GIP / GLP1 dual agonist therapeutic methods

Abstract

To provide a pharmaceutical composition for increasing HDL-C or lowering hypertension in a patient in need of HDL-C increase. Furthermore, the present invention provides a pharmaceutical composition for achieving normal HbA1c blood glucose levels in intractable type 2 diabetic patients.SOLUTION: Provided are pharmaceutical compositions comprising GIP / GLP1 agonists or pharmaceutically acceptable salts thereof for use in the treatment of elevated blood pressure in patients in need thereof, wherein the GIP / GLP1 agonists or pharmaceutically acceptable salts thereof are administered to the patients once a week, and wherein the GIP / GLP1 agonists or pharmaceutically acceptable salts thereof are compounds selected from the group consisting of specific sequences, or pharmaceutically acceptable salts thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to the field of medicine. It provides a treatment method for refractory type 2 diabetes (T2D) in patients who cannot reach the recommended glucose target values with metformin and SGLT-2 treatment. It also provides a method related to increasing the HDL-C level in patients who require an increase in the HDL-C level. And it provides a method for reducing blood pressure in patients who require a reduction in blood pressure. in patients who require a reduction in blood pressure.

Background Art

[0002] Glycated hemoglobin (HbA1c) is considered an important marker for blood glucose control in diabetology. The American Diabetes Association (ADA) guidelines indicate that patients with HbA1c of 5.7% or less are considered to have normal blood glucose. The treatment goal of a patient's HbA1c can vary depending on the patient. However, persistent poor HbA1c control disproportionately contributes to the development of diabetes-related complications. Patients with type 2 diabetes often cannot achieve normal blood glucose despite treatment using the ADA treatment paradigm. Despite not being within the normal range, the ADA guidelines suggest a reasonable HbA1c treatment target value of 7% or less according to the current treatment options of diet, exercise, metformin, oral diabetes treatment, and subsequently basal insulin. However, many patients cannot reach the HbA1c target value despite clinical treatment and are considered to have refractory type 2 diabetes.

[0003] Refractory type 2 diabetes generally develops over time against the background of (relatively stable) insulin resistance. This is explained by an increasingly severe defect in insulin secretion or beta cell damage. Patients who have been living with type 2 diabetes for 8 years have refractory type 2 diabetes. Therefore, it is highly likely that normal or positive blood glucose levels are present in patients with refractory type 2 diabetes. A therapeutic method that provides blood glucose levels that are consistently close to normal is desired. Providing normal or near-normal blood glucose in patients who have been treated for diabetes for at least 8 years There is a need for a treatment method that provides this.

[0004] Nearly half of American adults have high blood pressure or low HDL-C. High blood pressure can increase the risk of stroke, coronary artery disease, and stroke. Risk of coronary heart disease (CHD) and other serious health threats Many patients with type 2 diabetes and obesity develop hypertension. Approved treatments for diabetes typically have little or no effect on controlling high blood pressure. There is a need for treatment options to manage high blood pressure. Therefore, methods for treating hypertension in patients with hypertension are desirable.

[0005] High-density lipoprotein cholesterol (HD) Low serum levels of LC are another known risk factor for coronary heart disease (CHD). Patients with type 2 diabetes often have low serum levels of HDL-C. However, approved diabetes treatments generally fail to raise HDL-C. Population studies have shown that HDL-C is inversely and independently associated with the risk of developing CHD. It has been confirmed that HDL-C levels are elevated. Drug therapy to increase HDL-C levels is desirable. Therapeutic methods to increase HDL-C in patients with type 2 diabetes are needed. There are. Summary of the Invention [Means for solving the problem]

[0006] The present invention relates to a method for treating GIP / GLP1 agonists and their pharmaceutically acceptable salts. The present invention provides a method for treating, preventing, or delaying high blood pressure, comprising: 2. A method for treating a patient with a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof, comprising administering the method to a patient with a patient with a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof. for treating, preventing, or delaying hypertension in patients diagnosed with type 2 diabetes A method is further provided.

[0007] The present invention relates to a method for treating GIP / GLP1 agonists and their pharmaceutically acceptable salts. The present invention provides a method for treating, preventing, or delaying low HDL-C, comprising: The invention involves administering a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof. and to treat, prevent, or delay HDL-C in patients diagnosed with type 2 diabetes. A method for making the same is further provided.

[0008] The present invention relates to a method for treating GIP / GLP1 agonists and their pharmaceutically acceptable salts. Treating refractory type 2 diabetes in patients who have had type 2 diabetes for at least 8 years, including The present invention provides methods for preventing, delaying, or eliminating the effects of steroids.

[0009] The present invention relates to a method for treating GIP / GLP1 agonists and their pharmaceutically acceptable salts. Treating refractory type 2 diabetes in patients who have had type 2 diabetes for at least 8 years, including This provides a method for

[0010] In one embodiment, a patient in need of treatment for refractory type 2 diabetes has an HbA1c of more than 10%. It has.

[0011] In one embodiment, a patient in need of treatment for refractory type 2 diabetes has an HbA1c of greater than 11%. It has.

[0012] In one embodiment, a patient in need of treatment for refractory type 2 diabetes has an HbA1c of 5.7% or lower. In one embodiment, a patient in need of treatment for refractory type 2 diabetes has a therapeutic target value of 5 The HbA1c treatment target value is below 0.7%.

[0013] In one embodiment, a patient in need of treatment for refractory type 2 diabetes is receiving treatment for an HbA1c of 6%. It has a target value.

[0014] In one embodiment, a patient in need of treatment for refractory type 2 diabetes is receiving treatment for an HbA1c of 7%. It has a target value.

[0015] The present invention relates to a method for treating GIP / GLP1 agonists and their pharmaceutically acceptable salts. Non-responsive to metformin, SGLT-2, or metformin plus SGLT-2 inhibitors, including The present invention provides a method for treating refractory type 2 diabetes in a patient.

[0016] Thus, one embodiment provides a method for treating, preventing, or delaying hypertension in a patient in need thereof. A method for treating, preventing, or delaying hypertension, comprising administering to a patient an effective amount of G Weekly administration of an IP / GLP1 agonist or a pharmaceutically acceptable salt thereof, Further embodiments provide a method for treating hypertension in patients diagnosed with type 2 diabetes. The method comprises administering to a patient an effective amount of a GIP / GLP1 agonist or a pharmaceutical formulation thereof. The method comprises administering a compound acceptable to the subject once a week.

[0017] In another aspect, the present invention is a method for preventing or delaying hypertension in a patient. and administering to the patient a therapeutically effective amount of a GIP / GLP1 agonist once weekly. Provide the law.

[0018] In another aspect, the present invention provides a method for preventing hypertension in patients diagnosed with type 2 diabetes, or is a method for delaying steroid use, comprising administering to a patient a therapeutically effective amount of a GIP / GLP1 agonist once a week. The method includes administering

[0019] In another aspect, the present invention provides a method for treating, preventing, or delaying the onset of hypertension in a patient. The present invention provides the use of a GIP / GLP1 agonist for the preparation of a once-weekly medicament for do.

[0020] The present invention provides a method for treating, preventing, or slowing hypertension, such as A patient in need of treatment is administered an effective amount of a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof. The method includes administering a salt thereof.

[0021] In one embodiment, the patient in need of treatment for hypertension has type 2 diabetes and is non-obese. is.

[0022] In one embodiment, the patient in need of treatment for hypertension has type 2 diabetes and is obese. be.

[0023] In one embodiment, the patient in need of treatment for hypertension has refractory type 2 diabetes.

[0024] In one embodiment, the patient in need of treatment for hypertension has had type 2 diabetes for at least 8 years. It is.

[0025] Thus, one embodiment is directed to the treatment of hypertensive crises in patients with refractory type 2 diabetes. A method for treating, preventing, or delaying the onset of rheumatoid arthritis, comprising administering to a patient an effective amount of G Weekly administration of an IP / GLP1 agonist or a pharmaceutically acceptable salt thereof, A method is provided.

[0026] In one embodiment, the patient in need of treatment for hypertensive crisis has type 2 diabetes. , and are non-obese.

[0027] In one embodiment, the patient in need of treatment for hypertensive crisis has type 2 diabetes. , and obesity.

[0028] In one embodiment, the patient in need of treatment for hypertensive crisis has refractory type 2 diabetes. are.

[0029] In one embodiment, the patient in need of treatment for hypertensive crisis has type 2 diabetes at least I've been suffering for 8 years.

[0030] Thus, one embodiment provides a method for treating, preventing, or alleviating low HDL-C in a patient. A method for delaying the onset of GIP / GLP1 agonist, comprising administering to a patient an effective amount of a GIP / GLP1 agonist or its analogues. once weekly administration of a pharmaceutically acceptable salt of

[0031] In another aspect, the present invention provides a method for preventing or delaying a hypertensive crisis in a patient. The patient is administered an effective amount of a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof. once weekly.

[0032] In another aspect, the present invention provides a method for preventing or delaying low HDL-C in a patient. The patient is administered an effective amount of a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof. The method includes administering the compound once a week.

[0033] In another aspect, the present invention provides a method for treating a pulmonary arthritis (PA) syndrome that can be treated with steroids for at least 1 year, 2 years, 3 years, 4 years, or 5 years. Hypertension in patients with type 2 diabetes mellitus receiving clinical treatment with oral antidiabetic agents for a long period of time 1. A method for treating hypertension, comprising administering to a patient an effective amount of GIP, wherein the patient has an HbA1c greater than 7%. / A method comprising administering a GLP1 agonist or a pharmaceutically acceptable salt thereof once a week. to provide.

[0034] In another aspect, the present invention provides a method for treating a patient with type 2 diabetes mellitus who is at risk for hypertension. 1. A method for improving glycemic control in a patient, comprising administering to the patient an effective amount of GIP / GLP. 1 agonist or a pharmaceutically acceptable salt thereof once weekly, A method is provided that provides a reduced risk of developing a crisis.

[0035] In another aspect, the present invention provides a method for treating a patient with type 2 diabetes mellitus who is at risk for hypertension. 1. A method for improving glycemic control in a patient, comprising administering to the patient an effective amount of GIP / GLP. 1. Administration of an agonist or its pharmaceutically acceptable salt once a week for at least 30 weeks and providing a reduced risk of a patient experiencing a hypertensive crisis.

[0036] In another aspect, the present invention provides a method for improving weight management in patients who are obese and at risk for hypertension. The present invention relates to a method for improving the treatment of GIP / GLP1 syndrome, comprising administering to a patient an effective amount of a GIP / GLP1 agonist or a pharmaceutical formulation thereof. This includes weekly administration of a commercially acceptable salt, reducing the patient's risk of developing a hypertensive crisis. Provide below, provide a method.

[0037] In another aspect, the present invention provides a method for treating hypertension in a patient, comprising administering to the patient and administering an effective amount of a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof once a week. wherein the patient's weight is within the patient's normal weight range.

[0038] In another aspect, the present invention provides a method for improving weight management in patients who are obese and at risk for hypertension. The present invention relates to a method for improving the treatment of GIP / GLP1 syndrome, comprising administering to a patient an effective amount of a GIP / GLP1 agonist or a pharmaceutical formulation thereof. This includes weekly administration of a commercially acceptable salt, which reduces the patient's risk of developing hypertension. Provide a method to do so.

[0039] In another aspect, a G A GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof, The agonist is administered once a week, and the GIP / GLP1 agonist or its pharmaceutically acceptable salts are Provide salt.

[0040] In another aspect, the method includes administering a G A GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof, a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is administered once a week; or a pharmaceutically acceptable salt thereof.

[0041] In another aspect, one embodiment provides a weekly dose for the treatment, prevention, or delay of the onset of hypertension. A GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof for the preparation of a single-dose medicament. The use of salt is

[0042] In another embodiment, a once-weekly medication is provided for the treatment, prevention, or delay of the onset of hypertension. The present invention provides the use of a GIP / GLP1 agonist for the preparation of a medicament.

[0043] In another aspect, one embodiment is a compound for treating, preventing, or delaying the onset of a hypertensive crisis. GIP / GLP1 agonist or pharmaceutical composition thereof for the preparation of a once-weekly medicament for The use of salts that are acceptable for the purpose.

[0044] In another embodiment, once-weekly administration for treating, preventing, or delaying the onset of hypertensive crisis. The present invention provides the use of a GIP / GLP1 agonist for the preparation of a medicament for the treatment of a patient suffering from atopic dermatitis.

[0045] In one embodiment, the GIP / GLP1 agonist is a compound according to International Publication No. WO 2020 / 023386 No. 6,299,233 (Eli Lilly) filed on Dec. 1, 2002, and is claimed in US Pat. No. 6,299,233 (Eli Lilly).

[0046] As used herein, "hypertensive crisis" refers to a condition in which blood pressure becomes dangerously high and the patient Hypertensive crisis typically occurs in a minor High blood pressure is generally 130 / 80 systolic / diastolic. Blood pressure.

[0047] As used herein, "refractory type 2 diabetes" refers to a condition in which the patient is taking oral standard antidiabetics such as metformin. This refers to patients who are unable to achieve their HbA1c target levels using therapeutic drugs.

[0048] As used herein, "HbA1c target value" refers to the target HbA1c value determined by a patient's clinical treatment plan. Achieved by the patient, as determined and measured using clinically accepted methods The current ADA guidelines are based on diet, exercise, and 7% according to current treatment options of toformin, oral diabetes treatment, followed by basal insulin The following reasonable HbA1c treatment targets are suggested: Despite treatment, he was unable to reach his HbA1c target value and suffered from refractory type 2 diabetes. In one embodiment, the target HbA1c value is 7% or less. In this form, the target HbA1c value is 5.7% or less.

[0049] CH at baseline in the Framingham study (12-year follow-up period) Among men and women aged 49-82 who were not affected by D, those with high HDL-C levels Participants with a high HDL-C level (80th percentile) were significantly higher than participants with a low HDL-C level (20th percentile). 50 percent lower risk of cardiovascular events compared with the middle aged 2 Positive Mindset The Prospective Cardiovascular Munster (PROCAM) study (approximately 4, 500 volunteers, ages 16-65, followed for 6 years Therefore, individuals with HDL-C levels below 35 mg / dl were compared with individuals with HDL-C levels above 35 mg / dl. Assmann G et al. al.,High-density lipoprotein cholesterol as a predictor of coronary heart diseases e risk.The PROCAM experience and pathoph ysiological implications for reverse cho lesterol transport.Atherosclerosis.1996; 124(Suppl):S11-S20. Gordon et al. For every 1 mg / dl increase in blood cholesterol, there is a 2-3 percent reduction in the individual's combined cardiovascular risk. Gordon DJ et al. High-density l ipoprotein cholesterol and cardiovascula r disease:four prospective American stud ies.Circulation.1989;79:8-15. Veterans Affairs HDL Entrance Exam (Veterans Administration HDL Intervention The results of the VA-HIT Trial showed that patients with low HDL-C initially In this study, a moderate increase in HDL-C of only 6 percent significantly reduced coronary morbidity and mortality. Both were significantly reduced by 24 percent. Rubins HB, et al. al.,Gemfibrozil for the secondary preven tion of coronary heart disease in men wi th low levels of high-density lipoprotei n cholesterol.Veterans Affairs High-Dens ity Lipoprotein Cholesterol Intervention Trial Study Group.N Engl J Med.1999;341 :410-8. Current treatments for increasing HDL-C include bioavailability, such as increased exercise and reduced dietary fat. In many cases, lifestyle modifications will achieve the desired increase in HDL-C. Treatment options are needed for patients who need to increase HDL-C. There is a need for therapies to treat, prevent, or delay low HDL-C. There are.

[0050] As used herein, the terms "treatment," "treat," "treating," and the like mean This means to include slowing or attenuating the progression of a disease, condition, or disorder. The term "disorder" refers to a condition, even if the condition is not actually eliminated or Alleviating one or more symptoms of a disorder or condition, even if the progression itself is not slowed or reversed As used herein, "prevent" also includes "ameliorating, attenuating, eliminating, or mitigating." "," "preventing," "prevention," and the like terms refer to the reduction or reduction in the onset of a disease, condition, disorder, or symptom. As used herein, "delay" and "prevent" are meant to include "prevent" and "prevent" and "and" and the like terms mean an increase in the time period between the onset of a disease, condition, disorder, or symptom. When used herein in reference to multiple outcomes, "composite" is meant to include The term "HD" refers to the occurrence of the first of any of the outcomes. The term "increase in HDL-C" refers to an increase in measured HDL-C levels from baseline. In one embodiment, the increase in HDL-C change is a statistically significant increase. In an embodiment, the increase in HDL-C is an increase of more than 2% from baseline. In one embodiment, an increase in HDL-C is an increase of more than 5% from baseline. An increase in HDL-C is an increase of more than 7% from baseline. An increase is an increase of more than 10% from baseline.

[0051] A "therapeutically effective amount" is defined as the amount of a substance that will have a therapeutic effect on the health of a patient as determined by a researcher, physician, or other clinician. This will induce a biological or medical response or induce a desired therapeutic effect in the patient. GIP / GLP1 agonists or pharmaceutically acceptable salts thereof for the methods and uses of the invention or the amount of a salt thereof, or a GIP / GLP agonist or a drug thereof for the methods and uses of the present invention. An effective amount of a GIP / GLP1 agonist is defined as the amount of a pharmaceutical composition containing a physiologically acceptable salt thereof. The dosage of the compound or a pharmaceutically acceptable salt thereof may be determined based on factors such as the disease state, age, sex, and weight of the individual. Depending on the cause and the ability of the GIP / GLP1 agonist to elicit the desired response in the individual, An effective amount also means that the therapeutically beneficial effects outweigh any toxic or detrimental effects. In certain embodiments, the therapeutic agent for use in the methods described herein is The effective amount of the GIP / GLP1 agonist is administered as an oral dosage form. In certain embodiments, a therapeutically effective amount of a GIP / GLP1 agonist is administered once daily. In one embodiment, the therapeutically effective amount of the GIP / GLP1 agonist is administered twice daily. In certain embodiments, a therapeutically effective amount of a GIP / GLP1 agonist is administered daily as an oral formulation. It is given.

[0052] Additional embodiments are described below.

[0053] In one embodiment, the compound is intended to improve glycemic control in patients with type 2 diabetes mellitus. and a method for increasing HDL-C, comprising administering to a patient a therapeutically effective amount of GIP / GLP1 antagonist. The method involves administering a steroid agonist or a pharmaceutically acceptable salt thereof once a week for at least 30 weeks. Hmm, a method.

[0054] In one embodiment, the GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is at least In one embodiment, the GIP / GLP1 agonist or its pharmaceutical The physiologically acceptable salt is administered for at least 52 weeks.

[0055] High blood pressure and normal HbA1c blood sugar 1. A method of treating, preventing, or delaying the onset of hypertension in a patient, comprising: Patients are administered a therapeutically effective amount of a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof once a week. In one embodiment, the hypertension is a condition characterized by hypertension and hypertensive crisis. is selected from the group consisting of:

[0056] A method for preventing or delaying hypertension in a patient, comprising administering to the patient a therapeutically effective amount of G Weekly administration of an IP / GLP1 agonist or a pharmaceutically acceptable salt thereof, method.

[0057] A method for preventing or delaying hypertension in a patient, comprising administering to the patient a therapeutically effective amount of G The present invention relates to administering an IP / GLP1 agonist or a pharmaceutically acceptable salt thereof in an oral dosage form. Hmm, a method.

[0058] Improve glycemic control in patients diagnosed with type 2 diabetes mellitus A method for treating, preventing, or delaying hypertension comprising administering to a patient a therapeutically effective amount of G Weekly administration of an IP / GLP1 agonist or a pharmaceutically acceptable salt thereof, method.

[0059] Improve glycemic control in patients diagnosed with type 2 diabetes mellitus A method for treating, preventing, or delaying hypertension comprising administering to a patient a therapeutically effective amount of G The present invention relates to administering an IP / GLP1 agonist or a pharmaceutically acceptable salt thereof in an oral dosage form. Hmm, a method.

[0060] In one embodiment, the method results in a reduced risk of the patient developing hypertension. In embodiments, the method results in a reduced risk of a patient experiencing a hypertensive crisis. In one embodiment, the method reduces the patient's risk of clinically low HDL-C. is brought about.

[0061] 1. A method for improving glycemic control in a patient suffering from type 2 diabetes mellitus, comprising: Patients are administered a therapeutically effective amount of a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof once a week. and administering the compound once daily, resulting in a reduced risk of the patient developing hypertension.

