Long-acting GLP-1 / GIP dual agonist

Abstract

This provides an improved GLP-1RA class treatment for type 2 diabetes. [Solution] The present invention provides a long-acting glucagon-like peptide-1 and a human glucose-dependent insulinotropic polypeptide (GIP) agonist polypeptide that may be useful in treating type 2 diabetes, diabetes with obesity, obesity, and hyperlipidemia.

Description

Technical Field

[0001] The present invention relates to long-acting glucagon-like peptide-1 and human glucose-dependent insulinotropic polypeptide / gastric inhibitory polypeptide (GIP) agonist polypeptides that may be useful for the treatment of type 2 diabetes (T2D), diabetes associated with obesity, obesity and hyperlipidemia.

Background Art

[0002] Treatment of type 2 diabetes mellitus (T2DM) with glucagon-like peptide-1 receptor agonists (GLP-1RAs) results in improved glycemic control, weight loss, and improvement of some cardiovascular risk factors. These benefits are mediated by the glucagon-like peptide-1 receptor (GLP-1R), a member of the class B family of G protein-coupled receptors expressed on pancreatic beta cells, various cell types of the gastrointestinal tract, and neurons of both the central (CNS) and peripheral nervous systems. Activation of GLP-1R signaling by GLP-1RAs improves glucose homeostasis by enhancing glucose-stimulated insulin secretion, delaying gastric emptying, and reducing plasma glucagon levels, and reduces body weight by activating anorectic pathways in the brain. Due to the glucose-dependence of beta cell activation, GLP-1RAs are not associated with an increased risk of hypoglycemia. The broad metabolic benefits of GLP-1RAs have established this class in the T2DM treatment paradigm, but many patients do not reach HbA1c / glycemic targets, and the weight loss achieved with these agents thus requires higher doses, which also increases GI adverse events and is the most potent (T2DM) treatment results in improved glycemic control, weight loss, and improvement of some cardiovascular risk factors. These benefits are mediated by the glucagon-like peptide-1 receptor (GLP-1R), a member of the class B family of G protein-coupled receptors expressed on pancreatic beta cells, various cell types of the gastrointestinal tract, and neurons of both the central (CNS) and peripheral nervous systems. Activation of GLP-1R signaling by GLP-1RAs improves glucose homeostasis by enhancing glucose-stimulated insulin secretion, delaying gastric emptying, and reducing plasma glucagon levels, and reduces body weight by activating anorectic pathways in the brain. Due to the glucose-dependence of beta cell activation, GLP-1RAs are not associated with an increased risk of hypoglycemia. The broad metabolic benefits of GLP-1RAs have established this class in the T2DM treatment paradigm, but many patients do not reach HbA1c / glycemic targets, and the weight loss achieved with these agents thus requires higher doses, which also increases GI adverse events and is the most potent for obesity. (CNS) and neurons of both the central and peripheral nervous systems. Activation of GLP-1R signaling by GLP-1RAs improves glucose homeostasis by enhancing glucose-stimulated insulin secretion, delaying gastric emptying, and reducing plasma glucagon levels, and reduces body weight by activating anorectic pathways in the brain. Due to the glucose-dependence of beta cell activation, GLP-1RAs are not associated with an increased risk of hypoglycemia. The broad metabolic benefits of GLP-1RAs have established this class in the T2DM treatment paradigm, but many patients do not reach HbA1c / glycemic targets, and the weight loss achieved with these agents thus requires higher doses, which also increases GI adverse events and is the most potent for obesity. ​​​​​​​​​​​​​​​​​​​The results remain far lower than what can be achieved with bariatric surgery, a clinical intervention. Therefore, existing There is a great opportunity to improve treatment methods for the GLP-1RA class.

[0003] One new approach involves modifying basic GLP-1RA therapy with glucose-dependent insulin. Additional substances involved in nutritional and energy metabolism, such as phosphorus-stimulating polypeptides (GIPs). This involves combining it with pharmacological strategies that target the pathway. GIP responds to food and It is an incretin secreted from K cells in the small intestine and duodenum. Under normal physiological conditions Postprandial GIP levels are approximately four times higher compared to GLP-1. GIP is a function of the human body. It is responsible for the majority of the insulin-secreting incretin effect and is an important factor distinct from GLP-1. It has additional functions. Unlike GLP-1, GIP is glucose-dependent and contains glucagon It is both a secretoriginator and an insulin secretion promoter, and under hypoglycemic conditions, it is dose-dependent. It stimulates lucagon secretion, and under hyperglycemic conditions, it stimulates insulin secretion, and the released glucagon Insulin secretion is stimulated. Both the GIP receptor (GIPR) and GLP-1R are involved. Although present in adipose cells, GIPR is abundant in adipose tissue and is not found in many overlapping CNS cells. Because it is found in a different region, GIPR expression is distributed differently in extrapancreatic tissues. Its role in regulating glucose uptake, lipolysis, and lipoprotein lipase activity. This is involved in adipose tissue carbohydrate and lipid metabolism. These findings are related to the drug GIPR. This suggests that physical activation may have therapeutic benefits for peripheral energy metabolism. Recently, G A single-molecule, multifunctional peptide combining LP-1RA activity and GIP activity controls blood glucose and body It is being proposed as a new treatment for severe cases.

[0004] U.S. Patent No. 9474780 is for dual GLP-1 and GIP containing tilzepatide. We will disclose receptor agonists. [ka]

[0005] Chilzepatide is currently undergoing Phase III clinical trials for T2DM and obesity.

[0006] WIPO publication numbers WO201774714A1, WO202023386A1, WO2 020023388A1, WO2015067715A2, WO2016111971A 1 and WO2013164483A1 are GLP-1R and GIPR dual agonists. The company discloses a compound. [Overview of the project]

[0007] The present invention relates to a polypeptide comprising the following amino acid sequence or a pharmaceutically acceptable salt thereof. provide: Y-X1-EGTFTSDYSI-X2-L-Xaa15-KI- A-Xaa19-X3-Xaa21-FV-Xaa24-WL-X4-AGG- PSSGAPPPS-X5-X6-X7-X8-X9-X10-X11 (Sequence ID 1) In the formula, X1 is Aib, Ser(OMe), or (D)Ser(OMe), X2 is Tyr, Ser(OMe), (D)Ser(OMe), or Aib. X3 is either Gln or Lys, where if X3 is Lys, then the side chain amino of Lys. The (ε-amino) group is acylated at the following site: {―UWYZ In the formula, U is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH- In the formula,} is the attachment point with the base W, W is -C(O)-NH-(CH2) p -NH-], -C(O)-C(CH3)2-NH- ], and -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-] Selected from the group, where p is 3 or 4, and where ] is the attachment point with base Y, Y is -C(O)-(CH2)2-CH(COOH)NH-- and -- is group Z and It is the attachment point, Z is -C(O)-(CH2). n -COOH or -C(O)-(CH2) n -CH3 In the formula, n is an integer between 14 and 20. However, if XX3 is Lys and X2 is Aib, then W is -C(O)-CH2-O- [(CH2)2-O-(CH2)2-NH-], X4 is Leu, Ile, or Glu. X5 does not exist, or is Arg or Lys, and in the expression, if X5 is Lys, Lys The amino(ε-amino) group in the side chain of s is acylated at the following point: {―U'- W'-Y'-Z' In the formula, U' is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH- In the formula,} is the attachment point with the base W', W' is -C(O)-NH-(CH2) q -NH-], -C(O)-C(CH3)2-NH -] and -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-] Selected from the group, where q is 3 or 4, and in the formula, ] is the attachment point with base Y', Y' is -C(O)-(CH2)2-CH(COOH)NH-- and -- is the group Z It is the attachment point to ', Z' is -C(O)-(CH2). m -COOH or -C(O)-(CH2) m -CH3 Yes, in the formula, m is an integer between 14 and 20. X6 does not exist, or it is Lys. X7 does not exist, or it is Lys. X8 does not exist, or it is Lys. X9 does not exist, or it is Lys. X10 does not exist, or it is Lys. X11 does not exist, or it is Lys. Xaa15 is either Asp or Glu. Xaa19 is either Gln or Ala. Xaa21 is either Ala or Glu. Xaa24 is either Gln or Asn. In the formula, the acid group of the C-terminal amino acid is either a free carboxylic acid group or a C-terminal primary amino acid. It is amidized as a do, However, at least one of X3 and X5 is Lys.

[0008] Abbreviation A1: 2-aminoisobutyric acid DIPEA: N,N'-di-isopropylethylamine HOBt: 1-hydroxybenzotriazole DIPC: N,N'-di-isopropylcarbodiimide THF: Tetrahydrofuran DCM: Dichloromethane DMAP: 4-dimethylaminopyridine DIC: Diisopropylcarbodiimide DMAc: Dimethylacetamide [Modes for carrying out the invention]

[0009] This invention relates to the treatment of type 2 diabetes (T2D), diabetes with obesity, obesity and hyperlipidemia. Provides a stable, long-acting GLP-1 / GIP agonist polypeptide that may be useful. The polypeptide of the present invention is thought to be long-acting, and this is necessary. Frequent administration to patients requiring treatment may not be necessary.

[0010] Accordingly, in one embodiment, the present invention relates to a polypeptide or drug comprising the following amino acid sequence. Provide a scientifically acceptable salt: Y-X1-EGTFTSDYSI-X2-L-Xaa15-KI- A-Xaa19-X3-Xaa21-FV-Xaa24-WL-X4-AGG- PSSGAPPPS-X5-X6-X7-X8-X9-X10-X11 (Sequence ID 1) In the formula, X1 is Aib, Ser(OMe), or (D)Ser(OMe), X2 is Tyr, Ser(OMe), (D)Ser(OMe), or Aib. X3 is either Gln or Lys, where if X3 is Lys, then the side chain amino of Lys. The (ε-amino) group is acylated at the following site: {―UWYZ In the formula, U is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH- In the formula,} is the attachment point with the base W, W is -C(O)-NH-(CH2) p -NH-], -C(O)-C(CH3)2-NH- ], and -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-] Selected from the group, where p is 3 or 4, and where ] is the attachment point with base Y, Y is -C(O)-(CH2)2-CH(COOH)NH-- and -- is group Z and It is the attachment point, Z is -C(O)-(CH2).n -COOH or -C(O)-(CH2) n -CH3 where n is an integer from 14 to 20, provided that when XX3 is Lys and X2 is Aib, W is not -C(O)-CH2-O- (CH2)2-O-(CH2)2-NH-], X4 is Leu, Ile or Glu, X5 is absent or Arg or Lys, and when X5 is Lys, the side-chain amino (ε-amino) group of Lys is acylated with the following moiety, {―U’-W’-Y’-Z’ where U’ is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-}, where} is the attachment point to group W’, W’ is -C(O)-NH-(CH2) q -NH-], -C(O)-C(CH3)2-NH -], and -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-] selected from the group where p is 3 or 4, and ] is the attachment point to group Y’, , Y’ is -C(O)-(CH2)2-CH(COOH)NH--, and -- is the attachment point to group Z ’, Z’ is -C(O)-(CH2) m -COOH or -C(O)-(CH2) m -CH3 where m is an integer from 14 to 20, X6 is absent or Lys, X7 is absent or Lys, X8 is absent or Lys, X9 is absent or Lys, X10 is absent or Lys, X11 is absent or Lys, Xaa15 is either Asp or Glu. Xaa19 is either Gln or Ala. Xaa21 is either Ala or Glu. Xaa24 is either Gln or Asn. In the formula, the acid group of the C-terminal amino acid is either a free carboxylic acid group or a C-terminal primary amide. It is amidated as, However, at least one of X3 and X5 is Lys.

[0011] In one embodiment of the present invention, X1 is Aib.

[0012] In another embodiment of the present invention, X2 is Aib.

[0013] In another embodiment of the present invention, both X1 and X2 are Aib.

[0014] In another embodiment of the present invention, X1 is Aib, and X2 is Ser(OMe) or (D )Ser(OMe).

[0015] In another embodiment of the present invention, X1 is Ser(OMe) or (D)Ser(OMe) Yes, X2 is Aib.

[0016] In another embodiment of the present invention, X4 is Leu or Ile.

[0017] In another embodiment of the present invention, X4 is Ile.

[0018] In another embodiment of the present invention, X5 is Lys or Arg.

[0019] In another embodiment of the present invention, X3 is Lys, and X5 is absent or Arg. ru.

[0020] In another embodiment of the present invention, X3 is Gln and X5 is Lys.

[0021] In another embodiment of the present invention, W is -C(O)-C(CH3)2-NH-].

[0022] In another embodiment of the present invention, W is -C(O)-NH-(CH2) p -NH-] In the formula, p is either 3 or 4.

[0023] In another embodiment of the present invention, W is -C(O)-NH-(CH2)4-NH-].

[0024] In another embodiment of the present invention, W is -C(O)-CH2-O-(CH2)2-O-(CH 2) It is 2-NH-.

