TRIPLE AGONIST COMPOUND

Abstract

The present invention relates to the field of pharmaceutical synthesis. Provided is a GLP-1 / GIP / GCG triple agonist compound. The GLP-1 / GIP / GCG triple agonist compound is used in the preparation of a pharmaceutical composition for treating diseases. Further provided is the use of the pharmaceutical composition in the preparation of a drug for treating at least one of the following diseases. The diseases comprise type II diabetes, impaired glucose tolerance, type I diabetes, obesity, hypertension, metabolic syndrome, dyslipidemia, cognitive impairment, atherosclerosis, myocardial infarction, coronary heart disease, cardiovascular disease, stroke, inflammatory bowel syndrome and / or dyspepsia or gastric ulcer, hepatic fibrosis disease and pulmonary fibrosis disease.

Description

A tri-agonist compound

[0001] This application claims priority to the Chinese patent application filed with the China Patent Office on November 6, 2023, with application number 202311462756.3 and invention name “A Triagonist Compound”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present invention relates to a GLP-1 / GIP / GCG triple agonist compound and its use. The compound is a modified compound of a glucagon-like peptide-1 (GLP-1), human glucose-dependent insulinotropic polypeptide (GIP) and glucagon (CGC) triple agonist. Background Art

[0003] The most common side effects of GLP-1 compounds are the inability to achieve full glycemic control and weight loss, while GIP alone has very modest glucose-lowering potential in patients with type 2 diabetes. Both native GIP and GLP-1 are rapidly inactivated by the ubiquitous protease DPP IV and are therefore only useful for short-term metabolic control.

[0004] GIP is a 42 amino acid gastrointestinal regulatory peptide that plays a physiological role in glucose homeostasis by stimulating insulin secretion from pancreatic beta cells in the presence of glucose and protecting pancreatic beta cells. GLP-1 is a 37 amino acid peptide that stimulates insulin secretion, protects pancreatic beta cells, and inhibits glucagon secretion, gastric emptying, and food intake, leading to weight loss. GIP and GLP-1 are known as incretins; incretin receptor signaling plays a key physiological role in glucose homeostasis. In normal physiology, GIP and GLP-1 are secreted from the intestine after a meal, and these incretins enhance the physiological response to food, including satiety, insulin secretion, and nutrient disposal.

[0005] GCG, also known as glucagon, anti-insulin or insulin B, is a hormone secreted by the α cells of the pancreas of vertebrates along with insulin. It is antagonistic to insulin and plays a role in increasing blood sugar.

[0006] New research shows that GLP-1 / GIP / GCG triple receptor agonist compounds not only have better blood sugar control, but also have the effects of significantly reducing weight and treating non-alcoholic fatty liver disease.

[0007] Summary of the Invention

[0008] In view of this, the present invention provides a GLP-1 / GIP / GCG triple agonist compound and its use, which is a triple agonist compound of glucagon-like peptide-1 (GLP-1), human glucose-dependent insulinotropic polypeptide (GIP) and glucagon (CGC).

[0009] The first aspect of the present invention provides a GLP-1 / GIP / GCG triple agonist compound:

[0010] Tyr-Aib-Gln-Gly-Thr-AA1-Thr-Ser-Asp-Tyr-Ser-Ile-αMeLeu-Leu-Asp-Lys-Lys((CO(CH2) n1 PEG n2 ) n3 -(AA2) n4 -CO(CH2) n5 -COOH)-Ala-Gln-Aib-Ala-Phe-Ile-Glu-Tyr-Leu-Leu-Glu-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AA3

[0011] Structure I

[0012] in:

[0013] AA1 is selected from any one of αMePhe and αMePhe(2F);

[0014] AA2 is selected from any one of γGlu, δAad, εApm, and ζAsu;

[0015] AA3 is selected from any one of amino and hydroxyl groups;

[0016] n1=1-5, n2=1-30, n3=0 or =1-5, n4=0 or =1-5, n5=10-30;

[0017] Optionally, in the GLP-1 / GIP / GCG triple agonist compound, AA1 is selected as αMePhe, AA2 is selected as γGlu, AA3 is selected as amino, n1=1-5, n2=1-30, n3=0 or =1-5, n4=0 or =1-5, n5=10-30; preferably, AA1 is selected as αMePhe, AA2 is selected as γGlu, AA3 is selected as amino, n1=1, n2=2, n3=1, n4=1, n5=18;