[0062] The method of any of the above embodiments, wherein the patient is suffering from type 2 diabetes mellitus. The method of any of the above embodiments, wherein the patient has refractory type 2 diabetes. In any of the above embodiments, the patient has had type 2 diabetes for at least 8 years. Any of the above embodiments, wherein the patient has had type 2 diabetes for at least 10 years. The method according to any one of claims 1 to 4, wherein the once-weekly administration of the GIP / GLP1 agonist is The method of any of the above embodiments, wherein the patient is non-obese, 10. The method according to any of the preceding embodiments.

[0063] The patient has one or more of the following: T2DM, hypertension, reduced HDL-C, and obesity. 3. The method according to any of the preceding embodiments, wherein

[0064] In one embodiment, the patient has multiple cardiovascular risk factors, not including hypertension, or Either have multiple cardiovascular risk factors that do not include clinically significant hypertension.

[0065] In one embodiment, the patient has multiple cardiovascular risk factors or has a H bA1c levels.

[0066] As used herein, "cardiovascular risk factors" refers to current tobacco use (any forms of tobacco); at least one drug to treat hypercholesterolemia within the past 6 months Use of one approved lipid-modifying therapy or a lipid level of 3.4 mmol / L (100 mg / dL) or higher Untreated low-density lipoprotein cholesterol l, LDL-C) within the past 6 months; for men, 1.0 mmol / L (40 mg / dL), and for women, less than 1.3 mmol / L (50 mg / dL) for treated or untreated Treatment of high-density lipoprotein cholesterol (HDL-C) or triglycerides 2.3m mol / L (150 mg / dL) or higher; at least one method to treat hypertension Systolic blood pressure (systolic blood pressure) of 130 mmHg or higher, or untreated or using blood pressure medication , SBP) or diastolic blood pressure (DBP) of 80 mmHg or more ); a measured waist circumference of 102 cm for men and 88 cm for women This means increased risk of cardiovascular disease.

[0067] As used herein, "non-obese" refers to a patient who is not obese by applicable standards. In one embodiment, the non-obese patient has a body mass index of less than 30 BMI. .

[0068] As used herein, "co-occurring" refers to a condition in which a patient is diagnosed with two or more medical conditions. This means that

[0069] In one embodiment, the patient's risk of hypertensive crisis is reduced by at least about 14%.

[0070] In one embodiment, the patient's risk of hypertensive crisis is reduced by at least about 10%.

[0071] In one embodiment, HDL-C levels are increased. In one embodiment, HDL-C levels are In one embodiment, the patient is a patient with type 2 diabetes mellitus. 2. A method for improving glycemic control and increasing HDL-C in a patient, comprising administering A therapeutically effective amount of a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is administered once a week for a short period of time. The method includes administering the compound for at least 30 weeks.

[0072] In one embodiment, a reduced risk of occurrence of the composite of the following outcomes: hypertension hospitalization or death. do.

[0073] In one embodiment, the risk of death or hospitalization due to hypertension is reduced by administration of an effective amount of GIP / GLP1 antagonist. The level of vasopressin is reduced in patients treated with an agonist or a pharmaceutically acceptable salt thereof.

[0074] In one embodiment, the risk of developing a combination of the following outcomes: hypertension and HbA1c greater than 5.7% In one embodiment, the following outcomes are reduced: low HDL-C, high blood pressure, and Hb > 7%. Reduced risk of developing A1c combination.

[0075] In one embodiment, the following outcomes: low HDL-C, high blood pressure, and HbA1c greater than 5.7% The risk of developing complications is reduced.

[0076] In one embodiment, the following outcomes: a combination of low HDL-C, high blood pressure, and HbA1c greater than 6%. The risk of developing

[0077] It was a method to achieve normal HbA1c blood glucose in patients with refractory type 2 diabetes. and administering to the patient a therapeutically effective amount of a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof. The method comprises administering the compound once a week.

[0078] In one embodiment, the GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is administered at a dose of It is administered using a titration protocol.

[0079] In one embodiment, the patient is administered a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof. Use of one or two oral antidiabetic agents for at least one year prior to treatment with Inability to achieve HbA1c below 7%.

[0080] In one embodiment, the patient is administered a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof. 8% with one or two oral agents for at least 1 year prior to treatment with Inability to achieve HbA1c below 0.01.

[0081] In one embodiment, the patient is administered a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof. 10 years of treatment with one or two oral agents for at least 1 year prior to treatment with Unable to achieve HbA1c below %.

[0082] In one embodiment, a once-weekly dose of a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is administered. The administration of the GIP / GLP1 agonist is continued for at least 30 weeks. or a pharmaceutically acceptable salt thereof, is administered once a week for at least 40 weeks. In this form, once-weekly administration of a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is and continues for at least 50 weeks. In one embodiment, the GIP / GLP1 agonist or its The weekly administration of the pharmaceutically acceptable salt continues for at least two years. The once-weekly administration of a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is effective in at least In one embodiment, the GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is administered for 3 years. The weekly administration of the salts is continued for at least five years.

[0083] In one embodiment, the patient is administered a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof. Type 2 diabetes was diagnosed at least 8 years prior to administration.

[0084] In one embodiment, the patient is administered a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof. Type 2 diabetes was diagnosed at least 10 years prior to administration.

[0085] In one embodiment, the patient is administered a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof. Type 2 diabetes was diagnosed at least 13 years prior to administration.

[0086] In one embodiment, a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is administered. Patients to be treated must be at least 46 years old.

[0087] In one embodiment, a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is administered. Patients to be treated must be at least 55 years old.

[0088] In one embodiment, a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is administered. Patients to be treated must be at least 60 years old.

[0089] In one embodiment, a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is administered. Patients receiving this treatment also receive metformin and an oral SGLT2.

[0090] In one embodiment, a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is administered. Patients receiving this treatment will also receive an oral SGLT2.

[0091] In one embodiment, a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is administered. Patients receiving this treatment also receive metformin.

[0092] In one embodiment, a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is administered. Patients receiving this treatment also receive basal insulin.

[0093] In one embodiment, a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is administered. Patients receiving this treatment also receive metformin and basal insulin.

[0094] In one embodiment, a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is administered. Patients receiving this treatment also receive SGLT2 and basal insulin.

[0095] In one embodiment, a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is administered. Patients receiving this treatment also receive metformin, SGLT2, and basal insulin.

[0096] In one embodiment, the basal insulin is insulin glargine.

[0097] In one embodiment, the basal insulin is insulin degludec.

[0098] In one embodiment, a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is administered. Patients receiving this treatment also receive an oral SGLT2 agent.

[0099] In one embodiment, a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is administered. Patients receiving metformin, oral SGLT2, and insulin degludec were also treated. do.

[0100] In one embodiment, a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is administered. Patients receiving metformin, oral SGLT2, and insulin degludec were also treated. do.

[0101] In one embodiment, a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is administered. Patients receiving this treatment also receive metformin, oral SGLT2, and insulin glargine.

[0102] In one embodiment, a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is administered. Patients receiving this treatment also receive metformin and insulin glargine.

[0103] In another aspect, the present invention provides a GIP / Provided is a GLP1 agonist or a pharmaceutically acceptable salt thereof.

[0104] In another aspect, the present invention provides a method for preparing a medicament for any of the above embodiments. The present invention provides use of a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof in the treatment of rheumatoid arthritis.

[0105] In one embodiment, the GIP / GLP1 agonist is a compound of formula I, R1X1X2X3GTX6TSDX 10 X 11 X 12 X 13 X 14 DX 16 X 17 AX 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 (SEQ ID NO: 3) During the ceremony, R1 is absent or an Ac modification of the N-terminal amino group; X1 is selected from the group consisting of Y, H, D-Tyr, F, desH, and desY; X2 is selected from the group consisting of Aib, αMeP, A, P, and d-Ala; or X1 and X2 combine to form desH-ψ[NHCO]-Aib; X3 is selected from the group consisting of E, N, Aad, and cTA; X6 is selected from the group consisting of F, αMeF, and αMeF(2F); X 10 are A, L, H, 3Pal, 4Pal, V, Y, E, αMeF, αMeF(2F ), I, αMeY, Q, D-His, D-Tyr, cTA, and K(2-[2-(2-α Glucocorticoids (2-(γ-Glu)-CO-(CH2)qC) OH; X 11 is selected from the group consisting of S, αMeS, and D-Ser; X 12 I, S, D-Ile, and K(2-[2-(2-amino-ethoxy)-ethoxy]- [oxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H Selected, X 13 Nle, Aib, L, αMeL, and K(2-[2-(2-amino-ethoxy) Glucocorticoids consisting of 2-(γ-Glu)-(gamma-Glu)-CO-(CH2)qCO2H is selected from the group X 14 is selected from the group consisting of L and K, where K is C 16 -C 22 Binds to fatty acids wherein the fatty acid is optionally linked to the K via a linker; X 16 are K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK, R, and and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )—CO—(CH2)qCO2H; X 17 are K, Q, I, and C 16 -C 22 From the group consisting of amino acids that bind to fatty acids selected, wherein the fatty acid is optionally attached to the amino acid via a linker; X 19 Q, A, and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetate) (γ-Glu)-CO—(CH)COH; X 20 Aib, Q, H, R, K, αMeK, and K(2-[2-(2-amino- (gamma-Glu)-CO-(CH2)qCO2H is selected from the group consisting of X 21 H, Aad, D, Aib, T, A, E, I, and K(2-[2-(2-amino (γ-Glu)-CO-(CH) 2H, X 22 is selected from the group consisting of F and αMeF; X 23 are I, L, A, G, F, H, E, V, and K(2-[2-(2-amino-ethoxy) oxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H is selected from the group consisting of X 24 are S, Aad, D-Glu, E, Aib, H, V, A, Q, D, P, and K( 2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-C O—(CH2)qCO2H; X 25 is selected from the group consisting of Y and αMeY; X 26 L, αMeL, and K(2-[2-(2-amino-ethoxy)-ethoxy] -acetyl)2-(γ-Glu)-CO—(CH2)qCO2H , X 27 are L, I, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetate (γ-Glu)-CO—(CH)COH; X 28are E, A, S, D-Glu, and K(2-[2-(2-amino-ethoxy)- [ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H are selected from X 29 Aib, G, A, and K (2-[2-(2-amino-ethoxy)-ethoxy] ]-acetyl)2-(γ-Glu)-CO—(CH2)qCO2H R, X 30 C, G, G-R2, and K(2-[2-(2-amino-ethoxy)-ethoxy] Glucocorticoids (gamma-Glu)-CO-(CH2) q -CO2H Selected, X 31 is absent or PX 32 X 33 X 34 -R2 (SEQ ID NO: 4), PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 5), PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R2 (SEQ ID NO: 6), K[(2-[2-( 2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2 ) q -CO2H]X 32 X 33 X 34 -R2 (SEQ ID NO: 7), K[(2-[2-(2-a 2-(γ-Glu)-(C1H-2H)-(2-(γ-Glu)-2-ethoxy)-(2-(γ-Glu)-2-ethoxy)-acetyl q - CO2H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 8), and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-G lu)-CO-(CH2) q -CO2H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R2 (SEQ ID NO: 9), During the ceremony, X 32 S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl )2-(γ-Glu)-CO-(CH2) q -CO2H], X 33 S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl )2-(γ-Glu)-CO-(CH2) q -CO2H], X 34 G, C, and K [(2-[2-(2-amino-ethoxy)-ethoxy]-amino] Cetyl)2-(γ-Glu)-CO-(CH2) q -CO2H] , X 35 A or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl )2-(γ-Glu)-CO-(CH2) q -CO2H], X 36 P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl )2-(γ-Glu)-CO-(CH2)q -CO2H], X 37 P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl )2-(γ-Glu)-CO-(CH2) q -CO2H], X 38 P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl )2-(γ-Glu)-CO-(CH2) q -CO2H], X 39 C, S, and K[(2-[2-(2-amino-ethoxy)-ethoxy]-amino] Cetyl)2-(γ-Glu)-CO-(CH2) q -CO2H] , X 40 C and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl )2-(γ-Glu)-CO-(CH2) q -COH], q is selected from the group consisting of 14, 15, 16, 17, 18, 19, and 20; R2 is absent or an NH2 modification of the C-terminal group; X 30 If G-R2, then X 31 is absent, X 10 , X 12 , X 13 , X 14 , X 16 , X 17 , X 19 , X 20 , X 21 , X 23 、 X 24 , X 26 , X 27 , X 28 , X 29 , X 30 , X 31 , X 32 , X 33 , X34 , X 35 , X 36 , X 37 , X 38 , X 39 , and X 40 One of them contains fatty acids may be a substituent, X 30 , X 34 , X 39 , and X 40 may be C; X 30 , X 34 , X 39 , and X 40 If one of the is C, then X 10 , X 12 , X 13 , X 14 , X 16 , X 17 , X 19 , X 20 , X 21 , X 23、 X 24 , X 26 , X 27 , X 28 , X 29 , X 30 , X 31 , X 32 , X 33 , X 34 , X 35 , X 36 , X 37 , X 38 , X 39 , and X 40 None of the substituents contains a fatty acid. or a pharmaceutically acceptable salt thereof.

[0106] In one embodiment, the GIP / GLP1 agonist is X 17 But C 16 -C 22 an amino acid conjugated to a fatty acid, is optionally conjugated to the amino acid via a linker, X 30 is selected from the group consisting of G-R2 and G; X 30 If G, then X 31 But PX 32 X 33 X 34 -R2 (SEQ ID NO: 4) , X 32 is S and X 33 is S and X 34 is G (SEQ ID NO: 15), and P X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 5) (wherein X3 2 is S and X 33 is S and X 34 is G and X 35 is A and X 36 is P Yes, X 37 is P and X 38 is P and X 39 is S (SEQ ID NO: 16) A compound of formula II (hereinafter "compound of formula III") selected from the group consisting of: It is a commercially acceptable salt.

[0107] In one embodiment, X 17 The amino acid is conjugated to the fatty acid via a linker; A compound of formula III (hereinafter referred to as "compound of formula IIIa"), or a pharmaceutically acceptable salt thereof be.

[0108] In one embodiment, the GIP / GLP1 agonist is X 10 is A, L, H, 3PAl, 4PAl, V, Y, E, αMeF, αMeF(2F ), I, αMeY, Q, D-His, D-Tyr, and cTA; X 12 is selected from the group consisting of I, S, and D-Ile; X 13 is selected from the group consisting of Nle, Aib, L, and αMeL; X 14 is selected from the group consisting of L, and K; X 16 K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK, and R is selected from the group consisting of X 19 is selected from the group consisting of Q and A; X 20 is selected from the group consisting of Aib, Q, H, R, K, and αMeK; X 21 is selected from the group consisting of H, Aad, D, Aib, T, A, E, and I; X 23 is selected from the group consisting of I, L, A, G, F, H, E, and V; X 24 consists of S, Aad, D-Glu, E, Aib, H, V, A, Q, D, and P is selected from the group X 26 is selected from the group consisting of L, and αMeL; X 27 is selected from the group consisting of L, and I; X 28 is selected from the group consisting of E, A, S, and D-Glu; X 29 is selected from the group consisting of Aib, G, and A; X 30 is selected from the group consisting of G and G-R2; X 30 If G, then X 31 But PX 32 X 33 X 34 -R2 (SEQ ID NO: 4) , X 32 is S and X 33is S and X 34 is G (SEQ ID NO: 15), and P X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 5) (wherein X3 2 is S and X 33 is S and X 34 is G and X 35 is A and X 36 is P Yes, X 37 is P and X 38 is P and X 39 is S (SEQ ID NO: 16) Compounds of formula III and formula IIIa (hereinafter referred to as compounds of formula IIIb) selected from the group consisting of: ), or a pharmaceutically acceptable salt thereof.

[0109] In one embodiment, the GIP / GLP1 agonist is R1 is absent, X1 and X2 do not combine to form desH-ψ[NHCO]-Aib, X 17 But C 16 -C 22 K is a linker that binds to a fatty acid. and optionally linked to said amino acid via It is a possible salt.

[0110] In one embodiment, the GIP / GLP1 agonist is X1 is Y, X2 is Aib, X3 is E, X 10 is selected from the group consisting of A, L, H, 3Pal, 4Pal, V, and Y; X 11 But S, X 12 But I, X 14 But L, X 16 is selected from the group consisting of K, E, Orn, Dab, and Dap; X 17 But C 16 -C 22 K bound to a fatty acid (wherein the fatty acid is a linker optionally linked to the amino acid via X 19 But Q, X 20 But Aib, X 21 is selected from the group consisting of H, Aad, D, Aib, T, A, and E; X 22 But F, X 23 But I, X 24 is selected from the group consisting of S, Aad, D-Glu, and E; X 26 But L, X 28 is selected from the group consisting of E and A, or a pharmaceutically acceptable salt thereof It is an acceptable salt.

[0111] In one embodiment, the GIP / GLP1 agonist is X1 is Y, X2 is Aib, X3 is E, X6 is αMeF(2F), X 10 is selected from the group consisting of Y, 4-PaI, and V; X 11 But S, X 12 But I, X 13 is selected from the group consisting of L, Aib, and αMeL; X 14 But L, X 16 is selected from the group consisting of E, K, and Orn; X 17 But C 16 -C 22 K bound to a fatty acid (wherein the fatty acid is a linker optionally linked to the amino acid via X 19 But Q, X 20 But Aib, X 21 is selected from the group consisting of E, A, and T; X 22 But F, X 23 But I, X 24 is D-Glu, X 25 is selected from the group consisting of Y and αMeY; X 26 But L, X 27 But I, X 28 But E, X 29 But G, X 30 But G, X 31 But PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2(SEQ ID NO: 5 )(wherein, X 32 is S and X 33 is S and X 34 is G and X 35 is A , X 36 is P and X 37 is P and X 38 is P and X 39 is S (sequence number No. 16), or a pharmaceutically acceptable salt thereof.

[0112] In one embodiment, the GIP / GLP1 agonist is X 16 is Orn and X 13 is α MeL and X 25 is Y; or is a pharmaceutically acceptable salt thereof. In one embodiment, X 16 is E and X 13 is αM eL and X 25 wherein Y is a GIP / GLP1 agonist of formula III, formula IIIa and a compound of formula IIIb, or a pharmaceutically acceptable salt thereof. IP / GLP1 agonists are 16 is E and X 13 is αMeL and X 10 Y and X 25 is αMeY; or and pharmaceutically acceptable salts thereof. In one embodiment, the GIP / GLP1 agonist is X 16 is Orn and X 13 is αMeL and X 10 is 4Pal, and X 25 is Y Compounds of formula III, IIIa, and IIIb, or pharmaceutically acceptable salts thereof is.

[0113] In one embodiment, the GIP / GLP1 agonist is selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: a compound of formula I selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14, or and pharmaceutically acceptable salts thereof.

[0114] In one embodiment, the GIP / GLP1 agonist is selected from the group consisting of Y, F, and D-Tyr. X6 is F; and X 13 consists of Aib, L, and αMeL or a pharmaceutically acceptable salt thereof.

[0115] In one embodiment, the GIP / GLP1 agonist is one in which R1 is absent and X1 is Y, F, and D-Tyr, X6 is F, and X 13 However, Aib, L, and and αMeL, X2 is Aib, X3 is E, and X 10 is Y and X 11 is S and X 12 But I and X 14 But L and X 16 consists of K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK, and R selected from the group X 17 But C 16 -C 22 Amino acids bound to fatty acids (where the fatty acids The amino acid is optionally linked to the amino acid via a linker, and X 19 But Q and X 20 is selected from the group consisting of Aib, Q, H, and K; and X 21 But H, D, T, A, and E, 22 But F and X 23 But I and X 24 but, D-Glu and E, 26 But L and X 27 But I, X 28 is selected from the group consisting of E, A, S, and D-Glu; and X 29 But, Aib, G and A, 30 is selected from the group consisting of C, G, and G-R2 And X 31 is absent or PX 32 X 33 X 34-R2 (SEQ ID NO: 4), PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 5), and PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R2 (SEQ ID NO: 6) wherein X is selected from the group consisting of 32 is S and X 33 is S and X 34 is a group consisting of G and C Selected from X 35 is A and X 36 is P and X 37 is P and X 38 is P Yes, X 39 is selected from the group consisting of C and S, and X 40 is C; or is a pharmaceutically acceptable salt thereof.

[0116] In one embodiment, the GIP / GLP1 agonist is selected from the group consisting of Y, F, and D-Tyr. X6 is F; and X 13 consists of Aib, L, and αMeL selected from the group X 28 is A and X 29 But G and X 30 But it is G and X3 1 is PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 5) Ri, X 34 But G and X39 is S, or a pharmaceutically acceptable salt thereof. It is a salt that can be used.

[0117] In one embodiment, the GIP / GLP1 agonist is selected from the group consisting of X1 and D-Tyr. Selected from X 13 is αMeL, or a pharmaceutically acceptable salt thereof. be.