[0025] In another embodiment of the present invention, W' is -C(O)-C(CH3)2-NH-].

[0026] In another embodiment of the present invention, W' is -C(O)-NH-(CH2) q -NH-] In the formula, p is either 3 or 4.

[0027] In another embodiment of the present invention, W' is -C(O)-NH-(CH2)4-NH-] .

[0028] In another embodiment of the present invention, W' is -C(O)-CH2-O-(CH2)2-O-(C It is H2)2-NH-].

[0029] In another embodiment of the present invention, the C-terminal amino acid is amidated as a C-terminal primary amide. It can be done.

[0030] In another embodiment of the present invention, the acid group of the C-terminal amino acid is a free carboxylic acid.

[0031] In another embodiment of the present invention, n is 16, 17, 18, 19, or 20. Preferred In the embodiment, n is 18 or 20. In yet another preferred embodiment, n is 20 In another preferred embodiment, n is 16 or 18. In this case, n is 18.

[0032] In another embodiment of the present invention, Z is -C(O)-(CH2) n -COOH, and n is either 16 or 18.

[0033] In another embodiment of the present invention, m is 16, 17, 18, 19, or 20. Preferred In the embodiment, m is 18 or 20. In another more preferred embodiment, m is 20 In another preferred embodiment, m is 16 or 18. In this case, m is 18.

[0034] In another embodiment of the present invention, Z' is -C(O)-(CH2) m -COOH, and The value of m is either 16 or 18.

[0035] In another embodiment of the present invention, W is -C(O)-NH-(CH2)4-NH-], Z is -C(O)-(CH2). n It is -COOH, and n is 18.

[0036] In another embodiment of the present invention, W is -C(O)-C(CH3)2-NH- and Z is -C(O)-(CH2) n It is -COOH, and n is 16.

[0037] In another embodiment of the present invention, W is -C(O)-C(CH3)2-NH- and Z is -C(O)-(CH2) nIt is -COOH, and n is 18.

[0038] In another embodiment of the present invention, W is -C(O)-CH2-O-(CH2)2-O-(CH 2) [2-NH-], and Z is -C(O)-(CH2) n -COOH and n is It is 16.

[0039] In another embodiment of the present invention, W is -C(O)-CH2-O-(CH2)2-O-(CH 2) [2-NH-], and Z is -C(O)-(CH2) n -COOH and n is I am 18.

[0040] In another embodiment of the present invention, W' is -C(O)-NH-(CH2)4-NH- Z' is -C(O)-(CH2) m It is -COOH, and m is 18.

[0041] In another embodiment of the present invention, W' is -C(O)-C(CH3)2-NH-, and Z ' is -C(O)-(CH2) m It is -COOH, and m is 16.

[0042] In another embodiment of the present invention, W' is -C(O)-C(CH3)2-NH-, and Z ' is -C(O)-(CH2) m It is -COOH, and m is 18.

[0043] In another embodiment of the present invention, W' is -C(O)-CH2-O-(CH2)2-O-(C [H2)2-NH-], and Z' is -C(O)-(CH2) m -COOH, and m is 16.

[0044] In another embodiment of the present invention, W' is -C(O)-CH2-O-(CH2)2-O-(C [H2)2-NH-], and Z' is -C(O)-(CH2) m -COOH, and m is 18.

[0045] In another embodiment of the present invention, X5, X6, X7, X8, X9, X10 and X11 are None of them exist.

[0046] In another embodiment of the present invention, Xaa15 is Asp.

[0047] In another embodiment of the present invention, Xaa19 is Gln.

[0048] In another embodiment of the present invention, Xaa21 is Ala.

[0049] In another embodiment of the present invention, Xaa24 is Gln.

[0050] In another embodiment of the present invention, X1 is Aib, and X2 is Ser(OMe) It is Tyr.

[0051] In another embodiment of the present invention, X1 is Aib and X2 is Ser(OMe) ru.

[0052] In another embodiment of the present invention, X1 is Aib and X2 is Tyr.

[0053] In another embodiment of the present invention, X3 is Gln.

[0054] In another embodiment of the present invention, X4 is Leu.

[0055] In another embodiment of the present invention, X5 is Lys, where the side chain amino(ε-amino) of Lys is used in the formula. The group is acylated at the following point. {―U'- W'-Y'-Z'

[0056] In another embodiment of the present invention, W' is -C(O)-C(CH3)2-NH-, and Z ' is -C(O)(CH2) m It is -COOH, and m is 18.

[0057] In another embodiment of the present invention, Xaa15 is Glu.

[0058] In another embodiment of the present invention, Xaa19 is Ala.

[0059] In another embodiment of the present invention, Xaa21 is Glu.

[0060] In another embodiment of the present invention, Xaa24 is Asn.

[0061] In another embodiment of the present invention, X6, X7, X8, X9, X10, and X11 are all present. It does not exist.

[0062] In another embodiment, the present invention relates to a polypeptide comprising the following amino acid sequence or the pharmaceutically active Provide an acceptable amount of salt, Y-Aib-EGTFTSDYSI-Ser(OMe)-LDK -IAQ-X3-AFVQWL-X4-AGGPSSGA -PPPS-X5-X6-X7-X8-X9-X10-X11 (Sequence number 2), During the ceremony X3 is Lys, and in the formula, the amino(ε-amino) group of the Lys side chain is acylated at the following point. And so, {―UWYZ In the formula, U is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH- In the formula,} is the attachment point with the base W, W is -C(O)-NH-(CH2) p -NH-], -C(O)-C(CH3)2-NH- ], and -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-] Selected from the group, where p is 3 or 4, and where ] is the attachment point with base Y, Y is -C(O)-(CH2)2-CH(COOH)NH-- and -- is group Z and It is the attachment point, Z is -C(O)-(CH2). n -COOH or -C(O)-(CH2) n -CH3 In the formula, n is an integer between 14 and 20. X4 is either Ile or Glu. X5 does not exist, or it is Arg. X6 does not exist, or it is Lys. X7 does not exist, or it is Lys. X8 does not exist, or it is Lys. X9 does not exist, or it is Lys. X10 does not exist, or it is Lys. X11 does not exist, or it is Lys. In the formula, the acid group of the C-terminal amino acid is either a free carboxylic acid group or a C-terminal primary amide. It is amidated as follows.

[0063] In one embodiment of the present invention, X4 is Ile.

[0064] In another embodiment of the present invention, W is -C(O)-C(CH3)2-NH-].

[0065] In another embodiment of the present invention, W is -C(O)-NH-(CH2) p -NH-] In the formula, p is either 3 or 4.

[0066] In another embodiment of the present invention, W is -C(O)-NH-(CH2)4-NH-].

[0067] In another embodiment of the present invention, W is -C(O)-CH2-O-(CH2)2-O-(CH 2) It is 2-NH-.

[0068] In another embodiment of the present invention, the C-terminal amino acid is amidated as a C-terminal primary amide. It can be done.

[0069] In another embodiment of the present invention, n is 16, 17, 18, 19, or 20. Preferred In the embodiment, n is 18 or 20. In yet another preferred embodiment, n is 20 In another preferred embodiment, n is 16 or 18. In this case, n is 18.

[0070] In another embodiment of the present invention, Z is -C(O)-(CH2) n -COOH, and n is either 16 or 18.

[0071] In another embodiment of the present invention, W is -C(O)-C(CH3)2-NH- and Z is -C(O)-(CH2) n It is -COOH, and n is 16.

[0072] In another embodiment of the present invention, W is -C(O)-C(CH3)2-NH- and Z is -C(O)-(CH2) n It is -COOH, and n is 18.

[0073] In another embodiment of the present invention, W is -C(O)-CH2-O-(CH2)2-O-(CH 2) [2-NH-], and Z is -C(O)-(CH2) n -COOH and n is It is 16.

[0074] In another embodiment of the present invention, W is -C(O)-CH2-O-(CH2)2-O-(CH 2) [2-NH-], and Z is -C(O)-(CH2) n -COOH and n is I am 18.

[0075] In another embodiment of the present invention, X5, X6, X7, X8, X9, X10 and X11 are None of them exist.

[0076] In another embodiment, the present invention relates to a polypeptide comprising the following amino acid sequence or the pharmaceutically active Provide an acceptable amount of salt, Y-X1-EGTFTSDYSI-X2-LDKIAQ- X3-AFVQWL-X4-AGGPSSGAPPP- S (Sequence ID 3) In the formula, X1 is Aib, X2 is Ser(OMe) or Aib, and X4 is Ile or glue, X3 is Lys, and in the formula, the amino(ε-amino) group of the Lys side chain is acylated at the following point. And so, {―UWYZ In the formula, U is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH- In the formula,} is the attachment point with the base W, W is -C(O)-NH-(CH2) p -NH-], -C(O)-C(CH3)2-NH- ], and -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-] Selected from the group, where p is 3 or 4, and where ] is the attachment point with group Y, Y is -C(O)-(CH2)2-CH(COOH)NH-- and -- is group Z and It is the attachment point, Z is -C(O)-(CH2). n -COOH or -C(O)-(CH2) n -CH3 In the formula, n is an integer between 14 and 20. Furthermore, in the formula, the acid group of the C-terminal amino acid is either a free carboxylic acid group or the C-terminal first It is amidated as a grade amide, However, if X2 is Aib, then W is -C(O)-CH2-O-(CH2)2-O-(C It is not [H2)2-NH-].

[0077] In one embodiment of the present invention, X2 is Aib and X4 is Ile.

[0078] In another embodiment of the present invention, W is -C(O)-C(CH3)2-NH-].

[0079] In another embodiment of the present invention, W is -C(O)-NH-(CH2) p -NH-] In the formula, p is either 3 or 4.

[0080] In another embodiment of the present invention, W is -C(O)-NH-(CH2)4-NH-].

[0081] In another embodiment of the present invention, W is -C(O)-CH2-O-(CH2)2-O-(CH 2) It is 2-NH-.

[0082] In another embodiment of the present invention, the C-terminal amino acid is amidated as a C-terminal primary amide. It can be done.

[0083] In another embodiment of the present invention, n is 16, 17, 18, 19, or 20. Preferred In the embodiment, n is 18 or 20. In yet another preferred embodiment, n is 20 In another preferred embodiment, n is 16 or 18. In this case, n is 18.

[0084] In another embodiment of the present invention, Z is -C(O)-(CH2)n -COOH, and n is either 16 or 18.

[0085] In another embodiment of the present invention, W is -C(O)-NH-(CH2)4-NH-], Z is -C(O)-(CH2). n It is -COOH, and n is 18.

[0086] In another embodiment, W is -C(O)-C(CH3)2-NH- and Z is -C(O )-(CH2) n It is -COOH, and n is 16.

[0087] In another embodiment of the present invention, W is -C(O)-C(CH3)2-NH- and Z is -C(O)-(CH2) n It is -COOH, and n is 18.

[0088] In another embodiment of the present invention, X2 is Ser(OMe) and X4 is Ile ru.

[0089] In another embodiment of the present invention, W is -C(O)-C(CH3)2-NH- and Z is -C(O)-(CH2) n It is -COOH, and n is 16.

[0090] In another embodiment of the present invention, W is -C(O)-CH2-O-(CH2)2-O-(CH 2) [2-NH-], and Z is -C(O)-(CH2) n -COOH and n is It is 16.

[0091] In another embodiment of the present invention, W is -C(O)-CH2-O-(CH2)2-O-(CH 2) [2-NH-], and Z is -C(O)-(CH2) n -COOH and n is I am 18.

[0092] In another embodiment, the present invention relates to a polypeptide comprising the following amino acid sequence or the pharmaceutically active Provide an acceptable amount of salt, Y-Aib-EGTFTSDYSI-Aib-LDKIA- Q-X3-AFVQWL-Ile-AGGPSSGAPP -PS(Sequence ID 4) In the formula, X3 is Lys, and the side chain amino(ε-amino) group of Lys is in the following part Silified, {―UWYZ In the formula, U is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH- In the formula,} is the attachment point with the base W, W is -C(O)-NH-(CH2) p -NH- or -C(O)-C(CH3)2-N Selected from the group consisting of H-, where p is 3 or 4, and where ] is attached to group Y. It is a point, Y is -C(O)-(CH2)2-CH(COOH)NH-- and -- is group Z and It is the attachment point, Z is -C(O)-(CH2). n -COOH or -C(O)-(CH2) n -CH3 In the formula, n is an integer between 14 and 20. In the formula, the acid group of the C-terminal amino acid is either a free carboxylic acid group or a C-terminal primary amide. It is amidated as follows.

[0093] In another embodiment of the present invention, W is -C(O)-C(CH3)2-NH-].

[0094] In another embodiment of the present invention, W is -C(O)-NH-(CH2) p -NH-] In the formula, p is either 3 or 4.

[0095] In another embodiment of the present invention, W is -C(O)-NH-(CH2)4-NH-].

