GLP-1 / GIP dual agonist

Abstract

This invention provides a polypeptide or a pharmaceutically acceptable salt thereof that may be useful in the treatment of type 2 diabetes (T2D), diabetes mellitus with obesity, obesity, and hyperlipidemia. [Solution] Provides a long-acting glucagon-like peptide-1 and a human glucose-dependent insulin secretion-stimulating polypeptide (GIP) biagonal agonist polypeptide.

Description

[Technical Field]

[0001] This invention relates to the treatment of type 2 diabetes (T2D), diabetes with obesity, obesity and hyperlipidemia. Long-acting glucagon-like peptide-1 (GLP-1) and human glucoc --dependent insulin secretion-stimulating polypeptide / gastrointestinal peptide (GIP) dual agonist Regarding lipeptides. [Background technology]

[0002] Type 2 diabetes using glucagon-like peptide-1 receptor agonists (GLP-1RAs) Treatment for (T2DM) improves blood glucose control, weight loss, and several cardiovascular risk factors. This leads to improvements in pancreatic beta cells, various cell types of the gastrointestinal tract, and the central nervous system. G protein-coupled receptors expressed in neurons of both the central nervous system (CNS) and the peripheral nervous system. Glucagon-like peptide-1 receptor (GLP-1R), a member of the Class B family. It is mediated by. Activation of GLP-1R signaling by GLP-1RAs is mediated by It enhances glucose-stimulated insulin secretion, slows gastric emptying, and reduces plasma glucagon levels. By reducing the bell, glucose homeostasis is improved and appetite pathways in the brain are activated. It reduces body weight through sexualization. Due to the glucose dependence of beta cell activation, G LP-1RAs are not associated with an increased risk of hypoglycemia. The broad metabolic effects of GLP-1RAs... Benefits have established this class in the T2DM treatment paradigm, but many patients have H The bA1c / blood glucose target was not reached, and therefore the weight loss achieved with these drugs was not sufficient. It requires a high dose, which also increases the risk of adverse events associated with GI, making it the most potent drug 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 the GLP-1RA class.

[0003] One new approach involves modifying basic GLP-1RA therapy with glucose-dependent insulin. Phosphate-stimulated polypeptide (GIP) pathway and other pathways involved in nutrition and energy metabolism This involves combining it with pharmacological strategies that target the pathway. GIP responds to food. It is an incretin secreted from K cells in the upper small intestine and duodenum. Below, postprandial GIP levels are approximately four times higher than GLP-1 levels. GIP is a substance found in humans. It is responsible for the majority of the insulin-secreting incretin effect and is important in a different way from GLP-1. It has additional functions. Unlike GLP-1, GIP is a blood glucose-dependent substance, It is both a gon secretion-stimulating and insulin secretion-stimulating agent, and is dose-dependent under hypoglycemic conditions. It stimulates glucagon secretion, and under hyperglycemic conditions, it stimulates insulin secretion, and the released glucagon Kagon promotes insulin secretion, both through the GIP receptor (GIPR) and GLP-1R receptor. Although it is present in beta cells, GIPR is abundant in adipose tissue and overlaps in many CNS cells. Because it is found in areas where GIPR is absent, its expression is distributed differently in extrapancreatic tissues. P controls glucose uptake, lipolysis, and lipoprotein lipase activity. Through its action, it is involved in adipose tissue carbohydrate and lipid metabolism. These findings are related to GIPR. This suggests that the pharmacological activation of may have therapeutic benefits in peripheral energy metabolism. A single-molecule, multifunctional peptide combining GLP-1RA activity and GIP activity controls blood glucose and It is being proposed as a new treatment for weight management.

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

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

[0006] WIPO publication numbers WO2017 / 74714A1, WO2020 / 23386A1, W O2020 / 023388A1, WO2015 / 067715A2, WO2016 / 11 1971A1 and WO2013 / 164483A1 are GLP-1 R and GIP This document discloses an R-double agonist compound. [Overview of the Initiative]

[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, (L)-norvaline, or (D)-norvaline. X2 is Aib, Leu, (D)-Leu, Val, (D)-Val, Ile, (D)- Ile, and selected from the L or D isomers of the amino acids in the following formulas, [ka] During the ceremony, " [Chemical formula] "] represents the attachment point to Leu, and R is C 2-5 alkyl, C 3-7 cycloalkyl, C 3- 7 cycloalkyl-C 1-3 alkyl-, C 3-5 alkenyl, C 3-5 alkynyl, C 5-7 cycloalkenyl-CH2-, and C 1-3 haloalkyl- selected from, and alternatively, R together with the carbon to which it is attached forms a C 3-6 cycloalkyl ring, X3 is Gln or Lys. In the formula, when X3 is Lys, the side-chain amino (ε-amino) group is acylated with the following moiety, [Chemical formula] where U is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-}, and where}, is the attachment point to group 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 consisting of, where p is 3 or 4, and where ], is the attachment point to group Y, Y is -C(O)-(CH2)2-CH(COOH)NH--, and -- is the attachment point to group Z, and Z is -C(O)-(CH2) n -COOH or -C(O)-(CH2) n -CH3, and where n is an integer from 14 to 20, 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: [ka] 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 p is 3 or 4, and where ] is the attachment point to the group Y'. , Y' is -C(O)-(CH2)2-CH(COOH)NH--, and -- is a combination with the group Z'. It is an attachment point, Z' is -C(O)-(CH2). n -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 amide. It is amidated as such, and at least one of X3 and X5 is Lys, and However, if X1 is Aib, then X2 is not Aib.

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

[0009] 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. This compound contains acid addition salts that may be salts of organic acids such as amino acids. This compound is a pharmaceutically acceptable acid. Addition salts are formed by the addition of one or more acid equivalents, such as monohydrochloride or dihydrochloride salts. Contains salt. The salt can be prepared by any process, at the responsibility of a person skilled in the art. (See Berge et al.,J.Pharm.Sci.1977,66,1- 19; and Handbook of Pharmaceutical Salts, Properties,and Use;Stahl and Wermuth,Ed. ;Wiley-VCH and VHCA:Zurich,Switzerland,2 (See 002.) As used herein, the term "alkyl" refers to a structure whose backbone contains only carbon and hydrogen atoms. This refers to saturated hydrocarbon chain radicals, which, unless otherwise defined, include 1 to 6 of both. It has carbon atoms, is either linear or branched, and attaches to other molecules by single bonds. Suitable non-limiting examples of propyl groups include, for example, methyl, ethyl, n-propyl, 1- Examples include methyl ethyl (isopropyl), n-pentyl, and n-hexyl.

[0010] As used herein, the term "haloalkyl" means a single atom substituted with a halogen atom. The term "alkyl" refers to any alkyl group having the above hydrogen atoms, and halogen atoms include fluorine, chlorine, and odor. It can be selected from either element or iodine.

[0011] "C 2-5 The numbers in phrases like "C" indicate the number of carbon atoms in the chain. For example, "C 2-5 The term "alkyl" refers to an alkyl chain that has 2 to 5 carbon atoms.

[0012] As used herein, the term “alkenyl” means at least one carbon-carbon double twin Refers to a hydrocarbon chain containing a bond, which may have an (E) or (Z) configuration. Alkenyl Unless otherwise specified, the group may contain 2 to 8 carbon atoms. Unless otherwise specified, all alkenyl groups described herein are linear or fractional. It can form part of a branch chain. A suitable non-limiting example of an alkenyl group is, for example, ethyl Examples include 2-propenyl(allyl), 2-methyl-2-propenyl, and 2-butenyl. It can be done.

[0013] The term "alkynyl" refers to a hydrocarbon chain having at least one carbon-carbon triple bond. The alkynyl group may contain 2 to 8 carbon atoms unless otherwise specified. Unless otherwise stated or enumerated, all of the following in this specification are described or claimed. The alkynyl group can form part of a linear or branched chain. Non-restrictive examples of alkynyl groups. Examples include 2-propynyl, 3-butynyl, and propargyl.

[0014] As used herein, the term "cycloalkyl" means, unless otherwise specified, 3- This refers to a non-aromatic monocyclic ring system consisting of seven carbon atoms. Cycloalkyl rings are limited to... However, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclopropyl are not available. It contains chlorheptyl. The term "cycloalkenyl" refers to a non-aromatic compound having at least one carbon-carbon double bond. This refers to monocyclic 5-7 membered cycloalkyl ring systems. Non-restrictive examples include cycloalkenylmethyl groups. Examples include cyclopentenylmethyl and cyclohexenylmethyl.

[0015] 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 the compound. Therefore, the result is the alleviation of the signs, symptoms, or causes of the disease. It may be a sting or / or relief, or any other desirable change in the biological system. The "effective 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 the dosage may vary depending on the individual and the prescribing physician's judgment.

[0016] As used herein, the amino acid "norvaline" may also be represented by its structure. Ku, [ka] It may also be defined as "2-aminopentanoic acid" by its chemical name. (L)-norvaline and The term (D)-norvaline refers to the "L" and "D" isomers of norvaline, respectively. To point.

[0017] As used herein, the amino acid "norleucine" is also represented by its structure. often, [ka] It may also be defined as "2-aminohexanoic acid" by its chemical name. (L)-norleucine The term (D)-norleucine is derived from the "L" and "D" differences of norleucine, respectively. It refers to the sexual body.

[0018] As used herein, the amino acid "homoalanine" is also represented by its structure. often, [ka] It may also be defined as "2-aminobutyric acid" by its chemical name. (L)-homoalanine and ( The term D)-homoalanine refers to the "L" and "D" isomers of homoalanine, respectively. To point.

[0019] 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 long-acting, and this is for patients who need it. Frequent administration may not be necessary.