[0018] Optionally, in the GLP-1 / GIP / GCG triple agonist compound, AA1 is selected as αMePhe, AA2 is selected as δAad, AA3 is selected as amino, n1=1-5, n2=1-30, n3=0 or =1-5, n4=0 or =1-5, n5=10-30; preferably, AA1 is selected as αMePhe, AA2 is selected as δAad, AA3 is selected as amino, n1=1, n2=2, n3=1, n4=1, n5=18;

[0019] Optionally, in the GLP-1 / GIP / GCG triple agonist compound, AA1 is selected as αMePhe (2F), AA2 is selected as γGlu, AA3 is selected as amino, n1=1-5, n2=1-30, n3=0 or =1-5, n4=0 or =1-5, n5=10-30; preferably, AA1 is selected as αMePhe (2F), AA2 is selected as γGlu, AA3 is selected as amino, n1=1, n2=2, n3=1, n4=1, n5=18;

[0020] Optionally, in the GLP-1 / GIP / GCG triple agonist compound, AA1 is selected as αMePhe (2F), AA2 is selected as δAad, AA3 is selected as amino, n1=1-5, n2=1-30, n3=0 or =1-5, n4=0 or =1-5, n5=10-30; preferably, AA1 is selected as αMePhe (2F), AA2 is selected as δAad, AA3 is selected as amino, n1=1, n2=2, n3=1, n4=1, n5=18.

[0021] In some specific embodiments of the present invention, the GLP-1 / GIP / GCG triple agonist compound has:

[0022] (I) the amino acid sequence shown in any one of SEQ ID Nos. 2 to 13;

[0023] (II) an amino acid sequence obtained by substituting, deleting or adding 1, 2, 3 or more amino acids to the amino acid sequence described in (I) and having the same function as the amino acid sequence described in (I); or

[0024] (III) an amino acid sequence having 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or more homology to the amino acid sequence described in (I) or (II).

[0025] Optionally, the aforementioned GLP-1 / GIP / GCG triple agonist compound comprises a pharmaceutically acceptable salt, chelate or non-covalent complex formed by the compound and a precursor of the compound, or any mixture of the aforementioned forms.

[0026] A second aspect of the embodiments of the present invention provides a use of the GLP-1 / GIP / GCG triple agonist compound as described in any one of the first aspects above in preparing a pharmaceutical composition for treating a disease.

[0027] Optionally, the pharmaceutical composition for treating a disease is used for at least one of the following diseases, including type II diabetes, impaired glucose tolerance, type I diabetes, obesity, hypertension, metabolic syndrome, dyslipidemia, cognitive impairment, atherosclerosis, myocardial infarction, coronary heart disease, cardiovascular disease, stroke, inflammatory bowel syndrome and / or indigestion or gastric ulcer, liver fibrosis and pulmonary fibrosis.

[0028] Unless otherwise indicated, all references herein to amounts of various ingredients and reaction conditions should be interpreted as meaning "approximately" or "approximately." Accordingly, unless otherwise specified, the numerical parameters cited below and in the claims are approximate and may vary due to differences in standard deviations under individual experimental conditions.

[0029] In this document, when there is a discrepancy or ambiguity between the chemical formula and chemical name of a compound, the chemical formula is used to define the compound. The compounds described herein may contain one or more chiral centers and / or double bonds, as well as structures such as these. Stereoisomers may also exist, including double bond isomers (such as geometric isomers), optical enantiomers, or diastereomers. Accordingly, any chemical structure described herein, whether partially or as a whole, encompasses all possible enantiomers and diastereomers of the compound, including any single stereoisomer (such as a single geometric isomer, a single enantiomer, or a single diastereomer) and any mixtures of these isomers. These racemic isomers and mixtures of stereoisomers can also be further resolved into their constituent enantiomers or stereoisomers by those skilled in the art using various separation techniques or chiral molecular synthesis methods.