[0096] In another embodiment of the present invention, the C-terminal amino acid is amidated as a C-terminal primary amide. It can be done.

[0097] In another embodiment of the present invention, n is 16, 17, 18, 19, or 20. Preferred In the embodiment, n is 18 or 20. In yet another preferred embodiment, n is 20 In another preferred embodiment, n is 16 or 18. In this case, n is 18.

[0098] In another embodiment of the present invention, Z is -C(O)-(CH2) n -COOH, and n is either 16 or 18.

[0099] In another embodiment of the present invention, W is -C(O)-NH-(CH2)4-NH-], Z is -C(O)-(CH2). n It is -COOH, and n is 18.

[0100] In another embodiment of the present invention, W is -C(O)-C(CH3)2-NH- and Z is -C(O)-(CH2) n It is -COOH, and n is 16.

[0101] In another embodiment of the present invention, W is -C(O)-C(CH3)2-NH- and Z is -C(O)-(CH2) n It is -COOH, and n is 18.

[0102] In another embodiment, the present invention relates to a polypeptide comprising an amino acid sequence selected from the following or Providing the pharmaceutically acceptable salts thereof: i) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Ty r Ser Ile Aib Leu Asp Lys Ile Ala Gln X3 Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser, ii) Tyr Aib Glu Gly Thr Phe Thr Ser Asp T yr Ser Ile D-Ser-(OMe) Leu Asp Lys Ile A la Gln X3 Ala Phe Val Gln Trp Leu Ile Al a Gly Gly Pro Ser Ser Gly Ala Pro Pro Pr o Ser, iii) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Ser(OMe) Leu Asp Lys Ile Ala Gln X3 Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser, iv) Tyr Aib Glu Gly Thr Phe Thr Ser Asp T yr Ser Ile Aib Leu Asp Lys Ile Ala Gln X 3 Ala Phe Val Gln Trp Leu Ile Ala Gly Gl y Pro Ser Ser Gly Ala Pro Pro Pro Ser Ar g, v) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Ty r Ser Ile Tyr Leu Glu Lys Ile Ala Ala Ty r Glu Phe Val Asn Trp Leu Leu Ala Gly Gl y Pro Ser Ser Gly Ala Pro Pro Pro Ser X5 , vi)Tyr Aib Glu Gly Thr Phe Thr Ser Asp T yr Ser Ile Ser(OMe) Leu Glu Lys Ile Ala Ala Gln Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Cell X5, vii)Tyr D-Ser(OMe) Glu Gly Thr Phe Thr S er Asp Tyr Ser Ile Aib Leu Asp Lys Ile A la Gln X3 Ala Phe Val Gln Trp Leu Ile Al a Gly Gly Pro Ser Ser Gly Ala Pro Pro Pr o Ser, and vii)Tyr Ser(OMe) Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Aib Leu Asp Lys Ile Al a Gln X3 Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pr o Ser In the formula, X3 and X5 have the same meaning as above. In the formula, the acid group of the C-terminal amino acid is either a free carboxylic acid group or a C-terminal primary amide. It is amidated as follows.

[0103] In another embodiment, the present invention relates to a polypeptide comprising an amino acid sequence selected from the group consisting of the following: Provides cydos or pharmaceutically acceptable salts thereof: i)Tyr Aib Glu Gly Thr Phe Thr Ser Asp Ty r Ser Ile Aib Leu Asp Lys Ile Ala Gln Ly s Ala Phe Val Gln Trp Leu Ile Ala Gly Gl y Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH 2 (Sequence ID 5), ii)Tyr Aib Glu Gly Thr Phe Thr Ser Asp T yr Ser Ile D-Ser-(OMe) Leu Asp Lys Ile A la Gln Lys Ala Phe Val Gln Trp Leu Ile A la Gly Gly Pro Ser Ser Gly Ala Pro Pro P ro Ser-NH2 (SEQ ID NO: 9), iii)Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Ser(OMe) Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2 (SEQ ID NO: 10), iv)Tyr Aib Glu Gly Thr Phe Thr Ser Asp T yr Ser Ile Aib Leu Asp Lys Ile Ala Gln L ys Ala Phe Val Gln Trp Leu Ile Ala Gly G ly Pro Ser Ser Gly Ala Pro Pro Pro Ser A rg (SEQ ID NO: 11), v) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Ty r Ser Ile Tyr Leu Glu Lys Ile Ala Ala Gl n Glu Phe Val Asn Trp Leu Leu Ala Gly Gl y Pro Ser Ser Gly Ala Pro Pro Pro Ser Ly s-NH2 (SEQ ID NO: 12), vi) Tyr Aib Glu Gly Thr Phe Thr Ser Asp T yr Ser Ile Ser(OMe) Leu Glu Lys Ile Ala Ala Gln Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro​​​​​​​​​​​​​​​​​​​​ Pro Ser-NH2 (SEQ ID NO: 7).

[0104] In another embodiment, the present invention relates to polypeptides selected from representative compounds disclosed in Table 1. or to provide a pharmaceutically acceptable salt thereof.

[0105] In embodiments of the present invention, the following portion {―UWYZ The base U, W, Y and Z inside, or the following part {―U'- W'-Y'-Z' The groups U', W', Y', and Z' in the amino acids have the meanings defined herein. It should not be interpreted as a single character code, nor should it be mixed with other characters. In the formula, the bases -UWYZ and / or -U'-W'-Y'-Z' are disclosed in Table 2. A representative structure is selected from parts A, B, C, D, and E. The Ser(OMe) described herein has its hydroxyl group methylated and has the following structure It is an amino acid serine, preferably the L-isomer, having the characteristic [of the amino acid serine]. [ka]

[0106] Where applicable, (D)Ser(OMe) always refers to the D isomer of Ser(OMe). .

[0107] The Tyr-(OEt) described herein has a hydroxyl group that is ethylated, and has the following structure The amino acid tyrosine, preferably L-isomer, has (* indicates an attachment site to an adjacent residue). It is the body. [ka]

[0108] Where applicable, (D)Tyr(OEt) always refers to the D isomer of Tyr(OEt). .

[0109] The polypeptide sequences referred to herein are single amino acid sequences approved by IUPAC. It is represented by a character code or a three-letter code.

[0110] Unless otherwise specified, this specification covers both L and D isomers of amino acids in a sequence. The intention is to do so. However, in a preferred embodiment, unless otherwise suggested, All amino acids are of the "L" type.

[0111] The "pharmaceutically acceptable salt" according to the present invention is formed with either an organic or inorganic acid. It includes acid addition salts. Suitable pharmaceutically acceptable salts of the compounds of the present invention include, for example, hydrochloric acid and water bromide. Salts of inorganic acids such as nitrates and phosphoric acid, or, for example, acetic acid, benzenesulfonic acid, methanesulfonic acid. Acids, benzoic acid, citric acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, sucrose Phosphoric acid, azelaic acid, malic acid, tartaric acid, glutamic acid, or aspartic acid, etc. The present invention includes acid addition salts which may be salts of organic acids such as amino acids. Salting is the addition of one or more acid equivalents, such as monohydrochloride or dihydrochloride, to form a salt. It includes. Salt can be prepared by any process within the scope of the knowledge of those skilled in the art. Berge et al.,J.Pharm.Sci.1977,66,1-19;an d Handbook of Pharmaceutical Salts,Prope rties,and Use;Stahl and Wermuth,Ed.;Wile y-VCH and VHCA: Zurich, Switzerland, 2002, ref. (see).

[0112] Table 1 shows some representative compounds of the present invention. [Table 1] TIFF2026127620000005.tif183165 [Table 2]

[0113] In another embodiment, the present invention provides patients who require it with the polypeptide or This includes administering a pharmaceutically acceptable effective amount of salt to patients with hyperglycemia, type 2 diabetes, and tolerance. Glucose impairment, type 1 diabetes, obesity, hypertension, hyperlipidemia, X syndrome, dyslipidemia, cognitive impairment, A Arteriosclerosis, myocardial infarction, coronary heart disease, stroke, inflammatory bowel syndrome, indigestion, This invention provides methods for treating or preventing alcohol dependence and stomach ulcers.

[0114] In another aspect, the invention provides patients requiring such treatment with the polypeptide or A method of treating type 2 diabetes in patients, including administering an effective amount of the pharmaceutically acceptable salt. To provide.

[0115] In another aspect, the invention provides patients requiring such treatment with the polypeptide or The present invention provides a method for treating obesity in patients, which involves administering an effective amount of the pharmaceutically acceptable salt. do.

[0116] In another aspect, the invention provides patients requiring such treatment with the polypeptide or A method of treating hyperlipidemia in patients, including administering an effective amount of the pharmaceutically acceptable salt. provide.

[0117] As used herein, the term “effective dose” or “effective amount” means a given disease or condition The clinical symptoms and their complications beyond those expected in the absence of such treatment, When alleviating, reducing, or partially addressing the condition, a single or multiple dose is sufficient for the target. This refers to the amount of polypeptide. Therefore, the result is a reduction in the signs, symptoms, or causes of the disease. It may be a remedy or / or relief, or any other desirable change in the biological system. The "therapeutic dose" is determined by age, weight, the patient's overall condition, the condition being treated, and the severity of the condition being treated. It is understood that this may vary depending on the individual and the judgment of the prescribing physician.

[0118] In one embodiment, the present invention relates to one or more pharmaceutically acceptable carriers, diluents, or excipients. The present invention provides a pharmaceutical composition comprising the polypeptide or a pharmaceutically acceptable salt thereof. ru.

[0119] The polypeptide of the present invention or a pharmaceutically acceptable salt thereof can be administered via parenteral routes (e.g., subcutaneously). Formulated as a pharmaceutical composition to be administered intravenously, intraperitoneally, intramuscularly, or transdermally. It is preferable that such a pharmaceutical composition and the process for preparing it are described in this technology. It is well known in the field. (For example, Remington: The Science and 50 Practice of Pharmacy(DBTroy,Editor, 21st Edition, Lippincott, Williams & Wilki (See ns, 2006).

[0120] In another embodiment, the present invention relates to the polyp of the present invention for use in the treatment or prevention of a patient's disease. Butide or a pharmaceutically acceptable salt thereof, or polypeptide of the present invention or its pharmaceutically acceptable To provide a pharmaceutical composition containing an acceptable salt, wherein the disease is selected from the group consisting of hyperglycemia, type 2 diabetes, impaired glucose tolerance , type 1 diabetes, obesity, hypertension, hyperlipidemia, metabolic syndrome, dyslipidemia, cognitive impairment, atherosclerotic arteriosclerosis, myocardial infarction, coronary heart disease, stroke, inflammatory bowel syndrome, indigestion, alcohol dependence, and gastric ulcer.

[0121] In some embodiments, the polypeptide or its pharmaceutically acceptable salt, or the pharmaceutical composition is provided simultaneously, separately, or sequentially in combination with an effective amount of one or more additional therapeutic agents.

[0122] The present invention may involve one or more embodiments. The following embodiments are illustrative of the present invention, and it should be understood that they are not intended to limit the claims to the specific embodiments illustrated. Also, it should be understood that the embodiments defined herein can be used independently or in combination with any definition, any other embodiment defined herein. Therefore, the present invention contemplates all possible combinations and permutations of various independently described embodiments.

Examples

[0123] Equipment and analytical methods: The equipment used for the characterization and analysis of the compounds of the present invention is HP LC (Waters e2695 Alliance; Detector Waters (2489 UV / Visible)).

[0124] Equipment: HPLC: Waters e2695 Alliance; Detector: Acqui ty - QDa

[0125] The final compound of this disclosure was purified by a preparative HPLC procedure, as outlined below.

[0126] Preparative HPLC: Waters 2555 Quaternary gradient module (maximum total flow rate: 300 mL / min, maximum pressure: 3000 psi) or Shi Madzu LC-8A (Maximum total flow rate: 150 mL, Maximum pressure: 30 MPa), Column: Phenyl, 10μ flow rate: 75mL / min [Table 3]

[0127] The purity of the compounds disclosed herein was analyzed by RP-HPLC, as outlined below. .