[0020] 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, (L)-norvaline, or (D)-norvaline. X2 is Aib, Leu, (D)-Leu, Val, (D)-Val, Ile, (D)- Ile, and selected from the L or D isomers of the amino acids in the following formulas, [ka] During the ceremony, " [ka] " represents the attachment point to Leu, and R is C 2-5 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cyclolalkyl-C 1-3 Alkyl-, C 3-5 Alkenil, C 3-5 Alkinil, C 5-7 Cycloalkenyl-CH2-, and C 1-3 Selected from haloalkyl-, Alternatively, R is C along with the carbon to which it is attached. 3-6 Forming a cycloalkyl ring, 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: [ka] 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 -- indicates attachment to group Z. It is a 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 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: [ka] 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 p is 3 or 4, and where ] is the attachment point to the group Y'. , Y' is -C(O)-(CH2)2-CH(COOH)NH--, and -- is a combination with the group Z'. It is an attachment point, 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 amide. It is amidated as such, and at least one of X3 and X5 is Lys, and However, if X1 is Aib, then X2 is not Aib.

[0021] In one embodiment of the present invention, X1 is Aib.

[0022] In another embodiment of the present invention, X2 is Aib.

[0023] In another embodiment of the present invention, X4 is Ile.

[0024] In another embodiment of the present invention, X1 is (L)-norvaline.

[0025] In another embodiment of the present invention, X2 is Leu.

[0026] In another embodiment of the present invention, X2 is Ile.

[0027] In another embodiment of the present invention, X2 is selected from the L or D isomers of the following amino acids. And so, [ka] During the ceremony, " [ka] " represents the attachment point to Leu, and R is C 2-5 Alkyl, C 3-7 Cycloalkyl, C3 -7 Cyclolalkyl-C 1-3 Alkyl-, C 3-5 Alkenil, C 3-5 Alkinyl , C 5-7 Cycloalkenyl-CH2-, and C 1-3 Selected from haloalkyl-, Alternatively, R is C along with the carbon to which it is attached. 3-6 It forms a cycloalkyl ring.

[0028] In another embodiment of the present invention, X2 is an amino acid of the following formula: [ka] It exists in an "L" configuration.

[0029] In another embodiment of the present invention, X2 is an amino acid of the following formula: [ka] It exists in a "D" configuration.

[0030] In another embodiment of the present invention, X2 is an amino acid of the following formula: [ka] In the formula, R is C 2-5 It is alkyl. In another embodiment, R is ethyl, n-propyl, Selected from isopropyl and n-butyl.

[0031] In yet another embodiment of the present invention, X2 is an amino acid of the following formula: [ka] In the formula, R is n-propyl, and thus X2 is formed as norvaline. Another implementation In this embodiment, X2 is (L)-norvaline. In another embodiment, X2 is (D)-norvaline. It's phosphorus.

[0032] In yet another embodiment of the present invention, X2 is an amino acid of the following formula: [ka] In the formula, R is n-butyl, and therefore forms X2 as norleucine. Another embodiment In this embodiment, X2 is (L)-norleucine. In another embodiment, X2 is (D)-norleucine. It is Ishin.

[0033] In yet another embodiment of the present invention, X2 is an amino acid of the following formula: [ka] In the formula, R is ethyl, and thus forms X2 as homoalanine. Another embodiment In this embodiment, X2 is (L)-homoalanine. In another embodiment, X2 is (D)-homoalanine. It is ranine.

[0034] In another embodiment of the present invention, X2 is an amino acid of the following formula: [ka] In the formula, R is C 3-7 Cyclolalkyl-C 1-3 It is alkyl-. In another embodiment, R is cyclopropylmethyl-, cyclopentylmethyl-, and cyclohexylmethyl- Selected from.

[0035] In another embodiment of the present invention, X2 is an amino acid of the following formula: [ka]

[0036] In another embodiment of the present invention, X2 is an amino acid of the following formula: [ka]

[0037] In another embodiment of the present invention, X2 is an amino acid of the following formula: [ka]

[0038] In another embodiment of the present invention, X1 is Aib, and X2 is the L-isomer of an amino acid of the following formula. It is a body, [ka] In the formula, R is n-propyl, that is, X2 is (L)-norvaline.

[0039] In another embodiment of the present invention, X1 is Aib, and X2 is the L-isomer of an amino acid of the following formula. It is a body, [ka] In the formula, R is ethyl, and therefore X2 is (L)-homoalanine.

[0040] In another embodiment of the present invention, X1 is Aib, and X2 is the L-isomer of an amino acid of the following formula. It is a body, [ka] In the formula, R is n-butyl, and therefore X2 is (L)-norleucine.

[0041] In another embodiment of the present invention, X1 is Aib and X2 is Leu.

[0042] In another embodiment of the present invention, X1 is Aib and X2 is Ile.

[0043] In another embodiment of the present invention, X1 is (L)-norvaline and X2 is Aib be.

[0044] In another embodiment of the present invention, X1 is (L)-norvaline and X2 is ami of the following formula It is the L-isomer of an acid, [ka] In the formula, R is n-propyl, that is, X2 is (L)-norvaline.

[0045] In one embodiment of the present invention, X1 is Aib or (L)-norvaline, and X2 Aib, Leu, Ile, or the L-isomer of an amino acid with the following formulas: [ka] In the formula, R is n-propyl, and neither X1 nor X2 is Aib. In one embodiment of the present invention, X1 is Aib or (L)-norvaline, and X2 is Aib, Leu, Ile, or the L-isomer of an amino acid with the following formula: [ka] In the formula, R is n-butyl, and neither X1 nor X2 is Aib.

[0046] In one embodiment of the present invention, X1 is Aib or (L)-norvaline, and X2 Aib, Leu, Ile, or the L-isomer of an amino acid with the following formulas: [ka] In the formula, R is ethyl, and neither X1 nor X2 is Aib.

[0047] In one embodiment of the present invention, X1 is Aib or (L)-norvaline, and X2 is Ai b, Leu, Ile, or the L-isomer of an amino acid with the following formulas: [ka] In the formula, R is n-propyl, X4 is Ile, and both X1 and X2 are Aib. isn't it.

[0048] In one embodiment of the present invention, X1 is Aib or (L)-norvaline, and X2 is Ai b, Leu, Ile, or the L-isomer of an amino acid with the following formulas: [ka] In the formula, R is n-propyl, X5 is Arg, and both X1 and X2 are Aib. isn't it.

[0049] In one embodiment of the present invention, X3 is Lys, where the side chain amino(ε-amino) of Lys is... The group is acylated at the following point.

[0050] TIFF2026086912000034.tif1665 In another embodiment of the present invention, W is -C(O)-C(CH3)2-NH-].

[0051] In another embodiment of the present invention, W is -C(O)-NH-(CH2) p -NH-] In the formula, p is either 3 or 4.

[0052] In another embodiment of the present invention, W is -C(O)-CH2-O-(CH2)2-O-(CH 2) It is 2-NH-.

[0053] In another embodiment of the present invention, Z is -C(O)-(CH2) n -COOH, and n is 16, 17, 18, 19, or 20. In a preferred embodiment, n is 16, 18 or 20. In yet another preferred embodiment, n is 18 or 20.

[0054] In another preferred embodiment of the present invention, Z is -C(O)-(CH2) n -COOH , and n is 16 or 18. In yet another preferred embodiment, n is 18. .

[0055] 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 in the formula, n is 18.

[0056] 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 in the formula, n is 16.

[0057] 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, where n is It is 16.

[0058] 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, where n is I am 18.

[0059] In one embodiment of the present invention, X3 is Gln, X5 is Lys, and in the formula, Lys The side-chain amino(ε-amino) group is acylated at the following point.

[0060] [ka]

[0061] In one embodiment of the present invention, X1 is Aib or (L)-norvaline, and X2 is Ai b, Leu, Ile, or the L-isomer of an amino acid with the following formulas: [ka] In the formula, R is n-propyl, X3 is Gln, X5 is Lys, and X1 and Both X2 are not Aib, and in the formula, the side chain amino(amino) group of Lys is in the following part It becomes acylated. [ka]

[0062] In another embodiment of the present invention, W' is -C(O)-C(CH3)2-NH-].

[0063] In another embodiment of the present invention, W' is -C(O)-NH-(CH2) q -NH-] In the formula, p is either 3 or 4.

[0064] In another embodiment of the present invention, W' is -C(O)-CH2-O-(CH2)2-O-(C It is H2)2-NH-].

[0065] In another embodiment of the present invention, Z' is -C(O)-(CH2) m -COOH, and The values ​​of m are 16, 17, 18, 19, or 20. In a preferred embodiment, m is 16, 1 It is 8 or 20. In another, more preferred embodiment, m is 18 or 20.

[0066] In another preferred embodiment of the present invention, Z' is -C(O)-(CH2) m -COOH And m is 16 or 18. In another more preferred embodiment, m is 18. ru.

[0067] 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 in the formula, n is 18.

[0068] 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 in the formula, n is 16.

[0069] 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 in the formula, m is 16.

[0070] 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 in the formula, m is 18.

[0071] In one embodiment of the present invention, X1 is Aib, and X2 is the L-isomer of the amino acid shown in the following formula. And, [ka] In the formula, R is n-propyl, Xaa15 is Glu, and Xaa19 is Ala. X3 is Gln, Xaa21 is Glu, Xaa24 is Asn, and X4 is Leu is Lys, and the side chain amino(ε-amino) group of Lys is as follows: Partially acylated, [ka] In the formula, W' is -C(O)-C(CH3)2-NH-, Z' is -C(O)-(CH2). m -COOH, where m is 18.

[0072] In another embodiment of the present invention, the C-terminal amino acid is amidated as a C-terminal primary amide. It can be done.

[0073] In another embodiment of the present invention, X5, X6, X7, X8, X9, X10 and X11 are None of them exist.