[0030] The compounds of Structural Formula I include, but are not limited to, optical isomers, racemates, and / or other mixtures thereof. In such cases, individual enantiomers or diastereomers, such as optically active isomers, can be obtained by asymmetric synthesis or racemic resolution. Resolution of racemates can be achieved by various methods, such as conventional recrystallization with resolving agents or chromatographic methods. Furthermore, the compounds of Structural Formula I also include cis- and / or trans-isomers containing double bonds.

[0031] The compounds of the present invention include, but are not limited to, compounds of structural formula I and all of their pharmaceutically acceptable forms. Pharmaceutically acceptable forms of these compounds include various pharmaceutically acceptable salts, solvates, complexes, chelates, non-covalent complexes, prodrugs based on the above substances, and any mixtures of these forms.

[0032] In a third aspect, the present invention also provides a drug comprising the GLP-1 / GIP / GCG triple agonist compound.

[0033] In a fourth aspect, the present invention also provides a pharmaceutical composition comprising the GLP-1 / GIP / GCG triple agonist compound and any other active ingredients.

[0034] In a fifth aspect, the present invention also provides a method for treating a disease by administering the GLP-1 / GIP / GCG triple agonist compound, the drug or the pharmaceutical composition.

[0035] The compound shown in structure I provided by the present invention has stable properties and is a highly active GLP-1 / GIP / GCG triple receptor agonist compound with significant blood sugar lowering and body weight reducing effects. DETAILED DESCRIPTION

[0036] The present invention discloses a tri-agonist compound. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters to achieve it. It should be noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in the present invention. The methods and applications of the present invention have been described through preferred embodiments. It is obvious that relevant personnel can modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0037] The Chinese names corresponding to the English abbreviations involved in this invention are shown in the following table:

[0038] Example 1 Preparation of Compound

[0039] The preparation method comprises: preparing a peptide resin by solid-phase peptide synthesis, acid-hydrolyzing the peptide resin to obtain a crude product, and finally purifying the crude product to obtain a pure product; wherein the step of preparing the peptide resin by solid-phase peptide synthesis is to sequentially introduce corresponding protected amino acids or fragments in the polypeptide sequence into the carrier resin by solid-phase coupling synthesis to prepare the peptide resin:

[0040] In the above preparation method, the amount of the Fmoc-protected amino acid or protected amino acid fragment is 1.2 to 6 times the total molar number of the resin fed, preferably 2.5 to 3.5 times.

[0041] In the above preparation method, the substitution value of the carrier resin is 0.2 to 1.0 mmol / g resin, and the preferred substitution value is 0.3 to 0.5 mmol / g resin.

[0042] As a preferred embodiment of the present invention, the solid-phase coupling synthesis method comprises: removing the Fmoc protecting group from the protected amino acid-resin obtained in the previous step and then coupling the resin with the next protected amino acid. The deprotection time for the Fmoc removal is 10 to 60 minutes, preferably 15 to 25 minutes. The coupling reaction time is 60 to 300 minutes, preferably 100 to 140 minutes.

[0043] The coupling reaction requires the addition of a condensation reagent selected from DIC (N,N-diisopropylcarbodiimide), N,N-dicyclohexylcarbodiimide, benzotriazol-1-yl-oxytripyrrolidinophosphine hexafluorophosphate, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, or O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate; preferably N,N-diisopropylcarbodiimide. The molar amount of the condensation reagent is 1.2 to 6 times the total molar number of amino groups in the amino resin, preferably 2.5 to 3.5 times.

[0044] The coupling reaction requires the addition of an activation reagent selected from 1-hydroxybenzotriazole or N-hydroxy-7-azabenzotriazole, preferably 1-hydroxybenzotriazole. The amount of the activation reagent used is 1.2 to 6 times, preferably 2.5 to 3.5 times, the total molar number of amino groups in the amino resin.

[0045] As a preferred embodiment of the present invention, the Fmoc deprotection reagent is a PIP / DMF (piperidine / N,N-dimethylformamide) mixed solution containing 10-30% (v / v) piperidine. The amount of the Fmoc deprotection reagent used is 5-15 mL per gram of amino resin, preferably 8-12 mL per gram of amino resin.