[0128] HPLC method B1: Column: YMC Pack-Phenyl (4.6mm x 150mm, 3μ) Eluent: Mobile phase A: 0.1% trifluoroacetic acid in water Mobile phase B: 0.1% trifluoroacetic acid in acetonitrile Flow rate: 1.5mL / min Detection: UV detection at 210nm Column temperature: 50℃ Execution time: 50 minutes [Table 4]

[0129] HPLC method B2: Column: Xbridge Peptide BEH C18 (4.6mm x 250mm, 3.5 u) Eluent: Mobile phase A: Buffer: Acetonitrile (900:100) Mobile phase B: Buffer: Acetonitrile (300:700) Buffer solution: Orthophosphate dihydrogen phosphate in water, pH adjusted to 3.0±0.1 with orthophosphate. Lithium Flow rate: 1.0 mL / min Detection: UV detection at 210 nm Column temperature: 65 °C Sample tray temperature: 5 °C Run time: 40 minutes

Table 5

[0130] Method B3: Column: Xbridge Peptide BEH C18 (4.6 mm × 250 mm, 3.5 μm) Eluent: Mobile phase A: Buffer: Acetonitrile (900:100) Mobile phase B: Buffer: Acetonitrile (300:700) Buffer: Monobasic potassium phosphate in water adjusted to pH 3.0 ± 0.1 with orthophosphoric acid Lithium Flow rate: 1.0 mL / min Detection: UV detection at 210 nm Column temperature: 65 °C Sample tray temperature: 5 °C Run time: 65 minutes

Table 6

[0131] Method B4: Column: Xbridge Peptide BEH C18 (4.6 mm × 250 mm, 3.5 μm) Eluent: Mobile phase A: Buffer: Acetonitrile (900:100) Mobile phase B: Buffer: Acetonitrile (300:700) Buffer: Monobasic potassium phosphate in water adjusted to pH 3.0 ± 0.1 with orthophosphoric acid Lithium Flow rate: 0.8 mL / min Detection: UV detection at 210 nm Column temperature: 65 °C Sample tray temperature: 5 °C Execution time: 90 minutes [Table 7]

[0132] Method B5: Column: Xbridge Peptide BEH C18 (4.6mm x 250mm, 3.5 u) Eluent: Mobile phase A: Buffer: Acetonitrile (900:100) Mobile phase B: Buffer: Acetonitrile (300:700) Buffer solution: Orthophosphate dihydrogen phosphate in water, pH adjusted to 3.0±0.1 with orthophosphate. Rium Flow rate: 1.0mL / min Detection: UV detection at 210nm Column temperature: 65℃ Sample tray temperature: 10℃ Execution time: 60 minutes [Table 8]

[0133] Preparation method: Example 1 2-[2-[2-[[2-[[(4S)-5-tert-butoxy-4-[( 18-tert-butoxy-18-oxo-octadecanoyl)amino]-5-oxo- Pentanoylamino-2-methylpropanoylaminoethoxyethoxyvinegar Preparation of Acids (Partially A-di-tert-butyl esters) [ka] Partially A-di-tert-butyl ester using 2-chlorotrityl chloride resin Prepared using solid-phase synthesis: 2-[2-(2-Fmoc-aminoethoxy)ethoxy] Acetic acid is applied to a 2-chlorotrityl chloride resin in the presence of DIPEA, and 2-[2 -(2-Fmoc-aminoethoxy)ethoxy]acetic acid-2-Cl-Trt-resin was obtained. The Fmoc protecting group is removed by selective deblocking of the amino group using piperidine. Then, using DIPC and HOBt, Fmoc in THF:DMAc / THF -Aib-OH is bonded to 2-[2-[2-[(2-Fmoc-amino-2-methyl -Propanoyl)amino]ethoxy]ethoxy]acetic acid-2-Cl-Trt-resin was obtained. The Fmoc group is removed by selective deblocking using piperidine, and the free amino acid is released. The group is bound to Fmoc-Glu-OtBu using HOBt and DIPC, and 2 -[2-[2-[[2-[[(4S)-4-Fmoc-amino-5-tert-butoxy -5-oxopentanoyl]amino]-2-methylpropanoyl]amino]ethoxy A resin was obtained from ethoxyacetic acid-2-Cl-Trt. The Fmoc group of the obtained compound was py Selectively deblock using peridine, and then remove the free amino groups with octadecanediol. By bonding with monotertbutyl ester, 2-[2-[2-[[2-[[(4S)-5 -tert-butoxy-4-[(18-tert-butoxy-18-oxo-octadeca [Noyl)amino]-5-oxo-pentanoyl]amino]-2-methyl-propanoyl] -amino]ethoxy]ethoxy]acetic acid-2-Cl-Trt-resin was obtained. Then, truffle Luoroethanol:DCM (1:1) is used to convert the intermediate from 2-Cl-Trt-resin. The compound was cleaved to obtain the title compound (partially A-di-tert-butyl ester). (LCMS= m / z:786.39 (M+H + ))

[0134] Example 2 2-[2-[2-[[2-[[(4S)-5-tert-butoxy-4-[( 20-tert-butoxy-20-oxo-icosanoyl)amino]-5-oxo-pentamine Tanoyl]amino]-2-methyl-propanoyl]amino]ethoxy]ethoxy]acetic acid ( Preparation of partial β-di-tert-butyl ester [ka] 2-[2-[2-[[2-[[(4S)-4-Fmoc-amino-5-tert-but [Xy-5-oxo-pentanoyl]amino]-2-methyl-propanoyl]amino]eth Prepare the xyacetic acid-2-Cl-Trt resin as described in Example 1, and then add piperidine. The selective deprotection used was applied, followed by the removal of the free amino group by 20-(tert-butoxy )-20-oxoicosanoic acid is combined with 2-[2-[2-[[2-[[(4S )-5-tert-butoxy-4-[(20-tert-butoxy-20-oxo-ico Sanoyl)amino]-5-oxopentanoyl]amino]-2-methylpropanoyl [amino]ethoxy]ethoxy]acetic acid-2-Cl-Trt-resin was obtained. Next, truffle Luoroethanol:DCM (1:1) is used to convert the intermediate from 2-Cl-Trt-resin. The compound was cleaved to obtain a tile compound (partially B-di-tert-butyl ester). (LCMS) =m / z:814.10(M+H + ))

[0135] Example 3: 2-[2-[2-[[2-[2-[2-[[5-tert-butoxy-4-[ (18-tert-butoxy-18-oxo-octadecanoyl)amino]-5-oxo -Pentanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy Preparation of Acetic Acid (Partially C-Di-Tert-Butyl Ester) [ka]

[0136] Partially C-di-tert-butyl ester is used with 2-chlorotrityl chloride resin. It was prepared using solid-phase synthesis. 2-[2-(2-Fmoc-aminoethoxy)ethoxy Acetic acid is attached to a 2-chlorotrityl chloride resin in the presence of DIPEA, and 2-[ A resin was obtained that is 2-(2-Fmoc-aminoethoxy)ethoxy]acetic acid-2-Cl-Trt-resin. The Fmoc protecting group is removed by selective deblocking of the amino group using piperidine. Then, using DIPC and HOBt, 2-[2-(2-Fmoc in THF] -aminoethoxy)ethoxy]acetic acid is combined with {(Fmoc-amino-ethoxy)- Ethoxy-acetyl-{(-amino-ethoxy)-ethoxy}acetic acid-2-Cl-Tr t-Resin was obtained. The Fmoc group was selectively deblocked using piperidine. The free amino groups are removed using HOBt and DIPC, and Fmoc-Glu-O By combining with tBu, Fmoc-Glu({(amino-ethoxy)-ethoxy}-acetyl Lu-{(-amino-ethoxy)-ethoxy}-acetic acid-2-Cl-Trt-resin)-OtB u was obtained. The Fmoc group of the obtained compound was selectively deblocked using piperidine. Next, the free amino group is bonded to octadecanediic acid monotertbutyl ester. , 2-[2-[2-[[2-[2-[2-[[5-tert-butoxy-4-[(18- tert-butoxy-18-oxo-octadecanoyl)amino]-5-oxo-penta Noylaminoethoxyethoxyacetylaminoethoxyethoxyacetic acid A 2-Cl-Trt resin was obtained. Then, trifluoroethanol:DCM (1:1) Using this method, the intermediate is cut from the 2-Cl-Trt resin, and 2-[2-[2-[[2-[ 2-[2-[[5-tert-butoxy-4-[(18-tert-butoxy-18-o Xo-octadecanoyl)amino]-5-oxo-pentanoyl]amino]ethoxy]e Toxyacetylaminoethoxyethoxyacetic acid (partially C-di-tert-butyl) Ester) (LCMS=m / z:846.10(M+H + )) was obtained.

[0137] Example 4: 2-[2-[2-[[2-[2-[2-[[5-tert-butoxy-4-[ (20-tert-butoxy-20-oxo-icosanoyl)amino]-5-oxo-pe [Hentanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]vinegar Preparation of Acids (Partially D-di-tert-butyl ester) [ka]

[0138] Partially D-di-tert-butyl ester is converted to 2-chlorobutyl ester as schematically shown below. It was prepared using solid-phase synthesis with rotrityl chloride resin. 2-[2-(2-Fm oc-aminoethoxy)ethoxyacetic acid is converted to 2-chlorotritil acetate in the presence of DIPEA. Adhering to a lorido resin, 2-[2-(2-Fmoc-aminoethoxy)ethoxy]acetic acid A -2-Cl-Trt- resin was obtained. The Fmoc protecting group was modified using piperidine. Removed by selective deblocking, followed by DIPC and HOBt, TH By bonding with 2-[2-(2-Fmoc-aminoethoxy)ethoxy]acetic acid in F, {( Fmoc-amino-ethoxy)-ethoxy}-acetyl-{(-amino-ethoxy)-ethoxy} Toxy-acetic acid-2-Cl-Trt-Resin was obtained. The Fmoc group was replaced with piperidine. The free amino groups were removed by selective deblocking using HOBt and DIPC. By using Fmoc-Glu-OtBu to bind with Fmoc-Glu({(amino- Ethoxy)-ethoxy}-acetyl-{(-amino-ethoxy)-ethoxy}-acetic acid-2 -Cl-Trt-resin)-OtBu was obtained. The Fmoc group of the obtained compound was piperidine. Selectively deblock using and remove the free amino group, then 20-(tert-butoxy By combining with (C)-20-oxoicosanoinic acid, [2-[2-[2-[[2-[2-[2-[[5-tert-butoxy-4-[(20- tert-butoxy-20-oxo-icosanoyl)amino]-5-oxo-pentanoyl [Lu]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetic acid]-2 -Cl-Trt- resin was obtained. Then, trifluoroethanol:DCM (1:1) was used. Using this method, the intermediate is cut from the 2-Cl-Trt-resin, 2-[2-[2-[[2-[2-[2-[5-tert-butoxy-4-[(20-te rt-butoxy-20-oxo-icosanoyl)amino]-5-oxo-pentanoyl] Amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetic acid (partially D- (Di-tert-butyl ester) (LCMS=m / z:874.15(M+H) + )) Ta.

[0139] Example 5: 2-[2-[2-[4-[[5-tert-butoxy-4-[(20-ter t-Butoxy-20-oxo-icosanoyl)amino]-5-oxo-pentanoyl]a Mino-butylcarbamoylamino-ethoxy-ethoxy-acetic acid (partially E-di-tert- Preparation of butyl esters [ka]

[0140] Partially E-di-tert-butyl ester is used with 2-chlorotrityl chloride resin. It was prepared using solid-phase synthesis. 2-[2-(2-Fmoc-aminoethoxy)ethoxy Acetic acid is 2-chloromethylated in the presence of N,N'-diisopropylethylamine (DIPEA). By attaching it to trityl chloride resin, 2-[2-(2-Fmoc-aminoethoxy)eth A resin was obtained using xy]acetic acid-2-Cl-Trt-resin. The Fmoc protecting group was modified using piperidine. The amino groups are removed by selective deblocking, and then the free amino groups are treated with THF and The DIPEA was activated using p-nitrophenyl chloroformate, and then DI In the presence of PEA, the Fmoc-aminobutylamine hydrochloride in THF:DMAc was reacted. , 2-[2-[2-(4-Fmoc-aminobutylcarbamoylamino)ethoxy] Toxyacetic acid-2-Cl-Trt resin was obtained. The Fmoc group was selected using piperidine. Removed by selective deblocking, and then the free amino group is removed by 1-hydroxybenzo Reazole (HOBt) and N,N'-di-isopropylcarbodiimide (DIPC) Use to combine with Fmoc-Glu-OtBu, 2-[2-[2-[4-[[( [4S)-4-Fmoc-amino-5-tert-butoxy-5-oxo-pentanoyl] Amino]butylcarbamoylamino]ethoxy]ethoxy]acetate-2-Cl-Trt-reinforced The lipids are obtained and selectively deblocked using piperidine, and then 20-(ter By combining with t-butoxy)-20-oxoicosanoic acid, the intermediate 2-[2-[2- [4-[[5-tert-butoxy-4-[(20-tert-butoxy-20-oxo -Icosanoyl)amino]-5-oxo-pentanoyl]amino]butylcarbamoyl Mino[ethoxy]ethoxy]acetic acid-2-Cl-Trt-resin was obtained. Then, trifluor The intermediate was cleaved from the 2-Cl-Trt resin using ethanol:DCM (1:1). Then, 2-[2-[2-[4-[[5-tert-butoxy-4-[(20-tert- Butoxy-20-oxo-icosanoyl)amino]-5-oxo-pentanoyl]amino Butylcarbamoylaminoethoxyethoxyacetic acid (LCMS=m / z:843). 14(M+H + )) was obtained. (Partially E-di-tert-butyl ester).