[0118] In one embodiment, the GIP / GLP1 agonist is selected from the group consisting of SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 3 Formula I selected from the group consisting of SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, and SEQ ID NO: 26 or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, the GIP / GLP1 agonist is a compound of formula VI, X1X2EGTX6TSDX 10 X 11 X 12 X 13 LDX 16 X 17 AQX 20 X2 1X 22 IX 24 X 25 LIX 28 GX 30 (SEQ ID NO: 27) During the ceremony, X1 is selected from the group consisting of Y and R1Y; R1 is Ac modification of the N-terminal amino group, X2 is Aib, X6 is selected from the group consisting of αMeF and αMeF(2F); X 10 , 4Pal, Y, αMeF, αMeF(2F), αMeL, αMeV, Ac4 c, Ac5c, Ac6c, Bip, 1Nal, 2Nal, OMeY, hTyr, Nle, V, 4CPhe, ChG, ChA, Bzt, 2FA, 4TAA, 2TA, 3TA, and K Z1, X 11 is selected from the group consisting of S, αMeS, Aib, G, Dap, Ac5c, and Tle Selected, X 12 is selected from the group consisting of I and KZ1; X 13 is selected from the group consisting of αMeL and αMeF; X 16 But Orn, X 17 is selected from the group consisting of Q, I, and KZ1; X 20 is a group consisting of Aib, Orn, 4Pal, αMeF, Ac5c, and Ac6c is selected from X 21 is selected from the group consisting of E, KZ1, G, Orn, and 4Pal; X 22 But, F, 2ClPhe, 3ClPhe, 2FPhe, 3FPhe, 3,5FPh The group consisting of e, 1Nal, 2Nal, αMeF(2F), ChA, Bzt, and αMeF is selected from X 24 is selected from the group consisting of D-Glu, E, G, and KZ1; X 25 is selected from the group consisting of Y, αMeY, αMeF, and KZ1; X 28 is selected from the group consisting of E, Orn, and KZ1; X 30 is the group consisting of G, Orn, KZ1, K(Z1)R6, OrnR2, and GR2 is selected from R2 is X 31 , X 31 SSG (SEQ ID NO: 28), X 31 SSG-R3 (SEQ ID NO: 29 ), X 31 SSGX 35 PPPX39 (SEQ ID NO: 30), X 31 SSGX 35 PPPX3 9R3 (SEQ ID NO: 31), X 31 SSGX 35 PPPX 39 X 40 (SEQ ID NO: 32), X 31 SSGX 35 PPPX 39 X 40 R3 (SEQ ID NO: 33), and C-terminal modifications wherein the modification is NH2; R6 is PSSG (SEQ ID NO: 34), PSSG-R3 (SEQ ID NO: 35), PSSGX3 5PPPX 39 (SEQ ID NO: 36), PSSGX 35 PPPX 39 R3 (SEQ ID NO: 37), PSSGX 35 PPPX 39 X 40 (SEQ ID NO: 38), PSSGX 35 PPPX 39 X4 OR3 (SEQ ID NO: 39), and a C-terminal modification, wherein the modification The decoration is NH2, X 31 is selected from the group consisting of P and KZ1; X 35 is selected from the group consisting of A and Orn; X 39 is selected from the group consisting of S and Orn; X 40 But it is KZ1, R3 is a C-terminal modification, where the modification is NH2; X 10 , X 12 , X 17 , X 21 , X 24 , X 25 , X 28 , X 30 , X 31 , and X 40 two, and only two, of which are KZ1 or K(Z1)R6; Z1 is selected from the group consisting of R5 and -R4R5; R4 is a linker, R5 is a fatty acid; or and pharmaceutically acceptable salts thereof.

[0120] A compound of formula VII, X1X2EGTX6TSDX 10 X 11 X 12 X 13 LDX 16 X 17 AQX 20 X2 1X 22 IX 24 X 25 LIX 28 GX 30 (SEQ ID NO: 40) During the ceremony, X1 is selected from the group consisting of Y and R1Y; R1 is Ac modification of the N-terminal amino group, X2 is Aib, X6 is selected from the group consisting of αMeF and αMeF(2F); X 10 , 4Pal, Y, αMeF, αMeF(2F), αMeL, αMeV, Ac4 c, Ac5c, Ac6c, Bip, 1Nal, 2Nal, OMeY, hTyr, Nle, V, 4CPhe, ChG, ChA, Bzt, 2FA, 4TAA, 2TA, 3TA, and K Z1, X 11 is selected from the group consisting of Ac5c, S, αMeS, Aib, G, Dap, and Tle Selected, X 12 is selected from the group consisting of I and KZ1; X 13 is selected from the group consisting of αMeL and αMeF; X 16But Orn, X 17 is selected from the group consisting of Q, I, and KZ1; X 20 is a group consisting of Aib, Orn, 4Pal, αMeF, Ac5c, and Ac6c is selected from X 21 is selected from the group consisting of E, KZ1, G, Orn, and 4Pal; X 22 But, F, 2ClPhe, 3ClPhe, 2FPhe, 3FPhe, 3,5FPh The group consisting of e, 1Nal, 2Nal, αMeF(2F), ChA, Bzt, and αMeF is selected from X 24 is selected from the group consisting of D-Glu, E, G, and KZ1; X 25 is selected from the group consisting of Y, αMeY, αMeF, and KZ1; X 28 is selected from the group consisting of E, Orn, and KZ1; X 30 is selected from the group consisting of G, Orn, KZ1, and GR2; R2 is X 31 SSG (SEQ ID NO: 28), X 31 SSG-R3 (SEQ ID NO: 29), X3 1SSGX 35 PPPX 39 (SEQ ID NO: 30), X 31 SSGX 35 PPPX 39 R3( SEQ ID NO: 31), X 31 SSGX 35 PPPX 39 X 40 (SEQ ID NO: 32), X 31 SS GX 35 PPPX 39 X 40 R3 (SEQ ID NO: 33), and a C-terminal modification selected, wherein the modification is NH2, X 31is selected from the group consisting of P and KZ1; X 35 is selected from the group consisting of A and Orn; X 39 is selected from the group consisting of S and Orn; X 40 But it is KZ1, R3 is a C-terminal modification, where the modification is NH2; X 10 , X 12 , X 17 , X 21 , X 24 , X 25 , X 28 , X 30 , X 31 , and X 40 Two and only two of them are KZ1, Z1 is selected from the group consisting of R5 and -R4R5; R4 is a linker, R5 is a fatty acid; or Pharmaceutically acceptable salts thereof are provided.

[0121] In one embodiment, the GIP / GLP1 agonist is one in which Z1 is -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-CO-(CH2) 10 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-(4-(4-iodophenyl)butanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-(4-(4-tert-butylphenyl)butanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-CO-(CH2) 14 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-CO-(CH2) 12 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-CO-(CH2) 10 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH 2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(10-(4 -carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -CO-(CH2) 14 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -CO-(CH2) 10 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu )-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu )-CO-(CH2) 14 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(εK)-C O-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(εK)-( γ-Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(εK)-(γ -Glu)-CO-(CH2) 12 -CO2H, -(εK)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ -Glu)-CO-(CH2) 12 -CO2H, -(εK)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-( γ-Glu)-CO-(CH2) 12 -CO2H, -(εK)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(εK)-(γ-Glu)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-CO-(CH2) 12 -CO2H, -(εK)-(εK)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-(7-(4-carboxyphenoxy)heptanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-(8-(4-carboxyphenoxy)octanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -(4-(4-tert-butylphenyl)butanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-(11-(4-carboxyphenoxy)undecanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu )-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-CO-(CH2 ) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2 ) 12 -CO2H, -PEG3-(γ-Glu)-CO-(CH2) 12 -CO2H, -PEG4-(γ-Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu )-CO-(CH2)10 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-(11-(4-carboxyphenoxy)undecanoyl, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-CO-(CH2) 14 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-Ahx-(γ- Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-Aoc-(γ- Glu)-CO-(CH2) 12 -CO2H, -Ahx-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ- Glu)-CO-(CH2) 12 -CO2H, -Aoc-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ- Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-Ahx-(γ- Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-Aoc-(γ- Glu)-(10-(4-carboxyphenoxy)decanoyl), -Ahx-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ- Glu)-(10-(4-carboxyphenoxy)decanoyl), -Aoc-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ- Glu)-(10-(4-carboxyphenoxy)decanoyl), -PEG4-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -PEG3-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-Aoc-CO- (CH2) 12 -CO2H, -PEG6-(γ-Glu)-CO-(CH2) 12 -CO2H, -PEG5-(γ-Glu)-CO-(CH2) 12 -CO2H, -PEG6-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -PEG5-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-Trx-(γ -Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-Trx-(γ -Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-Trx-(γ- Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-Trx-(γ- Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )2-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )2-(10-(4-carboxyphenoxy)decanoyl), -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2) 12 -CO2H, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)- CO-(CH2) 12 -CO2H, and -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)- (10-(4-carboxyphenoxy)decanoyl), or a pharmaceutically acceptable salt thereof.

[0122] In one embodiment, the GIP / GLP1 agonist is one in which Z1 is -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-CO-(CH2) 10 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-(4-(4-iodophenyl)butanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-(4-(4-tert-butylphenyl)butanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-CO-(CH2) 14 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-CO-(CH2) 12 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-CO-(CH2) 10 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH 2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(10-(4 -carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -CO-(CH2) 14 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -CO-(CH2) 10 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu )-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu )-CO-(CH2) 14 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(εK)-C O-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(εK)-( γ-Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(εK)-(γ -Glu)-CO-(CH2) 12 -CO2H, -(εK)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ -Glu)-CO-(CH2) 12 -CO2H, -(εK)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-( γ-Glu)-CO-(CH2) 12 -CO2H, -(εK)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(εK)-(γ-Glu)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-CO-(CH2) 12 -CO2H, -(εK)-(εK)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-(7-(4-carboxyphenoxy)heptanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-(8-(4-carboxyphenoxy)octanoyl), and -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -(4-(4-tert-butylphenyl)butanoyl), I, or a pharmaceutically acceptable salt thereof.

[0123] In one embodiment, the GIP / GLP1 agonist is one in which Z1 is -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-CO-(CH2) 10 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-(4-(4-iodophenyl)butanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-(4-(4-tert-butylphenyl)butanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-CO-(CH2) 14 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-CO-(CH2) 12 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-CO-(CH2) 10 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH 2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(10-(4 -carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -CO-(CH2) 14 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -CO-(CH2) 10 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu )-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu )-CO-(CH2) 14 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(εK)-C O-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(εK)-( γ-Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(εK)-(γ -Glu)-CO-(CH2) 12 -CO2H, -(εK)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ -Glu)-CO-(CH2) 12 -CO2H, -(εK)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-( γ-Glu)-CO-(CH2) 12 -CO2H, -(εK)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(εK)-(γ-Glu)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-CO-(CH2) 12 -CO2H, -(εK)-(εK)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-(7-(4-carboxyphenoxy)heptanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-(8-(4-carboxyphenoxy)octanoyl), and -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -(4-(4-tert-butylphenyl)butanoyl), VI, or a pharmaceutically acceptable salt thereof.

[0124] In one embodiment, the GIP / GLP1 agonist is one in which R5 is -CO-(CH2) 12 -CO2H, -CO-(CH2) 10 -CO2H, -(10- (4-carboxyphenoxy)decanoyl), -(4-(4-iodophenyl)butanoyl -(4-(4-tert-butylphenyl)butanoyl), -CO-(CH2)1 4-CH3, -CO-(CH2) 12 -CH3, -CO-(CH2) 10 -CH3, -( 7-(4-carboxyphenoxy)heptanoyl), -(8-(4-carboxyphenoxy)heptanoyl) (11-(4-carboxyphenoxy)undecanoyl), -(1 2-(4-carboxyphenoxy)dodecanoyl), and -CO-(CH2) 14 -CO 2H, or a pharmaceutically acceptable salt thereof. .

[0125] In one embodiment, the GIP / GLP1 agonist is one in which R5 is -CO-(CH2) 12 -CO2H, -CO-(CH2) 10 -CO2H, -(10- (4-carboxyphenoxy)decanoyl), -(4-(4-iodophenyl)butanoyl -(4-(4-tert-butylphenyl)butanoyl), -CO-(CH2)1 4-CH3, -CO-(CH2) 12 -CH3, -CO-(CH2) 10 -CH3, -( 7-(4-carboxyphenoxy)heptanoyl), and -(8-(4-carboxyphenoxy)heptanoyl) a compound of formula VI selected from the group consisting of (a) octanoyl) hydroxyl) octanoyl) or a pharmaceutically acceptable salt thereof; It is an acceptable salt.

[0126] In one embodiment, the GIP / GLP1 agonist is one in which R4 is -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )2)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu )-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(εK)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(εK)-( γ-Glu)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(εK)-(γ -Glu)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-Trx-(γ- Glu)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-Trx-(γ -Glu)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-Aoc-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-Aoc-(γ- Glu)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-Ahx-(γ- Glu)-, -PEG3-(γ-Glu)-, -PEG4-(γ-Glu)-, -PEG5-(γ-Glu)-, -PEG6-(γ-Glu)-, -Ahx-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ- Glu)-, -Aoc-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ- Glu)-, -(εK)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ -Glu)-, -(εK)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-( γ-Glu)-, -(εK)-(γ-Glu)-, -(εK)-(γ-Glu)-(γ-Glu)-, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-, -(εK)-(εK)-(γ-Glu)-, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-, and (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)- (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)- or a pharmaceutically acceptable salt thereof.

[0127] In one embodiment, the GIP / GLP1 agonist is one in which R4 is -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )- -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu )-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(εK)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(εK)-( γ-Glu)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(εK)-(γ -Glu)-, -(εK)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ -Glu)-, -(εK)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-( γ-Glu)-, -(εK)-(γ-Glu)-, -(εK)-(γ-Glu)-(γ-Glu)-, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-, -(εK)-(εK)-(γ-Glu)-, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) - and -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu) -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)- The compound of formula VI, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

[0128] In one embodiment, the GIP / GLP1 agonist is X 17 and X 31 Each is KZ1 In one embodiment, GIP is a compound of formula VI, or a pharmaceutically acceptable salt thereof: / GLP1 agonists are X 17 and X 24 each is KZ1; or and pharmaceutically acceptable salts thereof. In one embodiment, the GIP / GLP1 agonist is X 17 and X 21 and each is KZ1, or a pharmaceutically acceptable salt thereof. In one embodiment, the GIP / GLP1 agonist is a salt of X 17 and X 28 Each of them is KZ1, or a pharmaceutically acceptable salt thereof. , GIP / GLP1 agonists are X 17 and X 40 each of which is KZ1; In one embodiment, the GIP / GLP1 agonist The strike is X 21 and X 40 each is KZ1, or a pharmaceutically acceptable salt thereof. In one embodiment, the GIP / GLP1 agonist is X 21 and X 28 and each is KZ1, or a pharmaceutically acceptable salt thereof. In the form, GIP / GLP1 agonists are 24 and X 28 are each KZ1, VI, or a pharmaceutically acceptable salt thereof.

[0129] In one embodiment, the GIP / GLP1 agonist is a compound wherein X1 is Y and X6 is αMe F(2F) and X 10 is selected from the group consisting of 4Pal, Y, and KZ1, and X1 1 is selected from the group consisting of S, αMeS, and Aib, and X 12 But I and X 13 is αMeL and X 16 But Orn and X 17 is selected from the group consisting of I and KZ1 Selected, X 20 But Aib and X 21 is selected from the group consisting of KZ1 and E; X 22 is selected from the group consisting of F and αMeF, and X 24 However, D-Glu and KZ1 X is selected from the group consisting of 25 is αMeY and X 28 is a group consisting of E and KZ1 Selected from X 30is selected from the group consisting of G and GR2, and R2 is X 31 SSG X 35 PPPX 39 (SEQ ID NO: 30), X 31 SSGX 35 PPPX 39 R3(sequence number 31), and X 31 SSGX 35 PPPX 39 X 40 (SEQ ID NO: 32), and the C-terminal wherein the modification is NH2 and X 31 But P and K Z1, and X 35 is selected from the group consisting of A and Orn, and X 39 is selected from the group consisting of S and Orn, and X 40 is selected from the group consisting of KZ1, R3 is a C-terminal modification, where the modification is NH2, and X 10 , X 17 , X 21 , X 24 , X 28 , and X 31 One and only one selected from the group consisting of KZ 1, Z1 is -R4R5, R4 is a linker, and R5 is a fatty acid , a compound of Formula VI, or a pharmaceutically acceptable salt thereof.

[0130] In one embodiment, the GIP / GLP1 agonist is a compound of formula VI, or a pharmaceutically acceptable salt thereof An acceptable salt of the compound is Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ -Glu)-CO-(CH2) 12 -CO2H)AQ-Aib-EFI-(D-Glu) -αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acet Glu)2-(γ-Glu)-CO-(CH2) 12 -CO2H)SSGAPPPS-NH 2 (SEQ ID NO: 41), Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ -Glu)-(10-(4-carboxyphenoxy)decanoyl))AQ-Aib-EF I-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy) -ethoxy]-acetyl)2-(γ-Glu)-(10-(4-carboxyphenoxy) Decanoyl)SSGAPPPS-NH2 (SEQ ID NO: 17), Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ -Glu)-(4-(4-iodophenyl)butanoyl))AQ-Aib-EFI-(D -Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]- [Ci]-acetyl)2-(γ-Glu)-(4-(4-iodophenyl)butanoyl))S SGAPPPS-NH2 (SEQ ID NO: 18), Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ -Glu)-(4-(4-tert-butylphenyl)butanoyl))AQ-Aib-E FI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy )-ethoxy]-acetyl)2-(γ-Glu)-(4-(4-tert-butylphenyl) 1) butanoyl) SSGAPPPS-NH2 (SEQ ID NO: 19), and Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ -Glu)-CO-(CH2) 10 -CH3)AQ-Aib-EFI-(D-Glu)- αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl Glu)2-(γ-Glu)-CO-(CH2) 10 -CH3)SSGAPPPS-NH2( SEQ ID NO: 19).

[0131] In one embodiment, the GIP / GLP1 agonist is a GIP / GLP1 agonist in which the R4 linker is ε- and γ-Glu In one embodiment, the compound is one to two amino acids selected from the group consisting of: The R4 linker is one to three (2-[2-(2-amino-ethoxy)-ethoxy]-acetate. In one embodiment, the GIP / GLP1 agonist comprises an R5 fatty acid moiety. , conjugated to the lysine by an R4 linker between the lysine and the R5 fatty acid; It is a compound.

[0132] In one embodiment, the GIP / GLP1 agonist is a GIP / GLP1 agonist wherein the R4 linker is 0 to 4 amino acids and 0 to 3 (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) moieties In one embodiment, GIP is a compound of formula VI, or a pharmaceutically acceptable salt thereof. / GLP1 agonist, wherein the R4 linker is independently selected from the group consisting of ε-K and γ-Glu In one embodiment, the compound comprises 1 to 3 amino acids selected from the group consisting of GIP / GL The P1 agonist is characterized in that each R4 linker is independently selected from the group consisting of εK and γ-Glu. or a pharmaceutically acceptable salt thereof, wherein the compound is of formula VI, In one embodiment, the GIP / GLP1 agonist has the formula V, which contains two Z1 fatty acid moieties. or a pharmaceutically acceptable salt thereof, wherein each R5 fatty acid of the Z1 moiety is R4 The R4 linker is conjugated to a different lysine of the peptide. In one embodiment, the GIP / GLP1 agonist The compound is a compound of formula VI containing two Z1 fatty acid moieties, or a pharmaceutically acceptable salt thereof. Each of the R5 fatty acids in Z1 is conjugated to a different lysine in the peptide via the R4 linker. R4 is a nucleotide sequence consisting of 1 to 3 amino acids and 1 to 3 (2-[2-(2-amino acids) In one embodiment, GIP / GL comprises a (amino-ethoxy)-ethoxy]-acetyl) moiety. P1 agonists include compounds of formula VI containing two identical Z1 fatty acid moieties, or pharmaceutically acceptable salts thereof. The R5 fatty acids of Z1 are each linked to a different peptide via an R4 linker. conjugated to lysine, and R4 each independently consists of εK and γ-Glu and 1 to 3 amino acids selected from the group consisting of 1 to 3 (2-[2 In one embodiment, G The IP / GLP1 agonist is a compound of formula VI containing two identical Z1 fatty acid moieties, or wherein each of the R5 fatty acids of Z1 is linked to a peptide via an R4 linker. R4 is conjugated to different lysines of the 2-(2-( Each independently γ-Gl bound to a 2-amino-ethoxy-ethoxy-acetyl) moiety It comprises up to three amino acids selected from the group consisting of u and εK.