[0046] Preferably, the peptide resin is acid-lyzed to remove the resin and side chain protecting groups to obtain a crude product:

[0047] Further preferably, the acid hydrolysis agent used in the acid hydrolysis of the peptide resin is a mixed solvent of trifluoroacetic acid (TFA), 1,2-ethanedithiol (EDT) and water, and the volume ratio of the mixed solvent is: TFA is 80-95%, EDT is 1-10%, and the balance is water.

[0048] More preferably, the volume ratio of the mixed solvent is: TFA is 89-91%, EDT is 4-6%, and the balance is water. Optimally, the volume ratio of the mixed solvent is: TFA is 90%, EDT is 5%, and the balance is water.

[0049] The amount of the acid hydrolysis agent used is 4 to 15 mL per gram of peptide resin; preferably, 7 to 10 mL per gram of peptide resin.

[0050] The time for cleavage using an acid hydrolyzing agent is 1 to 6 hours at room temperature, preferably 3 to 4 hours.

[0051] Furthermore, the crude product was purified by high performance liquid chromatography and freeze-dried to obtain a pure product.

[0052] 1. Synthesis of peptide resin

[0053] RinkAmide BHHA resin was used as a carrier resin, and the peptide resin was prepared by coupling with the protected amino acids corresponding to the polypeptide sequence in sequence through Fmoc removal and coupling reaction.

[0054] (1) Insert the first protected amino acid in the main chain

[0055] Take 0.03 mol of the first protected amino acid and 0.03 mol of HOBt and dissolve them in an appropriate amount of DMF; take another 0.03 mol of DIC and slowly add it to the protected amino acid DMF solution while stirring. Stir and react at room temperature for 30 minutes to obtain the activated protected amino acid solution, which is set aside.

[0056] 0.01 mol of Rink amide MBHA resin (substitution value about 0.4 mmol / g) was deprotected with 20% PIP / DMF solution for 25 minutes, washed and filtered to obtain the Fmoc-free resin.

[0057] The activated first protected amino acid solution is added to the Fmoc-removed resin, and the coupling reaction is carried out for 60 to 300 minutes. The resin is filtered and washed to obtain a resin containing one protected amino acid.

[0058] (2) Insertion of main chain protective amino acids

[0059] The same method as described above for inserting the first protected amino acid in the main chain was used to sequentially insert the protected amino acids corresponding to the corresponding polypeptide sequences to obtain a resin containing main chain amino acids.

[0060] (3) Insertion of the first protected amino acid in the side chain

[0061] Take 0.03 mol of the first protected amino acid of the side chain and 0.03 mol of HOBt and dissolve them in an appropriate amount of DMF; take another 0.03 mol of DIC and slowly add it to the protected amino acid DMF solution while stirring. Stir and react at room temperature for 30 minutes to obtain the activated protected amino acid solution.

[0062] Take 2.5 mmol of tetrakistriphenylphosphine palladium and 25 mmol of phenylsilane, dissolve them in an appropriate amount of dichloromethane, deprotect for 4 hours, filter and wash to obtain the de-Allocated resin for use.

[0063] The activated first side chain protected amino acid solution is added to the de-Allocated resin, and the coupling reaction is carried out for 60 to 300 minutes. The resin containing the first side chain protected amino acid is filtered and washed to obtain the resin.

[0064] (4) Inserting other protected amino acids or single protected fatty acids into the side chain

[0065] The same method as described above for inserting the first protected amino acid in the main chain was used to sequentially insert the corresponding protected amino acid and the single protected fatty acid in the side chain to obtain the peptide resin.

[0066] 2. Preparation of crude product

[0067] Take the above peptide resin, add a cleavage reagent with a volume ratio of TFA: water: EDT = 95:5:5 (cleavage reagent 10 mL / g resin), stir evenly, and react at room temperature for 3 hours. The reaction mixture is filtered using a sand core funnel, and the filtrate is collected. The resin is washed 3 times with a small amount of TFA. After combining the filtrates, it is concentrated under reduced pressure, added with anhydrous ether to precipitate, and then washed with anhydrous ether 3 times. The precipitate is dried to obtain an off-white powder as the crude product.

[0068] 3. Preparation of pure product

[0069] Take the above crude product, add water and stir, adjust the pH to 8.0 with ammonia water until it is completely dissolved, filter with a 0.45μm filter membrane and set aside.

