), collect the part containing the target substance, And freeze-dried to obtain 7.9 mg of white powder.

(M+H) ⁺ 4689.4 (calculated 4688.6) by mass analysis

HPLC dissolution time: 16.6 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 8

H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Oda)-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 17)

Measure the H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)-Aib-Ile- prepared in Reference Example 6 Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)- Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink Amide AM resin (0.096meq/ g, 104 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-Tyr(tBu)-OH (33.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. By repeating this cycle of condensation-Fmoc deprotection of Fmoc amino acids, Gly-Gly-Gly, Oda(OtBu) condenses sequentially. The resin was washed with MeOH and dried under reduced pressure to obtain Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Lys(-Gly-Gly-Gly-Gly-Oda(OtBu))-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt) -Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln( Trt)-Arg(Pbf)-Tyr(tBu)-Rink amide AM resin 104.1 mg.

To 104.1 mg of the obtained resin was added 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5), and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 61/39-51/49), collect the fraction containing the target substance, And freeze-dried to obtain 7.7 mg of white powder.

(M+H) ⁺ 4747.5 by mass analysis (calculated 4746.6)

HPLC dissolution time: 14.6 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, with A/B: 80/20 to 30/70 for linear concentration gradient dissolution (25 minutes).

Flow rate: 1.0mL/min

Example 9

Me-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 18)

Measure the H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)-Aib-Ile- prepared in Reference Example 6 Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)- Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink Amide AM resin (0.096meq/ g, 104 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-NMeTyr(tBu)-OH (35.1 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Add 20% after confirming that the Kather test is negative Piperidine in NMP and shaken for 1 min. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Fmoc-Gly-Gly-Gly-OH (41.1 mg), 0.5M OxymaPure (200 μL) NMP, and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, an NMP solution (200 μL) of Pal-OSu (35.4 mg) and DIPEA (17.4 μL) was added, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, the resin was washed with MeOH and dried under reduced pressure to obtain Boc-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser (tBu)-Asp(OtBu)-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf) -Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg( Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink amide AM resin 99.6 mg.

To 99.6 mg of the obtained resin, 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added, and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 57/43-47/53), collect the fraction containing the target substance, And freeze-dried to obtain 8.3 mg of white powder.

(M+H) ⁺ 4703.5 (calculated 4702.6) by mass analysis

HPLC dissolution time: 16.6 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 10

Me-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Oda)-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 19)

Measure the H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)-Aib-Ile- prepared in Reference Example 6 Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)- Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf) -Tyr(tBu)-Rink amide AM resin (0.096 meq/g, 104 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-NMeTyr(tBu)-OH (35.1 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Gly-Gly-Gly, Oda(OtBu) were condensed sequentially by repeating the cycle of condensation of Fmoc amino acid-Fmoc deprotection. The resin was washed with MeOH and dried under reduced pressure to obtain Boc-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Lys(-Gly-Gly-Gly-Gly-Oda(OtBu))-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt) -Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln( Trt)-Arg(Pbf)-Tyr(tBu)-Rink amide AM resin 110.6 mg.

To 110.6 mg of the obtained resin, 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added, and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 61/39-51/49), collect the fraction containing the target substance, And freeze-dried to obtain 7.9 mg of white powder.

(M+H) ⁺ 4761.5 by mass analysis (calculated 4760.6)

HPLC dissolution time: 14.6 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 11

H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Ala-Ile-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 20)

Measure the H-Aib-Glu prepared in the same way as in Reference Example 6 (OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)-Ala-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc) -Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt) -Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink Amide AM resin (0.089meq/g, 112mg) was placed in a reaction tube and swelled with NMP . After NMP was removed by filtration, Boc-Tyr(tBu)-OH (33.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Fmoc-Gly-Gly-Gly-OH (41.1 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperine was added again pyridine in NMP and shake for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, an NMP solution (200 μL) of Pal-OSu (35.4 mg) and DIPEA (17.4 μL) was added, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, the resin was washed with MeOH and dried under reduced pressure to obtain Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser (tBu)-Asp(OtBu)-Lys(-Gly-Gly-Gly-Gly-Pal)-Ala-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf) -Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg( Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink amide AM resin 103.9 mg.

To 103.9 mg of the obtained resin, 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added, and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 56/44-46/54), collect the fraction containing the target substance, And freeze-dried to obtain 8.8 mg of white powder.

(M+H) ⁺ 4675.5 (calculated 4674.6) by mass analysis

HPLC dissolution time: 16.6 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 12

H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Oda)-Ala-Ile-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 21)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Ala-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His (Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink Amide AM Resin (0.089 meq/g, 112 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-Tyr(tBu)-OH (33.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Gly-Gly-Gly, Oda(OtBu) were condensed sequentially by repeating the cycle of condensation of Fmoc amino acid-Fmoc deprotection. The resin was washed with MeOH and dried under reduced pressure to obtain Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Lys(-Gly-Gly-Gly-Gly-Oda(OtBu))-Ala-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt) -Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln( Trt)-Arg(Pbf)-Tyr(tBu)-Rink amide AM resin 103.2 mg.

To 103.2 mg of the obtained resin, 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added, and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 60/40-50/50), collect the fraction containing the target substance, And freeze-dried to obtain 8.5 mg of white powder.

(M+H) ⁺ 4732.1 (calculated 4732.6) by mass analysis

HPLC dissolution time: 14.5 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 13

Me-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Ala-Ile-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 22)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Ala-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His (Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink Amide AM Resin (0.089 meq/g, 112 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-NMeTyr(tBu)-OH was sequentially added to the resin (35.1 mg), 0.5M OxymaPure in NMP (200 μL) and diisopropylcarbodiimide (15.9 μL), shake overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Fmoc-Gly-Gly-Gly-OH (41.1 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, an NMP solution (200 μL) of Pal-OSu (35.4 mg) and DIPEA (17.4 μL) was added, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, the resin was washed with MeOH and dried under reduced pressure to obtain Boc-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser (tBu)-Asp(OtBu)-Lys(-Gly- Gly-Gly-Gly-Pal)-Ala-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe -Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr (tBu)-Rink amide AM resin 99.9 mg.

To 99.9 mg of the obtained resin, 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added, and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 56/44-46/54), collect the fraction containing the target substance, And freeze-dried to obtain 8.8 mg of white powder.

(M+H) ⁺ 4688.4 (calculated 4688.6) by mass analysis

HPLC dissolution time: 16.6 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 14

Me-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Oda)-Ala-Ile-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 23)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Ala-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His (Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink Amide AM Resin (0.089 meq/g, 112 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-NMeTyr(tBu)-OH (35.1 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed with NMP for 10 Second-rate. Gly-Gly-Gly, Oda(OtBu) were condensed sequentially by repeating the cycle of condensation of Fmoc amino acid-Fmoc deprotection. The resin was washed with MeOH and dried under reduced pressure to obtain Boc-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Lys(-Gly-Gly-Gly-Gly-Oda(OtBu))-Ala-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt) -Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln( Trt)-Arg(Pbf)-Tyr(tBu)-Rink amide AM resin 111.4 mg.

To 111.4 mg of the obtained resin was added 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5), and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA flow rate: 8 mL/min, A/B: 60/40-50/50), collect the target substance containing fraction, and freeze-dried to give 7.0 mg of a white powder.

(M+H) ⁺ 4746.2 (calculated 4746.6) by mass analysis

HPLC dissolution time: 14.5 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 15

H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Ser-Ile-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 24)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf )-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink Amine AM resin (0.088 meq/g, 113 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-Tyr(tBu)-OH (33.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. To the obtained resin, Fmoc-Gly-OH (29.7 mg) and 0.5 M OxymaPure were added in this order After adding NMP (200 μL) and diisopropylcarbodiimide (15.9 μL), shake overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Fmoc-Gly-Gly-Gly-OH (41.1 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, an NMP solution (200 μL) of Pal-OSu (35.4 mg) and DIPEA (17.4 μL) was added, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, the resin was washed with MeOH and dried under reduced pressure to obtain Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser (tBu)-Asp(OtBu)-Lys(-Gly-Gly-Gly-Gly-Pal)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg (Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu) -Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink amide AM resin 100.5 mg.

To 100.5 mg of the obtained resin, 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added, and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removal of the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 56/44-46/54), collect the fraction containing the target substance, And freeze-dried to obtain 7.8 mg of white powder.

(M+H) ⁺ 4690.3 (calculated 4690.6) by mass analysis

HPLC dissolution time: 16.6 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 16

H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Oda)-Ser-Ile-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 25)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-L ys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)- Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink Amide AM resin (0.088meq/g, 113mg) was placed in a reaction tube , and swelled with NMP. After NMP was removed by filtration, Boc-Tyr(tBu)-OH (33.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Gly-Gly-Gly, Oda(OtBu) were condensed sequentially by repeating the cycle of condensation of Fmoc amino acid-Fmoc deprotection. The resin was washed with MeOH and dried under reduced pressure to obtain Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Lys(-Gly-Gly-Gly-Gly-Oda(OtBu))-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln (Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(t Bu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink amide AM resin 96.8 mg.