[0133] In one embodiment, the GIP / GLP1 agonist has the formula VI, or a pharmaceutically acceptable salt thereof, wherein each of the R5 fatty acids of Z1 is an R4 fatty acid. and the R4 linker has the formula: -(εK) a1 -(γ-Glu) a2 -(2-[2-(2-amino-ethoxy)-ethoxy] oxy]-acetyl) a3 -(εK) b1 -(γ-Glu) b2 - wherein a1 is selected from the group consisting of 0, 1, and 2; and a2 is selected from the group consisting of 0, 1, and 2. a3 is selected from the group consisting of 0, 1, 2, and 3; b1 is selected from the group consisting of 0, 1, 2, and 3; or 1, and b2 is 0 or 1. In one embodiment, the GIP / GLP1 agonist is a compound of formula VI containing two identical Z1 fatty acid moieties, or a pharmaceutically acceptable salt thereof. wherein each R5 fatty acid of Z1 is conjugated via an R4 linker; But the following formula: -(εK) a1 -(γ-Glu) a2 -(2-[2-(2-amino-ethoxy)-ethoxy] oxy]-acetyl) a3 -(εK) b1 -(γ-Glu) b2 -CO-(CH2) q -C O2H, wherein a1 is selected from the group consisting of 0, 1, and 2, and a2 is a2 is selected from the group consisting of 0, 1, and 2, and a3 is selected from the group consisting of 0, 1, 2, and 3. b1 is 0 or 1, b2 is 0 or 1, and q is 10, 12, 14, and 16.

[0134] In one embodiment, the compound is a GIP / GLP1 agonist, wherein a1 is 1 and a2 is 0. a3 is 2, b1 is 0, b2 is 1, q is 12, and the structure is -(εK)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-( γ-Glu)-CO-(CH2) 12 -CO2H.

[0135] In one embodiment, the GIP / GLP1 agonist has the formula VI, or a pharmaceutically acceptable salt thereof, wherein each of the R5 fatty acids of Z1 is an R4 fatty acid. The R4 linker and R5 fatty acid moiety are conjugated via a linker as follows: formula:

[0136] [ka] wherein q2 is selected from the group consisting of 7, 8, 10, 11, and 12.

[0137] In one embodiment, the GIP / GLP1 agonist has the formula VI, or a pharmaceutically acceptable salt thereof, wherein each of the R5 fatty acids of Z1 is an R4 fatty acid. The R5 fatty acid is conjugated via a linker, and the R5 fatty acid is -(7-(4-carboxyphenyl)- -(8-(4-carboxyphenoxy)heptanoyl) and -(8-(4-carboxyphenoxy)octanoyl) In one embodiment, the GIP / GLP1 agonist is selected from the group consisting of: Compounds of formula VI containing two identical Z1 fatty acid moieties conjugated via a linker or a pharmaceutically acceptable salt thereof, wherein the R5 fatty acid is -(10-(4-carboxy -(phenoxy)decanoyl), -(4-(4-iodophenyl)butanoyl), and -(4 -(4-tert-butylphenyl)butanoyl).

[0138] In one embodiment, the GIP / GLP1 agonists are each conjugated via an R4 linker. A compound of formula VI containing two identical gated Z1 fatty acid moieties, or a pharmaceutically acceptable salt thereof. The R5 fatty acid is -CO-(CH2) 14 -CH3, -CO-(CH2 ) 12 -CH3 and -CO-(CH2) 10 -CH3.

[0139] In one embodiment, the GIP / GLP1 agonists are each conjugated via an R4 linker. A compound of formula VI containing two identical gated Z1 fatty acid moieties, or a pharmaceutically acceptable salt thereof. The R5 fatty acid is -CO-(CH2) 12 -COH and -CO-(C H2) 10 In one embodiment, the GIP / GLP1 antagonist is selected from the group consisting of: The agonist consists of two identical Z1 fatty acids, each conjugated via an R4 linker. A compound of formula VI comprising a moiety, or a pharmaceutically acceptable salt thereof, wherein the R5 fatty acid is -C O-(CH2) 10 -CH3 and -CO-(CH2) 12 -CH3 can be.

[0140] In one embodiment, the GIP / GLP1 agonist is a GIP / GLP1 agonist wherein the R5 fatty acid is -CO-(CH) 12 -CO2H, -CO-(CH2)10 -CO2H, -(10-(4-carboxyphenyl) -(4-(4-iodophenyl)butanoyl), -(4-(4- tert-butylphenyl)butanoyl), -CO-(CH2) 14 -CH3, -CO- (CH2) 12 -CH3, -CO-(CH2) 10 -CH3, -(7-(4-carboxy -(8-(4-carboxyphenoxy)heptanoyl), and -(8-(4-carboxyphenoxy)octanoyl ) is a compound selected from the group consisting of

[0141] A given GIP / GLP1 agonist is generally effective over a wide dosage range. For example, the dosage for once-weekly parenteral administration is 0.05 mg to about 30 mg per person per week. The range may be in the range of g.

[0142] GLP-1 is a 36 amino acid peptide, the major biologically active fragment of which is the 30 C-terminal amidated peptide of amino acids (GLP-1 7-36 ) (SEQ ID NO: 2) can be.

[0143] GIP is a 42 amino acid peptide ( SEQ ID NO: 1) and stimulates insulin secretion from pancreatic beta cells in the presence of glucose It plays a physiological role in glucose homeostasis by

[0144] In one embodiment, the GIP / GLP1 agonist compound is a compound that inhibits desirable GIP and GLP receptors. The GIP agonist potency is determined by the casein cAM described herein below. 2.5-5 times the GLP1 receptor potency as measured by the P assay, and this potency is normalized to native GIP and GLP on the day the assay was performed. , GIP / GLP1 agonist compounds have desirable GIP and GLP receptor activity, GIP agonist potency was determined by the casein cAMP assay described herein below. The potency is 2.5-10 times the GLP1 receptor potency measured by the assay. Normalized to native GIP and GLP on the day of administration.

[0145] As used herein, the term "amino acid" refers to naturally occurring amino acids and Amino acids are typically represented by their standard one-letter codes: (e.g., L=leucine), and alpha-methyl substituted residues of natural amino acids (e.g., α -methylleucine, or αMeL and α-methyllysine, or αMeK), and alpha Aminoisobutyric acid, or certain other Unnatural amino acids are used, the structures of which are shown below.

[0146] [ka]

[0147] [ka]

[0148] [ka]

[0149] [ka]

[0150] As used herein, "Orn" means ornithine. When used herein, "4Pal" means 3-(4-pyridyl)-L-alanine. When used in this context, "αMeF(2F)" refers to alpha-methyl 2-F-phenylalanine. As used herein, "αMeY", "αMeK", and "αMe "L" stands for alpha-methyl tyrosine, alpha-methyl lysine, and alpha-methyl As used herein, "e" and "D-Glu" each refer to D-leucine. As used herein, "D-His" and "h" refer to, respectively, As used herein, "D-Tyr" and "y" refer to D-histidine, respectively. and "Ser" and "Ser" each mean D-tyrosine. " each refer to D-serine. As used herein, "D-Ala" and "a" " each refers to D-alanine. As used herein, "αMeF(2F)" means alpha-methyl-F(2F) and alpha-methyl-Phe(2F). As used herein, "αMeF" refers to alpha-methyl-F and alpha-methyl- As used herein, "αMeY" means alpha-methyl-Phe. As used herein, "αMeK" means alpha-methyl- As used herein, "αMeL" means alpha-methyl-Lys. As used herein, "αMeS" means alpha-methyl-serine. As used herein, "αMeP" refers to alpha-methyl-Ser and alpha-methyl-Ser. means alpha-methyl-proline and alpha-methyl-Pro. As used herein, "desH" means desHis. "desY" means desTyr.

[0151] As used herein, "AEEA" refers to (2-[2-(2-amino-ethoxy) -ethoxy]-acetyl) ; "AEEA2" means (2-[2-(2-amino- "AEEA3" means (2-[2-(2-ethoxy)-ethoxy]-acetyl) -amino-ethoxy)-ethoxy]-acetyl)3.

[0152] As used herein, "Ahx" is 6-aminohexanoyl- and "Ao "c" is 8-aminooctanoyl- and "PEG3" is [3-(2-[2-(2- amino-ethoxy)-ethoxy]-ethoxy)-propanoyl]-, and "PEG4" is (3-[2-(2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy)-ethoxy PEG5 is [3-(2-[2-(2-[2- (2-amino-ethoxy)-ethoxy]-ethoxy)-ethoxy]-ethoxy)-propanol PEG6 is (3-[2-(2-(2-(2-(2-aminoyl)- No-ethoxy)-ethoxy]-ethoxy)-ethoxy]-ethoxy-ethoxy)-ethoxy "Tle" is tert-leucine.

[0153] As used herein with respect to one or more of the GIP or GLP-1 receptors, " "activate", "activate(s)", "activating(activa)" Terms such as "t[ing]" and "t[ing]" are used in conjunction with techniques known in the art, such as in vitro assays described below. of the compound, or a pharmaceutically acceptable salt thereof, as measured using assays known in the art. It refers to the ability to bind to a receptor and induce a response at the receptor.

[0154] GIP / GLP1 agonist compound or a pharmaceutically acceptable salt thereof, and GLP-1 receptors, can be measured, for example, by the techniques described in the Examples below. Receptor binding levels are measured using techniques known in the art, including The activity of GIP / GLP at each of these receptors can be measured by the K i value. The activity of agonist compounds can be further assessed, for example, using the in vitro activity assays described below. The concentration of ethylenediaminetetraacetic acid (EC 2.0) can also be measured using techniques known in the art, including, but not limited to, EC 50 By value This is expressed as the concentration of a compound that produces a half-maximal simulation in a dose-response curve. Concentration.

[0155] In one embodiment, the GIP / GLP1 agonist is a compound or a pharmaceutically acceptable salt thereof. The compound is a salt of guanosine 5'-(γ-thio)triphosphate-[ 35 S] (Guanosine 5'-(gamma-thio)Triphosphate-[ 35 Partial binding to GLP-1R demonstrated by GTPγS binding assay GL as a β-arrestin-2 recruitment assay A potent GIPR / GLP-1R dual agonist, a partial agonist for GLP-1R In one embodiment, the GIP / GLP1 agonist is a compound or a pharmaceutical and the compound is an acceptable salt thereof, wherein the compound binds to guanosine 5-phosphate dehydrogenase (GLP-1R) in HEK293 cell membranes. '-(γ-thio)triphosphate-[ 35 S] (GTPγS) binding assay Gα induced by R s In one embodiment, GIP / GLP1 receptors stimulate activation. The inhibitor was GLP-1R HEK293 cell membrane guanosine 5'-(γ-thio)triphosphate- [ 35 S](GTPγS) binding assay showed partial agonism of 75% or less and GL 35% or less partial arrest in the P-CHO cell β-arrestin recruitment assay It is a compound that exhibits agonism.

[0156] In one embodiment, the GIP / GLP1 agonist is GLP-CHO cell β-arrestin This refers to a compound that shows a GLP-1R H EK293 cell membrane guanosine 5'-(γ-thio)triphosphate-[ 35 S](GTPγS) An effective dose of compound that exhibits 75% or less partial agonism in the combined assay is administered.

[0157] As used herein, the term "effective amount" refers to a dose administered to a patient in one or more doses. The compounds of the present invention, or drugs thereof, which, when administered to a patient under diagnosis or treatment, provide a desired effect. The effective amount can be determined using known techniques and by analogy. This can be determined by one skilled in the art by observing the results obtained under certain circumstances. In determining the effective amount for a mammal, the species of mammal; its size, age, and general health; the specific disease or disorder involved; the extent or involvement or severity of the disease or disorder; the response of the individual patient Answer; specific compound administered; mode of administration; bioavailability characteristics of the administered preparation; selection including, but not limited to, the dosage regimen used; the use of concomitant medications; and other relevant circumstances. No, several factors are taken into consideration.

[0158] As used herein, "EDTA" means ethylenediaminetetraacetic acid. As used herein, "DMSO" means dimethyl sulfoxide. As used herein, "CPM" means counts per minute. When used herein, "IBMX" means 3-isobutyl-1-methylxanthine. As used herein, "LC / MS" means liquid chromatography / mass spectrometry. As used herein, "HTRF" means homogeneous time-resolved fluorescence. As used herein, "BSA" means bovine serum albumin.

[0159] The present invention is further illustrated by the following examples, which are given by way of example only and are not intended to be limiting. As used herein, "estimand" means a specific Evaluating to determine efficacy of GIP / GLP1 agonists as required by regulatory agencies The efficacy and treatment regimen used to evaluate the efficacy of the investigational drug. The study will evaluate outcomes in people before they discontinue or start rescue therapy for persistent severe hyperglycemia. Treatment regimens required by certain regulatory agencies, including the U.S. Food and Drug Administration The goal is to improve adherence to GIP / GLP1 agonists or rescue medications for persistent severe hyperglycemia. Evaluate the effects of treatment in people in studies independent of the introduction of alternative therapies.

[0160] In other embodiments, the present invention provides the following: Embodiment 1. A once-weekly administered steroid for use in treating refractory type 2 diabetes in a patient. A GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof. Embodiment 2. GIP, administered once weekly, for use in treating hypertension in a patient. / GLP1 agonist or a pharmaceutically acceptable salt thereof. Embodiment 3. A once-weekly administered steroid for use in raising HDL-C in a patient. A GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof. Embodiment 4. The method of any one of embodiments 1 to 3, wherein the patient has had type 2 diabetes for at least 8 years. A GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof for use as described in any one of the preceding claims. Acceptable salt. Embodiment 5. Any of Embodiments 1 to 4, wherein the patient's HbA1c target value is less than 7%. 1. A GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof for use as described in any one of claims 1 to 5. salt. Embodiment 6. The method according to any one of embodiments 1 to 5, wherein the patient's target HbA1c value is 5.7% or less. A GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof for use as described in any one of the preceding claims. Salt that can be used. Embodiment 7. Any one of embodiments 1 to 6, wherein the patient's HbA1c is greater than 10%. 2. A GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof for use as described in 1. Embodiment 8. Any one of embodiments 1 to 7, wherein the patient's HbA1c is greater than 11%. 2. A GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof for use as described in 1. Embodiment 9. Any one of embodiments 1 to 8, wherein the patient is at least 46 years old. 1. A GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof for use according to any one of the preceding claims. Embodiment 10. Any of Embodiments 1-9, wherein the patient is at least 60 years old. A GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof for use as described in one of the preceding paragraphs. . Embodiment 11. Any of Embodiments 1 to 10, wherein the patient is taking an SGLT2 inhibitor. a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof for use as described in any one of Salt. Embodiment 12. Any of Embodiments 1 to 11, wherein the patient is taking metformin. A GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof for use as described in one of the preceding paragraphs. . Embodiment 13. Any of embodiments 1 to 12, wherein the patient is not receiving basal insulin. 1. A GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof for use as described in any one of claims 1 to 5. salt. Embodiment 14. The patient has a Hb while taking metformin and an SGLT2 inhibitor. The use according to any one of embodiments 1 to 13, wherein the A1c target value cannot be reached. A GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof for the treatment of Embodiment 15. The GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is 15. The method of claim 14, wherein the compound is administered for at least 40 weeks. An IP / GLP1 agonist or a pharmaceutically acceptable salt thereof. Embodiment 16. The GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is 16. The method of claim 15, wherein the compound is administered for at least 50 weeks. An IP / GLP1 agonist or a pharmaceutically acceptable salt thereof. Embodiment 17. The GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is 17. A GI agonist for use according to any one of embodiments 1 to 16, administered for at least 2 years. P / GLP1 agonist or a pharmaceutically acceptable salt thereof. Embodiment 18. The use of any one of embodiments 1 to 17, wherein the patient is non-obese. A GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof for use in the treatment of rheumatoid arthritis. Embodiment 19. Any one of embodiments 1 to 18, wherein the patient has concurrent hypertension. 2. A GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof for use as described in 1. Embodiment 20. Any of embodiments 1 to 19, wherein the patient suffers from concomitant low HDL-C. 1. A GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof for use as described in any one of claims 1 to 5. salt. Embodiment 21. The method of any one of embodiments 1-17 or 19-20, wherein the patient suffers from concomitant obesity. A GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof for use as described in any one of the above. Salt to be used. Embodiment 22. The patient has at least two cardiovascular risk factors, 21. A GIP / GLP1 agonist or a pharmaceutical composition thereof for use according to any one of claims 1 to 21. Acceptable salts. Embodiment 23. Any of Embodiments 1 to 21, wherein the patient has no cardiovascular risk factors. a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof for use as described in any one of Salt. Embodiment 24. The patient has had type 2 diabetes for at least 10 years, as in embodiments 1 to 23. A GIP / GLP1 agonist or a pharmaceutical composition thereof for use according to any one of claims 1 to 23. Acceptable salts. [Example]

[0161] Example 1. Clinical trial using GIP / GLP1 agonists The enrollment criteria, listed in Table 1 below, are similar to patients seen in a typical diabetes practice. to include participants with type 2 diabetes who are refractory to oral treatment and It is designed to include elderly patients and last 52 weeks.

[0162] [Table 1]

[0163] The study consisted of a screening visit followed by a single-blind, 3-week placebo run-in period. The patient is then treated with a GIP / GLP1 agonist (escalating dose protocol) randomized to insulin degludec (dosed using standard titration protocol) or insulin degludec (standard titration protocol), and Patients receiving insulin degludec will be followed up at monthly intervals during the study period. During the study, standard insulin degludec titration protocols were followed. Using the method, blood pressure measurements at each visit and serum lipid profiles at the start of the study and at week 52 were performed. Contains the file.

[0164] The mean dose of insulin degludec at 52 weeks is approximately 48 units per day.

[0165] A greater percentage of patients randomized to insulin degludec had GIP / GLP Fewer than 7 percent of patients randomized to a 1-agonist met the American Diabetes Association recommended glucose target. target for people with diabetes) or less than 5.7 percent (people without diabetes) Achieve HbA1c levels below those seen in adults.

[0166] Example 2. Clinical trial using GIP / GLP1 agonists The enrollment criteria, listed in Table 2 below, included patients considered refractory to oral treatment for type 2 diabetes. However, oral diabetes treatment will continue throughout the study. The study will last for 40 weeks.

[0167] Clinical Trial 2, Table 2

[0168] [Table 2] The study was designed to consist of a screening visit followed by a 3-week run-in period. Patients were then pretreated with insulin glargine with or without metformin. Additionally, a 40-week randomized, double-blind study using a GIP / GLP1 agonist or placebo Initiate a study to determine insulin glargine doses using a validated "target-directed treatment" algorithm. Patients were titrated throughout the study using a "rhythm." Patients were titrated at approximately weekly intervals, then approximately Follow-up will be at monthly intervals. The study protocol will involve monitoring each visit using standard clinical methods. These will include blood pressure measurements at baseline and serum lipid profiles at 40 weeks.

[0169] This study aims to evaluate the effect of GIP / GLP1 agonist doses on the treatment of type 2 diabetes using clinical trial medications. Titrating insulin glargine with or without metformin in adults with rheumatoid arthritis In addition, it was shown to be effective in reducing HbA1c and weight loss from baseline compared to placebo. This shows that it is possible.

[0170] Example 3: Clinical trial using GIP / GLP1 agonists This study compared four weekly skin-based therapies with placebo in patients with type 2 diabetes. To investigate the safety and tolerability of the GIP / GLP1 agonist of Example 7 administered as an intravenous injection. This is a 4-week, multiple ascending dose study. Pre-specified safety parameters to be studied include: , including blood pressure.

[0171] The study included four cohorts for treatment with GIP / GLP1 agonists. Cohorts 1 and 2 will receive four fixed doses of 0.3 mg or 1 mg, respectively. 3 and 4 will receive weekly doses in escalating increments as shown in Table 3.

[0172] [Table 3]

[0173] Glycemic control is adequately controlled with diet and exercise or stable doses of metformin Establish criteria for enrolling unaccompanied patients. The total is shown in Table 4 below.

[0174] [Table 4]

[0175] Blood pressure results are provided in Table 5 below.

[0176] [Table 5]

[0177] As can be seen in Table 5, mean systolic blood pressure and mean diastolic blood pressure were significantly higher in the 100 mg / kg group compared to placebo. GIP / GLP1 declined in each of the cohorts at the end of the study period.

[0178] Peptide synthesis Example 4 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LDEK((2- [2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO- (CH 2 ) 18 -CO 2 H) AQ-Aib-EFI-(D-Glu)-YLIEGGPS SGAPPPS-NH 2 (SEQ ID NO: 10).