[0074] 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-X2-LDKIAQ -X3-AFVQWL-X4-AGGPSSGAPPP -S-X5-X6-X7-X8-X9-X10-X11 (Sequence number 2), In the formula, X2 is Leu, Ile, (L)-norvaline, (L)-homoalanine or (L) - Norleucine, X4 is Ile, 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. 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, [ka] 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 -- indicates attachment to group Z. It is a 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, and the acid group of the C-terminal amino acid is a free carboxylic acid. It is either a group or is amidated as a primary amide at the C-terminus.

[0075] In one embodiment of the present invention, X2 is (L)-norvaline.

[0076] In one embodiment of the present invention, X2 is (L)-homoalanine.

[0077] In one embodiment of the present invention, X2 is (L)-norleucine.

[0078] In another embodiment of the present invention, X2 is Leu.

[0079] In another embodiment of the present invention, X2 is Ile.

[0080] In another embodiment of the present invention, X2 is (L)-norvaline and X5 is Arg. be.

[0081] In another embodiment of the present invention, W is -C(O)-C(CH3)2-NH-].

[0082] In another embodiment of the present invention, W is -C(O)-NH-(CH2) 3-4 -NH-] ru.

[0083] In another embodiment of the present invention, W is -C(O)-CH2-O-(CH2)2-O-(CH 2) It is 2-NH-.

[0084] In another embodiment of the present invention, Z is -C(O)-(CH2) n -COOH, and n is 16, 17, 18, 19, or 20. In a preferred embodiment, n is 16, 18 or 20. In yet another preferred embodiment, n is 18 or 20.

[0085] In another preferred embodiment of the present invention, Z is -C(O)-(CH2) n -COOH , and n is 16 or 18. In yet another preferred embodiment, n is 18. .

[0086] 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 in the formula, n is 18.

[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 in the formula, n is 16.

[0088] 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, where n is It is 16.

[0089] 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, where n is I am 18.

[0090] In another embodiment of the present invention, the C-terminal amino acid is amidated as a C-terminal primary amide. It can be done.

[0091] In another embodiment of the present invention, X5, X6, X7, X8, X9, X10 and X11 are None of them exist.

[0092] In a preferred embodiment, X2 is (L)-norvaline, X4 is Ile, and X5 X6, X7, X8, X9, X10 and X11 do not exist, and W is -C(O)-C(CH 3) 2-NH-], and Z is -C(O)-(CH2) n -COOH, where n is I am 18.

[0093] In another aspect, the present invention provides 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-D-K-I-A-Q- X3-A-F-V-Q-W-L-X4-A-G-G-P-S-S-G-A-P-P-P- S (SEQ ID NO: 3) wherein X1 is Aib or (L)-norvaline, X2 is Aib, Leu, Ile, (L)-norvaline, (L)-homoalanine or (L)-norleucine, X4 is Ile, X3 is Lys, and the side chain amino (ε-amino) group of Lys is acylated with the following moiety and,

Chemical Formula

[0094] In one embodiment of the present invention, X1 is Aib.

[0095] In another embodiment of the present invention, X1 is (L)-norvaline.

[0096] In another embodiment of the present invention, X2 is Aib.

[0097] In another embodiment of the present invention, X2 is (L)-norvaline.

[0098] In another embodiment of the present invention, X2 is (L)-norleucine.

[0099] In another embodiment of the present invention, X2 is (L)-homoalanine.

[0100] In another embodiment of the present invention, X2 is Leu.

[0101] In another embodiment of the present invention, X2 is Ile.

[0102] In another embodiment of the present invention, X1 is Aib, and X2 is (L)-norvaline and.

[0103] In another embodiment of the present invention, X1 is Aib, and X2 is (L)-norleucine and.

[0104] In another embodiment of the present invention, X1 is Aib, and X2 is (L)-homoalanine and.

[0105] In another embodiment of the present invention, X1 is (L)-norvaline, and X2 is Aib and.

[0106] In another embodiment of the present invention, X1 is Aib, and X2 is Leu.

[0107] In another embodiment of the present invention, X1 is Aib and X2 is Ile.

[0108] In another embodiment of the present invention, X1 is (L)-norvaline and X2 is (L)- norvaline.

[0109] In another embodiment of the present invention, W is -C(O)-C(CH3)2-NH-].

[0110] In another embodiment of the present invention, W is -C(O)-NH-(CH2) 3-4 -NH-]. is.

[0111] In another embodiment of the present invention, W is -C(O)-CH2-O-(CH2)2-O-(CH 2)2-NH-].

[0112] In another embodiment of the present invention, Z is -C(O)-(CH2) n -COOH and n is 16, 17, 18, 19 or 20. In a preferred embodiment, n is 16, 18 or 20. In yet another preferred embodiment, n is 18 or 20.

[0113] In another preferred embodiment of the present invention, Z is -C(O)-(CH2) n -COOH and n is 16 or 18. In yet another preferred embodiment, n is 18. .

[0114] In another embodiment of the present invention, W is -C(O)-C(CH3)2-NH-] and Z is -C(O)-(CH2) n -COOH, wherein n is 18.

[0115] 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 in the formula, n is 16.

[0116] 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, where n is It is 16.

[0117] 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, where n is I am 18.

[0118] In another embodiment of the present invention, X1 is Aib and X2 is (L)-norvaline, 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, [ka] In the formula, W is -C(O)-C(CH3)2-NH- and Z is -C(O)-(CH2) n It is -COOH, and n is 18.

[0119] In another embodiment of the present invention, the C-terminal amino acid is amidated as a C-terminal primary amide. It can be done.

[0120] 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 Tyr Ser Ile L-Norvaline 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: 04) ii.) Tyr L-Norvaline Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Aib 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: 05) iii.) Tyr Aib Glu Gly Thr Phe Thr Ser As p Tyr Ser Ile Leu Leu Asp Lys Ile Ala Gl n Lys Ala Phe Val Gln Trp Leu Ile Ala Gl y Gly Pro Ser Ser Gly Ala Pro Pro Pro Se r-NH2(SEQ ID NO: 06) iv.) Tyr L-Norvaline Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile L-Norvaline 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: 07) v.) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile L-Norvaline 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-NH2 (SEQ ID NO: 08) vi.) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile L-norvaline 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 Arg (SEQ ID NO: 09) vii.) Tyr Aib Glu Gly Thr Phe Thr Ser As p Tyr Ser Ile L-homoalanine 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: 10) viii.) Tyr Aib Glu Gly Thr Phe Thr Ser A sp Tyr Ser Ile L-norleucine 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: 11) ix.) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Ile 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 (Sequence ID 12)

[0121] 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.

[0122] In embodiments of the present invention, the bases U, W, Y and Z in the following parts, [ka] Or the bases U', W', Y', and Z' in the following section are: [ka] It has the meaning defined herein and is interpreted as a single-letter code for an amino acid, or They should not be mixed together.

[0123] In embodiments of the present invention, the base {-UWYZ and / or {-U'-W'-Y'- Z' is selected from representative structures of parts A, B, C, and D disclosed in Table 2.

[0124] The polypeptide sequences referred to herein are single amino acid sequences approved by IUPAC. It is represented by a character code.

[0125] 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.

[0126] Tables 1 and 2 provide some representative compounds of the present invention.

[0127] [Table 1] TIFF2026086912000046.tif55167

[0128] [Table 2]

[0129] In another embodiment, the present invention provides patients who require it with the polypeptide or This includes administering a pharmaceutically acceptable effective dose 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.

[0130] In another aspect, the present invention provides to patients requiring such treatment the compound of the present invention or A treatment method for patients with type 2 diabetes, including administering an effective amount of pharmaceutically acceptable salt, is proposed. To provide.

[0131] In another aspect, the present invention provides to patients requiring such treatment the compound of the present invention or This invention provides a method for treating obesity in patients, which involves administering an effective amount of pharmaceutically acceptable salt. .

[0132] In another aspect, the present invention provides to patients requiring such treatment the compound of the present invention or This provides a method for treating hyperlipidemia in patients, including administering an effective amount of pharmaceutically acceptable salt. do.

[0133] 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, which includes the agent. To provide.

[0134] The compounds of the present invention can be administered via parenteral routes (e.g., subcutaneous, intravenous, intraperitoneal, intramuscular, or transdermal). It is preferable that such pharmaceutical composition be formulated as a pharmaceutical composition administered by ). The process for preparing it is well known in the art. (For example, Remi ngton:The Science and 50 Practice of Pha rmacy(DBTroy,Editor,21st Edition,Lippi (See ncott, Williams & Wilkins, 2006).

[0135] In another embodiment, the polypeptide of the present invention or a pharmaceutically acceptable salt thereof is used as a drug. Use.

[0136] In another embodiment, the polypeptide or so of the present invention used for the treatment or prevention of a patient's disease In pharmaceutically acceptable salts, the diseases include hyperglycemia, type 2 diabetes, impaired glucose tolerance, and type 1 diabetes. Diabetes, obesity, hypertension, hyperlipidemia, X syndrome, dyslipidemia, cognitive impairment, atherosclerosis Cognitive disorders, myocardial infarction, coronary heart disease, stroke, inflammatory bowel syndrome, indigestion, alcoholism The group consisting of and gastric ulcers is randomly selected.

[0137] In another embodiment, the polypeptide of the present invention or a pharmaceutically acceptable salt thereof is one or more It may be supplied simultaneously, separately, or sequentially in combination with an effective dose of additional therapeutic agents.

[0138] In another embodiment, a pharmaceutical composition according to the present invention, or a polypeptide of the present invention used as a pharmaceutical agent. or a pharmaceutically acceptable salt thereof.

[0139] In another embodiment, a pharmaceutical composition according to the present invention, used for the treatment or prevention of a patient's disease. The invention comprises the polypeptide or a pharmaceutically acceptable salt thereof, and the aforementioned diseases include hyperglycemia, 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 Patients are randomly selected from a group consisting of dyspepsia, alcoholism, and gastric ulcers.

[0140] In another embodiment, the pharmaceutical composition according to the present invention is combined with an effective amount of one or more additional therapeutic agents. The polypeptide or its pharmaceutically acceptable, provided together, simultaneously, separately, or sequentially. Contains generally acceptable salts.