[0070] Purification was performed by high performance liquid chromatography, using a 10 μm reverse phase C18 chromatographic filler, a 0.1% TFA / water solution-0.1% TFA / acetonitrile solution as the mobile phase system, a 30 mm*250 mm chromatographic column with a flow rate of 20 mL / min, a gradient elution system, and cyclic injection purification. The crude product solution was loaded onto the chromatographic column, the mobile phase elution was started, the main peak was collected, and the acetonitrile was evaporated to obtain a purified intermediate concentrate.

[0071] The purified intermediate concentrate was filtered through a 0.45 μm filter membrane for standby use, and the salt was exchanged by high performance liquid chromatography. The mobile phase system was 1% acetic acid / water solution-acetonitrile, the chromatographic filler for purification was 10 μm reverse phase C18, and the flow rate of the 30 mm*250 mm chromatographic column was 20 mL / min (the corresponding flow rate can be adjusted according to the different specifications of the chromatographic column); gradient elution and cyclic loading method were used, the sample was loaded into the chromatographic column, the mobile phase elution was started, the spectrum was collected, the change in absorbance was observed, the main peak of the salt exchange was collected and the purity was detected by analytical liquid phase, the main peak solutions of the salt exchange were combined, concentrated under reduced pressure to obtain a pure acetic acid aqueous solution, and freeze-dried to obtain the pure peptide.

[0072] The following compounds were synthesized using the above method:

[0073] Example 2 Activity determination

[0074] 1. GLP-1 activity assay

[0075] When stimulated by its specific agonist, GLP-1R activates the intracellular adenylate cyclase pathway, elevating cAMP levels and ultimately leading to the production and release of insulin. Stimulating a cell line stably transfected with GLP-1R with the test substance rapidly increases intracellular cAMP levels. Chemiluminescence is then used to measure the relative light units (RLU) after each dose of stimulation, and the EC50 of the agonist is then calculated. This activity assay is currently a commonly used method for detecting GLP-1 receptor agonist activity both domestically and internationally.

[0076] The CHO-K1 cell line stably expressing GLP-1R was used to stimulate the stably transfected cells with different concentrations of agonists. The EC of the agonist was calculated by measuring the relative light units after stimulation of the cells at each dose. 50 value.

[0077] 2. GIP activity determination method

[0078] When stimulated by specific agonists, GIPR activates the intracellular adenylate cyclase pathway, elevating cAMP levels and ultimately leading to insulin production and release. Stimulating a cell line stably transfected with GIPR with the test substance rapidly increases intracellular cAMP levels. Chemiluminescence is then used to measure the relative light units (RLU) after each dose of stimulation, and the EC50 of the agonist is then calculated. This activity assay is currently a commonly used method for detecting GIP receptor agonist activity both domestically and internationally.

[0079] Using a CHO-K1 cell line stably expressing GIPR, the stably transfected cells were stimulated with different concentrations of agonists. The EC of the agonist was calculated by measuring the relative light units after stimulation of the cells at each dose. 50 value.

[0080] 3. GCG activity determination method

[0081] When stimulated by its specific agonist, GCG-R activates the intracellular adenylate cyclase pathway, elevating cAMP levels and ultimately leading to the production and release of insulin. Stimulating a cell line stably transfected with GCG-R with the test substance rapidly increases intracellular cAMP levels. Chemiluminescence is then used to measure the relative light units (RLU) after each dose of stimulation, and the EC50 of the agonist is then calculated. This activity assay is currently a commonly used method for detecting GCG receptor agonist activity both domestically and internationally.

[0082] The CHO-K1 cell line stably expressing GCG-R was used to stimulate the stably transfected cells with different concentrations of agonists. The EC of the agonist was calculated by measuring the relative light units after stimulation of the cells at each dose. 50 value.

[0083] 4. Measurement results

[0084] The measurement results are shown in the table below:

[0085] The experimental results show that while maintaining the activity of GLP-1, the activity of the compound GIP in the examples is improved, and the activity of all the compounds GCG is greatly improved.

[0086] Example 3 Determination of preliminary pharmacokinetic properties

[0087] Among the above compounds, the principles of their long-term modification are basically the same, so the two compounds with the best activity were selected for preliminary pharmacokinetic property verification tests.