[0179] The structure of SEQ ID NO:10 is shown below using the standard one-letter amino acid code, with the exception that: , the amino acid residue structures are expanded: Aib2, αMeF(2F)6, and αMeL1 Exceptions are 3, K17, Aib20, D-Glu24, and Ser39.

[0180] [ka]

[0181] The peptide backbone of Example 4 is fluorenylmethyloxycarbonyl (Fluorenylmethyloxycarbonyl). using Fmoc / tert-butyl chemistry Peptide synthesizer Symphony X (Gyros Protein Technol It is synthesized in Tucson, AZ.

[0182] The resin was 1% DVB cross-linked polystyrene (Fmoc- Rink-MBHA Low Loading Resin, 100-200 Mesh, EMD Millipore). Standard side chain protecting groups were used. Fmoc-Lys( Mtt)-OH is used for lysine at position 17, and Boc-Tyr(tBu)-OH) is used for lysine at position 1 Before each coupling step (2 x 7 min), DMF The Fmoc group is removed using 20% ​​piperidine in water. All the cleavage reactions were carried out with Fmoc amino acids (0.3 mM), diisopropylcarbodiimide (0.9 mM), and cyclohexanediamine (0.9 mM). Using an equimolar ratio of 0.1 mM HCl (0.9 mM) and Oxyma (0.9 mM), the theoretical peptide loading was The reaction is carried out with a 9-fold molar excess for 1 hour for primary amines and 3 hours for secondary amines. , coupling to a Cα-methylated amino acid, which is coupled for 3 hours. After the synthesis of the peptide backbone was completed, the resin was washed thoroughly with DCM six times to remove residual DMF. The Mtt protecting group of lysine 17 is removed by 30% hexafluoroisopropyl ether in DCM. Treatment with propyl alcohol (Oakwood Chemicals) was performed twice (40 min treatment × 2 times), the peptide is selectively removed from the resin.

[0183] Subsequent attachment of the fatty acid linker moiety is achieved by 2-[2-(2-Fmoc-amino-ethoxy )-ethoxy]-acetic acid (Fmoc-AEEA-OH, ChemPep, Inc.), Fm oc-Glutamic acid α-t-butyl ester (Fmoc-Glu-OtBu, Ark P harm, Inc.), mono-OtBu-eicosanedioic acid (WuXi AppTec, S This is achieved by coupling with a 3-fold excess of the reagent (AA :PyAOP:DIPEA=1:1:1mol / mol) for each coupling of 1 hour length. Used for programming.

[0184] After synthesis is complete, the peptide resin is washed with DCM and thoroughly air-dried. The lipid was incubated in 10 mL of cleavage cocktail (trifluoroacetic acid:water:triisopropyl alcohol) for 2 h at room temperature. The resin was filtered off and each was treated with 2 mL of anhydrous silane. T ’ The combined filtrate was washed twice with FA and diluted with a five-fold excess of cold diethyl ether (-20°C). The crude peptide is precipitated by filtration. The peptide / ether suspension is then Centrifuge at 4°C for 2 min to form a solid pellet, decant the supernatant, and evaporate the solid pellet into ether. The crude peptide was triturated twice more with 20% acetonitrile / 20% The solution was solubilized in 100% acetonitrile and 0.1% TFA / water buffer. A linear gradient of acetonitrile (30-50% acetonitrile in 60 min) was applied to the 5 μm phenyl-hexamer. A preparative column (21 × 250 mm, Phenomenex) was used for RP-HPLC. The purity of the peptide was assessed using analytical RP-HPLC and purified. The purity of the main pool of compound 1 was found to be 98.0%. The final major product pool was then lyophilized, resulting in a lyophilized peptide TFA salt. The molecular weight was determined by LC-MS (observed value: M+3 = 1657.2 , calculated value: M+3=1657.0).

[0185] Example 5 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD-Orn-K ((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu) -CO-(CH 2 ) 16 -CO 2 H) AQ-Aib-EFI-(D-Glu)-YLIE GGPSSGAPPPS-NH 2 (SEQ ID NO: 11) The structure of SEQ ID NO:11 is shown below using the standard one-letter amino acid code, with the exception that: , the amino acid residue structures are expanded: Aib2, αMeF(2F)6, and αMeL1 3, Orn16, K17, Aib20 D-Glu24, and Ser39 are exceptions.

[0186] [ka]

[0187] The compound according to SEQ ID NO: 11 was prepared essentially as described in the procedure of Example 4. The molecular weight is determined by LC-MS (observed: M+3 = 1642.6, calculated: M+3=1642.8).

[0188] Example 6 Example 6 is a compound represented by the following description: Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD-Orn-K ((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu) -CO-(CH 2 ) 18 -CO 2 H) AQ-Aib-EFI-(D-Glu)-YLIE GGPSSGAPPPS-NH 2 (SEQ ID NO: 12)

[0189] The structure of SEQ ID NO:12 is shown below using the standard one-letter amino acid code, with the exception that: , the amino acid residue structures are expanded: Aib2, αMeF(2F)6, and αMeL1 3, Orn16, K17, Aib20, D-Glu24, and Ser39 are exceptions.

[0190] [ka]

[0191] The compound according to SEQ ID NO: 12 was prepared essentially as described in the procedure of Example 4. The molecular weight is determined by LC-MS (observed: M+3 = 1651.8, calculated: M+3=1652.2).

[0192] Example 7 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ -Glu)-CO-(CH 2 ) 16 -CO 2 H) AQ-Aib-EFI-(D-Glu) -αMeY-LIEGGPSSGAPPPS-NH 2 (SEQ ID NO: 13) The structure of SEQ ID NO:13 is shown below using the standard one-letter amino acid code, with the exception that: , the structure of amino acid residues is extended: Aib2, αMeF(2F)6, 4Pal1 0, αMeL13, Orn16, K17, Aib20, D-Glu24 αMeY25, and Ser39 are exceptions.

[0193] [ka]

[0194] The compound according to SEQ ID NO: 13 was prepared essentially as described in the procedure of Example 4. The molecular weight is determined by LC-MS (observed: M+3 = 1642.5, calculated: M+3=1642.1).

[0195] Example 8 Y-Aib-EGT-αMeF(2F)-TSDVSI-αMeL-LD-Orn-K ((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu) -CO-(CH 2 ) 16 -CO 2 H) AQ-Aib-EFI-(D-Glu)-αMeY -LIEGGPSSGAPPPS-NH 2 (SEQ ID NO: 14) The structure of SEQ ID NO:14 is shown below using the standard one-letter amino acid code, with the exception that: , the amino acid residue structures are expanded: Aib2, αMeF(2F)6, and αMeL1 3, Orn16, K17, Aib20, D-Glu24, αMeY25, and Ser39 is an exception.

[0196] [ka]

[0197] The compound according to SEQ ID NO: 14 was prepared essentially as described in the procedure of Example 4. The molecular weight is determined by LC-MS (observed: M+3 = 1626.1, calculated: M+3=1626.1).

[0198] Example 8 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2-amino-ethoxy )-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 ) 18 -CO 2 H)A Q-Aib-AFIEYLIAGGPSSGAPPPS-NH 2 (SEQ ID NO: 21) The structure of SEQ ID NO:21 is shown below using the standard one-letter amino acid code, with the exception that: , the structure of the amino acid residues is extended to residues Aib2, K17, Aib20, and Ser 39 is an exception.

[0199] [ka]

[0200] The compound according to SEQ ID NO: 21 was prepared essentially as described in the procedure of Example 4. The molecular weight is determined by LC-MS (observed: M+3 = 1602.5, calculated: M+3=1602.8).

[0201] Example 10 Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2-(2-amino -ethoxy)-ethoxy]-acetyl)2 -(γ-Glu)-CO-(CH 2 ) 18 -C O 2 H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH 2 (SEQ ID NO:2 2) The structure of SEQ ID NO:22 is shown below using the standard one-letter amino acid code, with the exception that: , the structure of the amino acid residues is extended residues Aib2, αMeL13, K17, Aib2 0 and Ser39 are exceptions.

[0202] [ka]

[0203] The compound according to SEQ ID NO: 22 was prepared essentially as described in the procedure of Example 4. The molecular weight is determined by LC-MS (observed: M+3 = 1626.8, calculated: M+3=1626.8).

[0204] Example 11 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- (2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 ) 18 -CO 2 H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH 2 (SEQ ID NO: 23) The structure of SEQ ID NO:23 is shown below using the standard one-letter amino acid code, with the exception that: , the amino acid residue structures are extended with residues D-Tyr1, Aib2, αMeL13, and K 17, Aib20, and Ser39 are exceptions.

[0205] [ka]

[0206] The compound according to SEQ ID NO: 23 was prepared essentially as described in the procedure of Example 4. The molecular weight is determined by LC-MS (observed: M+3 = 1626.6, calculated: M+3=1626.8).

[0207] Example 12 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn-K((2 -[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO -(CH 2 ) 18 -CO 2 H) AQ-Aib-AFI-(D-Glu)-YLIAGGP SSGAPPPS-NH 2 (SEQ ID NO: 24) The structure of SEQ ID NO:24 is shown below using the standard single letter amino acid code, with the exception that: The amino acid residues with extended structures are D-Tyr1, Aib2, αMeL13, and Or Exceptions are n16, K17, Aib20, D-Glu24, and Ser39.

[0208] [ka]

[0209] The compound according to SEQ ID NO: 24 was prepared essentially as described in the procedure of Example 4. The molecular weight is determined by LC-MS (observed: M+3 = 1602.4, calculated: M+3=1602.8).

[0210] Example 13 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- (2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 ) 18 -CO 2 H)AQ-Aib-EFIE-αMeY-LIAGGPSSGAPPP S-NH 2 (SEQ ID NO: 25) The structure of SEQ ID NO:25 is shown below using the standard one-letter amino acid code, with the exception that: , the amino acid residue structures are extended with residues D-Tyr1, Aib2, αMeL13, and K 17, Aib20, αMeY25, and Ser39 are exceptions.

[0211] [ka]

[0212] The compound according to SEQ ID NO: 25 was prepared essentially as described in the procedure of Example 4. The molecular weight is determined by LC-MS (observed: M+3 = 1631.3, calculated: M+3=1631.5).

[0213] Example 14 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn-K((2 -[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO -(CH 2 ) 18 -CO 2 H) AQ-Aib-EFIE-αMeY-LIAGGPSSG APPPS-NH 2 (SEQ ID NO: 26) The structure of SEQ ID NO:26 is shown below using the standard one-letter amino acid code, with the exception that: , the amino acid residue structures are extended with residues D-Tyr1, Aib2, αMeL13, and O Exceptions are rn16, K17, Aib20, αMeY25, and Ser39.

[0214] [ka]

[0215] The compound according to SEQ ID NO: 26 was prepared essentially as described in the procedure of Example 4. The molecular weight is determined by LC-MS (observed: M+3 = 1626.5, calculated: M+3=1626.8).

[0216] Peptide synthesis Example 15 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ -Glu)-CO-(CH 2 ) 12 -CO 2 H) AQ-Aib-EFI-(D-Glu) -αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acet Chill) 2 -(γ-Glu)-CO-(CH 2 ) 12 -CO 2 H)SSGAPPPS-NH 2 (SEQ ID NO: 41).

[0217] The structure of SEQ ID NO:41 is shown below using the standard one-letter amino acid code, with the exception that: ,The structure of these amino acid residues is extended, residues Aib2, αMeF(2F)6, 4Pal10, αMeL13, Orn16, K17, Aib20, D-Glu24, αM Exceptions are eY25, K31, and Ser39.

[0218] [ka]

[0219] The peptide backbone of Example 15 is fluorenylmethyloxycarbonyl (Fmoc) / t Symphony multiplex peptide synthesis using ert-butyl (t-Bu) chemistry Protein synthesis equipment (Gyros Protein Technologies, Tucson) ,AZ).

[0220] The resin was 1% DVB cross-linked polystyrene (Fmoc-Ri) with a substitution level of 0.35 mmol / g. nk-MBHA Low Loading Resin, 100~200 mesh, EMD Mi Standard side chain protecting groups were used. t)-OH is used for lysine residues at positions 17 and 31, and Boc-Tyr(tBu)-O H) was used for the tyrosine residue at position 1. Each coupling step (2 x 7 min) The Fmoc group is removed using 20% ​​piperidine in DMF prior to the addition of all standards. Typical amino acid coupling was performed using Fmoc amino acids (0.3 mM in DMF), diisopropyl Equimolar amounts of benzophenone (0.9 mM in DCM) and benzophenone (0.9 mM in DMF) were used. The reaction is carried out for 1 hour at a 9-fold molar excess over theoretical peptide loading using a 1:1 ratio. is the coupling to a Cα-methylated amino acid, which is coupled for 3 h After the synthesis of the peptide backbone was completed, the resin was washed extensively with DCM to remove residual DMF. The Mtt protecting groups on the lysine residues at positions 17 and 31 were removed by 30% hexafluoropropanediol in DCM. Oroisopropanol (Oakwood Chemicals) (3 x 1 hour treatments) The peptide was selectively removed from the resin by washing it thoroughly with DCM and DMF. do.

[0221] Subsequent attachment of the linker moiety can be accomplished using the procedures described above for standard coupling and deprotection reactions. Following this procedure, 2-[2-(2-Fmoc-amino-ethoxy)-ethoxy]-acetic acid (Fm oc-AEEA-OH, ChemPep, Inc.) and Fmoc-glutamic acid α-t -butyl ester (Fmoc-Glu-OtBu, Ark Pharm, Inc.) After the final Fmoc protecting group removal, mono-OtB u-Tetradecanedioic acid (WuXi AppTec, Shanghai, China) A four-fold excess of fatty acid, diisopropylcarbodiimide, and hydroxypropyltrimonium chloride in 1:1 DCM / DMF Coupling was performed overnight using 1:1:1 mol / mol / mol. Upon completion, the peptide-resin is washed with DCM and then thoroughly dried under vacuum.

[0222] The dried resin was incubated for 2 h at room temperature in 10 mL of cleavage cocktail (trifluoroacetic acid:water:trifluoroacetic acid). The resin was filtered off and each 2 ml L anhydrous T ’ The combined filtrate was washed twice with FA and diluted with a 5-fold excess of cold diethyl ether (-2 The crude peptide is precipitated by treatment with 2000 M NaCl at 2000 M NaCl (0.001%). Centrifuge at 1000 rpm for 2 minutes to form a solid pellet, decant the supernatant, and centrifuge the solid pellet. Triturate twice more with ether and dry in vacuo. Dissolve the crude peptide in 20 mL of 20% acetone. Solubilized in 100% acetonitrile / 20% acetic acid / 60% water and diluted with 100% acetonitrile and 0.1% A linear gradient of TFA / water buffer (35-55% acetonitrile in 60 min) was used. ryPrep 7 μm C18 preparative column (19 × 300 mm, Waters) Purified by RP-HPLC. Peptide purity assessed using analytical RP-HPLC. The pooling standard is >95%. The primary pool purity in Example 14 was 96.0%. The final main product pool was then freeze-dried, revealing that the freeze-dried pellet The peptide TFA salt was produced. The molecular weight was determined by LC-MS (observed value: M+3 =1853.9, calculated value: M+3=1854.1).

[0223] Example 16 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ -Glu)-(10-(4-carboxyphenoxy)decanoyl))AQ-Aib-EF I-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy) -ethoxy]-acetyl) 2 -(γ-Glu)-(10-(4-carboxyphenoxy) Decanoyl))SSGAPPPS-NH 2 (SEQ ID NO: 17) The structure of SEQ ID NO:17 is shown below using the standard one-letter amino acid code, with the exception that: , the structure of amino acid residues is extended: Aib2, αMeF(2F)6, 4Pal1 0, αMeL13, Orn16, K17, Aib20, D-Glu24, αMeY25, Exceptions are K31 and Ser39.

[0224] [ka]

[0225] The compound according to SEQ ID NO: 17 is 4-(9-carboxy-nonyloxy)benzoic acid tert-butyl ester. t-Butyl ester (WuXi AppTec, Shanghai, China) was used as the final Substantially the procedure of Example 15, except that in the coupling step The molecular weight is determined by LC-MS (observed value: M +3=1887.1, calculated value: M+3=1887.4).

[0226] Example 17 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ -Glu)-(4-(4-iodophenyl)butanoyl))AQ-Aib-EFI-(D -Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]- ci]-acetyl) 2 -(γ-Glu)-(4-(4-iodophenyl)butanoyl))S SGAPPPS-NH 2 (SEQ ID NO: 18) The structure of SEQ ID NO:18 is shown below using the standard one-letter amino acid code, with the exception that , the structure of amino acid residues is extended: Aib2, αMeF(2F)6, 4Pal1 0, αMeL13, Orn16, K17, Aib20, D-Glu24, αMeY25, Exceptions are K31 and Ser39.

[0227] [ka]

[0228] The compound according to SEQ ID NO: 18 is 4-(4-iodophenyl)butyric acid (WuXi AppT ec, Shanghai, China) was used in the final coupling step. Prepared essentially as described by the procedure of Example 15, except: is determined by LC-MS (observed: M+3 = 1875.1, calculated: M+3 = 1 875.2).

[0229] Example 18 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ -Glu)-(4-(4-tert-butylphenyl)butanoyl))AQ-Aib-E FI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy )-ethoxy]-acetyl) 2 -(γ-Glu)-(4-(4-tert-butylphenyl) Butanoyl SSGAPPPS-NH 2 (SEQ ID NO: 19) The structure of SEQ ID NO:19 is shown below using the standard one-letter amino acid code, with the exception that: , the structure of amino acid residues is extended: Aib2, αMeF(2F)6, 4Pal1 0, αMeL13, Orn16, K17, Aib20, D-Glu24, αMeY25, Exceptions are K31 and Ser39.

[0230] [ka]

[0231] The compound according to SEQ ID NO: 19 is 4-(4-tert-butylphenyl)butyric acid (WuXi AppTec, Shanghai, China) in the final coupling step Prepared essentially as described by the procedure of Example 15, except that 1,4-dichloro-2,4-dichloro- ... The molecular weight is determined by LC-MS (observed: M+3 = 1828.3, calculated: M+3=1828.7).

[0232] Example 19 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ -Glu)-CO-(CH 2 ) 10 -CH 3 )AQ-Aib-EFI-(D-Glu)- αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl L) 2 -(γ-Glu)-CO-(CH 2 ) 10 -CH 3 )SSGAPPPS-NH 2 ( SEQ ID NO: 19). The structure of SEQ ID NO:19 is shown below using the standard one-letter amino acid code, with the exception that: , the structure of amino acid residues is extended: Aib2, αMeF(2F)6, 4Pal1 0, αMeL13, Orn16, K17, Aib20, D-Glu24, αMeY25, Exceptions are K31 and Ser39.

[0233] [ka]

[0234] The compound according to SEQ ID NO: 19 was synthesized using lauric acid (Sigma Aldrich) as the final cutoff. Substantially by the procedure of Example 15, except that in the pulling step Prepared as described. Molecular weight determined by LC-MS (observed: M+3 =1815.1, calculated value: M+3=1815.4).

[0235] Binding assay Glucagon (also called Gcg) is manufactured by Eli Lilly and Company The standard sample prepared was GLP-1, 7-36-NH2 (referred to as GLP-1). , CPC Scientific (Sunnyvale, CA, 97.2% purity, 100 GIP1-42 (referred to as GIP) is obtained from 100 μM aliquots in 100% DMSO. ) was obtained from Lilly using peptide synthesis and HPLC chromatography as described above. Prepared in Research Laboratories (>80% purity, 100% D 100 μM aliquots in MSO). 125 I] radiolabeled Gcg, GLP-1, or GI P is 125 I]-lactoperoxidase, Perkin El mer (Boston, MA).

[0236] Stably transfected cell lines expressing receptor cDNA plus pcDNA3 The vector was subcloned into human embryonic kidney (HEK) 293 (h GcgR and hGLP-1R) or Chinese Hamster Ovary y, CHO) (hGIPR) cells were transfected with Geneticin (hG by selection with LP-1R (hGIPR) or hygromycin B (hGcgR). It is prepared as follows.

[0237] Two methods are used to prepare crude cell membranes.