[0141] Example 6: Preparation of Compound 1 The parent peptide was synthesized by a solid-phase method. The starting resin used in the synthesis was Fmoc-Rink ammonium compound. It was a resin. Piperidine was used to select the Fmoc protecting amino group of the rink amide resin. Selectively deblocking, followed by Fmoc-Ser(tBu)-OH in the Rink amide tree. It was bound to fat. The binding was done using DIPC-HOBt and Fmoc-Ser(tBu). -This is done by obtaining Rink amide resin, which completes one cycle. Acetic acid and DIPEA / pyridine are used to remove the unbound amino group in each amino acid bond. Termination / capping. Fmoc-Ser(tBu)-Rink using piperidine. Selective deblocking of amino groups in mid-resins, followed by HOBt and DIPC. Through binding with Fmoc-Pro-OH, Fmoc-Pro-Ser(tBu)-ri An nk amide resin was obtained. This completes the second cycle. Acetic anhydride and DIP EA / pyridine was used to terminate the unbound amino groups in each amino acid bond.

[0142] The three steps described above, namely the selective capture of Fmoc protection of amino acids attached to the resin Ping, deblocking, and the adjacent amino acid residue in the sequence with the Fmoc protected amino group The bonding is repeated for the remaining 36 amino acid residues, with the final bond being a Boc-protected amino acid. The acid was used (i.e., Boc-Tyr(tBu)-OH). Selective deblocking, In other words, the capping of unbonded amino groups is performed using acetic anhydride and DIPEA / pyridine. The procedure was carried out, and deprotection of the Fmoc / Boc group was performed using piperidine, and the adjacent Fmoc and Binding with Boc-protected amino acids was performed using HOBt / DIPC. Fmo The side chain of a c / Boc-protected amino acid is protected at a right angle, for example, the hydroxyl group of serine. Tyrosine or threonine is protected with a tert-butyl (-tBu) group, and lysine The mino groups are tert-butyloxycarbonyl (-Boc) and (4,4-di Methyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl(IVD The carboxylic acid group of aspartic acid or glutamic acid is protected by a tBu group, while the tBu group protects the tBu group. The glutamine amide group was protected with a trityl (-Trt) group. The process involves two steps: selective capping, deblocking, and the subsequent adjacent Fm After binding with an oc-protecting amino acid, Boc-Tyr(tBu)-OH is also used at the end. Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)- Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu) -Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc) -Ile-Ala-Gln(Trt)-Lys(IVDde)-Ala-Phe-Val -Gln(Trt)-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Se r(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser( A tBu)-Rink amide resin was obtained.

[0143] Deprotection of the IVDde group of peptide resin using hydrazine hydrate, followed by partial A-di -tert-butyl ester bonding was performed using DIPC-HOBt, and the protected compound Compound 1 resin was obtained.

[0144] Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu) -Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu )-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc )-Ile-Ala-Gln(Trt)-Lys(NH-partial A-tert-butyl Stell)-Ala-Phe-Val-Gln(Trt)-Trp-Leu-Ile-Al a-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala- Pro-Pro-Pro-Ser(tBu)-Rink amide resin. Ethane-1,2-di Using trifluoroacetic acid with thiols and triisopropylsilane, Disruption and deprotection, followed by purification by preparative HPLC, yielded compound 1. H of compound 1 PLC purity was evaluated by method B2. Mass (LCMS): m / z = 1182.41( MH4 4+ ), calculated mass = 4725.61, HPLC purity: 97.77% (Method B) 2), RT=19.9 minutes

[0145] Example 7: Synthesis of Compound 2: Compound 2 is used to bond the partial β-di-tert-butyl ester to the peptide resin. Except for the above, the materials are prepared by a solid-phase method according to a similar process described in Example 6, followed by cutting and deconsolidation. Compound 2 was obtained by preparative purification using HPLC. HPLC purity of Compound 2 This was evaluated using method B2.

[0146] Mass (LCMS): m / z=1189.36(MH4 4+ ), calculated mass = 475 3.41; HPLC purity: 94.50% (method B2), RT=22.1 min

[0147] Example 8: Synthesis of Compound 3: The parent peptide was synthesized by a solid-phase method. The starting resin used in the synthesis was Fmoc-Rink ammonium compound. It was a resin. Piperidine was used to select the Fmoc protecting amino group of the rink amide resin. Selectively deblocking, followed by Fmoc-Ser(tBu)-OH in the Rink amide tree. It was bound to fat. The binding was done using DIPC-HOBt and Fmoc-Ser(tBu). -This is done by obtaining Rink amide resin, which completes one cycle. Using acetate and diisopropylethylamine / pyridine, in each amino acid bond Unbound amino groups were terminated / capped. Fmoc-Ser(tB) using piperidine. Selective deblocking of amino groups in u)-Rink amide resins, followed by HOBt and By binding with Fmoc-Pro-OH using DIPC, Fmoc-Pro-Ser (tBu)-rink amide resin was obtained. This completes the second cycle. Anhydrous Using acetate and diisopropylethylamine / pyridine, in each amino acid bond The unbonded amino group was terminated.

[0148] The three steps described above, namely the selective capture of Fmoc protection of amino acids attached to the resin. Bumping, deblocking, and the Fmoc protecting amino group of an adjacent amino acid residue in the sequence. The binding was repeated for the remaining 37 amino acid residues. Selective deblocking, that is, Furthermore, the capping of unbonded amino groups is performed with acetic anhydride and diisopropylethylamine / The procedure was performed using pyridine, and deprotection of the Fmoc group was performed using piperidine, and the adjacent Fmo The binding with c-protected amino acids was performed using HOBt / DIPC. Fmoc-protected amino acids The side chains are protected at right angles, for example, the hydroxyl group of serine is tert-butyl(- Protected by a tBu group and a methyl (OMe) group, tyrosine or threonine is ter Protected by t-butyl (-tBu) groups, the amino groups of lysine are, respectively, tert-buty Luoxycarbonyl (-Boc) and (4,4-dimethyl-2,6-dioxocyclohex Protected by a x-1-ylidene-3-methylbutyl (IVDde) group, asparagine The carboxylic acid group of the acid or glutamic acid is protected with a tBu group, and the amide of glutamine The group was protected with a trityl (-Trt) group. The three steps described above, namely selective caching The process involves topping, deblocking, and subsequent binding with the adjacent Fmoc protective amino acid. Fmoc-Tyr(tBu)-(D)Ser(OMe)-Glu(OtBu)-Gly- Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu) -Lys(Boc)-Ile-Ala-Gln(Trt)-Lys(IVDde)-Al a-Phe-Val-Gln(Trt)-Trp-Leu-Ile-Ala-Gly-G ly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro -Pro-Ser(tBu)-Rink amide resin was obtained.

[0149] Fmoc-Tyr(tBu)-(D)Ser(OMe)-Glu(OtBu)-Gl y-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtB u)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtB u)-Lys(Boc)-Ile-Ala-Gln(Trt)-Lys(IVDde)- Ala-Phe-Val-Gln(Trt)-Trp-Leu-Ile-Ala-Gly -Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-P Deblotting using piperidine in ro-Pro-Ser(tBu)-Rink amide resin Following King, Boc protection of peptide resins using Boc anhydrous has led to Boc-T yr(tBu)-(D)Ser(OMe)-Glu(otBu)-Gly-Thr(tB u)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(t Bu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(B oc)-Ile-Ala-Gln(Trt)-Lys(IVDde)-Ala-Phe- Val-Gln(Trt)-Trp-Leu-Ile-Ala-Gly-Gly-Pro -Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-S An er(tBu)-Rink amide resin was obtained. A peptide resin using hydrazine hydrate was also obtained. Following the deprotection of the IVDde group, the bond of the partial B-di-tertbutyl ester is removed. Sopropylcarbodiimide, N-hydroxybenzotriazole (DIPC-HOBt) The procedure was carried out using as a coupling reagent, and in its presence, compound 3 resin was obtained.

[0150] Boc-Tyr(tBu)-(D)Ser(OMe)-Glu(OtBu)-Gly- Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu) -Lys(Boc)-Ile-Ala-Gln(Trt)-Lys(NH - Part B-J -tert (butyl ester)-Ala-Phe-Val-Gln(Trt)-Trp- Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu )-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Rink amide resin Trifluorovinegar using ethane-1,2-dithiol and triisopropylsilane. Acid-based cleavage and deprotection, followed by purification by preparative HPLC, yielded compound 3. The HPLC purity of compound 3 was evaluated by method B2.

[0151] Mass (LCMS): m / z=1193.70(MH4 4+ ), calculated mass = 477 0.77, HPLC purity: 91.96% (method B2), RT=29.0 min

[0152] Example 9: Synthesis of Compound 4: Compound 4 was prepared by a solid-phase method according to a similar process described in Example 8, but the compound In 4, Fmoc-Ser(OMe)-OH is used, and Fmoc-D-Ser(OMe)-OH is used. Instead, use at position 2, Boc-Tyr(tBu)-Ser(OMe)-Glu(O tBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)- Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu- Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt)-Lys( IVDde)-Ala-Phe-Val-Gln(Trt)-Trp-Leu-Ile- Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Al We obtained a-Pro-Pro-Pro-Ser(tBu)-Rink amide resin. Next, part The β-di-tert-butyl ester was then bonded, followed by cleavage, deprotection, and HPLC. Compound 4 was obtained by preparative purification using [method]. The HPLC purity of compound 4 was determined by method B2. I evaluated it.

[0153] Mass (LCMS): m / z=1193.68(MH4 4+ ), calculated mass = 477 0.69, HPLC purity: 95.52% (method B2), RT=26.2 min

[0154] Example 10: Synthesis of Compound 5: Compound 5 was prepared by a solid-phase method according to a similar process described in Example 8, but the compound In 5, Fmoc-(D)-Tyr(OEt)-OH is replaced with Fmoc-Tyr(tBu)-O Instead of H, use at position 1 to change Fmoc-Aib-OH to Fmoc-D-Ser(O Instead of Me)-OH, use Boc-(D)-Tyr(OEt)-Ai b-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Se r(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-A ib-Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Tr t)-Lys(IVDde)-Ala-Phe-Val-Gln(Trt)-Trp-L eu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu) -Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Rink amide resin I got it.

[0155] Next, it is bonded to a partial β-di-tertbutyl ester, followed by cleavage, deprotection, and Compound 5 was obtained by preparative purification using HPLC. The HPLC purity of compound 5 was determined by... The evaluation was conducted according to Law B3.

[0156] Mass (LCMS): m / z=1196.34(MH4 4+ ), calculated mass = 478 1.33, HPLC purity: 93.86% (Method B3), RT=38.8 min

[0157] Example 11: Synthesis of Compound 6: Compound 6 was prepared by a solid-phase method according to a similar process described in Example 8, but the compound In 6, replace Fmoc-(D)Ser(OMe)-OH with Fmoc-Aib-OH Used at position 13, Fmoc-Aib-OH is converted to Fmoc-D-Ser(OMe)-O Instead of H, use in position 2: Boc-Tyr(tBu)-Aib-Glu(OtB u)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-As p(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-(D)Ser(OMe )-Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt )-Lys(IVDde)-Ala-Phe-Val-Gln(Trt)-Trp-Le u-Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)- Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Rink amide resin is obtained. Ta.

[0158] Next, it is bonded to a partial β-di-tertbutyl ester, followed by cleavage, deprotection, and Compound 6 was obtained by preparative purification using HPLC. The HPLC purity of compound 6 was determined by... The evaluation was conducted according to Law B2.

[0159] Mass (LCMS): m / z=1191.03(MH4 4- ), calculated mass: 476 8.15; HPLC purity: 94.74% (method B2), RT=27.1 min

[0160] Example 12: Synthesis of Compound 7: Compound 7 was prepared by a solid-phase method according to a similar process described in Example 8, but the compound In position 7, Fmoc-Ser(OMe)-OH is used instead of Fmoc-Aib-OH at position 1. In step 3, replace Fmoc-Aib-OH with Fmoc-D-Ser(OMe)-OH. Rather, it is used in position 2, Boc-Tyr(tBu)-Aib-Glu(OtBu)- Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(O tBu)-Tyr(tBu)-Ser(tBu)-Ile-Ser(OMe)-Leu- Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt)-Lys( IVDde)-Ala-Phe-Val-Gln(Trt)-Trp-Leu-Ile- Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Al an a-Pro-Pro-Pro-Ser(tBu)-Rink amide resin was obtained.

[0161] Next, it is bonded to a partial β-di-tertbutyl ester, followed by cleavage, deprotection, and Compound 7 was obtained by preparative purification using HPLC. The HPLC purity of compound 7 was determined by... The evaluation was conducted according to Law B2.