To 96.8 mg of the obtained resin was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5), and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 60/40-50/50), collect the part containing the target substance, And freeze-dried to obtain 7.5 mg of white powder.

(M+H) ⁺ 4748.5 by mass analysis (calculated 4748.6)

HPLC dissolution time: 14.5 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 17

Me-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Ser-Ile-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 26)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf )-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink Amine AM resin (0.088 meq/g, 113 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-NMeTyr(tBu)-OH (35.1 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, Fmoc-Gly-Gly-Gly-OH (41.1 mg), 0.5M OxymaPure NMP (200 μL) and diisopropyl carbon were added in this order After adding diimide (15.9 μL), shake overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, an NMP solution (200 μL) of Pal-OSu (35.4 mg) and DIPEA (17.4 μL) was added, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, the resin was washed with MeOH and dried under reduced pressure to obtain Boc-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser (tBu)-Asp(OtBu)-Lys(-Gly-Gly-Gly-Gly-Pal)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg (Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu) -Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink amide AM resin 96.4 mg.

To 96.4 mg of the obtained resin, 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added, and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate, and after centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removal of the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 56/44-46/54), collect the part containing the target substance, And freeze-dried to obtain 7.9 mg of white powder.

(M+H) ⁺ 4704.3 (calculated 4704.6) by mass analysis

HPLC dissolution time: 16.6 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 18

Me-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Oda)-Ser-Ile-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 27)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf )-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink Amine AM resin (0.088 meq/g, 113 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-NMeTyr(tBu)-OH (35.1 mg), 0.5M OxymaPure NMP (200 μL) and diisopropyl carbon were added to the resin in sequence After adding diimide (15.9 μL), shake overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Gly-Gly-Gly, Oda(OtBu) were condensed sequentially by repeating the cycle of condensation of Fmoc amino acid-Fmoc deprotection. The resin was washed with MeOH and dried under reduced pressure to obtain Boc-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Lys(-Gly-Gly-Gly-Gly-Oda(OtBu))-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln (Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf) -Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink amide AM resin 115.1 mg.

To 115.1 mg of the obtained resin, 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added, and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate, and after centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA flow rate: 8 mL/min, A/B: 60/40-50/50), collect the target substance containing fraction, and freeze-dried to give 7.0 mg of a white powder.

(M+H) ⁺ 4762.7 by mass analysis (calculated 4762.6)

HPLC dissolution time: 14.5 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 19

H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib-Lys-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 28)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Aib-Lys(Boc)-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-V al-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr( tBu)-Rink amide AM resin (0.093 meq/g, 108 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-Tyr(tBu)-OH (33.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Fmoc-Gly-Gly-Gly-OH (41.1 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, an NMP solution (200 μL) of Pal-OSu (35.4 mg) and DIPEA (17.4 μL) was added After that, shake all night. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, the resin was washed with MeOH and dried under reduced pressure to obtain Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser (tBu)-Asp(OtBu)-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib-Lys(Boc)-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg (Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu) -Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink amide AM resin 105.4 mg.

To 105.4 mg of the obtained resin, 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added, and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 57/43-47/53), collect the part containing the target substance, And freeze-dried to obtain 10.0 mg of white powder.

(M+H) ⁺ 4703.5 by mass analysis (calculated 4703.6)

HPLC dissolution time: 16.0 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: use A solution: 0.1% TFA-water, B solution: contain 0.1% TFA The acetonitrile was dissolved in a linear concentration gradient with A/B: 80/20 to 30/70 (25 minutes).

Flow rate: 1.0mL/min

Example 20

H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Oda)-Aib-Lys-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 29)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Aib-Lys(Boc)-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf )-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink Amine AM resin (0.093 meq/g, 108 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-Tyr(tBu)-OH (33.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. To the obtained resin, Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were added in sequence, and the mixture was shaken to make up night. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Gly-Gly-Gly, Oda(OtBu) were condensed sequentially by repeating the cycle of condensation of Fmoc amino acid-Fmoc deprotection. The resin was washed with MeOH and dried under reduced pressure to obtain Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Lys(-Gly-Gly-Gly-Gly-Oda(OtBu))-Aib-Lys(Boc)-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln (Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf) -Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink amide AM resin 101.6 mg.

To 101.6 mg of the obtained resin, 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added, and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 61/39-51/49), collect the fraction containing the target substance, And freeze-dried to obtain 8.9 mg of white powder.

(M+H) ⁺ 4761.3 (calculated 4761.6) by mass analysis

HPLC dissolution time: 13.9 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 21

Me-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib-Lys-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 30)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Aib-Lys(Boc)-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf )-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink Amine AM resin (0.093 meq/g, 108 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-NMeTyr(tBu)-OH (35.1 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Kather test was negative, the To the resin was added 2% hydrazine in NMP and shaken for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Fmoc-Gly-Gly-Gly-OH (41.1 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, an NMP solution (200 μL) of Pal-OSu (35.4 mg) and DIPEA (17.4 μL) was added, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, the resin was washed with MeOH and dried under reduced pressure to obtain Boc-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser (tBu)-Asp(OtBu)-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib-Lys(Boc)-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg (Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu) - Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink Amide AM resin 106 mg.

To 106 mg of the obtained resin, 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added and stirred 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 57/43-47/53), collect the part containing the target substance, And freeze-dried to obtain 9.9 mg of white powder.

(M+H) ⁺ 4717.2 (calculated 4717.6) by mass analysis

HPLC dissolution time: 16.0 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 22

Me-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Oda)-Aib-Lys-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 31)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Aib-Lys(Boc)-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf )-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink Amine AM resin (0.093 meq/g, 108 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-NMeTyr(tBu)-OH (35.1 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Gly-Gly-Gly, Oda(OtBu) were condensed sequentially by repeating the cycle of condensation of Fmoc amino acid-Fmoc deprotection. The resin was washed with MeOH After cleaning, dry under reduced pressure to obtain Boc-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(-Gly -Gly-Gly-Gly-Oda(OtBu))-Aib-Lys(Boc)-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva -Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt) -Arg(Pbf)-Tyr(tBu)-Rink amide AM resin 98.4 mg.

To 98.4 mg of the obtained resin was added 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5), and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removal of the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 61/39-51/49), collect the fraction containing the target substance, And freeze-dried to obtain 8.8 mg of white powder.

(M+H) ⁺ 4775.5 by mass analysis (calculated 4775.6)

HPLC dissolution time: 13.9 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, with A/B: 80/20 to 30/70 for linear concentration gradient dissolution (25 minutes).

Flow rate: 1.0mL/min

Example 23

H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Ser-Lys-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 32)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Ser(tBu)-Lys(Boc)-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val- Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu) - Rink amide AM resin (0.084 meq/g, 119 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-Tyr(tBu)-OH (33.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed with NMP for 6 Second-rate. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, Fmoc-Gly-Gly-Gly-OH (41.1 mg), 0.5 M OxymaPure (200 μL) in NMP, and diisopropylcarbodiimide (15.9 μL) were sequentially added, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, an NMP solution (200 μL) of Pal-OSu (35.4 mg) and DIPEA (17.4 μL) was added, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, the resin was washed with MeOH and dried under reduced pressure to obtain Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser (tBu)-Asp(OtBu)-Lys(-Gly-Gly-Gly-Gly-Pal)-Ser(tBu)-Lys(Boc)-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt )-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr (tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink Amide AM resin 111.3 mg.

To 111.3 mg of the obtained resin, 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added, and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removal of the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 57/43-47/53), collect the part containing the target substance, And freeze-dried to obtain 9.3 mg of white powder.

(M+H) ⁺ 4705.3 (calculated 4705.6) by mass analysis

HPLC dissolution time: 16.0 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 24

H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Oda)-Ser-Lys-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 33)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Ser(tBu)-Lys(Boc)-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val- Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib -Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink Amide AM resin (0.084 meq/g, 119 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-Tyr(tBu)-OH (33.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Gly-Gly-Gly, Oda(OtBu) were condensed sequentially by repeating the cycle of condensation of Fmoc amino acid-Fmoc deprotection. The resin was washed with MeOH and dried under reduced pressure to obtain Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Lys(-Gly-Gly-Gly-Gly-Oda(OtBu))-Ser(tBu)-Lys(Boc)-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf )-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg (Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink Amide AM resin 101.8 mg.

To 101.8 mg of the obtained resin was added 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5), and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removal of the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 61/39-51/49), collect the fraction containing the target substance, And freeze-dried to obtain 8.5 mg of white powder.