[0238] Method 1: Tris HCl (pH 7.5) 50 mM, and Roche Complete Frozen cell pellets were collected in a hypotonic buffer containing protease inhibitors (including EDTA). The solution is thawed on ice. - Using an Elvehjem homogenizer, vortex the cell suspension 25 times. Centrifuge the pellet at 1100 x g for 10 minutes at 4°C. Collect the supernatant and store on ice. Meanwhile, the pellet is resuspended in homogenization buffer and rehomogenized as above. The pellet is centrifuged at 1100 x g for 10 minutes. The second supernatant is combined with the first and thawed. The resulting membrane pellet was centrifuged at 4000 x g for 1 hour at 4°C. The cells were resuspended in homogenization buffer containing approximately 1-3 mg / mL of ATP, flash frozen in liquid nitrogen, and used. Store in aliquots in a -80°C freezer until use.

[0239] Method 2: Tris HCl (pH 7.5) 50 mM, MgCl2 1 mM, Roch e Complete™ protease inhibitor (EDTA-free), and DNAse Frozen cell pellets were incubated in a hypotonic buffer containing 25 units / ml of IFN-γ (Invitrogen). The solution was thawed on ice. Using a 1 / 2" homogenizer, vortex the cell suspension 20-25 times. Centrifuge the lysate at 1800 x g for 15 minutes at 4°C. Collect the supernatant and store on ice. Meanwhile, the pellet was resuspended in homogenization buffer (without DNAse I) and purified as described above. The homogenate is centrifuged at 1800 x g for 15 minutes. The supernatant is combined with the first supernatant and centrifuged for an additional 15 minutes at 1800 x g. The membranes are centrifuged at 25,000 x g for 30 minutes at 4°C. The resulting membrane pellet is then purified by proteasome resorption. Homogenization buffer (without DNAse I) containing DNAse inhibitor at approximately 1-3 mg / mL and store in aliquots in a -80°C freezer until use.

[0240] Connection determination method The equilibrium binding dissociation constants (K d )teeth,[ 125 I] Due to the high propanol content of the stock material, the assay was performed using a homologous competitive binding assay rather than saturation binding. The K determined for the receptor preparation d The values ​​were as follows: hGcg R (3.9 nM), hGLP-1R (1.2 nM), and hGIPR (0.14 nM).

[0241] [ 125 I]-glucagon binding Wheat germ agglutinin (WGA) beads (Perkin Elme Scintillation Proximity Assay (SPA) with The human Gcg receptor binding assay is performed using a 100% RT-PCR format. The binding buffer has a pH of 7. 4, 25 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid ( HEPES), 2.5 mM CaCl2, 1 mM MgCl2, 0.1% (w / v) Citracin (Research Products), 0.003% (w / v) polyethylene Contains ethylene sorbitan monolaurate (TWEEN®-20), and EDTA. Contains Roche Complete™ protease inhibitors. Thaw and Gcg and serially dilute 3-fold in 100% DMSO (10-point concentration adjustment). Next, 45 μL of assay binding buffer or unlabeled Gcg control (non-specific binding or NSB, 1 μM final) Transfer 5 μL of serially diluted compound or DMSO to the assay plate. [ 125 I]-Gcg (0.15 nM final), 50 μL of human GcgR membrane (1.5 μg / well), and 50 μL of WGA SPA beads (80–150 μg / well) in Bio Add with a tek Multiflo dispenser. Seal the plate and Mix for 1 minute on the thermometer (setting 6) and incubate / stand at room temperature for 12 hours. ErkinElmer Trilux MicroBeta® Scintillation Read the plate on a chromatograph counter. Final assay concentration range of peptides tested in the response curve is typically 1150 nM to 0.058 nM, and the control Gcg is 1000 nM to It is 0.05nM.

[0242] [ 125 I]-GLP-1 binding The human GLP-1 receptor binding assay uses an SPA format with WGA beads. The binding buffer is 25 mM HEPES, 2.5 mM HCl, pH 7.4. M CaCl2, 1 mM MgCl2, 0.1% (w / v) bacitracin, 0.003 % (w / v) TWEEN®-20, and EDTA-free Roche C Contains complete™ protease inhibitors. Thaw peptides and GLP-1 and serially dilute 3-fold in 100% DMSO (10-point concentration-response curve). 5 µL of assay binding buffer or unlabeled GLP-1 control (non-specific binding or NSB, 0 Corning® 3632 clear-bottom assay plate containing 0.25 μM final Transfer 5 μL of serially diluted compound or DMSO to the plate. 125 I]-GLP-1 (0.15 nM final), 50 μL of human GLP-1R membranes (0.5 μg / well), and 50 μL of WGA SPA beads (100–150 μg / well) Add with otek Multiflo dispenser. Seal the plate and Mix on a cart (setting 6) for 1 minute, then incubate at room temperature for 5-12 hours. PerkinElmer Trilux MicroBeta® scintillation Read the plate on a pulse counter. The range is typically 1150 nM to 0.058 nM, with the control GLP-1 ranging from 250 nM to It is 0.013nM.

[0243] [125I]-GIP bond The human GIP receptor binding assay uses an SPA format with WGA beads. The binding buffer is 25 mM HEPES (pH 7.4), 2.5 mM Ca Cl2, 1 mM MgCl2, 0.1% (w / v) bacitracin, 0.003% (w / v) TWEEN®-20 and EDTA-free Roche Complete ( The peptide and GIP were thawed and diluted in 100% DMSO. Serially dilute 3-fold in 10-point concentration-response curves. Then, add 45 μL of assay solution. Contains either binding buffer or unlabeled GIP control (nonspecific binding or NSB, 0.25 μM final). Add 5 μL of the solution to a Corning® 3632 clear bottom assay plate. Transfer the diluted compound or DMSO. 125 I]-GIP(0.07 5–0.15 nM final), 50 μL of human GIPR membrane (3 μg / well), and 50 μL WGA SPA beads (100–150 μg / well) were placed in a Biotek Multif Add the 100 ml plate with the dispenser. Seal the plate and mix on a plate shaker for 1 minute. (Setting 6), after 2.5-12 hours of incubation / standing at room temperature, PerkinE Measured with a Imer Trilux MicroBeta® scintillation counter The final assay concentration range of the peptide tested in the response curve is typically is 1150 to 0.058 nM or 115 nM to 0.0058 nM, and the control GIP is , 250nM to 0.013nM.

[0244] Binding assay data analysis The CPM raw data of the peptide, Gcg, GLP-1, or GIP concentration curves were analyzed to obtain individual C PM values ​​indicate nonspecific binding (excessive unlabeled Gcg, GLP-1, or GIP). The total binding signal was calculated by subtracting the nonspecific binding (i.e., the binding when the nonspecific binding was not detected) and subtracting the nonspecific binding. Convert to percent inhibition by dividing the 4 parameters (curve maximum, curve minimum, I C 50 , Hill slope) nonlinear regression routines (Genedata Screener, Bar John 12.0.4, Genedata AG, Basal, Switzerland) Analyze the data using the affinity constant (K i ) is the formula K i =IC 50 / (1+D / K d ) based on absolute IC 50 where D is the radioligand used in the experiment. is the concentration of 50 is the concentration that causes 50% inhibition of binding, and K d is radioactive is the equilibrium binding dissociation constant of the ATP (see above). i Values ​​are reported as geometric means, with errors as mean. are expressed as standard error of the mean (SEM), n is independent replicates The geometric mean is calculated as follows: R: Geometric mean=10 (Log Ki値の加算平均)) The Ki ratio (Ki of the native control peptide / Ki of the test compound) was calculated for each receptor and species. The Ki ratio is a rapid indicator of the apparent affinity of a peptide relative to a native control peptide. A Ki ratio <1 indicates that the test peptide binds less strongly to the receptor than the native peptide. On the other hand, a Ki ratio > 1 indicates a high affinity for the test compound (higher Ki value). The peptide has a higher affinity (lower Ki value) for the receptor than the native peptide. Indicates that.

[0245] n=1 / x means that out of the total number of replicates (x), only one value is used to represent the average. SEM is calculated only when there are n=2 or more non-matching results. are expressed as geometric means, with standard error of the mean (SEM) and number of replicates (n) in parentheses. vinegar.

[0246] [Table 6]

[0247] [Table 7]

[0248] cAMP pharmacological function assay in the presence of casein One additional set of cAMP assays for human GLP-1 receptor (GLP-1R), gastric inhibition Gastric inhibitory peptide receptor (GIPR), glucagon receptor The study was carried out in HEK293 cells expressing the glucagon receptor (GcgR). The pharmacological activity of 1R / GIPR peptides is related to the human GLP-1 receptor (GLP-1R), gastric inhibitory Stably expressing the peptide receptor (GIPR) or the GLP-2 receptor (GLP-2R) The assay is performed in HEK293 cells containing 0.1% casein (S igma Catalog No. C4765), 250 μM IBMX, 1X GlutaMAX ( (Gibco Cat. No. 35050), and 20 mM HEPES (HyClo DMEM (Gibco catalog no. SH30237.01) supplemented with 100% ethanol. Treat each receptor overexpressing cell line (20 μl) with the test peptide in The increase in intracellular cAMP that occurred after 60 minutes of incubation at room temperature was measured as Ci sBio cAMP Dynamic 2 HTRF Assay Kit (62AM4PEJ) Next, the cAMP-d2 conjugate (20 μl) was added to Lys s Buffer solution and the antibody anti-cAMP-Eu3+-cryptate (20 μl) were added, and cA After 1 hour of incubation at room temperature, HTRF signals were measured using Envision Detection was performed using a 2104 plate reader (PerkinElmer). After measuring the fluorescence emission at 65 nm and calculating the ratio between 620 nm and 665 nm, Convert to nM cAMP per well using an AMP standard curve. The response curves were normalized to the minimum (buffer only) and maximum (maximum concentration of each control ligand). Plotted as a percentage of the stimulated response and fitted with a four-parameter model with a variable slope. Analyze using nonlinear regression (Genedata Screener 13). EC5 0 is the concentration of compound that produces half-maximal simulation of the dose-response curve. Percent maximum response versus concentration of added peptide fitted to a parametric logistic equation Relative EC values ​​were calculated by nonlinear regression analysis using the 50 Find the value.

[0249] Homogeneous time-resolved fluorometry was used to determine the intrinsic potency of example and comparative molecules. The assay was performed using 100 mg of 10 ... ) was performed in the presence of casein, which corresponds to the fatty acid moiety of the analyzed molecule. Does not interact.

[0250] Intracellular cAMP levels are determined by extrapolation using a standard curve. Dose-response curves were normalized to the minimum (buffer only) and maximum (maximum concentration of each control ligand) values. Plotted as a percentage of stimulation received and fitted with a variable slope, four-parameter Analyze using nonlinear regression (Genedata Screener 13). EC5 0 is the concentration of compound that simulates half-maximal dose in the dose-response curve. Each relative EC50 value of the mean calculation is determined from the curve fitting.

[0251] Compound concentration-response curves were plotted against minimum (buffer only) and maximum (maximum concentration of each control ligand) values. ) as a percentage of normalized stimulation and fitted with a variable slope. Analyze using a parametric nonlinear regression fit (Genedata Screener 13) EC50 is the value of the compound that simulates half the maximum dose in the dose-response curve. Concentration.

[0252] EC 50 Summary statistics are calculated as follows: Geometric mean: GM=10^(log 10 The arithmetic mean of EC 50 Convert to value)

[0253] The standard error of the mean is reported as follows: SEM=geometric mean×(log 10 Conversion EC 50 (standard deviation of values / square root of number of runs) x 1 log of 0 e

[0254] Logarithmic transformation is EC 50 Explain that the values ​​are on a multiplicative scale, not an arithmetic scale. do.

[0255] Test peptide, natural ligands GIP and GLP-1, baseline (minimum) The buffer solution alone and the highest concentration of each GIP and GLP-1 standard were used as the maximum value for calculations. Assays are performed each day. Illustratively, as shown in Example 4, the test peptides For the avoidance of doubt, the assays in Table 3 for hGIPamide and hG LP-1 amide EC50 is an example of the geometric mean of a series of 18 assay values, with the values ​​of 0.01 and 0.01 in buffer zero. Therefore, each example uses the geometric mean of these values. Example assays are normalized.

[0256] [Table 8]

[0257] As shown by the data in Table 8, the compounds of the examples exhibited a high solubility in the presence of 0.1% casein. , stimulates cAMP from human GLP-1R and GIPR.

[0258] Amino acid sequence SEQ ID NO: 1 GIP (human) YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHN ITQ SEQ ID NO: 2 GLP-1(7-36)(human) HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2 SEQ ID NO: 3 R1X1X2X3GTX6TSDX 10 X 11 X 12 X 13 X 14 DX 16 X 17 A X1X20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 SEQ ID NO:4 PX 32 X 33 X 34 -R2 SEQ ID NO:5 PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 SEQ ID NO:6 PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R2 SEQ ID NO:7 K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Gl u)-CO-(CH2) q -CO2H]X 32 X 33 X 34 -R2 SEQ ID NO:8 K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Gl u)-CO-(CH2) q -CO2H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 SEQ ID NO:9 K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Gl u)-CO-(CH2) q -CO2H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R2 SEQ ID NO: 10 Example 3 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LDEK((2- [2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO- (CH2) 18 -CO2H)AQ-Aib-EFI-(D-Glu)-YLIEGGPS SGAPPPS-NH2 SEQ ID NO: 11 Example 4 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD-Orn-K ((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu) -CO-(CH2) 16 -CO2H)AQ-Aib-EFI-(D-Glu)-YLIE GGPSSGAPPPS-NH2 SEQ ID NO: 12 Example 5 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD-Orn-K ((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu) -CO-(CH2) 18 -CO2H)AQ-Aib-EFI-(D-Glu)-YLIE GGPSSGAPPPS-NH2 SEQ ID NO: 13 Example 6 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ -Glu)-CO-(CH2) 16 -CO2H)AQ-Aib-EFI-(D-Glu) -αMeY-LIEGGPSSGAPPPS-NH2 SEQ ID NO: 14 Example 7 Y-Aib-EGT-αMeF(2F)-TSDVSI-αMeL-LD-Orn-K ((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu) -CO-(CH2) 16 -CO2H)AQ-Aib-EFI-(D-Glu)-αMeY -LIEGGPSSGAPPPS-NH2 SEQ ID NO: 15 PSSG-R2 SEQ ID NO: 16 PSSGAPPPS-R2 SEQ ID NO: 17 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ -Glu)-(10-(4-carboxyphenoxy)decanoyl))AQ-Aib-EF I-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy) -ethoxy]-acetyl)2-(γ-Glu)-(10-(4-carboxyphenoxy) Decanoyl))SSGAPPPS-NH2 SEQ ID NO: 18 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ -Glu)-(4-(4-iodophenyl)butanoyl))AQ-Aib-EFI-(D -Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]- [Ci]-acetyl)2-(γ-Glu)-(4-(4-iodophenyl)butanoyl))S SGAPPPS-NH2 SEQ ID NO: 19 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ -Glu)-(4-(4-tert-butylphenyl)butanoyl))AQ-Aib-E FI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy )-ethoxy]-acetyl)2-(γ-Glu)-(4-(4-tert-butylphenyl) Butanoyl SSGAPPPS-NH2 SEQ ID NO: 20 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ -Glu)-CO-(CH2) 10 -CH3)AQ-Aib-EFI-(D-Glu)- αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl Glu)2-(γ-Glu)-CO-(CH2) 10 -CH3)SSGAPPPS-NH2 SEQ ID NO: 21 Y-(Aib)-EGTFTSDYSILLDKK((2-[2-(2-amino-ethoxy) (oxy)-ethoxy]-acetyl) 2- (γ-Glu)-CO-(CH2)18 -CO2H )AQ-(Aib)-AFIEYLIAGGPSSGAPPPS-NH2 SEQ ID NO: 22 Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2-(2-アノ -Al)-Al]-Al)2-(γ-Glu)-CO-(CH2) 18 -C O2H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH2 SEQ ID NO: 23 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- (2-Diphthalene-Diphthalene)-Diphthalene]-Diphthalene)2-(γ-Glu)-CO-(CH 2) 18 -CO2H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH2 SEQ ID NO: 24 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn-K((2). -[2-(2-Diphenyl-dimer)-dimer]-dimer)2-(γ-Glu)-CO -(CH2) 18 -CO2H)AQ-Aib-AFI-(D-Glu)-YLIAGGP SSGAPPPS-NH2 SEQ ID NO: 25 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- (2-Diphthalene-Diphthalene)-Diphthalene]-Diphthalene)2-(γ-Glu)-CO-(CH 2) 18 -CO2H)AQ-Aib-EFIE-αMeY-LIAGGPSSGAPPP S-NH2 SEQ ID NO: 26 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn-K((2). -[2-(2-アミノ-エトキシ)-エトキシ]-アセチル)2-(γ-Glu)-CO -(CH2) 18 -CO2H)AQ-Aib-EFIE-αMeY-LIAGGPSSG APPPS-NH2 SEQ ID NO: 27 X1X2EGTX6TSDX 10 X 11 X 12 X 13 LDX 16 X 17 AQX 20 X2 1X 22 IX 24 X 25 LIX 28 GX 30 SEQ ID NO: 28 X 31 SSG SEQ ID NO: 29 X 31 SSG-R3 SEQ ID NO: 30 X 31 SSGX 35 PPPX 39 SEQ ID NO: 31 X 31 SSGX 35 PPPX 39 R3 SEQ ID NO: 32 X 31 SSGX 35 PPPX 39 X 40 SEQ ID NO: 33 X 31 SSGX 35 PPPX 39 X 40 R3 SEQ ID NO: 34 PSSG SEQ ID NO: 35 PSSG-R3 SEQ ID NO: 36 PSSGX35 PPPX 39 SEQ ID NO: 37 PSSGX 35 PPPX 39 R3 SEQ ID NO: 38 PSSGX 35 PPPX 39 X 40 SEQ ID NO: 39 PSSGX 35 PPPX 39 X 40 R3 SEQ ID NO: 40 X1X2EGTX6TSDX 10 X 11 X 12 X 13 LDX 16 X 17 AQX 20 X2 1X 22 IX 24 X 25 LIX 28 GX 30 SEQ ID NO: 41 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-pro-mol)-mol]-mol)2-(γ -Glu)-CO-(CH2) 12 -CO2H)AQ-Aib-EFI-(D-Glu) -αMeY-LIEGGK((2-[2-(2-dilute-dilute)-dilute]-dilute 3)2-(γ-Glu)-CO-(CH2) 12 -CO2H)SSGAPPPS-NH 2

Claims

1. A method for treating refractory type 2 diabetes in a patient in need of treatment for refractory type 2 diabetes wherein the patient is administered an effective amount of a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof. Administering the salt once a week.

2. 10. The method of claim 1, wherein the patient has had type 2 diabetes for at least 8 years.

3. 3. The method of claim 1 or 2, wherein the patient's HbA1c target value is less than 7%.

4. The method according to any one of claims 1 to 3, wherein the target HbA1c value of the patient is 5.7% or less. How to post.

5. The method of any one of claims 1 to 4, wherein the patient's HbA1c is greater than 10%.

6. The method of any one of claims 1 to 4, wherein the patient's HbA1c is greater than 11%.

7. The method of any one of claims 1 to 6, wherein the patient is at least 46 years old. 。

8. The method according to any one of claims 1 to 7, wherein the patient is at least 60 years old. 。

9. The method according to any one of claims 1 to 8, wherein the patient is taking an SGLT2 inhibitor. Law.

10. The method of any one of claims 1 to 9, wherein the patient is taking metformin.

11. The method according to any one of claims 1 to 10, wherein the patient is not administered basal insulin. Law.

12. The patient achieved HbA1c target while taking metformin and an SGLT2 inhibitor. The method according to any one of claims 1 to 11, wherein the surface of the substrate is inaccessible.

13. Treatment with the GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is at least 13. The method of any one of claims 1 to 12, which lasts for 40 weeks.

14. The patient is administered at least one of the GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof. The method of any one of claims 1 to 13, wherein the compound is administered for 50 weeks.

15. The patient is administered at least one of the GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof. The method of any one of claims 1 to 14, wherein the medicament is administered for at least two years.

16. The method of any one of claims 1 to 15, wherein the patient is non-obese.

17. The method of any one of claims 1 to 16, wherein the patient suffers from concomitant hypertension.

18. The method of any one of claims 1 to 17, wherein the patient suffers from concomitant low HDL-C. Law.

19. 19. The method according to any one of claims 1 to 15 or 16 to 18, wherein the patient suffers from concomitant obesity. How to post.

20. 20. The method according to claim 1, wherein the patient has at least two cardiovascular risk factors. The method described in paragraph .

21. The method according to any one of claims 1 to 19, wherein the patient has no cardiovascular risk factors. 。

22. 22. The method according to claim 1, wherein the patient has had type 2 diabetes for at least 10 years. The method described in paragraph .

23. 1. A method of treating hypertension in a patient in need thereof, comprising administering to said patient: Administering an effective amount of a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof once a week and

24. 24. The method of claim 23, wherein the patient has had type 2 diabetes for at least 8 years.