[0141] The present invention may be accompanied by one or more embodiments. The following embodiments illustrate the present invention. It is understood that the claims are not intended to limit the scope to the specific embodiments illustrated. It should be. Furthermore, the embodiments defined herein may be used independently or in conjunction with this specification. It should also be understood that any definition may be used in conjunction with any other embodiment. Therefore, the present invention is applicable to all possible combinations of various independently described embodiments. The aim is to create permutations and arrangements.

[0142] Other features of the present invention will become apparent from the following examples. In general, the present invention is Any novel features disclosed in the specification (including the attached claims and drawings) , or any novel combination. Therefore, in particular aspects and embodiments of the present invention, Alternatively, any features, integers, characteristics, compounds, or chemical parts described in conjunction with the examples are inconsistent. Unless otherwise specified, any other aspects, embodiments, or examples described herein will not apply. This should be understood as follows.

[0143] Furthermore, unless otherwise stated, any features disclosed herein are the same or similar. It can be replaced by an alternative feature that serves the same purpose. [Examples]

[0144] Instruments and analytical methods: The instruments used for characterizing and analyzing the compounds of the present invention were HPL C(Waters e2695 Alliance; Detector Waters (2489 UV / Visible))

[0145] Equipment: HPLC: Waters e2695 Alliance; Detector: Acqui ty-QDa.

[0146] The final compound of this disclosure was purified by a preparative HPLC procedure, as outlined below.

[0147] 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

[0148] [Table 3]

[0149] The purity of the compounds disclosed herein was analyzed by one of the RP-HPLC methods outlined below. .

[0150] HPLC method A: 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: 0.8mL / min Detection: UV detection at 210nm Column temperature: 65℃ Sample tray temperature: 5°C Execution time: 90 minutes

[0151] [Table 4]

[0152] HPLC method B: Column: XSelect CSH C18 (4.6mm x 150mm, 2.5μ) 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: 0.8mL / min Detection: UV detection at 210nm Column temperature: 65℃ Sample tray temperature: 5°C Execution time: 90 minutes

[0153] [Table 5]

[0154] HPLC method C: 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: 5°C Execution time: 60 minutes

[0155] [Table 6]

[0156] HPLC method D: Column: XSelect CSH C18 (4.6mm x 150mm, 2.5μ) Eluent: Mobile phase A: Buffer: Acetonitrile (900:100) Mobile phase B: Buffer: Acetonitrile (300:700) Buffer solution: Water to which triethylamine has been added, and the pH has been adjusted to 2.5 ± 0.1 with orthophosphate. Potassium dihydrogen orthophosphate inside Flow rate: 0.5mL / min Detection: UV detection at 214nm Column temperature: 60℃ Sample tray temperature: 10℃ Execution time: 90 minutes

[0157] [Table 7]

[0158] Preparation method: Example 1: 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 A-di-tert-butyl ester [ka] Partially A-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 deblockage of the amino group using piperidine. Next, DIPC and HOBt are used to bind to Fmoc-Aib-OH in THF. Let it happen, 2-[2-[2-[(2-Fmoc-amino-2-methyl-propanoyl)ami A resin was obtained by removing the Fmoc group from the piperix. Removed by selective deblocking using din, and then the free amino groups are removed by HOBt And using DIPC, it is bound with Fmoc-Glu-OtBu, 2-[2-[2- [[2-[[(4S)-4-Fmoc-amino-5-tert-butoxy-5-oxo- Pentanoylamino-2-methylpropanoylaminoethoxyethoxyvinegar Acid-2-Cl-Trt-resin was obtained. The Fmoc group of the obtained compound was treated with piperidine. It selectively deblocks the free amino group, and then removes the 20-(tert-butoxy)- By combining with 20-oxoicosanoic acid, 2-[2-[2-[[2-[[(4S)-5-t ert-butoxy-4-[(20-tert-butoxy-20-oxo-icosanoyl) [amino]-5-oxo-pentanoyl]amino]-2-methyl-propanoyl]amino [ethoxy]ethoxy]acetic acid-2-Cl-Trt resin was obtained. Next, this intermediate was Cleavage 2-Cl-Trt resin using trifluoroethanol:DCM (1:1). Then, 2-[2-[2-[[2-[[(4S)-5-tert-butoxy-4-[(20 -tert-butoxy-20-oxo-icosanoyl)amino]-5-oxo-pentano Il-amino-2-methyl-propanoyl-amino-ethoxy-ethoxyacetic acid was obtained. (Partially A-di-tert-butyl ester) (LCMS=m / z:814.10(M +H + ))

[0159] Example 2: 2-[2-[2-[[2-[[(4S)-5-tert-butoxy-4-[( 18-tert-butoxy-18-oxo-octadecanoyl)amino]-5-oxo- Pentanoylamino-2-methylpropanoylaminoethoxyethoxyvinegar Preparation of Acids [ka] Partially B-di-tert-butyl ester Partially β-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 deblockage of the amino group using piperidine. Next, DIPC and HOBt are used to bind to Fmoc-Aib-OH in THF. And, 2-[2-[2-[(2-Fmoc-amino-2-methyl-propanoyl)amino A resin was obtained from which the Fmoc group was removed by piperido. The free amino groups are removed by selective deblocking using , and HOBt and D Using IPC, Fmoc-Glu-OtBu is bound, 2-[2-[2-[[2- [[(4S)-4-Fmoc-amino-5-tert-butoxy-5-oxo-pentano [yl]amino]-2-methyl-propanoyl]amino]ethoxy]ethoxy]acetic acid-2- A Cl-Trt resin was obtained. The Fmoc group of the obtained compound was selected using piperidine. It is then deblocked, and the free amino group is removed by octadecane dioxide monotert-butyl ester. Combined with tert, 2-[2-[2-[[2-[[(4S)-5-tert-butoxy- 4-[(18-tert-butoxy-18-oxo-octadecanoyl)amino]-5- Oxo-pentanoyl]amino]-2-methyl-propanoyl]-amino]ethoxy]e Toxyacetic acid-2-Cl-Trt resin was obtained. Next, this intermediate was converted into a trifluoroethanolamine resin. Cut from 2-Cl-Trt-resin using NL:DCM(1:1), 2-[2- [2-[[2-[[(4S)-5-tert-butoxy-4-[(18-tert-but [Xy-18-oxo-octadecanoyl)amino]-5-oxo-pentanoyl]amino ]-2-methyl-propanoyl]amino]ethoxy]ethoxy]acetic acid was obtained. (Partial B- (Di-tert-butyl ester) (LCMS=m / z:786.39(M+H) + ))

[0160] 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] 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.

[0161] 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] Partially D-di-tert-butyl esters are 2-c as schematically shown below. It was prepared using solid-phase synthesis with lorototrityl chloride resin. 2-[2-(2-F moc-aminoethoxy)ethoxyacetic acid is converted to 2-chlorotrityl acetate in the presence of DIPEA. Attached to a chloride resin, 2-[2-(2-Fmoc-aminoethoxy)ethoxy]vinegar Acid-2-Cl-Trt resin was obtained. The Fmoc protecting group was an amino group using piperidine. Removed by selective deblocking, followed by DIPC and HOBt, T By combining it with 2-[2-(2-Fmoc-aminoethoxy)ethoxy]acetic acid in HF, { (Fmoc-amino-ethoxy)-ethoxy}-acetyl-{(-amino-ethoxy)- Ethoxy-acetic acid-2-Cl-Trt-Resin was obtained. The Fmoc group was replaced with piperidine. The free amino groups were removed by selective deblocking used, and then HOBt and DIP. C is used to bind with Fmoc-Glu-OtBu, and 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 piperid Selectively deblock using , free amino groups, then 20-(tert-but By combining with xy)-20-oxoicosanoic 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.

[0162] Example 5: Preparation of Compound 1 The parent peptide was synthesized by a solid-phase method. The starting resin used in the synthesis was Fmoc-Rink. It was a midi resin. Selective deblockage of the Fmoc-protecting amino group of the Rink amide resin, This is done using peridine to obtain Rink amide resin, and then Fmoc-Ser(tBu By bonding with )-OH, we obtained Fmoc-Ser(tBu)-Rink amide resin. The coupling reaction uses diisopropylcarbodiimide and N-hydride as coupling reagents. This was done using roxybenzotriazole (DIPC-HOBt). The process is completed. Using acetic anhydride and diisopropylethylamine / pyridine, each The unbonded amino group was terminated / capped in the amino acid bond. Fmoc-Ser(tBu Selective deblockage of amino groups in )-Rink amide resins was performed using piperidine. Subsequently, HOBt and DIPC are used for coupling with Fmoc-Pro-OH. This yielded Fmoc-Pro-Ser(tBu)-rink amide resin. Then the second cycle is completed. Using acetic anhydride and diisopropylethylamine / pyridine This was used to terminate the unbound amino groups in each amino acid bond.

[0163] The three steps described above, namely, selective capping, and the Fmo of amino acids attached to the resin Deblocking of c-protection and bonding of adjacent amino acid residues in the sequence with the Fmoc-protected amino group. The process was repeated for the remaining 37 amino acid residues. Selective deblocking, in other words, The capping of unbonded amino groups is performed using acetic anhydride and diisopropylethylamine / p The procedure was performed using lysine, and deprotection of the Fmoc group was performed using piperidine, and the adjacent Fmoc The binding with the protective amino acid was performed using HOBt / DIPC. The side chains are protected at a right angle, for example, by the hydroxyl group of serine, tyrosine, or threonine. The amino groups of lysine are protected with tert-butyl (-tBu) groups, respectively. t-butyloxycarbonyl (-Boc) and (4,4-dimethyl-2,6-dioxo Protected with a cyclohex-1-ylidene)-3-methylbutyl (IVDde) group, as The carboxylic acid group of paraglycylate or glutamic acid is protected with a -tBu group, and glutamic acid The amide group of n was protected with a trityl (-Trt) group. The three steps described above, namely, Selective capping, deblocking, and subsequent binding with neighboring Fmoc protective amino acids. The combination is Fmoc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr (tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Ty r(tBu)-Ser(tBu)-Ile-[L-norvaline]-Leu-Asp(Ot Bu)-Lys(Boc)-Ile-Ala-Gln(Trt)-Lys(IVDde) -Ala-Phe-Val-Gln(Trt)-Trp-Leu-Ile-Ala-Gl y-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro- Pro-Pro-Ser(tBu)-resin was obtained.