(M+H) ⁺ 4763.4 by mass analysis (calculated 4763.6)

HPLC dissolution time: 13.9 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 25

Me-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Ser-Lys-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 34)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Ser(tBu)-Lys(Boc)-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val- Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu) - Rink amide AM resin (0.084 meq/g, 119 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-NMeTyr(tBu)-OH (35.1 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Fmoc-Gly-Gly-Gly-OH (41.1 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that Casser tested negative, Add 20% piperidine in NMP and shake for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, an NMP solution (200 μL) of Pal-OSu (35.4 mg) and DIPEA (17.4 μL) was added, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, the resin was washed with MeOH and dried under reduced pressure to obtain Boc-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser (tBu)-Asp(OtBu)-Lys(-Gly-Gly-Gly-Gly-Pal)-Ser(tBu)-Lys(Boc)-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt )-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr (tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink amide AM resin 104.3 mg.

To 104.3 mg of the obtained resin was added 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5), and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removal of the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 57/43-47/53), collect the part containing the target substance, And freeze-dried to obtain 8.2 mg of white powder.

(M+H) ⁺ 4719.7 by mass analysis (calculated 4719.6)

HPLC dissolution time: 16.0 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 26

Me-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Oda)-Ser-Lys-Aib-Leu-Asp-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 35)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Ser(tBu)-Lys(Boc)-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val- Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu) - Rink amide AM resin (0.084 meq/g, 119 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-NMeTyr(tBu)-OH (35.1 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that Casser tested negative, A 2% hydrazine in NMP solution was added to the resulting resin and shaken for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Gly-Gly-Gly, Oda(OtBu) were condensed sequentially by repeating the cycle of condensation of Fmoc amino acid-Fmoc deprotection. The resin was washed with MeOH and dried under reduced pressure to obtain Boc-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Lys(-Gly-Gly-Gly-Gly-Oda(OtBu))-Ser(tBu)-Lys(Boc)-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf )-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Mtt)-Aib-Thr(tBu)-Arg (Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Rink Amide AM resin 125.9 mg.

To 125.9 mg of the obtained resin, 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added, and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 61/39-51/49), collect the fraction containing the target substance, And freeze-dried to obtain 10.6 mg of white powder.

(M+H) ⁺ 4777.5 by mass analysis (calculated 4777.6)

HPLC dissolution time: 13.9 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 27

H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 36)

Measure the H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)-Aib-Ile- prepared in Reference Example 8 Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu -Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber amide resin (0.122meq/g, 102.3mg ) in the reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-Tyr(tBu)-OH (33.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Fmoc-Gly-Gly-Gly-OH (41.1 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, an NMP solution (200 μL) of Pal-OSu (35.4 mg) and DIPEA (17.4 μL) was added, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, the resin was washed with MeOH and dried under reduced pressure to obtain Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(-Gly-Gly-Gly-Gly-Pal )-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His( Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber Amide Resin 104.5mg .

To 104.5 mg of the obtained resin, 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added, and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 57/43-47/53), collect the part containing the target substance, And freeze-dried to obtain 13.3 mg of white powder.

(M+H) ⁺ 4604.3 (calculated 4603.6) by mass analysis

HPLC dissolution time: 17.1 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 28

H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Oda)-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 37)

Measure the H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)-Aib-Ile- prepared in Reference Example 8 Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu -Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber amide resin (0.122meq/g, 102.3mg ) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-Tyr(tBu)-OH (33.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After removing the solution by filtration, 20% piperidine in NMP solution was added and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Gly-Gly-Gly, Oda(OtBu) were condensed sequentially by repeating the cycle of condensation of Fmoc amino acid-Fmoc deprotection. The resin was washed with MeOH and dried under reduced pressure to obtain Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Lys(-Gly-Gly-Gly-Gly-Oda(OtBu))-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Iva- Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)- Arg(Pbf)-Tyr(tBu)-Sieber amide resin 109.1 mg.

To 109.1 mg of the obtained resin was added 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5), and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 60/40-50/50), collect the part containing the target substance, And freeze-dried to obtain 12.4 mg of white powder.

(M+H) ⁺ 4662.3 (calculated 4661.6) by mass analysis

HPLC dissolution time: 15.1 minutes

Dissolution Conditions: Column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 29

Me-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 38)

Measure the H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)-Aib-Ile- prepared in Reference Example 8 Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu -Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber amide resin (0.122meq/g, 102.3mg ) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-NMeTyr(tBu)-OH (35.1 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the obtained resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH was sequentially added to the obtained resin (29.7 mg), 0.5M OxymaPure in NMP (200 μL) and diisopropylcarbodiimide (15.9 μL), shake overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Fmoc-Gly-Gly-Gly-OH (41.1 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, an NMP solution (200 μL) of Pal-OSu (35.4 mg) and DIPEA (17.4 μL) was added, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, the resin was washed with MeOH and dried under reduced pressure to obtain Boc-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser (tBu)-Asp(OtBu)-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln( Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)- Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber amide resin 105.8 mg.

To 105.8 mg of the obtained resin was added 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5), and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 56/44-46/54), collect the fraction containing the target substance, And freeze-dried to obtain 14.3 mg of white powder.

(M+H) ⁺ 4618.2 (calculated 4617.6) by mass analysis

HPLC dissolution time: 17.1 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 30

Me-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-0da)-Aib-Ile-Aib-Leu-Asp-Lys-Gln-Ala- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 39)

Measure the H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde prepared in Reference Example 8 )-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His( Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber Amide Resin (0.122 meq/g, 102.3 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-NMeTyr(tBu)-OH (35.1 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Gly-Gly-Gly, Oda(OtBu) were condensed sequentially by repeating the cycle of condensation of Fmoc amino acid-Fmoc deprotection. The resin was washed with MeOH and dried under reduced pressure to obtain Boc-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Lys(-Gly-Gly-Gly-Gly-Oda(OtBu))-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Iva- Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt )-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber amide resin 118 mg.

To 118 mg of the obtained resin, 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added and stirred 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 60/40-50/50), collect the part containing the target substance, And freeze-dried to obtain 12.1 mg of white powder.

(M+H) ⁺ 4676.2 (calculated 4675.6) by mass analysis

HPLC dissolution time: 15.1 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 31

H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib-Ile-Aib-Leu-Glu-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 40)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Aib-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His (Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber Amide Resin ( 0.115 meq/g, 108.3 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-Tyr(tBu)-OH (33.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, Fmoc-Gly-Gly-Gly-OH (41.1 mg), 0.5M OxymaPure NMP (200 μL) and diisopropyl carbon were added in this order After adding diimide (15.9 μL), shake overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, an NMP solution (200 μL) of Pal-OSu (35.4 mg) and DIPEA (17.4 μL) was added, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, the resin was washed with MeOH and dried under reduced pressure to obtain Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser (tBu)-Asp(OtBu)-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf) -Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg( Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber amide resin 131.4 mg.

To 131.4 mg of the obtained resin was added 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5), and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removal of the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: flow rate formed by acetonitrile containing 0.1% TFA: 8 mL/min, A/B: 57/43-47/53), collect the target substance containing fraction, and freeze-dried to give 12.4 mg of a white powder.

(M+H) ⁺ 4703.2 (calculated 4702.6) by mass analysis

HPLC dissolution time: 16.5 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 32

H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-oda)-Aib-Ile-Aib-Leu-Glu-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 41)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Aib-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His (Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber Amide Resin ( 0.115 meq/g, 108.3 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-Tyr(tBu)-OH (33.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the The resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Gly-Gly-Gly, Oda(OtBu) were condensed sequentially by repeating the cycle of condensation of Fmoc amino acid-Fmoc deprotection. The resin was washed with MeOH and dried under reduced pressure to obtain Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Lys(-Gly-Gly-Gly-Gly-Oda(OtBu))-Aib-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt) -Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln( Trt)-Arg(Pbf)-Tyr(tBu)-Sieber amide resin 104.3 mg.

To 104.3 mg of the obtained resin was added 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5), and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removal of the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 61/39-51/49), collect the fraction containing the target substance, And freeze-dried to obtain 12.0 mg of white powder.

(M+H) ⁺ 4761.3 (calculated 4760.6) by mass analysis

HPLC dissolution time: 14.5 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 33

Me-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib-Ile-Aib-Leu-Glu-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 42)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Aib-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His (Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)- Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber amide resin (0.115 meq/g, 108.3 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-NMeTyr(tBu)-OH (35.1 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Fmoc-Gly-Gly-Gly-OH (41.1 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, an NMP solution (200 μL) of Pal-OSu (35.4 mg) and DIPEA (17.4 μL) was added, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed with NMP for 6 Second-rate. After confirming that the Casser test was negative, the resin was washed with MeOH and dried under reduced pressure to obtain Boc-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser (tBu)-Asp(OtBu)-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf) -Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg( Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber amide resin 108.5 mg.

1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added to 108.5 mg of the obtained resin, and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, liquid A: 0.1% was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250×20 mm ID). TFA-water, liquid B: acetonitrile containing 0.1% TFA Flow rate: 8 mL/min, A/B: 57/43-47/53 linear concentration gradient dissolution (60 minutes), collect the fraction containing the target , and freeze-dried to obtain 12.0 mg of white powder.