25. 25. The method of claim 23 or 24, wherein the patient suffers from refractory type 2 diabetes.

26. 26. The method of claim 24 or 25, wherein the patient's HbA1c target is less than 7%.

27. Any one of claims 23 to 26, wherein the patient's HbA1c target value is 5.7% or less. The method described below.

28. The method according to any one of claims 23 to 27, wherein the patient's HbA1c is greater than 10%. Law.

29. The method according to any one of claims 23 to 28, wherein the patient's HbA1c is greater than 11%. Law.

30. 30. The method of claim 23, wherein the patient is at least 46 years old. method.

31. 31. The method of claim 23, wherein the patient is at least 60 years old. method.

32. 32. The method of claim 23, wherein the patient is taking an SGLT2 inhibitor. How to do it.

33. The method according to any one of claims 23 to 32, wherein the patient is taking metformin. Law.

34. 34. The method of claim 23, wherein the patient is not administered basal insulin. method.

35. The patient achieved HbA1c target while taking metformin and an SGLT2 inhibitor.

35. The method of any one of claims 23 to 34, wherein the surface of the membrane is inaccessible.

36. 23. The method of claim 22, wherein said treatment with the GIP / GLP1 agonist continues for at least 40 weeks.

36. The method according to any one of claims 1 to 35.

37. The method of any one of claims 23 to 36, wherein the patient suffers from concomitant obesity.

38. 38. The method of any one of claims 23 to 37, wherein the patient is non-obese.

39. 39. The method of any one of claims 23 to 38, wherein the patient suffers from concomitant low HDL-C. method.

40. Any of claims 23 to 39, wherein the patient has at least two cardiovascular risk factors.

10. The method according to claim 1.

41. 41. The method of any one of claims 23 to 40, wherein the hypertension is a hypertensive crisis.

42. 42. The method of any one of claims 23 to 41, wherein the method prevents a hypertensive crisis. 。

43. 43. The method of any one of claims 23 to 42, wherein the method prevents stroke.

44. A method for increasing HDL-C in a patient in need thereof. and administering to said patient an effective amount of a GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof. The method comprises administering the compound once a week.

45. 45. The method of claim 44, wherein the patient has had type 2 diabetes for at least 8 years.

46. 46. ​​The method of claim 44 or 45, wherein the patient has refractory type 2 diabetes.

47. 57. The method of claim 44, wherein the patient is at least 46 years old. method.

48. 48. The method of claim 44, wherein the patient is at least 60 years old. method.

49. 49. The method of any one of claims 44 to 48, wherein the patient is taking an SGLT2 inhibitor. How to do it.

50. The method according to any one of claims 44 to 49, wherein the patient is taking metformin. Law.

51. 51. The method of any one of claims 44 to 50, wherein the patient is not administered basal insulin. method.

52. 44. The method of claim 44, wherein said treatment with the GIP / GLP1 agonist continues for at least 40 weeks.

52. The method according to any one of claims 1 to 51.

53. 53. The method of any one of claims 44 to 52, wherein the patient is non-obese.

54. Any of claims 44 to 53, wherein the patient has at least two cardiovascular risk factors.

10. The method according to claim 1.

55. 55. The method of any one of claims 44 to 54, wherein the patient suffers from concomitant hypertension.

56. 44 to 46, wherein the administration of the GIP / GLP1 agonist continues for at least 50 weeks.

53. The method of any one of claims 53 to 53.

57. 4. The once-weekly administration of the GIP / GLP1 agonist is continued for at least two years.

57. The method of any one of claims 4 to 56.

58. The GIP / GLP1 agonist compound has the following formula: R １ X １ X ２ X ３ GTX ６ TSDX １０ X １１ X １２ X １３ X １４ DX １６ X １７ AX １９ X ２０ X ２１ X ２２ X ２３ X ２４ X ２５ X ２６ X ２７ X ２８ X ２９ X ３０ X ３１ (SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof. In the formula, R １ is absent or is an Ac modification of the N-terminal amino group, X １ is selected from the group consisting of Y, H, D-Tyr, F, desH, and desY; X ２ is selected from the group consisting of Aib, αMeP, A, P, and D-Ala; or teeth X １ and X ２ binds to form desH-ψ[NHCO]-Aib, X ３ is selected from the group consisting of E, N, Aad, and cTA; X ６ is selected from the group consisting of F, αMeF, and αMeF(2F); 8 １０ が、Z、4、N、30、40、6、1、X、α50、α00(2 ), I, αMeY, Q, D-His, D-Tyr, cTA, and K (2-[2-(2-α (amino-ethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) qC O ２ H; X １１ is selected from the group consisting of S, αMeS, and D-Ser; X １２ I, S, D-Ile, and K(2-[2-(2-amino-ethoxy)-ethoxy]- hydroxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ Selected from the group consisting of H Selected, X １３ Nle, Aib, L, αMeL, and K(2-[2-(2-amino-ethoxy) [Ci)-ethoxy]-acetyl ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ From H is selected from the group X １４ is selected from the group consisting of L and K, where K is C １６ -C ２２ Fatty acids wherein the fatty acid is optionally conjugated to the K via a linker. is installed, X １６ K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK, R, and and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ -(γ-Glu )-CO-(CH ２ ) qCO ２ H; X １７ are K, Q, I, and C １６ -C ２２ Amino acids conjugated to fatty acids wherein said fatty acid is optionally attached to said amino acid via a linker. conjugated with X １９ Q, A, and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetate) Chill) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ H; X ２０ Aib, Q, H, R, K, αMeK, and K(2-[2-(2-amino- [ethoxy]-ethoxy]-acetyl ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ H? is selected from the group consisting of X ２１ H, Aad, D, Aib, T, A, E, I, and K (2-[2-(2-amino (no-ethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ H; X ２２ is selected from the group consisting of F and αMeF; X ２３ I, L, A, G, F, H, E, V, and K (2-[2-(2-amino-ethoxy) [oxy]-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ From H is selected from the group consisting of 8 ２４ が、″、Aad、D-1lu、E、Aib、ｨ、6、A、ｱ、､、. 2-[2-(2-amino-ethoxy)-ethoxy]-acetyl ２ -(γ-Glu)-C O-(CH ２ ) qCO ２ H; X ２５ is selected from the group consisting of Y and αMeY; X ２６ L, αMeL, and K(2-[2-(2-amino-ethoxy)-ethoxy] -acetyl) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ H 、 X ２７ are L, I, and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetate Chill) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ H; X ２８ E, A, S, D-Glu, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ Is it a group consisting of H? are selected from X ２９ Aib, G, A, and K (2-[2-(2-amino-ethoxy)-ethoxy] ]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ H R, X ３０ But C, G, G-R ２ , and K(2-[2-(2-amino-ethoxy)-ethoxy] Ci]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ Selected from the group consisting of H Selected, X ３１ is absent or PX ３２ X ３３ X ３４ -R ２ (SEQ ID NO: 4), PX ３２ X ３３ X ３４ X ３５ X ３６ X ３７ X ３８ X ３９ -R ２ (SEQ ID NO: 5) 、 PX ３２ X ３３ X ３４ X ３５ X ３６ X ３７ X ３８ X ３９ X ４０ -R ２ (SEQ ID NO: 6) 、 K [(2-[2-( 2-amino-ethoxy)-ethoxy]-acetyl ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H]X ３２ X ３３ X ３４ -R ２ (SEQ ID NO: 7) 、 K[(2-[2-(2-A (amino-ethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) ｑ - CO ２ H]X ３２ X ３３ X ３４ X ３５ X ３６ X ３７ X ３８ X ３９ -R ２ (SEQ ID NO: 8) 、 and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ -(γ-G lu)-CO-(CH ２ ) ｑ -CO ２ H]X ３２ X ３３ X ３４ X ３５ X ３６ X ３７ X ３８ X ３９ X ４０ -R ２ (SEQ ID NO: 9), wherein: X ３２ is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl L) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H], X ３３ is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl L) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H], X ３４ G, C, and K [(2-[2-(2-amino-ethoxy)-ethoxy]- Acetyl) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H] R, X ３５ is A or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl L) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H], X ３６ is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl L) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H], X ３７ is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl L) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H], X ３８ is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl L) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H], X ３９ C, S, and K[(2-[2-(2-amino-ethoxy)-ethoxy]- Acetyl) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H] R, X ４０ C and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl L) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H], q is selected from the group consisting of 14, 15, 16, 17, 18, 19, and 20; R ２ is a modification of the C-terminal group, wherein said modification is NH ２ or absent 、 X ３０ G-R ２ If X ３１ is absent, X １０ 、X １２ 、X １３ 、X １４ 、X １６ 、X １７ 、X １９ 、X ２０ 、X ２１ 、X ２３ 、X ２４ 、X ２６ 、X ２７ 、X ２８ 、X ２９ 、X ３０ 、X ３１ 、X ３２ 、X ３３ 、X ３４ , X ３５ , X ３６ , X ３７ , X ３８ , X ３９ , and X ４０ Not more than one of the may be a substituent including X ３０ , X ３４ , X ３９ , and X ４０ may be C; X ３０ , X ３４ , X ３９ , and X ４０ If one of １０ , X １２ , X １３ 、X １４ 、X １６ 、X １７ 、X １９ 、X ２０ 、X ２１ 、X ２３ 、X ２４ 、X ２６ 、 X ２７ 、X ２８ 、X ２９ 、X ３０ 、X ３１ 、X ３２ 、X ３３ 、X ３４ 、X ３５ 、X ３６ 、 X ３７ , X ３８ , X ３９ , and X ４０ None of the substituents contains a fatty acid.

23. The method of any one of claims 1 to 22.

59. The GIP / GLP1 agonist compound has the following formula: R １ X １ X ２ X ３ GTX ６ TSDX １０ X １１ X １２ X １３ X １４ DX １６ X １７ AX １９ X ２０ X ２１ X ２２ X ２３ X ２４ X ２５ X ２６ X ２７ X ２８ X ２９ X ３０ X ３１ (SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof. In the formula, R １ is absent or is an Ac modification of the N-terminal amino group, X １ is selected from the group consisting of Y, H, D-Tyr, F, desH, and desY; X ２ is selected from the group consisting of Aib, αMeP, A, P, and D-Ala; or teeth X １ and X ２ binds to form desH-ψ[NHCO]-Aib, X ３ is selected from the group consisting of E, N, Aad, and cTA; X ６ is selected from the group consisting of F, αMeF, and αMeF(2F); 8 １０ が、Z、4、N、30、40、6、1、X、α50、α00(2 ), I, αMeY, Q, D-His, D-Tyr, cTA, and K (2-[2-(2-α (amino-ethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) qC O ２ H; X １１ is selected from the group consisting of S, αMeS, and D-Ser; X １２ I, S, D-Ile, and K(2-[2-(2-amino-ethoxy)-ethoxy]- hydroxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ Selected from the group consisting of H Selected, X １３ Nle, Aib, L, αMeL, and K(2-[2-(2-amino-ethoxy) [Ci)-ethoxy]-acetyl ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ From H is selected from the group X １４ is selected from the group consisting of L and K, where K is C １６ -C ２２ Fatty acids wherein the fatty acid is optionally conjugated to the K via a linker. is installed, X １６ K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK, R, and and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ -(γ-Glu )-CO-(CH ２ ) qCO ２ H; X １７ are K, Q, I, and C １６ -C ２２ Amino acids conjugated to fatty acids wherein said fatty acid is optionally attached to said amino acid via a linker. conjugated with X １９ Q, A, and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetate) Chill) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ H; X ２０ Aib, Q, H, R, K, αMeK, and K(2-[2-(2-amino- [ethoxy]-ethoxy]-acetyl ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ H? is selected from the group consisting of X ２１ H, Aad, D, Aib, T, A, E, I, and K (2-[2-(2-amino (no-ethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ H; X ２２ is selected from the group consisting of F and αMeF; X ２３ I, L, A, G, F, H, E, V, and K (2-[2-(2-amino-ethoxy) [oxy]-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ From H is selected from the group consisting of 8 ２４ が、″、Aad、D-1lu、E、Aib、ｨ、6、A、ｱ、､、. 2-[2-(2-amino-ethoxy)-ethoxy]-acetyl ２ -(γ-Glu)-C O-(CH ２ ) qCO ２ H; X ２５ is selected from the group consisting of Y and αMeY; X ２６ L, αMeL, and K(2-[2-(2-amino-ethoxy)-ethoxy] -acetyl) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ H 、 X ２７ are L, I, and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetate Chill) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ H; X ２８ E, A, S, D-Glu, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ Is it a group consisting of H? are selected from X ２９ Aib, G, A, and K (2-[2-(2-amino-ethoxy)-ethoxy] ]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ H R, X ３０ But C, G, G-R ２ , and K(2-[2-(2-amino-ethoxy)-ethoxy] Ci]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ Selected from the group consisting of H Selected, X ３１ is absent or PX ３２ X ３３ X ３４ -R ２ (SEQ ID NO: 4), PX ３２ X ３３ X ３４ X ３５ X ３６ X ３７ X ３８ X ３９ -R ２ (SEQ ID NO: 5) 、 PX ３２ X ３３ X ３４ X ３５ X ３６ X ３７ X ３８ X ３９ X ４０ -R ２ (SEQ ID NO: 6) 、 K [(2-[2-( 2-amino-ethoxy)-ethoxy]-acetyl ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H]X ３２ X ３３ X ３４ -R ２ (SEQ ID NO: 7) 、 K[(2-[2-(2-A (amino-ethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) ｑ - CO ２ H]X ３２ X ３３ X ３４ X ３５ X ３６ X ３７ X ３８ X ３９ -R ２ (SEQ ID NO: 8) 、 and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ -(γ-G lu)-CO-(CH ２ ) ｑ -CO ２ H]X ３２ X ３３ X ３４ X ３５ X ３６ X ３７ X ３８ X ３９ X ４０ -R ２ (SEQ ID NO: 9), wherein: X ３２ is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl L) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H], X ３３ is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl L) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H], X ３４ G, C, and K [(2-[2-(2-amino-ethoxy)-ethoxy]- Acetyl) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H] R, X ３５ is A or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl L) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H], X ３６ is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl L) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H], X ３７ is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl L) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H], X ３８ is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl L) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H], X ３９ C, S, and K[(2-[2-(2-amino-ethoxy)-ethoxy]- Acetyl) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H] R, X ４０ C and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl L) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H], q is selected from the group consisting of 14, 15, 16, 17, 18, 19, and 20; R ２ is a modification of the C-terminal group, wherein said modification is NH ２ or absent 、 X ３０ G-R ２ If X ３１ is absent, X １０ 、X １２ 、X １３ 、X １４ 、X １６ 、X １７ 、X １９ 、X ２０ 、X ２１ 、X ２３ 、X ２４ 、X ２６ 、X ２７ 、X ２８ 、X ２９ 、X ３０ 、X ３１ 、X ３２ 、X ３３ 、X ３４ , X ３５ , X ３６ , X ３７ , X ３８ , X ３９ , and X ４０ Not more than one of the may be a substituent including X ３０ , X ３４ , X ３９ , and X ４０ may be C; X ３０ , X ３４ , X ３９ , and X ４０ If one of １０ , X １２ , X １３ 、X １４ 、X １６ 、X １７ 、X １９ 、X ２０ 、X ２１ 、X ２３ 、X ２４ 、X ２６ 、 X ２７ 、X ２８ 、X ２９ 、X ３０ 、X ３１ 、X ３２ 、X ３３ 、X ３４ 、X ３５ 、X ３６ 、 X ３７ , X ３８ , X ３９ , and X ４０ None of the substituents contains a fatty acid. The method according to any one of claims 23 to 43.

60. The GIP / GLP1 agonist compound has the following formula: R １ X １ X ２ X ３ GTX ６ TSDX １０ X １１ X １２ X １３ X １４ DX １６ X １７ AX １９ X ２０ X ２１ X ２２ X ２３ X ２４ X ２５ X ２６ X ２７ X ２８ X ２９ X ３０ X ３１ (SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof. In the formula, R １ is absent or is an Ac modification of the N-terminal amino group, X １ is selected from the group consisting of Y, H, D-Tyr, F, desH, and desY; X ２ is selected from the group consisting of Aib, αMeP, A, P, and D-Ala; or teeth X １ and X ２ binds to form desH-ψ[NHCO]-Aib, X ３ is selected from the group consisting of E, N, Aad, and cTA; X ６ is selected from the group consisting of F, αMeF, and αMeF(2F); 8 １０ が、Z、4、N、30、40、6、1、X、α50、α00(2 ), I, αMeY, Q, D-His, D-Tyr, cTA, and K (2-[2-(2-α (amino-ethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) qC O ２ H; X １１ is selected from the group consisting of S, αMeS, and D-Ser; X １２ I, S, D-Ile, and K(2-[2-(2-amino-ethoxy)-ethoxy]- hydroxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ Selected from the group consisting of H Selected, X １３ Nle, Aib, L, αMeL, and K(2-[2-(2-amino-ethoxy) [Ci)-ethoxy]-acetyl ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ From H is selected from the group X １４ is selected from the group consisting of L and K, where K is C １６ -C ２２ Fatty acids wherein the fatty acid is optionally conjugated to the K via a linker. is installed, X １６ K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK, R, and and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ -(γ-Glu )-CO-(CH ２ ) qCO ２ H; X １７ are K, Q, I, and C １６ -C ２２ Amino acids conjugated to fatty acids wherein said fatty acid is optionally attached to said amino acid via a linker. conjugated with X １９ Q, A, and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetate) Chill) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ H; X ２０ Aib, Q, H, R, K, αMeK, and K(2-[2-(2-amino- [ethoxy]-ethoxy]-acetyl ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ H? is selected from the group consisting of X ２１ H, Aad, D, Aib, T, A, E, I, and K (2-[2-(2-amino (no-ethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ H; X ２２ is selected from the group consisting of F and αMeF; X ２３ I, L, A, G, F, H, E, V, and K (2-[2-(2-amino-ethoxy) [oxy]-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ From H is selected from the group consisting of 8 ２４ が、″、Aad、D-1lu、E、Aib、ｨ、6、A、ｱ、､、. 2-[2-(2-amino-ethoxy)-ethoxy]-acetyl ２ -(γ-Glu)-C O-(CH ２ ) qCO ２ H; X ２５ is selected from the group consisting of Y and αMeY; X ２６ L, αMeL, and K(2-[2-(2-amino-ethoxy)-ethoxy] -acetyl) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ H 、 X ２７ are L, I, and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetate Chill) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ H; X ２８ E, A, S, D-Glu, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ Is it a group consisting of H? are selected from X ２９ Aib, G, A, and K (2-[2-(2-amino-ethoxy)-ethoxy] ]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) qCO ２ H R, X ３０ But C, G, G-R ２ , and K(2-[2-(2-amino-ethoxy)-ethoxy] Ci]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ Selected from the group consisting of H Selected, X ３１ is absent or PX ３２ X ３３ X ３４ -R ２ (SEQ ID NO: 4), PX ３２ X ３３ X ３４ X ３５ X ３６ X ３７ X ３８ X ３９ -R ２ (SEQ ID NO: 5) 、 PX ３２ X ３３ X ３４ X ３５ X ３６ X ３７ X ３８ X ３９ X ４０ -R ２ (SEQ ID NO: 6), K[(2-[2-( 2-amino -ethoxy]-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -C O ２ H]X ３２ X ３３ X ３４ -R ２ (SEQ ID NO: 7) 、 K[(2-[2-(2-amino -ethoxy]-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -C O ２ H]X ３２ X ３３ X ３４ X ３５ X ３６ X ３７ X ３８ X ３９ -R ２ (Allocation number 8) 、 and and K[(2-[2-(2-amino -ethoxy]-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -C O ２ H]X ３２ X ３３ X ３４ X ３５ X ３６ X ３７ X ３８ X ３９ X ４０ -R ２ (SEQ ID NO: 9 ) wherein: X ３２ is S or K[(2-[2-(2-amino -ethoxy]-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -C O ２ H], X ３３ is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl L) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H], X ３４ G, C, and K [(2-[2-(2-amino-ethoxy)-ethoxy]- Acetyl) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H] R, X ３５ is A or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl L) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H], X ３６ is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl L) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H], X ３７ is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl L) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H], X ３８ is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl L) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H], X ３９ C, S, and K[(2-[2-(2-amino-ethoxy)-ethoxy]- Acetyl) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H] R, X ４０ C and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl L) ２ -(γ-Glu)-CO-(CH ２ ) ｑ -CO ２ H], q is selected from the group consisting of 14, 15, 16, 17, 18, 19, and 20; R ２ is a modification of the C-terminal group, wherein said modification is NH ２ or absent 、 X ３０ G-R ２ If X ３１ is absent, X １０ 、X １２ 、X １３ 、X １４ 、X １６ 、X １７ 、X １９ 、X ２０ 、X ２１ 、X ２３ 、X ２４ 、X ２６ 、X ２７ 、X ２８ 、X ２９ 、X ３０ 、X ３１ 、X ３２ 、X ３３ 、X ３４ , X ３５ , X ３６ , X ３７ , X ３８ , X ３９ , and X ４０ Not more than one of the may be a substituent including X ３０ , X ３４ , X ３９ , and X ４０ may be C; X ３０ , X ３４ , X ３９ , and X ４０ If one of １０ , X １２ , X １３ 、X １４ 、X １６ 、X １７ 、X １９ 、X ２０ 、X ２１ 、X ２３ 、X ２４ 、X ２６ 、 X ２７ 、X ２８ 、X ２９ 、X ３０ 、X ３１ 、X ３２ 、X ３３ 、X ３４ 、X ３５ 、X ３６ 、 X ３７ , X ３８ , X ３９ , and X ４０ None of the substituents contains a fatty acid. The method of any one of claims 44 to 57.