[0162] Mass (LCMS): m / z=1193.67(MH4 4+ ), calculated mass = 477 0.65, HPLC purity: 95.4% (Method B2), RT=26.4 min

[0163] Example 13: Compound 8: Compound 8 was prepared by a solid-phase method according to a similar process described in Example 8, but the compound In position 8, Fmoc-Aib-OH is used instead of Fmoc-D-Ser(OMe)-OH. Used in the second position, Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly- Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu) -Lys(Boc)-Ile-Ala-Gln(Trt)-Lys(IVDde)-Al a-Phe-Val-Gln(Trt)-Trp-Leu-Ile-Ala-Gly-G ly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro -Pro-Ser(tBu)-Rink amide resin was obtained.

[0164] Next, it is bonded to a partial E-di-tertbutyl ester, followed by cleavage, deprotection, and Compound generation using HPLC is achieved by preparative purification using HPLC. Compound 8 was obtained. The HPLC purity of compound 8 was evaluated by method B4.

[0165] Mass (LCMS): m / z=1196.55(MH4 4+ ), calculated mass = 478 2.168, HPLC purity: 97.37% (Method B4), RT=25.6 min

[0166] Example 14: Synthesis of Compound 9: Compound 9 was prepared by a solid-phase method according to a similar process described in Example 8, but the compound In position 9, Fmoc-Ser(OMe)-OH is used instead of Fmoc-Aib-OH at position 1. In step 3, replace Fmoc-Aib-OH with Fmoc-D-Ser(OMe)-OH. Rather, it is used in position 2, Boc-Tyr(tBu)-Aib-Glu(OtBu)- Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(O tBu)-Tyr(tBu)-Ser(tBu)-Ile-Ser(OMe)-Leu- Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt)-Lys( IVDde)-Ala-Phe-Val-Gln(Trt)-Trp-Leu-Ile- Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Al an a-Pro-Pro-Pro-Ser(tBu)-Rink amide resin was obtained.

[0167] Next, it is bonded to a partial C-di-tertbutyl ester, followed by cleavage, deprotection, and Compound 9 was obtained by preparative purification using HPLC. The HPLC purity of compound 9 was determined by... The evaluation was conducted according to Law B2.

[0168] Mass (LCMS): m / z=1201.7(MH4 4+ ), calculated mass = 4802 .8, HPLC purity: 97.30% (method B2), RT=15.3 min

[0169] Example 15: Synthesis of Compound 10: Compound 10 was prepared by a solid-phase method according to a similar process described in Example 8, but the compound In substance 10, Fmoc-Ser(OMe)-OH is used instead of Fmoc-Aib-OH. Use in position 13 to convert Fmoc-Aib-OH to Fmoc-D-Ser(OMe)-OH Instead, use in position 2, Boc-Tyr(tBu)-Aib-Glu(OtBu )-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp (OtBu)- Tyr(tBu)-Ser(tBu)-Ile-Ser(OMe)-L eu-Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt)-L ys(IVDde)-Ala-Phe-Val-Gln(Trt)-Trp-Leu-I le-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly -Ala-Pro-Pro-Pro-Ser(tBu)-Rink amide resin was obtained.

[0170] Next, it is bonded to a partial D-di-tertbutyl ester, followed by cleavage, deprotection, and Compound 10 was obtained by preparative purification using HPLC. The HPLC purity of compound 10 was The results were evaluated using method B2.

[0171] Mass (LCMS): m / z=1610.78(MH3 3+ ), calculated mass = 482 9.316, HPLC purity: 93.41% (method B2), RT=20.3 min

[0172] Example 16: Synthesis of Compound 11: The parent peptide was synthesized by a solid-phase method. The starting resin used in the synthesis was Wang resin. Fmoc-protected Arg(pbf) was used for bonding with Wang resin. The bond was made with 4-dimethyl In the presence of diaminopyridine (DMAP), diisopropylcarbodiimide, N-hydro The procedure was performed using xibenzotriazole (DIC-HOBt) as the binding agent, and Fmo c-Arg(pbf)-Wang resin was obtained. Fmoc-Arg( Selective deblocking of amino groups in pbf)-Wang resin, followed by HOBt / DIP Through bonding with Fmoc-Ser(tBu)-OH using C, Fmoc-Ser(t Bu)-Arg(pbf)-Wang resin was obtained. This completes one cycle. Using acetic anhydride and diisopropylethylamine / pyridine, each amino acid bond The unbonded amino group was then terminated.

[0173] The three steps described above, namely, selective deblotting of Fmoc protection of amino acids attached to the resin King, binding to the Fmoc-protected amino group of an adjacent amino acid residue in the sequence, and capping Repeat the process for the remaining 38 amino acid residues, and position the side chain of the Fmoc-protecting amino acid at a right angle. Protects, for example, the hydroxyl group of serine, tyrosine, or threonine, tert-br Protected with a til (-tBu) group, the amino group of lysine is tert-butyloxycarbonyl (-Boc) and (4,4-dimethyl-2,6-dioxocyclohex-1-ylide The 3-methylbutyl (IVDde) group protects each of the aspartic acid groups. Alternatively, the carboxylic acid group of glutamic acid is protected with a -tBu group, and the glutamine amide is formed. The group was protected with a trityl (-Trt) group, and the arginine side chain was protected with a pbf group. The three steps described above are: selective capping, deblocking, and subsequent adjacent The Fmoc-Tyr(tBu)-Aib-Glu is formed by binding with the Fmoc-protecting amino acid. (OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu )-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Le u-Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt)-Ly s(IVDde)-Ala-Phe-Val-Gln(Trt)-Trp-Leu-Il e-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly- Ala-Pro-Pro-Pro-Ser(tBu)-Arg(pbf)-Wang resin I obtained it.

[0174] Fmoc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu )-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tB u)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Bo c)-Ile-Ala-Gln(Trt)-Lys(IVDde)-Ala-Phe-V al-Gln(Trt)-Trp-Leu-Ile-Ala-Gly-Gly-Pro- Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Se Deblocking of r(tBu)-Arg(pbf)-Wang resin using piperidine Following this, Boc protection of peptide resins using Boc anhydrous is achieved, Boc-Tyr( tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr( tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu )-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala -Gln(Trt)-Lys(IVDde)-Ala-Phe-Val-Gln(Trt )-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)-S er(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Arg (pbf)-Wang resin was obtained. Hydrazine hydrate was used to obtain IVDd of the peptide resin. The e group is deprotected, and then diisopropylcarbodiimide and N-hydroxybenzo are used. Using riazole (DIPC-HOBt) as a coupling reagent, partial B-di-t The intermediate protective compound 11 resin was obtained by bonding with ert butyl ester. -A tree using trifluoroacetic acid with dithiol and triisopropylsilane. Cleavage and deprotection from the fat, followed by purification by preparative HPLC, yielded compound 11.

[0175] The HPLC purity of compound 11 was evaluated using method B2.

[0176] Mass (LCMS): m / z=1228.8(MH4 4+ ), calculated mass = 4911 .17, HPLC purity: 98.22% (Method B2), RT=23.3 min

[0177] Example 17: Synthesis of Compound 12: Compound 12 is bonded to the peptide resin, specifically the partial C-di-tert-butyl ester. Except for the process described in Example 16, the preparation was carried out by a solid-phase method, followed by cutting. Compound 12 was obtained by deprotection and preparative purification using HPLC. The HPLC of compound 12 was also performed. LC purity was evaluated using method B2.

[0178] Mass (LCMS): m / z=1236.56(MH4 4+ ), calculated mass = 494 2.21, HPLC purity: 97.2% (Method B2), RT=11.703 min

[0179] Example 18: Synthesis of Compound 13: Compound 13 is bonded to the peptide resin by partially attaching the A-di-tert-butyl ester. Except for the above, the preparation is carried out by a solid-phase method according to a similar process described in Example 12, followed by cutting. Compound 13 was obtained by deprotection and preparative purification using HPLC. The purity of the PLC was evaluated using method B2.

[0180] Mass (LCMS): m / z=1579.52(MH3 3- ), calculated mass = 474 1.548, HPLC purity: 96.5% (Method B2), RT=14.76 min

[0181] Example 19: Synthesis of Compound 14: The parent peptide was synthesized by a solid-phase method. The starting resin used in the synthesis was Fmoc-Rink ammonium compound. It was a resin. Piperidine was used to select the Fmoc protecting amino group of the rink amide resin. Selectively deblocking, followed by Fmoc-Lys(IVDde)-OH and Rink amine. The resin was bonded using DIPC-HOBt and Fmoc-Lys(IV). This is done by obtaining Dde)-Rink amide resin, which completes one cycle. Using acetic anhydride and diisopropylethylamine / pyridine, each amino acid bond The unbonded amino group was terminated / capped at the end. Fmoc- using piperidine Selective deblocking of the amino group Fmoc of Lys(IVDde)-Rink amide resin. Then, through subsequent binding with a second amino acid using HOBt and DIPC, Fmo This yielded a c-Ser(tBu)-Lys(IVDde)-rink amide resin. Then the second cycle is completed. As mentioned earlier, acetic anhydride and diisopropylethyl anhydride Min / pyridine was used to terminate the unbound amino groups in each amino acid bond.

[0182] The three steps described above, namely, deblocking of Fmoc protection of amino acids attached to the resin. The binding of the Fmoc-protecting amino group to the adjacent amino acid residue in the sequence, and selective capping The process was repeated for the remaining 38 amino acid residues. The Fmoc protected amino acid used was The side chain of the acid is protected at a right angle, for example, the hydroxyl group of serine, tyrosine or threonine The 'n' group is protected with a tert-butyl (-tBu) group, and the amino group of lysine is protected with a tert-butyl (-tBu) group, respectively. rt-butyloxycarbonyl(-Boc) and (4,4-dimethyl-2,6-dioxycarbonyl Protected with a socyclohex-1-ylidene)-3-methylbutyl (IVDde) group, as Protect the carboxylic acid group of paratic acid or glutamic acid with a tBu group, and glutamine and The amide group of sparagine was protected with a trityl (-Trt) group. The three steps described above, that is, Selective capping, deblocking, and subsequent protection of adjacent Fmoc amino acids The following combination is performed: Fmoc-Tyr(tBu)-Aib-Glu(OtBu)-Gly- Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Tyr(tBu)-Ser(tBu)-Ile-Tyr(tBu)-Leu-Glu( OtBu)-Lys(Boc)-Ile-Ala-Ala-Gln(Trt)-Glu( OtBu)-Phe-Val-Asn(Trt)-Trp-Leu-Leu-Ala-G ly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro -Pro-Pro-Ser(tBu)-Lys(IVDde)-Rink amide resin is obtained. Ta.

[0183] Fmoc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu )-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tB u)-Ser(tBu)-Ile-Tyr(tBu)-Leu-Glu(OtBu)-L ys(Boc)-Ile-Ala-Ala-Gln(Trt)-Glu(OtBu)-P he-Val-Asn(Trt)-Trp-Leu-Leu-Ala-Gly-Gly- Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pr Uses piperidine from o-Ser(tBu)-Lys(IVDde)-Rink amide resin. Following the deblocking, the peptide resin was protected with Boc anhydrous. , Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu) -Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu )-Ser(tBu)-Ile-Tyr(tBu)-Leu-Glu(OtBu)-Ly s(Boc)-Ile-Ala-Ala-Gln(Trt)-Glu(OtBu)-Ph e-Val-Asn(Trt)-Trp-Leu-Leu-Ala-Gly-Gly-P ro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro -Ser(tBu)-Lys(IVDde)-Rink amide resin was obtained. Hydrazine water Following the deprotection of the IVDde group of the peptide resin using the Japanese compound, a partial B-di-tert group was used. The tyl ester bond is formed by diisopropylcarbodiimide and N-hydroxybenzotriaz The procedure was carried out using DIPC-HOBt as the coupling reagent, and in its presence, the chemical reaction occurred. Compound 14 resin was obtained.

[0184] Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu) -Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu )-Ser(tBu)-Ile-Tyr(tBu)-Leu-Glu(OtBu)-Ly s(Boc)-Ile-Ala-Ala-Gln(Trt)-Glu(OtBu)-Ph e-Val-Asn(Trt)-Trp-Leu-Leu-Ala-Gly-Gly-P ro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro -Ser(tBu)-Lys(NH portion B-di-tertbutyl ester)-Rink The amide resin uses ethane-1,2-dithiol and triisopropylsilane. The process involves cleavage and deprotection using refluoroacetic acid, followed by purification by preparative HPLC. Compound 14 was obtained. The HPLC purity of compound 14 was evaluated using method B5.

[0185] Mass (LCMS): m / z=993.06(MH55+ ), calculated mass = 4960 .26, HPLC purity: 95.8% (Method B5), RT=28.308 min

[0186] Example 20: Synthesis of Compound 15: Compound 15 was prepared by a solid-phase method according to a similar process described in Example 19, but In compound 15, Fmoc-Ser(OMe)-OH is replaced with Fmoc-Tyr(tBu). Use at position 13, Fmoc-Tyr(tBu)-Aib-Glu(OtBu)- Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(O tBu)-Tyr(tBu)-Ser(tBu)-Ile-Ser(OMe)-Leu- Glu(OtBu)-Lys(Boc)-Ile-Ala-Ala-Gln(Trt)- Glu(OtBu)-Phe-Val-Asn(Trt)-Trp-Leu-Leu-A la-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala -Pro-Pro-Pro-Ser(tBu)-Lys(IVDde)-Rink amide Resin was obtained.