(M+H) ⁺ 4717.4 by mass analysis (calculated 4716.6)

HPLC dissolution time: 16.6 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, with A/B: 80/20 to 30/70 for linear concentration gradient dissolution (25 minutes).

Flow rate: 1.0mL/min

Example 34

Me-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Oda)-Aib-Ile-Aib-Leu-Glu-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 43)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Aib-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His (Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber Amide Resin ( 0.115 meq/g, 108.3 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-NMeTyr(tBu)-OH (35.1 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. confirm After the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Gly-Gly-Gly, Oda(OtBu) were condensed sequentially by repeating the cycle of condensation of Fmoc amino acid-Fmoc deprotection. The resin was washed with MeOH and dried under reduced pressure to obtain Boc-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Lys(-Gly-Gly-Gly-Gly-Oda(OtBu))-Aib-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt) -Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln( Trt)-Arg(Pbf)-Tyr(tBu)-Sieber amide resin 117.9 mg.

To 117.9 mg of the obtained resin, 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added, and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removal of the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 61/39-51/49), collect the fraction containing the target substance, And freeze-dried to obtain 8.6 mg of white powder.

(M+H) ⁺ 4775.3 (calculated 4774.7) by mass analysis

HPLC dissolution time: 14.5 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 35

H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Ala-Ile-Aib-Leu-Glu-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 44)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Ala-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His (Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber Amide Resin ( 0.116 meq/g, 108.1 mg) in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-Tyr(tBu)-OH (33.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. filter After removing the solution, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Fmoc-Gly-Gly-Gly-OH (41.1 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, an NMP solution (200 μL) of Pal-OSu (35.4 mg) and DIPEA (17.4 μL) was added, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, the resin was washed with MeOH and dried under reduced pressure to obtain Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser (tBu)-Asp(OtBu)-Lys(-Gly-Gly-Gly-Gly-Pal)-Ala-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf) -Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg( Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber amide resin 120.1 mg.

To 120.1 mg of the obtained resin, 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added, and the Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate, and after centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removal of the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 57/43-47/53), collect the fraction containing the target substance, And freeze-dried to obtain 10.9 mg of white powder.

(M+H) ⁺ 4689.1 (calculated 4688.6) by mass analysis

HPLC dissolution time: 16.5 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 36

H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Oda)-Ala-Ile-Aib-Leu-Glu-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 45)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Ala-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His (Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber Amide Resin ( 0.116 meq/g, 108.1 mg) in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-Tyr(tBu)-OH (33.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Gly-Gly-Gly, Oda(OtBu) were condensed sequentially by repeating the cycle of condensation of Fmoc amino acid-Fmoc deprotection. The resin was washed with MeOH and dried under reduced pressure to obtain Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Lys(-Gly- Gly-Gly-Gly-Oda(OtBu))-Ala-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu) )-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf )-Tyr(tBu)-Sieber amide resin 107.9 mg.

To 107.9 mg of the obtained resin, 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added, and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 61/39-51/49), collect the fraction containing the target substance, And freeze-dried to obtain 9.2 mg of white powder.

(M+H) ⁺ 4747.3 (calculated 4746.6) by mass analysis

HPLC dissolution time: 14.5 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 37

Me-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Ala-Ile-Aib-Leu-Glu-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 46)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Ala-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His (Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber Amide Resin ( 0.116 meq/g, 108.1 mg) in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-NMeTyr(tBu)-OH (35.1 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After removing the solution by filtration, add 20% piperidine in NMP again, And shake for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Fmoc-Gly-Gly-Gly-OH (41.1 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, an NMP solution (200 μL) of Pal-OSu (35.4 mg) and DIPEA (17.4 μL) was added, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, the resin was washed with MeOH and dried under reduced pressure to obtain Boc-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser (tBu)-Asp(OtBu)-Lys(-Gly-Gly-Gly-Gly-Pal)-Ala-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf) -Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg( Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber amide resin 117.8 mg.

To 117.8 mg of the obtained resin, 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added, and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removal of the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 57/43-47/53), collect the fraction containing the target substance, And freeze-dried to obtain 11.4 mg of white powder.

(M+H) ⁺ 4703.3 (calculated 4702.6) by mass analysis

HPLC dissolution time: 16.5 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 38

Me-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Oda)-Ala-Ile-Aib-Leu-Glu-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 47)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Ala-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His (Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber Amide Resin ( 0.116 meq/g, 108.1 mg) in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-NMeTyr(tBu)-OH (35.1 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Gly-Gly-Gly, Oda(OtBu) were condensed sequentially by repeating the cycle of condensation of Fmoc amino acid-Fmoc deprotection. The resin was washed with MeOH and dried under reduced pressure to obtain Boc-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Lys(-Gly-Gly-Gly-Gly-Oda(OtBu))-Ala-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt) -Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln( Trt)-Arg(Pbf)-Tyr(tBu)-Sieber amide resin 116 mg.

To 116 mg of the obtained resin, 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added and stirred 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 61/39-51/49), collect the fraction containing the target substance, And freeze-dried to obtain 11.0 mg of white powder.

(M+H) ⁺ 4761.2 (calculated 4760.6) by mass analysis

HPLC dissolution time: 14.5 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 39

H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Ser-Ile-Aib-Leu-Glu-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 48)

Measure H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu) prepared in the same manner as in Reference Example 8 -Asp(OtBu)-Lys(ivDde)-Ser(tBu)-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu (OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg (Pbf)-Tyr(tBu)-Sieber amide resin (0.116 meq/g, 107.5 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-Tyr(tBu)-OH (33.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Fmoc-Gly-Gly-Gly-OH (41.1 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. filter to remove After the solution, the resin was washed 10 times with NMP. To the obtained resin, an NMP solution (200 μL) of Pal-OSu (35.4 mg) and DIPEA (17.4 μL) was added, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, the resin was washed with MeOH and dried under reduced pressure to obtain Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser (tBu)-Asp(OtBu)-Lys(-Gly-Gly-Gly-Gly-Pal)-Ser(tBu)-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg (Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu) -Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber amide resin 124 mg.

To 124 mg of the obtained resin, 1 mL of TFA: m-cresol: thioanisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added and stirred 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removal of the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 57/43-47/53), collect the fraction containing the target substance, And freeze-dried to obtain 8.9 mg of white powder.

(M+H) ⁺ 4705.1 (calculated 4704.6) by mass analysis

HPLC dissolution time: 16.6 minutes

Dissolution Conditions: Column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 40

H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Oda)-Ser-Ile-Aib-Leu-Glu-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 49)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Ser(tBu)-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf )-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber Amine resin (0.116 meq/g, 107.5 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-Tyr(tBu)-OH (33.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. to get After adding Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) to the resin in sequence, it was shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Gly-Gly-Gly, Oda(OtBu) were condensed sequentially by repeating the cycle of condensation of Fmoc amino acid-Fmoc deprotection. The resin was washed with MeOH and dried under reduced pressure to obtain Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Lys(-Gly-Gly-Gly-Gly-Oda(OtBu))-Ser(tBu)-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln (Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf) -Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber amide resin 116.8 mg.

To 116.8 mg of the obtained resin, 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5) was added, and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 61/39-51/49), collect the part containing the target substance, And freeze-dried to obtain 13.1 mg of white powder.

(M+H) ⁺ 4763.0 (calculated 4762.6) by mass analysis

HPLC dissolution time: 14.5 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 41

Me-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Ser-Ile-Aib-Leu-Glu-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 50)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Ser(tBu)-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf )-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber Amine resin (0.116 meq/g, 107.5 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-NMeTyr(tBu)-OH (35.1 mg), 0.5M OxymaPure NMP (200 μL) and diisopropyl carbon were added to the resin in sequence After adding diimide (15.9 μL), shake overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. Fmoc-Gly-Gly-Gly-OH (41.1 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed 10 times with NMP. To the obtained resin, an NMP solution (200 μL) of Pal-OSu (35.4 mg) and DIPEA (17.4 μL) was added, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, the resin was washed with MeOH and dried under reduced pressure to obtain Boc-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser (tBu)-Asp(OtBu)-Lys(-Gly-Gly-Gly-Gly-Pal)-Ser(tBu)-Ile-Aib-Leu-Glu(OtBu)-Lys(Bo c)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys( Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber amide resin 104.3 mg.

To 104.3 mg of the obtained resin was added 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5), and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removal of the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 57/43-47/53), collect the fraction containing the target substance, And freeze-dried to obtain 11.3 mg of white powder.