[0164] Fmoc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu )-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tB u)-Ser(tBu)-Ile-[L-norvaline]-Leu-Asp(OtBu)- Lys(Boc)-Ile-Ala-Gln(Trt)-Lys(IVDde)-Ala -Phe-Val-Gln(Trt)-Trp-Leu-Ile-Ala-Gly-Gl y-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro- Following deblocking of Pro-Ser(tBu)-resin using piperidine, Bo Boc protection of peptide resin using anhydrous c results in Boc-Tyr(tBu)-Ai b-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Se r(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-[ L-norvaline]-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)-Se Obtain r(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-resin The IVDde group of the peptide resin was deprotected using hydrazine hydrate, and then , diisopropylcarbodiimide, N-hydroxybenzotriazole (DIP Using C-HOBt) as a coupling reagent, partial A-di-tert-butylester It is bonded to the intermediate compound resin Boc-Tyr(tBu)-Aib-Glu(O tBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)- Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-[L-norvaline ]-Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt )-Lys(NH-partial A di-tert-butyl ester)-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)-resin is obtained, and this is mixed with ethane-1,2-dithiol and triisopropylsilamine. The solution was cleaved and deprotected using trifluoroacetic acid, followed by preparative HPLC. Compound 1 was obtained by purification.

[0165] Mass (LCMS): m / z=1192.7(MH4 4+ ), calculated mass = 4766 .77, HPLC purity: (Method B) 98.60%, RT=33.8 min

[0166] Example 6: Synthesis of Compound 2: Compound 2 was prepared by a solid-phase method according to a similar process described in Example 5, but Fm Use oc-[L-norvaline]-OH at position 2 instead of Fmoc-Aib-OH. Therefore, replace Fmoc-Aib-OH with Fmoc-[L-norvaline]-OH at position Used in 13, Boc-Tyr(tBu)-[L-norvaline]-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(IVDd e)-Ala-Phe-Val-Gln(Trt)-Trp-Leu-Ile-Ala- Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pr We obtained o-Pro-Pro-Ser(tBu)-resin.

[0167] Next, it is bonded to a partial A-di-tertbutyl ester and then cut according to Example 5. Compound 2 was obtained by decontamination, deprotection, and preparative purification using HPLC.

[0168] Mass (LCMS): m / z=1192.6(MH4 4+ ), calculated mass = 4766 .4, HPLC purity: (Method B) 96.09%, RT=25.6 min Example 7: Synthesis of Compound 3: Compound 3 was prepared by a solid-phase method according to a similar process described in Example 5, but Fm Use oc-Leu-OH at position 13 instead of Fmoc-[L-norvaline]-OH Using Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(t Bu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr( tBu)-Ser(tBu)-Ile-Leu-Leu-Asp(OtBu)-Lys( Boc)-Ile-Ala-Gln(Trt)-Lys(IVDde)-Ala-Phe -Val-Gln(Trt)-Trp-Leu-Ile-Ala-Gly-Gly-Pr o-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro- Ser(tBu)-resin was obtained.

[0169] Next, it is bonded to a partial A-di-tertbutyl ester and then cut according to Example 5. Compound 3 was obtained by decontamination, deprotection, and preparative purification using HPLC.

[0170] Mass (LCMS): m / z=1196.1(MH44+ )、Calculated mass = 4780 .4, HPLC purity: (Method A) 95.27%, RT = 39.1 minutes.

[0171] Example 8: Synthesis of Compound 4: Compound 4 was prepared by the solid-phase method according to a similar process described in Example 5, but Fm oc-[L-Norvaline]-OH was used at position 2 instead of Fmoc-Aib-OH and Boc-Tyr(tBu)-[L-Norvaline]-Glu(OtBu)-Gly-T hr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)- Tyr(tBu)-Ser(tBu)-Ile-[L-Norvaline]-Leu-Asp( OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt)-Lys(IVDd e)-Ala-Phe-Val-Gln(Trt)-Trp-Leu-Ile-Ala- Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pr o-Pro-Pro-Ser(tBu)-resin was obtained.

[0172] Next, it was coupled with the partial A-di-tert-butyl ester, and according to Example 5, followed by cleavage, deprotection, and preparative purification using HPLC to obtain Compound 4.

[0173] Mass (LCMS): m / z = 1196.32 (MH4 4+ )、Calculated mass = 478 1.25, HPLC purity: (Method A) 94.21%, RT = 29.8 minutes.

[0174] Example 9: Synthesis of Compound 5: Deprotection of the IVDde group of the peptide resin: Boc-Tyr(tBu)-Aib-Glu( OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu) -Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-[L-Norbali ]-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)-resin (according to Example 5) The prepared product is then carried out using hydrazine hydrate, and diisopropylcarbodiimide is used. N-hydroxybenzotriazole (DIPC-HOBt) is used as the coupling reagent. Then, it is coupled with a partial C-di-tert-butyl ester, and the intermediate compound resin is Bo c-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Ph e-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-S er(tBu)-Ile- [L-norvaline]-Leu-Asp(OtBu)-Lys (Boc)-Ile-Ala-Gln(Trt)-Lys(NH-part C ji-tert -butyl ester)-Ala-Phe-Val-Gln(Trt)-Trp-Leu-I le-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly -Ala-Pro-Pro-Pro-Ser(tBu)- resin is obtained, and this is converted to ethane-1 , cleaved with trifluoroacetic acid along with 2-dithiol and triisopropylsilane. Compound 5 was obtained by deprotection and subsequent purification by preparative HPLC.

[0175] Mass (LCMS): m / z=1600.80(MH3 3+ ), calculated mass = 479 9.376, HPLC purity: (Method A) 98.64%, RT=15.9 min

[0176] Example 10: Synthesis of Compound 6: Compound 6 was prepared by a solid-phase method according to a similar process described in Example 9, and a partial D-di was prepared. Bonding with -tert-butyl ester is performed, followed by cleavage, deprotection, and according to Example 9. Compound 6 was obtained by preparative HPLC purification using the same method.

[0177] Mass (LCMS): m / z=1609.98(MH3 3+ ), calculated mass = 482 6.916, HPLC purity (method A): 96.31%, RT=26.7 min

[0178] Example 11: Synthesis of Compound 7: Compound 7 was prepared by a solid-phase method according to a similar process described in Example 9, and a partial B-di Bonding with -tert-butyl ester is performed, followed by cleavage, deprotection, and according to Example 9. Compound 7 was obtained by preparative HPLC purification using the same method.

[0179] Mass (LCMS): m / z=1580.64(MH3 3+ ), calculated mass = 47 38.896, HPLC purity (method A): 98.43%, RT=18.5 min Example 12: Synthesis of Compound 8: The parent peptide was synthesized by a solid-phase method. The starting resin used in the synthesis was Fmoc-Rink. It was a midi resin. Piperidine was used to protect the Fmoc amino group of the rink amide resin. Selective deblocking followed by Fmoc-Lys(IVDde)-OH and Rink Mido resin was bonded. Bonding was performed using DIPC-HOBt and Fmoc-Lys(I This is done by obtaining VDde)-Rink amide resin, and this completes one cycle. This was done. Acetic anhydride and diisopropylethylamine / pyridine were used to bond each amino acid. At the end of the compounding process, the unbound amino group was terminated / capped. Fmoc using piperidine. Selective deblocking of the amino group Fmoc of -Lys(IVDde)-Rink amide resin Then, through subsequent bonding with a second amino acid using HOBt and DIPC, Fm We obtained oc-Ser(tBu)-Lys(IVDde)-rink amide resin. With this, The second cycle is complete. As mentioned earlier, acetic anhydride and diisopropylethylamine / Pyridine is used to terminate the unbound amino group [capping] after each amino acid bond. I made them do it.

[0180] 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-L-norvaline-Leu-Glu(O tBu)-Lys(Boc)-Ile-Ala-Ala-Gln(Trt)-Glu(O tBu)-Phe-Val-Asn(Trt)-Trp-Leu-Leu-Ala-Gl y-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro- Pro-Pro-Ser(tBu)-Lys(IVDde)-Rink amide resin obtained Ta.

[0181] Fmoc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu )-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tB u)-Ser(tBu)-Ile-L-norvaline-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 Fmoc group Deblockage is performed using piperidine followed by the peptide resin using Boc anhydride. Boc protection allows Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly- Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Tyr(tBu)-Ser(tBu)-Ile-L-norvaline-Leu-Glu(O tBu)-Lys(Boc)-Ile-Ala-Ala-Gln(Trt)-Glu(O tBu)-Phe-Val-Asn(Trt)-Trp-Leu-Leu-Ala-Gl y-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro- Pro-Pro-Ser(tBu)-Lys(IVDde)-Rink amide resin obtained Ta.

[0182] Following deprotection of the IVDde group of the peptide resin using hydrazine hydrate, partial A- The di-tert-butyl ester bond is separated by diisopropylcarbodiimide, N-hydroxy The procedure was carried out using benzotriazole (DIPC-HOBt) as the coupling reagent. Compound 8 resin was obtained.