[0187] Next, it is bonded to a partial β-di-tertbutyl ester, followed by cleavage, deprotection, and Compound 15 was obtained by preparative purification using HPLC. The HPLC purity of compound 15 was The evaluation was performed using method B4.

[0188] Mass (LCMS): m / z=980.77(MH5 5+ ), calculated mass = 4898 .8, HPLC purity: 94% (method B4), RT=41.5 min

[0189] Example 21: Synthesis of Compound 16: Compound 16 is bonded to the peptide resin, specifically the partial D-di-tert-butyl ester. Except for the process described in Example 16, the preparation was carried out by a solid-phase method, followed by cutting. Compound 16 was obtained by deprotection and preparative purification using HPLC. The HPLC of compound 16... LC purity was evaluated using method B2.

[0190] Mass (LCMS): m / z=1243.60(MH4 4+ ), calculated mass = 497 0.37, HPLC purity: 97.5% (Method B2), RT=19.183 min

[0191] Biological research Example 22: Reduction of HbA1c in db / db2 diabetic mice after chronic treatment For compound 2, %HbA1c, insulin, triglyceride levels, food consumption and body The effect on weight was studied in mice. This study used type 2 diabetic mice (db / db) models. The study was conducted in a laboratory setting. Animals were divided into six treatment groups (n=8 per group), namely a diabetes control group and a compound Substance 2 (4.5 nM / kg, 9 nM / kg and 18 nM / kg), and tilzepatide ( Patients were divided into two treatment groups: 90 nM / kg and 180 nM / kg. All treatments were administered every three days. Ten doses (q3d*10) were administered subcutaneously. %HbA1c, insulin, triglycerides The levels were measured on day 0, day 14, and day 28. Cumulative food intake from day 0 to day 28 The amount of food intake and the percentage change in body weight compared to day 0 were calculated on day 28. The results are shown in Table 3. ru. [Table 9]

[0192] As is clear from the results, compound 2 at doses of 4.5, 9, and 18 nM / kg was 1 A statistically significant change in HbA1c was observed compared to diabetic controls on both day 4 and day 28. The decrease in HbA1c with compound 2 was observed with tilzepatide at a dose of 90 nM / kg. The change exceeded the expected level. Compound 2 showed a similar effect on insulin levels, reaching 9 nM / At a dose of kg, insulin levels were statistically significant compared to the diabetic control group on day 14. An increase was observed. The increase in insulin levels was maintained even on day 28. Compared to the previous 10 times... Chilzepatide at a dose of 90 nM / kg showed comparable effects on insulin levels. Furthermore, the insulin level indicated by compound 2 at a dose of 18 nM / kg was... The effect is equivalent to that shown by tilzepatide at a dose of 180 nM / kg. It was a surprising finding. The insulin level of compound 2 at 18 nM was 1 Similar levels were maintained on both day 4 and day 28, but with tilzepatide treatment, 2 Insulin levels on day 8 tended to be slightly lower than those on day 14. Compound 2 at doses of 4.5, 9, and 18 nM / kg was compared to the diabetic control group on day 28. In comparison, it showed a statistically significant decrease in body weight. Surprisingly, the chemical reaction to weight loss... The effect of substance 2 is demonstrated by tilzepatide at a dose of 180 nM / kg (20 times the dose). The effect was superior to what was expected. Compound 2 at test doses (4.5, 9, and 18 nm / kg) Furthermore, compared to the diabetic control group during the study, there was a statistically significant decrease in cumulative food consumption. This was shown. Surprisingly, the effect of compound 2 on food consumption was 10 times the dose of compound 2. The effect was equivalent to that shown by tilzepatide at twice the dose. Similarly, 4.5, 9 Compound 2 at a dose of 18 nM / kg showed a reduction in triglycerides compared to the diabetic control group. A statistically significant decrease was observed. The effect was maintained, with a slight improvement on day 28. The effectiveness of compound 2 in reducing ligceride levels is surprising, and compound 2 At approximately 20 times the dose, similar efficacy to that shown by tilzepatide was observed. The study examined the effects of compound 2 on the reduction of HbA1c and triglyceride levels. Surprisingly, it was observed that the effect improved on day 28 compared to day 14. For example, the reduction in HbA1c on day 29 at doses of 9 nM / kg and 18 nM / kg. The decrease was more than 40% greater than the decrease on day 14. In comparison, at a dose of 180 nM / kg... Chilzepatide showed a slight improvement in HbA1c reduction between day 14 and day 28. .

[0193] Example 23: cAMP assay In vitro efficacy measurements were performed using the cAMP assay. The ligand binding followed by the G-cell Activation of protein-coupled receptors (GPCRs) triggers a series of secondary messengers that lead to a cellular response. The JAR cascade is initiated. Signaling by GLP-1R and GIP-R is This involves activation of denylyl cyclase and cAMP production. cAMP Hunter (trademark) ) Using the eXpress GPCR assay (Eurofins DiscoveRx) Then, we determined the cellular cAMP production.

[0194] In a cell-based cAMP assay, compound 2 was found to be present at a concentration of 4.1 nM in GLP-1R-expressing cells. It has a semi-maximal effective concentration, while the ratio of tilzepatide / compound 2 is 1.68. In cytoplasm, the concentration was approximately 6.86 nM. Furthermore, in GIPR-expressing cells, compound 2 exhibited a half-maximal concentration. The effective concentration is 2.3 nM, while the ratio of tilzepatide / compound 2 is 0.81. The concentration for zepatide was 1.89 nM. These results indicate that representative compound 2 potently inhibits both GLP-1 and GIP receptors. This indicates that it is a harmful substance.

[0195] Example 24: Effects on blood glucose levels, body weight, and food intake. The effect of the compound of the present invention on blood glucose levels was studied in mice. This study was conducted in mice with type 2 diabetes. The study was conducted using a (db / db) model. The animals were divided into eight treatment groups (n=6 per group), that is, Diabetic control group, Compounds 2-7 (3 nM / kg) and Chilzepatide (10 nM / kg) The subjects were divided into treatment groups (kg). Compound 1 (6 nM / kg) and Compound 2 (6 nM / kg) were administered. In a separate trial (treatment n=5), it was compared with tilzepatide (59 nM / kg). Blood glucose levels were measured in all animals. Each test compound was administered subcutaneously to all animals. Blood glucose levels were measured at 4, 12, 24, 48, 72, and 96 hours after the procedure. The values ​​were measured. The delta blood glucose level (mM) was calculated. The results are shown in Table 4. Similarly, weight Changes and cumulative food consumption were measured 96 hours after treatment. The results are shown in Table 5 below. . [Table 10] [Table 11]

[0196] The effects of compound 2 and compound 7 on blood glucose levels were measured at 10 nM / kg and 30, respectively. Further tests were conducted in mice at doses of nM / kg, at 4, 8, and 12 hours post-treatment. Blood glucose levels were measured at 24, 48, and 72 hours, and tilzepatide (90 nM / kg) was administered. This was compared with the results shown in Table 6 below. Similarly, weight change and cumulative food consumption were compared. Measurements were taken 72 hours after the procedure. The results are shown in Table 7 below. [Table 12] [Table 14]

[0197] The results showed that the compound of the present invention can effectively reduce T2D blood glucose levels. The results also show that the compound of the present invention is effective for a long period of time. Surprisingly, blood The effect of compound 2 on reducing sugar levels was observed at a dose approximately 9 times higher than that of compound 2. The effect was similar to that shown by [the drug]. Furthermore, surprisingly, the effect lasted for 72 hours. This was maintained. Similarly, the compound showed a statistically significant decrease in food intake and body weight. Ta.

[0198] Another study showed that in mice, compounds 2, 8, 9, and 10 affected blood glucose levels and food intake. The effects on body weight were studied. This study was conducted using a type 2 diabetes mouse (db / db) model. The study was conducted by dividing animals into five treatment groups (n=6), a diabetes control group, and a compound 2 (10 nM / kg ), compound 8 (10 nM / kg), compound 9 (10 nM / kg), and compound 10 (1 They were divided into groups of 0 nM / kg. Baseline blood glucose levels were measured in all animals. The test compound was administered subcutaneously. Blood glucose levels were monitored at 4, 12, 24, and 48 hours after the procedure. Measurements were taken at intervals of 72 hours and 96 hours. Delta blood glucose levels (mM) were calculated. The results are shown in the table. As shown in 8, weight change and cumulative food consumption were measured 96 hours after treatment. The results are shown in Table 9. The effects of compounds 11-15 on blood glucose levels, food intake, and body weight are shown. All compounds except for compound 13 were tested in separate trials. The results are shown in Table 8 (Effect on blood glucose levels) and Table 9. (Effects on body weight and food consumption) are shown. [Table 15] [Table 16]

[0199] Compounds 2, 8, 9, 10, 11, and 14 after treatment It showed a statistically significant reduction in blood glucose levels. In addition, compared to diabetic controls, food intake and A statistically significant decrease in body weight was also observed.

[0200] The above results indicate that the compound of the present invention is a potent inhibitor of GLP-1 and GIP receptors. It has been shown that it may be effective in treating type 2 diabetes, diabetes with obesity, obesity, and hyperlipidemia. vinegar.

Claims

1. A polypeptide comprising the following amino acid sequence or a pharmaceutically acceptable salt thereof, Y-X1-E-G-T-F-T-S-D-Y-S-I-X2-L-Xaa15-K-I- A-Xaa19-X3-Xaa21-F-V-Xaa24-W-L-X4-AGG- P-S-S-G-A-P-P-PS-X5-X6-X7-X8-X9-X10-X11 (Sequence No. 1) During the ceremony X1 is Aib, Ser(OMe) or (D)Ser(OMe), X2 is Tyr, Ser(OMe), (D)Ser(OMe), or Aib. X3 is either Glun or Lys, and in the formula, if X3 is Lys, then the side chain mesh of Lys The no(ε-amino) group is acylated at the following site: {-U-W-Y-Z In the formula, U is -C(O)-CH ２ -O-(CH ２ ) ２ -O-(CH ２ ) ２ -NH-} In the formula, {} is the attachment point with the base W. Wは-C(O)-NH-(CH ２ ) ｐ -NHH-]、-C(O)-C(CH ３ ) ２ -NH -], and -C(O)-CH ２ -O-(CH ２ ) ２ -O-(CH ２ ) ２ -NH- Selected from the group, where p is 3 or 4, and where ] is the attachment point with group Y, Y is -C(O)-(CH ２ ) ２ -CH(COOH)NH-- and -- is the base Z It is the point of attachment, Z is -C(O)-(CH ２ ) ｎ -COOH or -C(O)-(CH ２ ) ｎ -CH ３ in Yes, in the formula, n is an integer between 14 and 20. However, if X3 is Lys and X2 is Aib, then W is -C(O)-CH ２ -O- (CH ２ ) ２ -O-(CH ２ ) ２ -NH-] not, X4 is Leu, Ile, or Glu. X5 does not exist, or is Arg or Lys, and in the expression, if X5 is Lys, L The amino (ε-amino) group in the ys side chain is acylated at the following site: {-U'-W'-Y'-Z' In the formula, U' is -C(O)-CH ２ -O-(CH ２ ) ２ -O-(CH ２ ) ２ -NH-} Yes, in the formula,} is the attachment point with the base W', W'は-C(O)-NH-(CH ２ ) ｑ -NH-]、-C(O)-C(CH ３ ) ２ -N H-, and -C(O)-CH ２ -O-(CH ２ ) ２ -O-(CH ２ ) ２ -NH-] Selected from the following group, where p is 3 or 4, and where ] is the attachment point with group Y'. the law of nature, Y' is -C(O)-(CH ２ ) ２ -CH(COOH)NH-- and -- is the base This is the attachment point with Z', Z' is -C(O)-(CH ２ ) ｍ -COOH or -C(O)-(CH ２ ) ｍ -CH ３ In the formula, m is an integer between 14 and 20. X6 does not exist, or it is Lys. X7 does not exist, or it is Lys. X8 does not exist, or it is Lys. X9 does not exist, or it is Lys. X10 does not exist, or it is Lys. X11 does not exist, or it is Lys. Xaa15 is either Asp or Glu. Xaa19 is Glun or Ala, Xaa21 is Ala or Glu, Xaa24 is either GLn or Asn. In the formula, the acid group of the C-terminal amino acid is either a free carboxylic acid group or a C-terminal primary amino acid. It is amidized as a do, However, at least one of X3 or X5 is a polypeptide or Lys. The pharmaceutically acceptable salt.