(M+H) ⁺ 4719.3 (calculated 4718.6) by mass analysis

HPLC dissolution time: 16.6 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Example 42

Me-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Oda)-Ser-Ile-Aib-Leu-Glu-Lys-Gln-Arg- Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 51)

H-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Lys(ivDde)- Ser(tBu)-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln(Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf )-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber Amine resin (0.116 meq/g, 107.5 mg) was placed in a reaction tube and swelled with NMP. After NMP was removed by filtration, Boc-NMeTyr(tBu)-OH (35.1 mg), 0.5M OxymaPure NMP (200 μL) and diisopropylcarbodiimide (15.9 μL) were sequentially added to the resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, a 2% hydrazine in NMP solution was added to the resulting resin, followed by shaking for 3 hours. After the solution was removed by filtration, 2% hydrazine in NMP was added again and shaken overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. Fmoc-Gly-OH (29.7 mg), 0.5M OxymaPure NMP (200 μL), and diisopropylcarbodiimide (15.9 μL) were sequentially added to the obtained resin, followed by shaking overnight. After removing the reaction solution by filtration, the resin was washed 6 times with NMP. After confirming that the Casser test was negative, 20% piperidine in NMP was added and shaken for 1 minute. After the solution was removed by filtration, 20% piperidine in NMP was added again and shaken for 20 minutes. After removing the solution by filtration, the resin was washed with NMP for 10 Second-rate. Gly-Gly-Gly, Oda(OtBu) were condensed sequentially by repeating the cycle of condensation of Fmoc amino acid-Fmoc deprotection. The resin was washed with MeOH and dried under reduced pressure to obtain Boc-NMeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Lys(-Gly-Gly-Gly-Gly-Oda(OtBu))-Ser(tBu)-Ile-Aib-Leu-Glu(OtBu)-Lys(Boc)-Gln(Trt)-Arg(Pbf)-Gln (Trt)-Iva-Glu(OtBu)-Phe-Val-Arg(Pbf)-His(Trt)-Leu-Leu-Asn(Trt)-Lys(Boc)-Aib-Thr(tBu)-Arg(Pbf) -Gln(Trt)-Arg(Pbf)-Tyr(tBu)-Sieber amide resin 109.1 mg.

To 109.1 mg of the obtained resin was added 1 mL of TFA: m-cresol: anisole: ethanedithiol: H ₂ O: triisopropylsilane (80:5:5:5:2.5:2.5), and Stir for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed, and the operation was repeated three times to wash the precipitate. The residue was extracted with 50% aqueous acetic acid, and after removing the resin by filtration, a linear concentration gradient dissolution was performed by fractionation HPLC using a YMC-Actus Triart Prep C8 S-10 μm 20 nm column (250 x 20 mm ID). (60 minutes) (A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA, flow rate: 8 mL/min, A/B: 61/39-51/49), collect the fraction containing the target substance, And freeze-dried to obtain 10.5 mg of white powder.

(M+H) ⁺ 4777.2 (calculated 4776.6) by mass analysis

HPLC dissolution time: 14.5 minutes

Dissolution conditions: column YMC Triart C8 (100×4.6mm I.D.)

Elution solution: Use solution A: 0.1% TFA-water, solution B: acetonitrile containing 0.1% TFA, and perform linear concentration gradient elution (25 minutes) with A/B: 80/20 to 30/70.

Flow rate: 1.0mL/min

Test Example 1

Assessment of agonist activity of human NPY2R, human GIPR, and human GLP-1R using changes in intracellular cAMP concentration as an indicator

(1) Construction of cells expressing human NPY2R gene

The human NPY2R gene having the same sequence as the Genbank accession number AC104407 was cloned into the pAKKO1114 vector to make hNPY2R/pAKKO1114. Next, pGL4.29 (Promega) was introduced into CHO-K1 cells and screened with hygromycin to construct Cre-luc reporter cells. The cells were co-transfected with hNPY2R/pAKKO1114 and pcDNA3.1 (Life technologies), and cells were screened with geneticin. Next, by adding human PYY(3-36), a cell line induced to express luciferase, that is, pAKKO1114/hNPY2R#481No.88 cells, was selected from the obtained transformants.

(2) Construction of cells expressing human GIPR gene

The human GIPR gene having the same sequence as the Genbank accession number U39231 was cloned into the pMSRα-neo vector to make hGIPR/pMSRα-neo. Transformants were obtained by introducing (1) this vector into the resulting Cre-luc reporter cells. Next, by adding GIP, a cell line induced to express luciferase, that is, hGIPR/CHO-K1 cells, was selected from the obtained transformants.

(3) Construction of cells expressing human GLP-1R gene

The human GLP-1R gene having the same sequence as Genbank accession number NM_002062 was cloned into the pIRESneo3 vector (Clontech) to produce hGLP-1R/pIRESneo3. Transformants were obtained by introducing (1) this vector into the resulting Cre-luc reporter cells. Next, a cell line induced to express luciferase, ie, hGLP-1R/Crel cells, was selected from the obtained transformants by addition of human GLP-1(7-37) peptide.

(4) Reporter assay of human NPY2R gene

The pAKKO1114/hNPY2R#481No.88 cells were seeded to 5,000 cells/well in 25 μL each into a 384-well white culture plate (Corning, 3570), containing 10% fetal bovine serum, 100 U/mL penicillin, 100 μg/ In the HamF12 medium of streptomycin, culture it overnight in a _CO2 incubator at 37°C. The next day, the medium was removed, and 25 μL of assay medium (HamF12 medium containing 0.1% BSA, 100 U/mL penicillin, and 100 μg/mL streptomycin) was added each so that the final concentration of forskolin was 1.2 μM. Then, 5 μL of assay medium containing the test compound was added, and the cells were incubated at a final concentration of 1 μM in a CO ₂ incubator at 37° C. for 4 hours. 30 μL of Steady glow (Promega) was added to each, and the cells were allowed to stand for 20 minutes under shading. Luciferase activity was determined using the plate reader Envision (Perkin-Elmer). The luciferase activity in the case of adding DMSO was taken as 100%, the luciferase activity in the case of adding 1 μM human PYY(3-36) instead of the test compound was taken as 0%, and the decrease in intracellular cAMP concentration was taken as 0%. As an index, the NPY2R agonist activity was calculated. The results are shown in Table 2.

(5) Reporter detection of human GIPR and GLP-1R genes Certainly

hGIPR/CHO-K1 cells or hGLP-1R/Crel cells were seeded at 5,000 cells/well in 25 μL each into a 384-well white culture dish (Corning, 3570), and plated with 10% fetal bovine serum, 100 U /mL penicillin, 100μg/mL streptomycin in HamF12 medium, cultured in a CO ₂ incubator at 37°C for one night. The next day, 5 μL of the medium containing the test compound was added to the cells, and the cells were incubated at a final concentration of 1 μM in a CO ₂ incubator at 37° C. for 4 hours. 30 μL of Steady glow (Promega) was added to each, and the cells were shaken in the dark. After 30 minutes, luciferase activity was measured using the plate reader Envision (Perkin-Elmer). In the case of GIPR agonist activity, the luciferase activity in the presence of 10 μM GIP was taken as 100%, the luciferase activity in the case of adding DMSO instead of the test compound was taken as 0%, and the intracellular luciferase activity was taken as 0%. The increase in cAMP concentration was used as an index, and the GIPR agonist activity was calculated. The results are shown in Table 2.

In the case of GLP-1R agonist activity, the same assay as above was performed using hGLP-1R/Crel cells. The luciferase activity in the presence of 10 μM GLP-1 was regarded as 100%, the luciferase activity in the case of adding DMSO instead of the test compound was regarded as 0%, and the increase in the intracellular cAMP concentration was used as an index to calculate GLP-1R agonist activity. The results are shown in Table 2.

Test Example 2

Assessment of Feeding Inhibition Following a Single Dosing

The food intake inhibitory activity of the test compounds was investigated according to the following method.

The test compound was dissolved in a solvent (physiological saline containing 10% DMSO) so that the concentration might be 30 or 100 nmol/2 mL. The test compound solution was subcutaneously administered to 8- to 9-week-old male C57BL/6J mice (20-26°C, bait and water ad libitum, with a 12-hour light period-12-hour dark period at a volume of 2 mL/kg). way of rearing) on the back. Voting is done once a day for 3 days. After the injection, the animals were individually reared in a cage, given pre-weighed bait, and the bait intake was measured for 3 days from the start of the injection. The amount of bait taken is calculated by subtracting the remaining amount of bait from the weight of the bait given on the day of administration. The food intake inhibitory activity of each test compound was evaluated by taking the food intake of the control group to which only the solvent was administered as an inhibition rate of 0%, and evaluated the cumulative food intake from the start of administration to 3 days. The food intake inhibition rate (%) of the test compound was defined as (feed amount of the control group - food intake of the test compound administered group)/feed amount of the control group×100.

As shown in Table 3, the compounds of the present invention have a feeding inhibitory effect.