[0183] Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu) -Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu )-Ser(tBu)-Ile-L-norvaline-Leu-Glu(OtBu)-Lys (Boc)-Ile-Ala-Ala-Gln(Trt)-Glu(OtBu)-Phe -Val-Asn(Trt)-Trp-Leu-Leu-Ala-Gly-Gly-Pr o-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro- Ser(tBu)-Lys(NH portion A-di-tert butyl ester)-RinkAm Trifluorescein resin with ethane-1,2-dithiol and triisopropylsilane The chemical compounds are cleaved and deprotected using acetic acid, followed by purification by preparative HPLC. Component 8 was obtained. The HPLC purity of compound 8 was evaluated by the following method: mass (LCMS). :m / z=980.42(MH5 5+) Calculated mass = 4897.06 HPLC pure Degree (Method D): 94.55%, RT=44.9 minutes

[0184] Example 13: Synthesis of Compound 9: The parent peptide was synthesized by a solid-phase method. The starting resin used in the synthesis was Wang resin. Fmoc protective Arg(Pbf) was used for bonding with Wang resin. The bond was made with 4-dimethyl In the presence of tylaminopyridine (DMAP), diisopropylcarbodiimide, N-hydr The procedure was performed using roxybenzotriazole (DIC-HOBt) as the binding agent, and Fm We obtained oc-Arg(Pbf)-Wang resin. Fmoc-Arg using piperidine Selective deblocking of amino groups in (Pbf)-Wang resin, followed by HOBt / DI Through binding with Fmoc-Ser(tBu)-OH using PC, Fmoc-Ser( We obtained tBu)-Arg(Pbf)-Wang resin. This completes one cycle. Using hydroxylate and diisopropylethylamine / pyridine, each amino acid bond is used The unbonded amino group was terminated.

[0185] The two steps described above, namely the selective deblotting of Fmoc-protected amino acids attached to the resin King, the bond between the Fmoc-protected amino group of the adjacent amino acid residue in the sequence and the remaining 38 amino acids Repeating the no-acid residues, the side chain of the Fmoc-protected amino acid is protected at a right angle, for example, celery The hydroxyl group, tyrosine, or threonine is replaced with a tert-butyl (-tBu) group. Protects the amino group of lysine, with tert-butyloxycarbonyl (-Boc) and ( 4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyrate The (IVDde) group protects each of the aspartic acid or glutamic acid groups. Each rubonic acid group was protected with a -tBu group. The three steps described above, namely selective Capping, deblocking, and subsequent binding with the adjacent Fmoc protective amino acid are performed. Fmoc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tB u)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(t Bu)-Ser(tBu)-Ile-L-norvaline-Leu-Asp(OtBu)-L ys(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-Pro-P We obtained the ro-Ser(tBu)-Arg(Pbf)-Wang resin.

[0186] Fmoc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu )-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tB u)-Ser(tBu)-Ile-L-norvaline-Leu-Asp(OtBu)-Ly s(Boc)-Ile-Ala-Gln(Trt)-Lys(IVDde)-Ala-P he-Val-Gln(Trt)-Trp-Leu-Ile-Ala-Gly-Gly- Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pr Debrovone using piperidine in o-Ser(tBu)-Arg(Pbf)-Wang resin Following the initial coating, Boc protection of the peptide resin using Boc anhydrous was achieved, resulting in Boc- Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe- Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser (tBu)-Ile-L-norvaline-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)-Arg(Pbf)-Wang resin was obtained. Peptide was used with hydrazine hydrate. Following the deprotection of the IVDde group of the resin, the bond of the partial A-di-tertbutyl ester is , diisopropylcarbodiimide, N-hydroxybenzotriazole (DIPC-HO The procedure was carried out using Bt) as a coupling reagent to obtain compound 9-Wang resin.

[0187] Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu) -Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu )-Ser(tBu)-Ile-L-norvaline-Leu-Asp(OtBu)-Lys (Boc)-Ile-Ala-Gln(Trt)- Lys(NH part A-ji-te rt (butyl ester)-Ala-Phe-Val-Gln(Trt)-Trp-Leu -Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-G ly-Ala-Pro-Pro-Pro-Ser(tBu)-Arg(Pbf)-Wan g resin.

[0188] Trifluorovinegar using ethane-1,2-dithiol and triisopropylsilane The cleavage and deprotection of the resin using acid, followed by purification by preparative HPLC, revealed compound 9. This resulted in: Mass (LCMS): m / z = 985.88 (MH5 5+ ), calculated quality Amount=4924.36, HPLC purity: (Method C) 93.52%, RT=27.8 min

[0189] Example 14: Synthesis of Compound 10: Compound 10 was prepared by a solid-phase method according to a similar process described in Example 5, but F moc-[2-aminobutyric acid] is replaced with Fmoc-[L-norvaline]-OH at position 1 Used in 13, Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-T hr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)- Tyr(tBu)-Ser(tBu)-Ile-2-aminobutyric acid-Leu-Asp(O tBu)-Lys(Boc)-Ile-Ala-Gln(Trt)-Lys(IVDde )-Ala-Phe-Val-Gln(Trt)-Trp-Leu-Ile-Ala-G ly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro -Pro-Pro-Ser(tBu)- resin was obtained.

[0190] Next, it is bonded to a partial A-di-tertbutyl ester and then cut according to Example 5. Compound 10 was obtained by discontinuation, deprotection, and preparative purification using HPLC.

[0191] Mass (LCMS): m / z=1189.57(MH4 4+ ), calculated mass = 475 4.248, HPLC purity: (Method D) 96.79%, RT=42.6 min

[0192] Example 15: Synthesis of Compound 11: Compound 11 was prepared by solid-phase method according to a similar process described in Example 5, but F moc-norleucine was used at position 13 instead of Fmoc-[L-norvaline]-OH to give Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr( tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr (tBu)-Ser(tBu)-Ile-norleucine-Leu-Asp(OtBu)- Lys(Boc)-Ile-Ala-Gln(Trt)-Lys(IVDde)-Ala -Phe-Val-Gln(Trt)-Trp-Leu-Ile-Ala-Gly-Gl y-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro- Pro-Ser(tBu)-resin was obtained.

[0193] Next, it was coupled with the partial A-di-tert-butyl ester and, following Example 5, Compound 11 was obtained by cleavage, deprotection, and preparative HPLC purification.

[0194] Mass (LCMS): m / z = 1196.66 (MH4 4+ ), calculated mass = 478 2.608, HPLC purity: (Method D) 95.43%, RT = 58.7 min

[0195] Example 16: Synthesis of Compound 12: Compound 12 was prepared by solid-phase method according to a similar process described in Example 5, but F moc-Ile-OH was used at position 13 instead of Fmoc-[L-norvaline]-OH to give Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr( tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr (tBu)-Ser(tBu)-Ile-Ile-Leu-Asp(OtBu)-Lys (Boc)-Ile-Ala-Gln(Trt)-Lys(IVDde)-Ala-Ph e-Val-Gln(Trt)-Trp-Leu-Ile-Ala-Gly-Gly-P ro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro -Ser(tBu)- resin was obtained.

[0196] Next, it is bonded with a partial A-di-tert-butyl ester, and then, according to Example 5, Compound 12 was obtained by cleavage, deprotection, and preparative HPLC purification.

[0197] Mass (LCMS): m / z=1196.32(MH4 4+ ), calculated mass = 478 1.25, HPLC purity: (Method D) 94.38%, RT=47.7 min.

[0198] biological research Example 12: Efficacy study in db / db mice at a dose of 10 nM / kg The effects of the compound of this invention on blood glucose levels, food intake, and body weight were studied in mice. This was conducted using a type 2 diabetes mouse (db / db) model. The animals were divided into four treatment groups (n=6). ), diabetes control group, compound 1 (10 nM / kg), compound 2 (10 nM / kg), and The animals were divided into groups based on the dosage of tilzepatide (10 nM / kg). Baseline blood glucose levels were measured in all animals. The test compound was administered subcutaneously to all animals. Blood glucose levels were monitored at 4 hours, 8 hours, and 1 hour after treatment. Measurements were taken at 2 hours, 24 hours, 48 ​​hours, 72 hours, and 96 hours. Delta blood glucose (m M) was calculated. The results are provided in Table 3. Similarly, weight change and cumulative food consumption were calculated. Measurements were taken at 48 and 96 hours after administration. The results of weight change are shown in Table 4, along with cumulative food consumption. This is shown in Table 5. Similarly, compounds 3 and 4 in db / db mice at a dose of 10 nM / kg. The efficacy of 5, 6, and 7 was tested in separate trials. Animals were divided into seven treatment groups (n=6). ), diabetes control group, compound 1, compound 3, compound 4, compound 5, compound 6, and compound The animals were divided into 7 groups. Baseline blood glucose levels were measured in all animals. The test compound was applied to all animals. The substance was administered subcutaneously. Blood glucose levels were monitored at 4, 8, 12, 24, and 48 hours after the procedure. Measurements were taken at 72 and 96 hours. Delta blood glucose levels (mM) were calculated. The results also included: Table 3 also provides this information. Similarly, weight change and cumulative food consumption were recorded 48 hours and 9 hours after treatment. Measurements were taken over a 6-hour period. Weight change results are provided in Table 4, and cumulative food consumption is provided in Table 5. Similarly, the efficacy of compounds 8 and 9 in db / db mice at a dose of 10 nM / kg. Sex was investigated in separate trials. Animals were divided into three treatment groups (n=5), a diabetes control group, and a compound The samples were divided into 8 substances and 9 compounds. Baseline blood glucose levels were measured from all animals. The test compound was administered subcutaneously to the subject. Blood glucose levels were monitored at 4, 8, 12 hours, and 2 hours after the procedure. Measurements were taken at 4 hours, 48 ​​hours, 72 hours, and 96 hours. Delta blood glucose (mM) was calculated. The results are shown in Table 3. Similarly, weight change and cumulative food consumption were measured 48 hours after treatment. Measurements were taken between meals and over 96 hours. The results of weight change are shown in Table 4, and cumulative food consumption is shown in Table 5. Compounds 10, 11, and 12 were compared in db / db mice at a dose of 10 nM / kg. Another separate efficacy trial was conducted. Animals were divided into four treatment groups (n=5) and a diabetes control group. The compounds were divided into compound 10, compound 11, and compound 12. Baseline blood glucose levels were measured from all animals. Measurements were taken. All animals were administered the test compound subcutaneously. Blood glucose levels were measured 4 hours after treatment. Measurements were taken at 8 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, and 96 hours. Delta Blood glucose levels (mM) were calculated. The results are shown in Table 3. Similarly, weight change and cumulative food consumption were also calculated. The amount of energy expended was measured at 48 and 96 hours after the procedure. The results of weight change are shown in Table 4, and the cumulative amount is also measured. Food consumption figures are shown in Table 5.