61. The GIP / GLP1 agonist compound has the following formula: X １ X ２ EGTX ６ TSDX １０ X １１ X １２ X １３ LDX １６ X １７ AQX ２０ X ２ １ X ２２ IX ２４ X ２５ LIX ２８ GX ３０ (SEQ ID NO: 27), or a pharmaceutically acceptable salt thereof; During the ceremony, X １ However, Y and R １ Y is selected from the group consisting of R １ is Ac modification of the N-terminal amino group, X ２ is Aib, X ６ is selected from the group consisting of αMeF and αMeF(2F); 8 １０ が、40、1、α50、α5(20)、α50、α53 c, Ac5c, Ac6c, Bip, 1Nal, 2Nal, OMeY, hTyr, Nle, V, 4CPhe, ChG, ChA, Bzt, 2FA, 4TAA, 2TA, 3TA, and K Z １ is selected from the group consisting of X １１ is selected from the group consisting of S, αMeS, Aib, G, Dap, Ac5c, and Tle Selected, X １２ However, I and KZ １ is selected from the group consisting of X １３ is selected from the group consisting of αMeL and αMeF; X １６ is Orn, X １７ Q, I, and KZ １ is selected from the group consisting of X ２０ is a group consisting of Aib, Orn, 4Pal, αMeF, Ac5c, and Ac6c is selected from X ２１ But E, KZ １ , G, Orn, and 4Pal; ︸ ２２ が. A group consisting of e, 1Nal, 2Nal, αMeF(2F), ChA, Bzt, and αMeF is selected from X ２４ D-Glu, E, G, and KZ １ is selected from the group consisting of X ２５ Y, αMeY, αMeF, and KZ １ is selected from the group consisting of X ２８ E, Orn, and KZ １ is selected from the group consisting of X ３０ But, G, Orn, KZ １ , K(Z １ ) R ６ , OrnR ２ , and G.R. ２ A group consisting of is selected from R ２ But, X ３１ , X ３１ SSG (SEQ ID NO: 28), X ３１ SSG-R ３ (SEQ ID NO: 29 ), X ３１ SSGX ３５ PPPX ３９ (SEQ ID NO: 30), X ３１ SSGX ３５ PPPX ３ ９ R ３ (SEQ ID NO: 31), X ３１ SSGX ３５ PPPX ３９ X ４０ (SEQ ID NO: 32), X ３１ SSGX ３５ PPPX ３９ X ４０ R ３ (SEQ ID NO: 33), and a C-terminal modification wherein said modification is selected from the group consisting of NH ２ and R ６ However, PSSG (SEQ ID NO: 34), PSSG-R ３ (SEQ ID NO: 35), PSSGX ３ ５ PPPX ３９ (SEQ ID NO: 36), PSSGX ３５ PPPX ３９ R ３ (SEQ ID NO: 37), PSSGX ３５ PPPX ３９ X ４０ (SEQ ID NO: 38), PSSGX ３５ PPPX ３９ X ４ ０ R ３ (SEQ ID NO: 39), and a C-terminal modification, wherein said modification Decoration is NH ２ and X ３１ However, P and KZ １ is selected from the group consisting of X ３５ is selected from the group consisting of A and Orn; X ３９ is selected from the group consisting of S and Orn; X ４０ But, KZ １ and R ３ is a modification of the C-terminal group, wherein said modification is NH ２ and X １０ 、X １２ 、X １７ 、X ２１ 、X ２４ 、X ２５ 、X ２８ 、X ３０ 、X ３１ 、and X ４０ Two of them and only two of them are KZ １ or K(Z １ ) R ６ and Z １ But, R ５ and -R ４ R ５ is selected from the group consisting of R ４ is the linker, R ５ is a fatty acid, 23. The method according to any one of claims 1 to 22.

62. The GIP / GLP1 agonist compound has the following formula: X １ X ２ EGTX ６ TSDX １０ X １１ X １２ X １３ LDX １６ X １７ AQX ２０ X ２ １ X ２２ IX ２４ X ２５ LIX ２８ GX ３０ (SEQ ID NO: 27), or a pharmaceutically acceptable salt thereof; During the ceremony, X １ However, Y and R １ Y is selected from the group consisting of R １ is Ac modification of the N-terminal amino group, X ２ is Aib, X ６ is selected from the group consisting of αMeF and αMeF(2F); 8 １０ が、40、1、α50、α5(20)、α50、α53 c, Ac5c, Ac6c, Bip, 1Nal, 2Nal, OMeY, hTyr, Nle, V, 4CPhe, ChG, ChA, Bzt, 2FA, 4TAA, 2TA, 3TA, and K Z １ is selected from the group consisting of X １１ is selected from the group consisting of S, αMeS, Aib, G, Dap, Ac5c, and Tle Selected, X １２ However, I and KZ １ is selected from the group consisting of X １３ is selected from the group consisting of αMeL and αMeF; X １６ is Orn, X １７ Q, I, and KZ １ is selected from the group consisting of X ２０ is a group consisting of Aib, Orn, 4Pal, αMeF, Ac5c, and Ac6c is selected from X ２１ But E, KZ １ , G, Orn, and 4Pal; ︸ ２２ が. A group consisting of e, 1Nal, 2Nal, αMeF(2F), ChA, Bzt, and αMeF is selected from X ２４ D-Glu, E, G, and KZ １ is selected from the group consisting of X ２５ Y, αMeY, αMeF, and KZ １ is selected from the group consisting of X ２８ E, Orn, and KZ １ is selected from the group consisting of X ３０ But, G, Orn, KZ １ , K(Z １ ) R ６ , OrnR ２ , and G.R. ２ A group consisting of is selected from R ２ But, X ３１ , X ３１ SSG (SEQ ID NO: 28), X ３１ SSG-R ３ (SEQ ID NO: 29 ), X ３１ SSGX ３５ PPPX ３９ (SEQ ID NO: 30), X ３１ SSGX ３５ PPPX ３ ９ R ３ (SEQ ID NO: 31), X ３１ SSGX ３５ PPPX ３９ X ４０ (SEQ ID NO: 32), X ３１ SSGX ３５ PPPX ３９ X ４０ R ３ (SEQ ID NO: 33), and a C-terminal modification wherein said modification is selected from the group consisting of NH ２ and R ６ However, PSSG (SEQ ID NO: 34), PSSG-R ３ (SEQ ID NO: 35), PSSGX ３ ５ PPPX ３９ (SEQ ID NO: 36), PSSGX ３５ PPPX ３９ R ３ (SEQ ID NO: 37), PSSGX ３５ PPPX ３９ X ４０ (SEQ ID NO: 38), PSSGX ３５ PPPX ３９ X ４ ０ R ３ (SEQ ID NO: 39), and a C-terminal modification, wherein said modification Decoration is NH ２ and X ３１ However, P and KZ １ is selected from the group consisting of X ３５ is selected from the group consisting of A and Orn; X ３９ is selected from the group consisting of S and Orn; X ４０ But, KZ １ and R ３ is a modification of the C-terminal group, wherein said modification is NH ２ and X １０ 、X １２ 、X １７ 、X ２１ 、X ２４ 、X ２５ 、X ２８ 、X ３０ 、X ３１ 、and X ４０ Two of them and only two of them are KZ １ or K(Z １ ) R ６ and Z １ But, R ５ and -R ４ R ５ is selected from the group consisting of R ４ is the linker, R ５ is a fatty acid, 44. The method according to any one of claims 23 to 43.

63. The GIP / GLP1 agonist compound has the following formula: X １ X ２ EGTX ６ TSDX １０ X １１ X １２ X １３ LDX １６ X １７ AQX ２０ X ２ １ X ２２ IX ２４ X ２５ LIX ２８ GX ３０ (SEQ ID NO: 27), or a pharmaceutically acceptable salt thereof; During the ceremony, X １ However, Y and R １ Y is selected from the group consisting of R １ is Ac modification of the N-terminal amino group, X ２ is Aib, X ６ is selected from the group consisting of αMeF and αMeF(2F); 8 １０ が、40、1、α50、α5(20)、α50、α53 c, Ac5c, Ac6c, Bip, 1Nal, 2Nal, OMeY, hTyr, Nle, V, 4CPhe, ChG, ChA, Bzt, 2FA, 4TAA, 2TA, 3TA, and K Z １ is selected from the group consisting of X １１ is selected from the group consisting of S, αMeS, Aib, G, Dap, Ac5c, and Tle Selected, X １２ However, I and KZ １ is selected from the group consisting of X １３ is selected from the group consisting of αMeL and αMeF; X １６ is Orn, X １７ Q, I, and KZ １ is selected from the group consisting of X ２０ is a group consisting of Aib, Orn, 4Pal, αMeF, Ac5c, and Ac6c is selected from X ２１ But E, KZ １ , G, Orn, and 4Pal; ︸ ２２ が. A group consisting of e, 1Nal, 2Nal, αMeF(2F), ChA, Bzt, and αMeF is selected from X ２４ D-Glu, E, G, and KZ １ is selected from the group consisting of X ２５ Y, αMeY, αMeF, and KZ １ is selected from the group consisting of X ２８ E, Orn, and KZ １ is selected from the group consisting of X ３０ But, G, Orn, KZ １ , K(Z １ ) R ６ , OrnR ２ , and G.R. ２ A group consisting of is selected from R ２ But, X ３１ , X ３１ SSG (SEQ ID NO: 28), X ３１ SSG-R ３ (SEQ ID NO: 29 ), X ３１ SSGX ３５ PPPX ３９ (SEQ ID NO: 30), X ３１ SSGX ３５ PPPX ３ ９ R ３ (SEQ ID NO: 31), X ３１ SSGX ３５ PPPX ３９ X ４０ (SEQ ID NO: 32), X ３１ SSGX ３５ PPPX ３９ X ４０ R ３ (SEQ ID NO: 33), and a C-terminal modification wherein said modification is selected from the group consisting of NH ２ and R ６ However, PSSG (SEQ ID NO: 34), PSSG-R ３ (SEQ ID NO: 35), PSSGX ３ ５ PPPX ３９ (SEQ ID NO: 36), PSSGX ３５ PPPX ３９ R ３ (SEQ ID NO: 37), PSSGX ３５ PPPX ３９ X ４０ (SEQ ID NO: 38), PSSGX ３５ PPPX ３９ X ４ ０ R ３ (SEQ ID NO: 39), and a C-terminal modification, wherein said modification Decoration is NH ２ and X ３１ However, P and KZ １ is selected from the group consisting of X ３５ is selected from the group consisting of A and Orn; X ３９ is selected from the group consisting of S and Orn; X ４０ But, KZ １ and R ３ is a modification of the C-terminal group, wherein said modification is NH ２ and X １０ 、X １２ 、X １７ 、X ２１ 、X ２４ 、X ２５ 、X ２８ 、X ３０ 、X ３１ 、and X ４０ Two of them and only two of them are KZ １ or K(Z １ ) R ６ and Z １ But, R ５ and -R ４ R ５ is selected from the group consisting of R ４ is the linker, R ５ is a fatty acid, 58. The method of any one of claims 44 to 57.

64. The GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO Selected from the group consisting of sequence number 11, sequence number 12, sequence number 13, and sequence number 14 The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof. method.

65. The GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO Selected from the group consisting of sequence number 11, sequence number 12, sequence number 13, and sequence number 14 The compound according to any one of claims 23 to 43, or a pharmaceutically acceptable salt thereof. How to do it.

66. The GIP / GLP1 agonist or a pharmaceutically acceptable salt thereof is selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO Selected from the group consisting of sequence number 11, sequence number 12, sequence number 13, and sequence number 14 The compound according to any one of claims 44 to 57, or a pharmaceutically acceptable salt thereof. How to do it.

67. The GIP / GLP1 agonist compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, and SEQ ID NO: 26 The method of any one of claims 1 to 22, wherein the compound is selected from the group consisting of:

68. The GIP / GLP1 agonist compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, and SEQ ID NO: 26 The method of any one of claims 23 to 43, wherein the compound is selected from the group consisting of:

69. The GIP / GLP1 agonist compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, and SEQ ID NO: 26 58. The method of any one of claims 44 to 57, wherein the compound is selected from the group consisting of:

70. The GIP / GLP1 agonist is Y-Aib-EGT-αMeF (2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ - (γ -Glu)-CO-(CH ２ ) １２ -CO ２ H)AQ-Aib-EFI-(D-Glu) -αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetate Chill) ２ -(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H) SSGAPPPS-NH ２ (SEQ ID NO: 41), Y-Aib-EGT-aMeF (2F)-TSD-4Pal-SI-aMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ - (γ -Glu)-(10-(4-carboxyphenoxy)decanoyl))AQ-Aib-EF I-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy) -ethoxy]-acetyl) ２ -(γ-Glu)-(10-(4-carboxyphenoxy) Decanoyl)SSGAPPPS-NH ２ (SEQ ID NO: 17), Y-Aib-EGT-aMeF (2F)-TSD-4Pal-SI-aMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ - (γ -Glu)-(4-(4-iodophenyl)butanoyl))AQ-Aib-EFI-(D -Glu)-aMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy] Ci]-acetyl) ２ -(γ-Glu)-(4-(4-iodophenyl)butanoyl))S SGAPPPS-NH ２ (SEQ ID NO: 18), Y-Aib-EGT-aMeF (2F)-TSD-4Pal-SI-aMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ - (γ -Glu)-(4-(4-tert-butylphenyl)butanoyl))AQ-Aib-E FI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy )-ethoxy]-acetyl) ２ -(γ-Glu)-(4-(4-tert-butylphenyl) (I) butanoyl) SSGAPPPS-NH ２ (SEQ ID NO: 19), and Y-Aib-EGT-αMeF (2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ - (γ -Glu)-CO-(CH ２ ) １０ -CH3)AQ-Aib-EFI-(D-Glu)- αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl ル) ２ -(γ-Glu)-CO-(CH ２ ) １０ -CH ３ )SSGAPPPS-NH ２ ( SEQ ID NO: 19), or a pharmaceutically acceptable salt thereof.

23. The method according to any one of claims 1 to 22.

71. The GIP / GLP1 agonist is Y-Aib-EGT-αMeF (2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ - (γ -Glu)-CO-(CH ２ ) １２ -CO ２ H)AQ-Aib-EFI-(D-Glu) -αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetate Chill) ２ -(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H) SSGAPPPS-NH ２ (SEQ ID NO: 41), Y-Aib-EGT-aMeF (2F)-TSD-4Pal-SI-aMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ - (γ -Glu)-(10-(4-carboxyphenoxy)decanoyl))AQ-Aib-EF I-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino -ethoxy]-ethoxy]-acetyl) ２ -(γ-Glu)-(10-(4-carboxylate) Cyphenoxy)decanoyl)SSGAPPPS-NH ２ (SEQ ID NO: 17), Y-Aib-EGT-aMeF (2F)-TSD-4Pal-SI-aMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ - (γ -Glu)-(4-(4-iodophenyl)butanoyl))AQ-Aib-EFI-(D -Glu)-aMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy] Ci]-acetyl) ２ -(γ-Glu)-(4-(4-iodophenyl)butanoyl))S SGAPPPS-NH ２ (SEQ ID NO: 18), Y-Aib-EGT-aMeF (2F)-TSD-4Pal-SI-aMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ - (γ -Glu)-(4-(4-tert-butylphenyl)butanoyl))AQ-Aib-E FI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy )-ethoxy]-acetyl) ２ -(γ-Glu)-(4-(4-tert-butylphenyl) (I) butanoyl) SSGAPPPS-NH ２ (SEQ ID NO: 19), and Y-Aib-EGT-αMeF (2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ - (γ -Glu)-CO-(CH ２ ) １０ -CH3)AQ-Aib-EFI-(D-Glu)- αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl ル) ２ -(γ-Glu)-CO-(CH ２ ) １０ -CH ３ )SSGAPPPS-NH ２ ( SEQ ID NO: 19), or a pharmaceutically acceptable salt thereof.

44. The method according to any one of claims 23 to 43.

72. The GIP / GLP1 agonist is Y-Aib-EGT-αMeF (2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ - (γ -Glu)-CO-(CH ２ ) １２ -CO ２ H)AQ-Aib-EFI-(D-Glu) -αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetate Chill) ２ -(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H) SSGAPPPS-NH ２ (SEQ ID NO: 41), Y-Aib-EGT-aMeF (2F)-TSD-4Pal-SI-aMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ - (γ -Glu)-(10-(4-carboxyphenoxy)decanoyl))AQ-Aib-EF I-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy) -ethoxy]-acetyl) ２ -(γ-Glu)-(10-(4-carboxyphenoxy) Decanoyl)SSGAPPPS-NH ２ (SEQ ID NO: 17), Y-Aib-EGT-aMeF (2F)-TSD-4Pal-SI-aMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ - (γ -Glu)-(4-(4-iodophenyl)butanoyl))AQ-Aib-EFI-(D -Glu)-aMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy] Ci]-acetyl) ２ -(γ-Glu)-(4-(4-iodophenyl)butanoyl))S SGAPPPS-NH ２ (SEQ ID NO: 18), Y-Aib-EGT-aMeF (2F)-TSD-4Pal-SI-aMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ - (γ -Glu)-(4-(4-tert-butylphenyl)butanoyl))AQ-Aib-E FI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy )-ethoxy]-acetyl) ２ -(γ-Glu)-(4-(4-tert-butylphenyl) (I) butanoyl) SSGAPPPS-NH ２ (SEQ ID NO: 19), and Y-Aib-EGT-αMeF (2F)-TSD-4Pal-SI-αMeL-LD- Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ - (γ -Glu)-CO-(CH ２ ) １０ -CH3)AQ-Aib-EFI-(D-Glu)- αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl ル) ２ -(γ-Glu)-CO-(CH ２ ) １０ -CH ３ )SSGAPPPS-NH ２ ( SEQ ID NO: 19), or a pharmaceutically acceptable salt thereof.

58. The method according to any one of claims 44 to 57.

73. The GIP / GLP1 agonist inhibits β-arrestin recruitment in GLP-CHO cells. GLP-1R HEK2 93 Cell membrane guanosine 5'-(γ-thio)triphosphate-[ ３５ S] (GTPγS) binding The compound according to any one of claims 1 to 22, which is a compound that exhibits partial agonism in How to post.

74. GIP / GLP1 agonists bind to the GLP-1R guanosine 5'- (γ-thio)triphosphate-[ ３５ S] (GTPγS) binding assay It is a compound that exhibits β-arrestin recruitment activity in GLP-CHO cell β-arrestin recruitment assay.

23. The compound according to claim 1, wherein the compound exhibits 35% or less of the IL-12 activity. The method described below.

75. GIP / GLP1 agonists bind to the GLP-1R guanosine 5'- (γ-thio)triphosphate-[ ３５ S] (GTPγS) binding assay It is a compound that exhibits β-arrestin recruitment activity in GLP-CHO cell β-arrestin recruitment assay.

44. The method according to claim 23, wherein the compound is co-administered with a compound exhibiting a serotonin-releasing activity of 35% or less in the presence of hydroxybenzoates. The method described in paragraph .

76. GIP / GLP1 agonists bind to the GLP-1R guanosine 5'- (γ-thio)triphosphate-[ ３５ S] (GTPγS) binding assay It is a compound that exhibits β-arrestin recruitment activity in GLP-CHO cell β-arrestin recruitment assay.

58. The method according to claim 44, wherein the compound is co-administered with a compound exhibiting an activity of 35% or less in the The method described in paragraph .

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