Test Example 3

Repeated administration test in DIO (diet-induced obese) mice

repeated administration

Male DIO C57BL/6J mice (40 weeks old) were divided according to body weight, food intake, and plasma indices for clustering. The vehicle or the compound (P41) of Example 41 was subcutaneously administered once a day for 4 weeks. In the test, body weight and food intake were measured. Compounds were dissolved in 10% DMSO/saline. After the test, blood was collected, and plasma indexes were measured. On the 29th day, body composition was measured by EchoMRI (Hitachi Aloka Medical, Ltd., Japan). After the animals were slaughtered, livers were isolated from DIO mice 4 weeks after drug administration, and hematoxylin-eosin (HE) staining was performed. Livers were fixed with 4% paraformaldehyde, embedded in paraffin, sectioned, and stained with HE. After processing, sections were examined by light microscopy (NanoZoomer, Hamamatsu Photonics).

real-time quantitative PCR

All RNA was isolated from liver using QIAzol reagent (Quiagen, Tokyo, Japan) and cDNA was synthesized using High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems, CA, USA). Quantitative RT-PCR was performed using the ABI Prism 7900 Sequence Detection System (Thermo Fisher Scientific Inc. MA. USA) with EXPRESS qPCR Super Mix. mRNA quantification was performed using primer mixes and probes (Applied Biosystems) (Table 4). Expression levels were normalized to the expression levels of beta actin and peptidyl isomerase.

test methods

Plasma glucose, triglyceride (TG), total cholesterol (TC), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were determined by Autoanalyzer 7180 (Hitachi High-Technologies Corporation, Japan )analyze. Glycated hemoglobin (GHb) in blood was measured with an automatic GHb analyzer (HLC-723G8, Tosoh, Tokyo, Japan). Liver triglyceride content was determined in the following manner. The tissue pieces were homogenized in physiological saline, and a hexane:isopropanol (3:2) solution was added to extract lipids. The lipid layer was recovered, dried and dissolved in isopropanol. The concentration of triglycerides was measured by a triglyceride E-test (Triglyceride E-test (Wako Pure Chemical Industries, Ltd, Japan)), and the amount of triglycerides per 1 g was calculated. Plasma insulin was detected by ELISA kit (Shibayagi Co. Ltd., Japan) measurement.

Anti-obesity effect of P41 in DIO mice

The anti-obesity effect of P41 was assessed by repeated administration of DIO mice for 4 weeks. By daily administration of P41 at doses of 3, 10 and 30 nmol/kg, body weight was reduced by 14.6%, 30.0% and 37.1%, respectively (Fig. 1(a)). In the P41 treatment group, it was observed that the cumulative food intake decreased and the degree of decrease was dependent on the dosage (Fig. 1(b)). In the analysis of body composition using EchoMRI, in the P41-administered group, the amount of fat was only slightly decreased compared to the amount without fat, but a significant decrease in the amount of fat was observed depending on the dosage (Fig. 1 (c), (d)) . In relation to this result, P41 significantly reduced groin, mesenteric and epididymal fat body weight in a dose-dependent manner (Fig. 1(e)). In the measurement of biochemical indicators, plasma TC and insulin concentrations were significantly improved in a dose-dependent manner in all P41-treated groups. Regarding the effect on fatty liver, liver weight (Fig. 1(f)), TG content in liver (Fig. 1(g)), plasma AST and ALT (Table 5) were significantly reduced by P41 and the degree of reduction was dependent for dosage. Decreased lipid droplets in the liver were observed by HE staining of liver sections (Fig. 1h). Analysis of gene expression in the liver, such as tissue inhibitor of matrix metalloproteinase I (Timpl), fibrosis-related genes of type I collagen α1 (Colla), and inflammation-related genes such as CC chemokine ligand 2 (CCl2) Genes tended to decrease, such as the fiber inhibitor of matrix metalloproteinase 2 (MMP2), which tended to increase (Fig. 1(i)). In conclusion, by treating DIO mice with P41 for 4 weeks, a strong anti-obesity effect and ameliorating effect of fatty liver were confirmed.

Test Example 4

Repeated administration test in ob/ob mice

Male ob/ob mice (9 weeks old) were grouped according to the values of body weight, food intake, and plasma indices. The vehicle or P41 was subcutaneously administered once a day for 4 weeks. In the test, body weight and food intake were measured. Compounds were dissolved in 10% DMSO/saline. After the test, blood was collected, and plasma indexes were measured. On day 29, the animals are slaughtered.

test methods

Plasma glucose, triglyceride (TG), total cholesterol (TC), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were analyzed with Autoanalyzer 7180 (Hitachi High-Technologies Corporation, Japan) analysis. Glycated hemoglobin (GHb) in blood was measured by an automatic GHb analyzer (HLC-723G8, Tosoh, Tokyo, Japan). Liver triglyceride content was determined as follows. The tissue pieces were homogenized in physiological saline, and a hexane:isopropanol (3:2) solution was added to extract lipids. The lipid layer was recovered, dried and dissolved in isopropanol. The concentration of triglycerides was determined by the triglyceride E-test (Triglyceride E-test (Wako Pure Chemical Industries, Ltd, Japan)), and calculated per 1 g amount of triglycerides. Plasma insulin was measured with an ELISA test kit (Shibayagi Co. Ltd., Japan).

Anti-obesity and anti-diabetic effects of P41 in ob/ob mice Next, the anti-obesity and anti-diabetic effects of P41 in ob/ob mice were evaluated. Administering P41 at doses of 10, 30 and 100 nmol/kg for 4 weeks showed a significant decrease in GHb (Fig. 2(a)) and plasma glucose concentrations (Fig. 2(b)). A dose-dependent decrease in plasma insulin concentration was also observed in the P41-treated group (Fig. 2(c)). Regarding the anti-obesity effect, P41 showed a potent and dose-dependent reduction in body weight and cumulative food intake relative to vehicle (Fig. 2(d), (e)). Similar to the weight loss, P41 decreased the weight of each adipose tissue in the liver, mesentery, upper testis and groin, and TG content in the liver in a dose-dependent manner (Fig. 2(f), (g)). In terms of biochemical indexes, plasma TC, TG, AST and ALT were significantly improved in a dose-dependent manner in the P41 treatment group (Table 6).

Test Example 5

Repeated administration of P41 in KKA ^y mice

Male ^KKAy mice (10 weeks old) were grouped according to the values of body weight, food intake, glycated heme (GHb), and plasma indices. The P41 line was subcutaneously administered once a day for 4 weeks. Compounds were dissolved in 10% DMSO/saline. In the test, body weight and food intake were measured. After the test, blood was collected, and GHb and plasma indexes were measured. The animals were slaughtered, and the liver and adipose tissue were isolated and weighed. Lipids were extracted from liver tissue pieces, and the content of triglycerides (TG) in the liver was determined.

test methods

Plasma glucose and TG were measured with Autoanalyzer 7180 (Hitachi High-Technologies Corporation, Japan). GHb in blood was measured using an automatic GHb analyzer (HLC-723G8, Tosoh, Tokyo, Japan). Plasma insulin was measured using an ELISA test kit (Shibayagi Co., Ltd., Japan). The TG content in the liver was measured in the following manner. The tissue pieces were homogenized in physiological saline, and a hexane:isopropanol (3:2) solution was added to extract lipids. The lipid phase was recovered, dried, and then dissolved in isopropanol. The TG concentration was measured by the triglyceride E-test (E-test (Wako Pure Chemical Industries)), and the TG content per 1 g of the liver was calculated.

4W repeated administration test of P41 in male KKA ^y mice

To evaluate the anti-obesity and anti-diabetic effects of P41, a 4-week repeated administration experiment in KKA ^y mice was performed. Daily subcutaneous injection of P41 at doses of 10, 30, and 100 nmol/kg reduced body weight by 4.2, 9.8, and 30.1%, respectively, relative to the vehicle group (Figure 3(a)). A dose-dependent reduction in cumulative food intake was observed in the P41 treated group (Figure 3(b)). Regarding the antidiabetic effect, P41 showed significant and dose-dependent reductions in GHb, plasma glucose, and plasma insulin concentrations (Fig. 3 (c) to (e)). Consistent with the reduction in body weight, a reduction in liver tissue weight was observed in the P41 treated group (Fig. 3(f)).

Test Example 6

Conditioned taste aversion (CTA) test

Male C57BL/6J (9-week-old) mice were acclimated for 1 week with time-limited vials of water (2-3 hours/day) and subcutaneous injection of normal saline. The mice were grouped according to the values of body weight and water intake. The CTA test was carried out according to the following procedure. For initial training, on day 1, mice were given 0.1% sodium saccharin solution for 3 hours. After 10 minutes of supplying the saccharin solution, vehicle, liraglutide or P41 were administered subcutaneously. In addition, liraglutide has a GLP-1 receptor activating effect. On the 2nd day, the mice were supplied with tap water for 3 hours, and then injected with physiological saline subcutaneously. On the 3rd day, the second training will be carried out in the same order as on the 1st day. On the 4th day, the mice were not given subcutaneous injection, but tap water was supplied for 3 hours. On day 5, mice were not injected subcutaneously, but Both tap water and saccharin solution were taken for 3 hours, and the intake of each liquid was measured. The saccharin preference rate (%) was calculated as {(saccharin intake)/(saccharin intake+tap water intake)}×100.