[0199] [Table 8] TIFF2026086912000058.tif37168

[0200] [Table 9]

[0201] [Table 10]

[0202] The results showed that compound 1 and compound 2 demonstrated a statistically significant reduction in blood glucose up to 96 hours after treatment. This indicates that the compound's effect on blood glucose reduction was observed when tested at the same concentration. It was better than Do.

[0203] Compounds 1 and 2 also showed statistically significant weight loss comparable to that of tilzepatide. Compound 1 showed a significant reduction in food consumption comparable to that of tilzepatide. Diabetes vs. Compared to the group with compound 2, no significant decrease in food consumption was observed.

[0204] Similarly, the results show that compounds 3, 4, 5, 6, and 7 of the present invention are statistically effective up to 96 hours post-treatment. This indicates a significant reduction in blood glucose levels. Furthermore, these compounds were compared to a diabetic control group. In comparison, statistically significant decreases in food intake and body weight were also observed.

[0205] Example 13: Efficacy study in db / db mice at doses of 3 and 20 nM / kg The effects of the compound of the present invention on blood glucose levels, food intake, and body weight were studied in mice. This study was conducted in mice. The study was conducted using a type 2 diabetes mouse (db / db) model. The animals were divided into five treatment groups (per group). n=8), i.e., a diabetes control group, compound 1 (3 nM / kg and 20 nM / kg), The test was divided into two doses: thyroxine and thyroxine (3 nM / kg and 20 nM / kg). Baseline blood glucose levels The blood glucose level was measured in all animals. The test compound was administered subcutaneously to all animals. Measurements were taken at 4, 24, 48, and 72 hours after administration. The delta blood glucose level (mM) was calculated. Weight change and cumulative food consumption were measured 72 hours after the procedure. The results of delta glucose were also measured. This is provided in Table 6. Similarly, the results of weight change are shown in Table 7, and food consumption is presented in Table 8. .

[0206] [Table 11]

[0207] [Table 12]

[0208] [Table 13]

[0209] The results showed that compound 1 at 3 nM / kg and 20 nM / kg reduced glucose levels up to 72 hours. This indicates a dose-dependent improvement in the effect. The effect was greater than that of tilzepatide at similar doses. It was also excellent.

[0210] The effect of compound 1 on food intake and body weight at doses of 3 and 20 nM / kg was significant. It was dose-dependent and equivalent to tilzepatide.

[0211] 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.

[0212] Example 16: Cellular 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.

[0213] Cells of Chilzepatide, Compound 1, Compound 3, Compound 6, Compound 10, and Compound 11 The cAMP assay was performed to determine the semi-effective concentration on GLP-1R-expressing cells and GIPR-expressing cells. The degrees are listed in Table 9 below.

[0214] [Table 14]

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-A-G-G -P-S-S-G-A-P-P-PS-X5-X6-X7-X8-X9-X10-X1 1 (Sequence No. 1) In the formula, X1 is Aib, (L)-norvaline, or (D)-norvaline. X2 is Aib, Leu, (D)-Leu, Val, (D)-Val, Ile, (D)- Ile, and selected from the L or D isomers of the following amino acids: 【Chemistry 1】 During the ceremony, 「 【Chemistry 2】 」 represents the attachment point to Leu, and R is C ２－５ Alkyl, C ３－７ Cycloalkyl, C ３－ ７ Cyclolalkyl-C １－３ Alkyl-, C ３－５ Alkenil, C ３－５ Alkinil, C ５－７ Cycloalkenyl-CH ２ -, and C １－３ selected from haloalkyl, also R is along with the carbon to which it is attached, C ３－６ Forming a cycloalkyl ring, 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: 【Transformation 3】 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--, where -- is attached to the base Z. The destination, 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. 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: 【Chemistry 4】 In the formula, U' is -C(O)-CH ２ -O-(CH ２ ) ２ -O-(CH ２ ) ２ -NH-} In the formula, {} represents 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--, where -- is the base Z' and It is the attachment point, 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 amidated as, and at least one of X3 and X5 is Lys, and However, if X1 is Aib, then X2 is not Aib, but a polypeptide or drug. A scientifically acceptable salt.

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

3. The polypeptide according to claim 1, wherein X1 is (L)-norvaline or the pharmaceutically Acceptable salt.

4. X2 is an L or D isomer of an amino acid, such as Aib, Leu, Ile, or one of the following formulas. can be, 【Transformation 5】 During the ceremony, 「 【Transformation 6】 」 represents the aforementioned attachment point to Leu, and R is C ２－５ Alkyl, C ３－７ Cycloalkyl, C ３ －７ Cyclolalkyl-C １－３ Alkyl-, C ３－５ Alkenil, C ３－５ Alkinyl , C ５－７ Cycloalkenyl-CH ２ -, and C １－３ Selected from haloalkyls, Or R, together with the carbon to which it is attached, C ３－６ Forms a cycloalkyl ring, claim The polypeptide described in item 1 or a pharmaceutically acceptable salt thereof.

5. R is C ２－５ The polypeptide according to claim 4, which is alkyl, or a pharmaceutically acceptable one. Possible salt.

6. The polypeptide according to claim 5, wherein R is ethyl, and a pharmaceutically acceptable salt thereof.

7. The polypeptide according to claim 5, wherein R is n-propyl or the pharmaceutically acceptable Salt.

8. The polypeptide according to claim 5, wherein R is n-butyl, or the pharmaceutically acceptable salt.

9. X2 is the L or D isomer of the amino acid of the following formula: 【Transformation 7】 The polypeptide according to claim 2 or the pharmaceutically acceptable polypeptide, wherein R is n-propyl. Possible salt.

10. X2 is the L or D isomer of the amino acid of the following formula: 【Transformation 8】 The polypeptide according to claim 3 or the pharmaceutically acceptable polypeptide, wherein R is n-propyl. Possible salt.

11. X2 is the L or D isomer of the amino acid of the following formula: 【Chemistry 9】 In the formula, R is n-butyl, the polypeptide according to claim 2 or the pharmaceutically acceptable A good salt.

12. X2 is the L or D isomer of the amino acid of the following formula: 【Chemistry 10】 、 In the formula, R is ethyl, the polypeptide according to claim 2 or the pharmaceutically acceptable salt.

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

14. A polypeptide according to claim 2, wherein X2 is Leu, or a pharmaceutically acceptable salt thereof. 。

15. A polypeptide according to claim 2, wherein X2 is Ile, or a pharmaceutically acceptable salt thereof. 。

16. Claims 1 to 15, wherein X5, X6, X7, X8, X9, X10, and X11 do not exist. A polypeptide as described in any one of the items or a pharmaceutically acceptable salt thereof.

17. X2 is the L or D isomer of the amino acid of the following formula: 【Chemistry 11】 、 In the formula, R is n-propyl and X5 is Arg, the polypeptide according to claim 2. Tide or a pharmaceutically acceptable salt thereof.

18. It contains the following amino acid sequence, Y-Aib-E-G-T-F-T-S-D-Y-S-I-X2-L-DK-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), In the formula, X2 is Leu, Ile, (L)-norvaline, (L)-homoalanine, or (L ) - Norleucine, X3 is Lys, and in the formula, the amino (ε-amino) group in the side chain of Lys is acyl in the following part. transformed, 【Chemistry 12】 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--, where -- is attached to the base Z. The destination, 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. X4 is Ile, 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 amino acid. The polypeptide according to claim 1 or the pharmaceutically acceptable salt.

19. The polypeptide according to claim 18, wherein X2 is (L)-norvaline or the pharmaceutically acceptable A salt that is acceptable for this purpose.

20. The polypeptide or pharmaceutically acceptable substance according to claim 18, wherein X2 is (L)-norleucine. A generally acceptable salt.

21. The polypeptide or its pharmaceutically acceptable form according to claim 18, wherein X2 is (L)-homoalanine. A generally acceptable salt.

22. The polypeptide according to claim 18, wherein X2 is Leu, or the pharmaceutically acceptable salt.

23. The polypeptide according to claim 18, wherein X2 is Ile, or the pharmaceutically acceptable salt.

24. Claims 18-23, in which X5, X6, X7, X8, X9, X10, and X11 do not exist. A polypeptide as described in any one of the paragraphs or a pharmaceutically acceptable salt thereof.

25. The polypeptide according to claim 19, wherein X5 is Arg, or the pharmaceutically acceptable salt.

26. X4 is Ile, X5, X6, X7, X8, X9, X10 and X11 do not exist. W is -C(O)-C(CH ３ ) ２ -NH-] and Z is -C(O)-(CH ２ ) ｎ -COOH, wherein n is 18, claim 19 The polypeptide described herein or a pharmaceutically acceptable salt thereof.

27. It contains 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) In the formula, X1 is Aib or (L)-norvaline, and X2 is Aib, Leu, Ile , (L)-norvaline, (L)-homoalanine, or (L)-norleucine, X4 is Ile, X3 is Lys, and in the formula, the amino (ε-amino) group in the side chain of Lys is acyl in the following part. transformed, 【Chemistry 13】 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--, where -- is attached to the base Z. The destination, 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. Furthermore, in the formula, the acid group of the C-terminal amino acid is either a free carboxylic acid group or a C-terminal acid group. It is amidated as a primary amide, However, if X1 is Aib, then X2 is not Aib, the polypeptide according to claim 1. Tide or a pharmaceutically acceptable salt thereof.