2. A polypeptide according to claim 1, wherein X1 is Aib, or a pharmaceutically acceptable salt thereof. 。

3. A polypeptide according to claim 1, wherein X2 is Aib, or a pharmaceutically acceptable salt thereof. 。

4. The polypeptide or drug according to claim 1, wherein both X1 and X2 are Aib. A scientifically acceptable salt.

5. X1 is Aib, and X2 is Ser(OMe) or (D)Ser(OMe) A polypeptide according to claim 1 or a pharmaceutically acceptable salt thereof.

6. X1 is Ser(OMe) or (D)Ser(OMe), and X2 is Aib A polypeptide according to claim 1 or a pharmaceutically acceptable salt thereof.

7. The polypeptide or agent according to any one of claims 1 to 6, wherein X4 is Ile A scientifically acceptable salt.

8. The polypeptide or agent according to any one of claims 1 to 7, wherein X5 is Arg. A scientifically acceptable salt.

9. The polypeptide according to claim 1, wherein X1 is Aib and X2 is Tyr. It is its pharmaceutically acceptable salt.

10. The following amino acid sequence: Y-Aib-E-G-T-F-T-S-D-Y-S-I-Ser(OMe)-LD-K -I-A-Q-X3-A-F-V-Q-W-L-X4-A-G-G-P-S-S-G-A -P-P-P-S-X5-X6-X7-X8-X9-X10-X11 (SEQ ID NO: 2) A polypeptide according to any one of claims 1, 2, and 5, or pharmaceutically Acceptable salt.

11. The polypeptide according to claim 10, wherein X4 is Ile, or the pharmaceutically acceptable salt.

12. The following amino acid sequence: Y-X1-E-G-T-F-T-S-D-Y-S-I-X2-L-DK-I-A-Q- X3-A-F-V-Q-W-L-X4-AG-G-P-S-G-A-P-P-P- S (Sequence ID 3) Includes, In the formula, X1 is Aib, X2 is Ser(OMe) or Aib, and X4 is Il The polypeptide or agent according to any one of claims 1 to 2, wherein e is or Glu. A scientifically acceptable salt.

13. The polypeptide according to claim 12, wherein X2 is Aib and X4 is Ile or its pharmaceutically acceptable salt.

14. The following amino acid sequence: Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-DK-I-A- Q-X3-A-F-V-Q-W-L-Ile-A-G-G-P-S-S-G-A-P-P -P-S (Sequence No. 4) Includes, In the formula, X3 is Lys, and the portion {-U-W-Y-Z is acetylated, and W is -C(O)-NH-(CH ２ ) ｐ -NH-] or -C(O)-C(CH ３ ) ２ - Selected from the group consisting of NH-, where ] is the attachment point with group Y, and p is 3 or 4. A polypeptide according to claim 1 or a pharmaceutically acceptable salt thereof.

15. The amino acid sequence to be selected from the following group: i) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Ty r Ser Ile Aib Leu Asp Lys Ile Ala Gln Ly s Ala Phe Val Gln Trp Leu Ile Ala Gly Gl y Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH ２ (Sequence No. 5) ii) Tyr Aib Glu Gly Thr Phe Thr Ser Asp T yr Ser Ile D-Ser-(OMe) Leu Asp Lys Ile A la Gln Lys Ala Phe Val Gln Trp Leu Ile A la Gly Gly Pro Ser Ser Gly Ala Pro Pro P ro Ser-NH ２ (Sequence No. 9) iii) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Ser(OMe) Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH ２ (Sequence No. 10) iv) Tyr Aib Glu Gly Thr Phe Thr Ser Asp T yr Ser Ile Aib Leu Asp Lys Ile Ala Gln L ys Ala Phe Val Gln Trp Leu Ile Ala Gly G ly Pro Ser Ser Gly Ala Pro Pro Pro Ser A rg (SEQ ID NO: 11), v) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Ty r Ser Ile Tyr Leu Glu Lys Ile Ala Ala Gl n Glu Phe Val Asn Trp Leu Leu Ala Gly Gl y Pro Ser Ser Gly Ala Pro Pro Pro Ser Ly s-NH ２ (Sequence No. 12) vi) Tyr Aib Glu Gly Thr Phe Thr Ser Asp T yr Ser Ile Ser(OMe) Leu Glu Lys Ile Ala Ala Gln Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Lys-NH ２ (Sequence No. 13) vii) Tyr D-Ser (OMe) Glu Gly Thr Phe Thr S er Asp Tyr Ser Ile Aib Leu Asp Lys Ile A la Gln Lys Ala Phe Val Gln Trp Leu Ile A la Gly Gly Pro Ser Ser Gly Ala Pro Pro P ro Ser-NH ２ (Sequence No. 6), and viii) Tyr Ser (OMe) Glu Gly Thr Phe Thr Se r Asp Tyr Ser Ile Aib Leu Asp Lys Ile A la Gln Lys Ala Phe Val Gln Trp Leu Ile A la Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH ２ (Sequence No. 7) A polypeptide according to claim 1, comprising the same, wherein a pharmaceutically acceptable salt thereof.

16. Claims 1 to 11 all exist, where X5, X6, X7, X8, X9, 10, and X11 do not exist. A polypeptide as described in any one of item 11.

17. W is -C(O)-C(CH ３ ) ２ -NH-] in any one of claims 1 to 16 The polypeptides described herein or their pharmaceutically acceptable salts.

18. W is -C(O)-NH-(CH ２ ) ｐ -NH-] and p is 3 or 4 , the polypeptide according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof 。

19. W is -C(O)-NH-(CH ２ ) ４ -NH-] any one of claims 1 to 16 The polypeptides described in the section or their pharmaceutically acceptable salts.

20. W is -C(O)-CH ２ -O-(CH ２ ) ２ -O-(CH ２ ) ２ -NH-] is, please The polypeptide or the polypeptide described in any one of the requests 1-2, 5, 7-11, or 15-16. Pharmaceutically acceptable salts.

21. Z is -C(O)-(CH ２ ) ｎ -COOH, and n is 16 or 18, A polypeptide according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof.

22. W is -C(O)-NH-(CH ２ ) ４ -NH-] and Z is -C(O)-(CH ２ ) ｎ -COOH and n is 18, according to any one of claims 1 to 16 Lipeptides or their pharmaceutically acceptable salts.

23. W is -C(O)-C(CH ３ ) ２ -NH-] and Z is -C(O)-(CH ２ ) ｎ - The polypter according to any one of claims 1 to 16, wherein it is COOH and n is 18. Butyrate or a pharmaceutically acceptable salt thereof.

24. W is -C(O)-CH ２ -O-(CH ２ ) ２ -O-(CH ２ ) ２ -NH-] and Z ga-C(O)-(CH ２ ) ｎ Claims 1-2, which are -COOH and n is 16 Polypeptides described in any one of paragraphs 5-12 or 15-16 or pharmaceutically acceptable Salt.

25. W is -C(O)-CH ２ -O-(CH ２ ) ２ -O-(CH ２ ) ２ -NH-], and Z ga-C(O)-(CH ２ ) ｎ Claims 1-2, which are -COOH and n is 18, Polypeptides described in any one of paragraphs 5-12 or 15-16 or pharmaceutically acceptable Salt.

26. W' is -C(O)-C(CH ３ ) ２ Claims 1 to 7, 9 to 11, and NH are as follows: A polypeptide according to any one of items (b) 15 or a pharmaceutically acceptable salt thereof.

27. W' is -C(O)-NH-(CH ２ ) ｑ -NH-], and p is 3 or 4 or the polypeptide according to any one of claims 1 to 7, 9 to 11, and 15 or A pharmaceutically acceptable salt of [the substance].

28. W' is -C(O)-NH-(CH ２ ) ４ Claims 1-7, 9-11, are -NH-] and a polypeptide according to any one of paragraphs 15 or a pharmaceutically acceptable salt thereof.

29. W' is -C(O)-CH ２ -O-(CH ２ ) ２ -O-(CH ２ ) ２ -NH-] Polypeptide or agent according to any one of claims 1 to 7, 9 to 11, and 15 A scientifically acceptable salt.

30. Z' is -C(O)-(CH ２ ) ｍ -COOH and m is 16 or 18 , the polypeptide or the polypeptide according to any one of claims 1 to 7, 9 to 11, and 15 Pharmaceutically acceptable salts.

31. W' is -C(O)-NH-(CH ２ ) ４ -NH-] and Z' is -C(O)-(CH ２ ) ｍ Claims 1-7, 9-11, and 15, which are -COOH and m is 18. A polypeptide as described in any one of the paragraphs or a pharmaceutically acceptable salt thereof.

32. W' is -C(O)-NH-(CH ３ ) ２ -NH-] and Z' is -C(O)-(CH ２ ) ｍ Claims 1-7, 9-11, and 15, which are -COOH and m is 18. A polypeptide as described in any one of the paragraphs or a pharmaceutically acceptable salt thereof.

33. W' is -C(O)-CH ２ -O-(CH ２ ) ２ -O-(CH ２ ) ２ -NH-] Z' is -C(O)-(CH ２ ) ｍ -COOH, and n is 16, claims 1 to Polypeptides according to any one of paragraphs 7, 9-11, and 15 or pharmaceutically acceptable Possible salt.

34. W' is -C(O)-CH ２ -O-(CH ２ ) ２ -O-(CH ２ ) ２ -NH-] Z' is -C(O)-(CH ２ ) ｍ -COOH and n is 18, claims 1 to Polypeptides according to any one of paragraphs 7, 9-11, and 15 or pharmaceutically acceptable Possible salt.

35. -U-W-Y-Z and / or -U'-W'-Y'-Z' are the following groups: 【Chemistry 1】 A polypeptide according to any one of claims 1 to 34, selected from the following, or its pharmaceutically acceptable properties A salt that is acceptable for this purpose.

36. The C-terminal amino acid is amidated as a C-terminal primary amide, according to claims 1 to 35. A polypeptide as described in any one of the items or a pharmaceutically acceptable salt thereof.

37. The acid group of the C-terminal amino acid is a free carboxylic acid, any one of claims 1 to 35. The polypeptide described herein or a pharmaceutically acceptable salt thereof.

38. The following groups: 【Chemistry 2】 【change】 【Transformation 3】

39. A polypeptide according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof , and a pharmaceutical comprising one or more of a carrier, diluent, or pharmaceutically acceptable excipient. composition.

40. A polypeptide according to any one of claims 1 to 38 for use as a pharmaceutical agent a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 39.

41. For use in the treatment or prevention of a patient's disease, any one of claims 1 to 38 The polypeptide described or a pharmaceutically acceptable salt thereof, or the pharmaceutical combination described in claim 39. A finished product.

42. The aforementioned diseases include hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, and hyperlipidemia. Syndrome X, dyslipidemia, cognitive impairment, atherosclerosis, myocardial infarction, coronary heart disease A group consisting of disease, stroke, inflammatory bowel syndrome, indigestion, alcoholism, and gastric ulcer. A polypeptide for use according to claim 41 or the pharmaceutically acceptable polypeptide selected from among them. A suitable salt or pharmaceutical composition.

43. The polypeptide or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition, in an effective amount Provided simultaneously, separately, or sequentially in combination with one or more additional therapeutic agents. Polypeptides or pharmaceutically acceptable salts thereof for use as described in items 40-42. This is a pharmaceutical composition.

44. For patients who require it, the polypeptide according to any one of claims 1 to 38 or This involves administering an effective dose of the pharmaceutically acceptable salt to the patient with hyperglycemia and type 2 diabetes. Impaired glucose tolerance, type 1 diabetes, obesity, hypertension, hyperlipidemia, X syndrome, dyslipidemia, cognitive impairment atherosclerosis, myocardial infarction, coronary heart disease, stroke, inflammatory bowel syndrome, indigestion Good, methods for treating or preventing alcoholism and stomach ulcers.

45. The method described above administers an effective amount of the pharmaceutical composition described in claim 39 to a patient who requires it. This includes treating patients with hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, and hypertension. Hyperlipidemia, X syndrome, dyslipidemia, cognitive impairment, atherosclerosis, myocardial infarction, coronary artery disease Treats arterial heart disease, stroke, inflammatory bowel syndrome, indigestion, alcoholism, and stomach ulcers. Or a way to prevent it.

46. Administering one or more therapeutic drugs in combination in effective doses simultaneously, separately, or sequentially. The method according to any one of claims 44 to 45, further comprising the above.

47. Hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, hyperlipidemia, syndrome X , dyslipidemia, cognitive impairment, atherosclerosis, myocardial infarction, coronary heart disease, stroke, A drug for the treatment or prevention of inflammatory bowel syndrome, indigestion, alcoholism, and stomach ulcers. Polypeptide according to any one of claims 1 to 38 or for use in the preparation of a drug A pharmaceutically acceptable salt of, or the composition according to claim 39.

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