Taste aversion test in mice

To evaluate emesis in mice, a CTA test was performed. Compared with liraglutide at a dose of 10 nmol/kg, the saccharin preference rate was significantly reduced, showing that CTA was induced, and P41 did not induce CTA even at a dose of 3 nmol/kg. This dose was the dose that showed a stronger anti-obesity effect than liraglutide in DIO mice (FIG. 4).

Test Example 7

Experiment on cynomolgus monkeys

One male cynomolgus monkey and one female cynomolgus monkey (4 years old, body weight: male 3.9 kg, female 2.7 kg) were used. The monkeys were housed in cages at 22 to 27° C. on a 12-hour light: 12-hour dark schedule, and were given 100 g of pellet food (Oriental Yeast Co. Ltd) once a day. The bait, on the day of administration, was administered 8 hours after the clinical observation was completed. Others during the experiment Days, after the inspection is completed, the bait is provided every day, and the remaining bait is removed the next morning. P41 was dissolved in 0.5w/v% mannitol solution. 0.05 mg/kg of compound was administered subcutaneously on day 1, followed by 0.15 mg/kg of compound on day 4. The body weight was measured once during the pre-administration period and on the 1st day, the 4th day, the 8th day, the 11th day, and the 15th day. Food intake was measured daily during the experimental period.

P41 showed no emesis and reduced food intake in cynomolgus monkeys.

The effect of P41 on food intake in cynomolgus monkeys was investigated, and the efficacy and emesis inhibitory effect on primates were confirmed. P41 was administered subcutaneously in increasing doses (0.05 and 0.15 mg/kg; approximately 10 and 30 nmol/kg). Under the two dosages of P41, the food consumption of male and female cynomolgus monkeys almost completely disappeared after administration. The inhibitory effect of prey consumption lasts for at least 2 days (Fig. 5). P41 did not induce emesis during the experiment, indicating that the potent feeding inhibitory effect of P41 and the effect on CTA observed in mice may also extend to non-human primates.

Formulation Example 1

10.0 mg of the compound of Example 1 and 3.0 mg of magnesium stearate were added to 0.07 mL of an aqueous solution of soluble starch (7.0 mg for soluble starch) After granulation, it was dried, and mixed with 70.0 mg of lactose and 50.0 mg of corn starch. The mixture is compressed to obtain lozenges.

Formulation Example 2

5.0 mg of the compound of Example 1 and 20.0 mg of table salt were dissolved in distilled water, and water was added to make the total amount 2.0 mL. The solution was filtered and filled into 2 mL ampoules under sterile conditions. The ampoule is sterilized and sealed to obtain a solution for injection.

[Industrial Availability]

The compound of the present invention has Y2 receptor, GLP-1 receptor and GIP receptor activating effect, and is suitable for the prevention/prevention of various diseases related to Y2 receptor, GLP-1 receptor and GIP receptor, such as obesity or diabetes, etc. therapeutic medicine.

All publications, patents and patent applications cited in this specification are incorporated by reference in their original form and incorporated into this specification.

[Sequence listing free text]

SEQ ID NO: 1: Artificial sequence (synthetic peptide (formula (I), formula (II) or formula (III)))

SEQ ID NO: 2: Artificial sequence (synthetic peptide (Reference Example 1))

SEQ ID NO: 3: Artificial sequence (synthetic peptide (Reference Example 2))

SEQ ID NO: 4: Artificial sequence (synthetic peptide (Reference Example 3))

SEQ ID NO: 5: Artificial sequence (synthetic peptide (Reference Example 4))

SEQ ID NO: 6: Artificial sequence (synthetic peptide (Reference Example 5))

SEQ ID NO: 7: Artificial sequence (synthetic peptide (Reference Example 6))

SEQ ID NO: 8: Artificial sequence (synthetic peptide (Reference Example 7))

SEQ ID NO: 9: Artificial sequence (synthetic peptide (Reference Example 8))

SEQ ID NO: 10: Artificial sequence (synthetic peptide (Example 1))

SEQ ID NO: 11: Artificial sequence (synthetic peptide (Example 2))

SEQ ID NO: 12: Artificial sequence (synthetic peptide (Example 3))

SEQ ID NO: 13: Artificial sequence (synthetic peptide (Example 4))

SEQ ID NO: 14: Artificial sequence (synthetic peptide (Example 5))

SEQ ID NO: 15: Artificial sequence (synthetic peptide (Example 6))

SEQ ID NO: 16: Artificial sequence (synthetic peptide (Example 7))

SEQ ID NO: 17: Artificial sequence (synthetic peptide (Example 8))

SEQ ID NO: 18: Artificial sequence (synthetic peptide (Example 9))

SEQ ID NO: 19: Artificial sequence (synthetic peptide (Example 10))

SEQ ID NO: 20: Artificial sequence (synthetic peptide (Example 11))

SEQ ID NO: 21: Artificial sequence (synthetic peptide (Example 12))

SEQ ID NO: 22: Artificial sequence (synthetic peptide (Example 13))

SEQ ID NO: 23: Artificial sequence (synthetic peptide (Example 14))

SEQ ID NO: 24: Artificial sequence (synthetic peptide (Example 15))

SEQ ID NO: 25: Artificial sequence (synthetic peptide (Example 16))

SEQ ID NO: 26: Artificial sequence (synthetic peptide (Example 17))

SEQ ID NO: 27: Artificial sequence (synthetic peptide (Example 18))

SEQ ID NO: 28: Artificial sequence (synthetic peptide (Example 19))

SEQ ID NO: 29: Artificial sequence (synthetic peptide (Example 20))

SEQ ID NO: 30: Artificial sequence (synthetic peptide (Example 21))

SEQ ID NO: 31: Artificial sequence (synthetic peptide (Example 22))

SEQ ID NO: 32: Artificial sequence (synthetic peptide (Example 23))

SEQ ID NO: 33: Artificial sequence (synthetic peptide (Example 24))

SEQ ID NO: 34: Artificial sequence (synthetic peptide (Example 25))

SEQ ID NO: 35: Artificial sequence (synthetic peptide (Example 26))

SEQ ID NO: 36: Artificial sequence (synthetic peptide (Example 27))

SEQ ID NO: 37: Artificial sequence (synthetic peptide (Example 28))

SEQ ID NO: 38: Artificial sequence (synthetic peptide (Example 29))

SEQ ID NO: 39: Artificial sequence (synthetic peptide (Example 30))

SEQ ID NO: 40: Artificial sequence (synthetic peptide (Example 31))

SEQ ID NO: 41: Artificial sequence (synthetic peptide (Example 32))

SEQ ID NO: 42: Artificial sequence (synthetic peptide (Example 33))

SEQ ID NO: 43: Artificial sequence (synthetic peptide (Example 34))

SEQ ID NO: 44: Artificial sequence (synthetic peptide (Example 35))

SEQ ID NO: 45: Artificial sequence (synthetic peptide (Example 36))

SEQ ID NO: 46: Artificial sequence (synthetic peptide (Example 37))

SEQ ID NO: 47: Artificial sequence (synthetic peptide (Example 38))

SEQ ID NO: 48: Artificial sequence (synthetic peptide (Example 39))

SEQ ID NO: 49: Artificial sequence (synthetic peptide (Example 40))

SEQ ID NO: 50: Artificial sequence (synthetic peptide (Example 41))

SEQ ID NO: 51: Artificial sequence (synthetic peptide (Example 42))

<110> TAKEDA PHARMACEUTICAL COMPANY LIMITED

<120> Peptide compounds

<130> PT38-5015 TW

<140> TW106140294

<141> 2017-11-21

<160> 51

<170> PatentIn version 3.5

<210> 1

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptides (formula (I)/(II)/(III))

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> N-terminal modified with P1

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

<223> In the case of formulas (I) and (III), the linked alkyl chain as shown in (Gly-Gly-Gly-Gly-X) is bonded to the ε amino group of the lysine residue; formula ( X=Oda or Pal in I), X=H in formula (III)

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib, Ala or Ser

<220>

<221> MISC_FEATURE

<222> (12)..(12)

<223> Xaa stands for Ile or Lys

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (15)..(15)

<223> Xaa represents Asp or Glu

<220>

<221> MISC_FEATURE

<222> (18)..(18)

<223> Xaa stands for Ala or Arg

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (35)..(35)

<223> Xaa stands for Tyr or Phe(2-F)

<220>

<221> MISC_FEATURE

<222> (35)..(35)

<223> Amination

<400> 1

<210> 2

<211> 16

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Reference Example 1)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (2)..(15)

<223> functional groups are protected at positions 2, 5, 6, 9, 10, 12, 13, 14 and 15

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (16)..(16)

<223> 2-Fluorophenylalanine

<400> 2

<210> 3

<211> 34

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Reference Example 2)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (2)..(33)

<223> functional groups are protected at positions 2, 4, 6, 7, 8, 9, 14, 15, 16, 18, 20, 23, 24, 27, 28, 30, 31, 32 and 33