28. The polypeptide according to claim 27, wherein X1 is Aib or the pharmaceutically acceptable salt.

29. The polypeptide according to claim 27, wherein X1 is (L)-norvaline or the pharmaceutically acceptable A salt that is acceptable for this purpose.

30. The polypeptide according to claim 27, wherein X2 is Aib or the pharmaceutically acceptable salt.

31. The polypeptide according to claim 27, wherein X2 is Leu, or the pharmaceutically acceptable salt.

32. The polypeptide according to claim 27, wherein X2 is Ile, or the pharmaceutically acceptable salt.

33. The polypeptide according to claim 27, wherein X2 is (L)-norvaline or the pharmaceutically acceptable A salt that is acceptable for this purpose.

34. The polypeptide or pharmaceutically acceptable substance according to claim 27, wherein X2 is (L)-norleucine. A generally acceptable salt.

35. The polypeptide or its pharmaceutically acceptable form according to claim 27, wherein X2 is (L)-homoalanine. A generally acceptable salt.

36. The present invention according to claim 27, wherein X1 is Aib and X2 is (L)-norvaline. Lipeptides or their pharmaceutically acceptable salts.

37. The polypeptide according to claim 27, wherein X1 and X2 are (L)-norvaline or The pharmaceutically acceptable salt.

38. The present invention according to claim 27, wherein X1 is Aib and X2 is (L)-norleucine. A polypeptide or a pharmaceutically acceptable salt thereof.

39. The present invention according to claim 27, wherein X1 is Aib and X2 is (L)-homoalanine. A polypeptide or a pharmaceutically acceptable salt thereof.

40. The patent according to claim 27, wherein X1 is (L)-norvaline and X2 is Aib. Lipeptides or their pharmaceutically acceptable salts.

41. The polypeptide according to claim 27, wherein X1 is Aib and X2 is Leu. or its pharmaceutically acceptable salt.

42. The polypeptide according to claim 27, wherein X1 is Aib and X2 is Ile or its pharmaceutically acceptable salt.

43. X1 is Aib, X2 is (L)-norvaline, W is -C(O)-C(CH ３ ) ２ -NH-] and Z is -C(O)-(CH ２ ) ｎ Claim 27, which is -COOH, where n is 18 in the formula. The polypeptide described herein or a pharmaceutically acceptable salt thereof.

44. W and / or W' are -C(O)-C(CH ３ ) ２ -NH- or -C(O)-C H ２ -O-(CH ２ ) ２ -O-(CH ２ ) ２ Any of claims 1 to 43, which is -NH-] A polypeptide as described in item 1 or a pharmaceutically acceptable salt thereof.

45. Z and / or Z' are -C(O)-(CH ２ ) ｎ -COOH and / or -C(O) )-(CH ２ ) ｍ -COOH, and n or m is 16 or 18, claims 1 to A polypeptide as described in any one of paragraphs 43 or a pharmaceutically acceptable salt thereof.

46. W and / or W' are -C(O)-C(CH ３ ) ２ -NH-] and Z and / ma taha Z'ga-C(O)-(CH ２ ) ｎ -COOH and / or -C(O)-(CH ２ ) ｍ Any one of claims 1 to 43, wherein it is -COOH and n or m is 18. The polypeptide described herein or a pharmaceutically acceptable salt thereof.

47. W and / or W' are -C(O)-C(CH ３ ) ２ -NH-] and Z and / ma taha Z'ga-C(O)-(CH ２ ) ｎ -COOH and / or -C(O)-(CH ２ ) ｍ Any one of claims 1 to 43, wherein it is -COOH and n or m is 16. The polypeptide described herein or a pharmaceutically acceptable salt thereof.

48. W and / or W' are -C(O)-CH ２ -O-(CH ２ ) ２ -O-(CH ２ ) ２ - NH-] and Z and / or Z' are -C(O)-(CH ２ ) ｎ -COOH and / or -C(O)-(CH ２ ) ｍ -COOH, and n or m is 16, The polypeptide or the pharmaceutically acceptable substance according to any one of claims 1 to 25 and 27 to 42 A salt that is acceptable for this purpose.

49. W and / or W' are -C(O)-CH ２ -O-(CH ２ ) ２ -O-(CH ２ ) ２ - NH-] and Z and / or Z' are -C(O)-(CH ２ ) ｎ -COOH and / or -C(O)-(CH ２ ) ｍ -COOH, and n or m is 18, The polypeptide or the pharmaceutically acceptable substance according to any one of claims 1 to 25 and 27 to 42 A salt that is acceptable for this purpose.

50. A polypeptide according to claim 1, comprising an amino acid sequence selected from the group consisting of the following: or its pharmaceutically acceptable salt. i. ) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile L-norvaline 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 ID 04) ii.) Tyr L-norvaline Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Aib 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 ID 05) iii. ) Tyr Aib Glu Gly Thr Phe Thr Ser As p Tyr Ser Ile Leu Leu Asp Lys Ile Ala Gl n Lys Ala Phe Val Gln Trp Leu Ile Ala Gl y Gly Pro Ser Ser Gly Ala Pro Pro Pro Se r-NH ２ (Sequence No. 06) iv.) Tyr L-Norvaline Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile L-Norvaline 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 ID 07) v.) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile L-Norvaline 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. 08) vi.) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile L-Norvaline 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 Arg (SEQ ID NO: 09) vii.) Tyr Aib Glu Gly Thr Phe Thr Ser As p Tyr Ser Ile L-Homoalanine 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. 10) viii.) Tyr Aib Glu Gly Thr Phe Thr Ser A sp Tyr Ser Ile L-Norleucine 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. 11) ix.) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Ile 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. 12)

51. -U-W-Y-Z and / or -U'-W'-Y'-Z' are selected from the following group. The polypeptide according to any one of claims 1 to 50 or the pharmaceutically acceptable A good salt. 【Chemistry 14】

52. The C-terminal amino acid is amidated as a C-terminal primary amide, according to claims 1 to 51. A polypeptide as described in any one of the items or a pharmaceutically acceptable salt thereof.

53. The C-terminal amino acid is a free carboxylic acid, as described in any one of claims 1 to 51. polypeptides or pharmaceutically acceptable salts thereof.

54. A polypeptide or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following: Compound 1: 【Chemistry 15】 ； Compound 2: 【Chemistry 16】 ； Compound 3: 【Chemistry 17】 ； Compound 4: [Chemistry 18] ； Compound 5: 【Chemistry 19】 ； Compound 6: 【Chemistry 20】 ； Compound 7: 【Chemistry 21】 ； Compound 8: 【Chemistry 22】 ； Compound 9: 【Chemistry 23】 ； Compound 10: 【Chemistry 24】 ； Compound 11: 【Chemistry 25】 And, Compound 12: 【Chemistry 26】 ； In the formula, part A is, 【Chemistry 27】 ； Part B is, 【Chemistry 28】 ； Part C is, 【Chemistry 29】 And, Part D is, 【Transformation 30】 ．

55. A polypeptide according to any one of claims 1 to 54 or a pharmaceutically acceptable salt thereof A pharmaceutical composition comprising, and one or more pharmaceutically acceptable excipients.

56. A pharmaceutical composition according to claim 55 for use as a drug.

57. A pharmaceutical composition according to claim 55, for use in the treatment or prevention of a patient's disease.

58. 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 pharmaceutical composition for use according to claim 57, selected from among the above.

59. The pharmaceutical composition may be used simultaneously or separately in combination with one or more additional therapeutic agents in an effective amount. or a pharmaceutical composition for use according to claims 56 to 58, provided in succession.

60. Patients with hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, hyperlipidemia, X Syndrome, dyslipidemia, cognitive impairment, atherosclerosis, myocardial infarction, coronary heart disease, brain Treating or preventing stroke, inflammatory bowel syndrome, indigestion, alcoholism, and stomach ulcers. A method wherein the method provides to a patient who requires the pharmaceutical composition described in claim 55 A method comprising administering an effective dose.

61. Administering one or more therapeutic drugs in combination in effective doses simultaneously, separately, or sequentially. The method according to claim 60, further comprising the above.

62. Hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, X syndrome, dyslipidemia Diseases, cognitive impairment, atherosclerosis, myocardial infarction, coronary heart disease, stroke, inflammatory bowel disease For the preparation of drugs for the treatment or prevention of symptoms, indigestion, alcoholism, and gastric ulcers. The pharmaceutical composition according to claim 55, to be used.

63. A polypeptide according to any one of claims 1 to 54 for use as a pharmaceutical agent It is its pharmaceutically acceptable salt.

64. For use in the treatment or prevention of a patient's disease, as described in any one of claims 1 to 54 polypeptides or pharmaceutically acceptable salts thereof.

65. 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 64 or the pharmaceutically acceptable polypeptide selected from among them. A good salt.

66. The polypeptide or a pharmaceutically acceptable salt thereof is an effective dose of one or more additional therapeutic agents. The drug, as described in claims 63 to 65, is provided simultaneously, separately, or sequentially in combination with the drug. A polypeptide or a pharmaceutically acceptable salt thereof.

67. For patients who require it, the polypeptide according to any one of claims 1 to 54 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 Methods for treating or preventing alcoholism and stomach ulcers.

68. Administering one or more therapeutic drugs in combination in effective doses simultaneously, separately, or sequentially. The method according to any one of claim 67, further comprising the above.

69. Hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, X syndrome, dyslipidemia Diseases, cognitive impairment, atherosclerosis, myocardial infarction, coronary heart disease, stroke, inflammatory bowel disease For the preparation of drugs for the treatment or prevention of symptoms, indigestion, alcoholism, and gastric ulcers. Use of the polypeptide according to any one of claims 1 to 54 or its pharmaceutically acceptable Possible salt.

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