<220>

<221> MISC_FEATURE

<222> (5)..(5)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (12)..(12)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (19)..(19)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (29)..(29)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (34)..(34)

<223> 2-Fluorophenylalanine

<400> 3

<210> 4

<211> 16

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Reference Example 3)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (2)..(15)

<223> functional groups are protected at positions 2, 5, 6, 9, 10, 12, 13, 14 and 15

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (16)..(16)

<223> 2-Fluorophenylalanine

<400> 4

<210> 5

<211> 34

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Reference Example 4)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (2)..(33)

<223> functional groups are protected at positions 2, 4, 6, 7, 8, 9, 14, 15, 16, 17, 18, 20, 23, 24, 27, 28, 30, 31, 32 and 33

<220>

<221> MISC_FEATURE

<222> (5)..(5)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (12)..(12)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (19)..(19)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (29)..(29)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (34)..(34)

<223> 2-Fluorophenylalanine

<400> 5

<210> 6

<211> 16

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Reference Example 5)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (2)..(16)

<223> functional groups are protected at positions 2, 5, 6, 9, 10, 12, 13, 14, 15 and 16

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<400> 6

<210> 7

<211> 34

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Reference Example 6)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (2)..(34)

<223> The functional group at positions 2, 4, 6, 7, 8, 9, 14, 15, 16, 17, 18, 20, 23, 24, 27, 28, 30, 31, 32, 33 and 34 was Protect

<220>

<221> MISC_FEATURE

<222> (5)..(5)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (12)..(12)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (19)..(19)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (29)..(29)

<223> Xaa stands for Aib

<400> 7

<210> 8

<211> 16

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Reference Example 7)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (2)..(16)

<223> functional groups are protected at positions 2, 5, 6, 9, 10, 12, 13, 14, 15 and 16

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<400> 8

<210> 9

<211> 34

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Reference Example 8)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (2)..(34)

<223> functional groups are protected at positions 2, 4, 6, 7, 8, 9, 14, 15, 16, 18, 20, 23, 24, 27, 28, 30, 31, 32, 33 and 34

<220>

<221> MISC_FEATURE

<222> (5)..(5)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (12)..(12)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (19)..(19)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (29)..(29)

<223> Xaa stands for Aib

<400> 9

<210> 10

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 1)

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Pal) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (35)..(35)

<223> 2-Fluorophenylalanine

<400> 10

<210> 11

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 2)

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Oda) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (35)..(35)

<223> 2-Fluorophenylalanine

<400> 11

<210> 12

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 3)

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Pal) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (35)..(35)

<223> 2-Fluorophenylalanine

<400> 12

<210> 13

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 4)

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Oda) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (35)..(35)

<223> 2-Fluorophenylalanine

<400> 13

<210> 14

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 5)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> N-terminal methylation

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Pal) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (35)..(35)

<223> 2-Fluorophenylalanine

<400> 14

<210> 15

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 6)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> N-terminal methylation

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Oda) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (35)..(35)

<223> 2-Fluorophenylalanine

<400> 15

<210> 16

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 7)

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Pal) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 16

<210> 17

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 8)

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Oda) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 17

<210> 18

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 9)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> N-terminal methylation

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Pal) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 18

<210> 19

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 10)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> N-terminal methylation

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Oda) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 19

<210> 20

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 11)

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Pal) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 20

<210> 21

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 12)

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Oda) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 21

<210> 22

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 13)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> N-terminal methylation

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Pal) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 22

<210> 23

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 14)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> N-terminal methylation

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Oda) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 23

<210> 24

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 15)

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Pal) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 24

<210> 25

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 16)

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Oda) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 25

<210> 26

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 17)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> N-terminal methylation

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Pal) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 26

<210> 27

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 18)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> N-terminal methylation

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Oda) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 27

<210> 28

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 19)

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Pal) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 28

<210> 29

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 20)

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Oda) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 29

<210> 30

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 21)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> N-terminal methylation

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Pal) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 30

<210> 31

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 22)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> N-terminal methylation

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Oda) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 31

<210> 32

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 23)

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Pal) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 32

<210> 33

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 24)

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Oda) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 33

<210> 34

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 25)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> N-terminal methylation

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Pal) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 34

<210> 35

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 26)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> N-terminal methylation

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Oda) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 35

<210> 36

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 27)

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Pal) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 36

<210> 37

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 28)

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Oda) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 37

<210> 38

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 29)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> N-terminal methylation

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Pal) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 38

<210> 39

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 30)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> N-terminal methylation

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Oda) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 39

<210> 40

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 31)

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Pal) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 40

<210> 41

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 32)

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Oda) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 41

<210> 42

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 33)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> N-terminal methylation

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Pal) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 42

<210> 43

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 34)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> N-terminal methylation

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Oda) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (11)..(11)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 43

<210> 44

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 35)

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Pal) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 44

<210> 45

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 36)

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Oda) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 45

<210> 46

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 37)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> N-terminal methylation

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Pal) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 46

<210> 47

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 38)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> N-terminal methylation

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Oda) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 47

<210> 48

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 39)

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Pal) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 48

<210> 49

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 40)

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Oda) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 49

<210> 50

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 41)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> N-terminal methylation

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Pal) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 50

<210> 51

<211> 35

<212> PRT

<213> Artificial sequences

<220>

<223> Synthetic peptide (Example 42)

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> N-terminal methylation

<220>

<221> MISC_FEATURE

<222> (2)..(2)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (6)..(6)

<223> α-methylation

<220>

<221> MISC_FEATURE

<222> (10)..(10)

The linked alkyl chain shown by <223> (Gly-Gly-Gly-Gly-Oda) is bonded to the ε amine group of lysine

<220>

<221> MISC_FEATURE

<222> (13)..(13)

<223> Xaa stands for Aib

<220>

<221> MISC_FEATURE

<222> (20)..(20)

<223> Xaa stands for Iva

<220>

<221> MISC_FEATURE

<222> (30)..(30)

<223> Xaa stands for Aib

<400> 51

The drawings of the present invention are all experimental data graphs, which are not sufficient to represent the present invention. Therefore, there is no designated representative map in this case.

Claims (15)

A peptide of formula (I) or a salt thereof, the formula (I) is: P ¹ -Tyr-Aib-Glu-Gly-Thr-α-MePhe-Thr-Ser-Asp-Lys(-Gly-Gly -Gly-Gly-R ^A10 )-A11-A12-Aib-Leu-A15-Lys-Gln-A18-Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr -Arg-Gln-Arg-A35-NH ₂ In the formula, P ¹ represents a group represented by the following formula: -R ^A1 , -CO-R ^A1 , -CO-OR ^A1 , -CO-COR ^A1 , -SO-R ^A1 , -SO ₂ -R ^A1 , -SO ₂ -OR ^A1 , -CO-NR ^A2 R ^A3 , -SO ₂ -NR ^A2 R ^A3 , or -C(=NR ^A1 )-NR ^A2 R ^A3 In the formula, R ^A1 , R ^A2 and R ^A3 independently represent a hydrogen atom, a substituted hydrocarbon group, or a substituted heterocyclic group; R ^A10 represents Pal or Oda; A11 represents Aib, Ala or Ser; A12 represents Ile or Lys; A15 Represents Asp or Glu; A18 represents Ala or Arg; A35 represents Tyr or Phe(2-F). The peptide or its salt according to claim 1, wherein P ¹ is a hydrogen atom or a methyl group. The peptide or its salt according to claim 1, wherein R ^A10 is Pal. The peptide or its salt according to item 1 of the claimed scope, wherein A12 is Ile. The peptide or its salt according to claim 1, wherein A15 is Glu. The peptide or its salt according to claim 1, wherein A18 is Arg. The peptide or its salt according to claim 1, wherein A35 is Tyr. A peptide or its salt, the peptide is H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Aib-Ile-Aib -Leu-Glu-Lys-Gln-Arg-Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr- _NH2 . A peptide or its salt, the peptide is H-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Ala-Ile-Aib -Leu-Glu-Lys-Gln-Arg-Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr- _NH2 . A peptide or its salt, the peptide is Me-Tyr-Aib-Glu-Gly-Thr-αMePhe-Thr-Ser-Asp-Lys(-Gly-Gly-Gly-Gly-Pal)-Ser-Il e- Aib-Leu-Glu-Lys-Gln-Arg-Gln-Iva-Glu-Phe-Val-Arg-His-Leu-Leu-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Tyr- _NH2 . A medicine containing the peptide or its salt described in the first item of the scope of application. The medicine according to item 11 of the application scope is an activator of Y2 receptor, GLP-1 receptor and GIP receptor. The medicine according to item 11 of the scope of the application, which is a prophylactic/therapeutic agent for obesity or diabetes. A use of the peptide or its salt described in the first item of the scope of the application is for the manufacture of a preventive/therapeutic agent for obesity or diabetes. The peptide or its salt as described in item 1 of the claimed scope is used for the prevention/treatment of obesity or diabetes.

Images