[0088] The experimental animals were male cynomolgus monkeys. Two cynomolgus monkeys were used for each compound, administered subcutaneously at a dose of 0.2 mg / kg. Blood was collected venously before drug administration (0 h) and at 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, 24 h, 48 h, 96 h, 144 h, and 168 h after administration. Plasma samples were separated by centrifugation and the blood concentrations of the corresponding compounds in the plasma samples were determined by liquid chromatography-mass spectrometry. The half-lives of the compounds after subcutaneous (SC) administration are shown in the table below:

[0089] The results of preliminary pharmacokinetic characterization experiments in crab-eating monkeys showed that the subcutaneous administration half-life of compound 2 and compound 6 was greater than 80 hours, fully meeting the requirements of long-acting drug delivery.

[0090] The above is a detailed introduction to a tri-agonist compound provided by the present invention. This article uses specific examples to illustrate the principles and implementation methods of the present invention. The description of the above examples is only used to help understand the method of the present invention and its core concept. It should be pointed out that for those skilled in the art, without departing from the principles of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A triple GLP-1 / GIP / MHC agonist compound having the structure of Formula I Tyr-Aib-Gln-Gly-Thr-AA1-Thr-Ser-Asp-Tyr-Ser-Ile-αMeLeu-Leu-Asp-Lys-Lys((CO(CH2) n1 PEG n2 ) n3 -(AA2) n4 -CO(CH2) n5 -COOH)-Ala-Gln-Aib-Ala-Phe-Ile-Glu-Tyr-Leu-Leu-Glu-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AA3 Formula I Where AA1 is selected from the group consisting of αMePhe and αMePhe(2F); AA2 is selected from the group consisting of γGlu, δAad, εApm and ζAsu; AA3 is selected from the group consisting of amino and hydroxyl; n1=1-5, n2=1-30, n3=0 or n3=1-5, n4=0 or n4=1-5 and n5=10-30.

2. The GLP-1 / GIP / MHC triple agonist compound of claim 1, wherein AA1 is αMePhe, AA2 is γGlu, AA3 is amino, n1=1-5, n2=1-30, n3=0 or n3=1-5, n4=0 or n4=1-5, and n5=10-30.

3. The GLP-1 / GIP / MHC triple agonist compound of claim 2, wherein AA1 is αMePhe, AA2 is γGlu, AA3 is amino, n1=1, n2=2, n3=1, n4=1, and n5=18.

4. The GLP-1 / GIP / MHC triple agonist compound of claim 1, wherein AA1 is αMePhe, AA2 is δAad, AA3 is amino, n1=1-5, n2=1-30, n3=0 or n3=1-5, n4=0 or n4=1-5, and n5=10-30.

5. The GLP-1 / GIP / MHC triple agonist compound of claim 4, wherein AA1 is αMePhe, AA2 is δAad, AA3 is an amine, n1=1, n2=2, n3=1, n4=1, and n5=18.

6. The GLP-1 / GIP / MHC triple agonist compound of claim 1, wherein AA1 is αMePhe(2F), AA2 is γGlu, AA3 is amino, n1=1-5, n2=1-30, n3=0 or n3=1-5, n4=0 or n4=1-5, and n5=10-30.

7. The GLP-1 / GIP / MHC triple agonist compound of claim 6, wherein AA1 is αMePhe(2F), AA2 is γGlu, AA3 is amino, n1=1, n2=2, n3=1, n4=1, and n5=18.

8. The GLP-1 / GIP / MHC triple agonist compound of claim 1, wherein AA1 is αMePhe(2F), AA2 is δAad, AA3 is amino, n1=1-5, n2=1-30, n3=0 or n3=1-5, n4=0 or n4=1-5, and n5=10-30.

9. The GLP-1 / GIP / MHC triple agonist compound of claim 8, wherein AA1 is αMePhe(2F), AA2 is δAad, AA3 is amino, n1=1, n2=2, n3=1, n4=1, and n5=18.

10. A triple GLP-1 / GIP / MHC agonist compound according to any one of claims 1-9, wherein the compound has: (I) the amino acid sequence shown in any one of SEQ ID NOs: 2-13; (II) an amino acid sequence obtained by substitution, deletion or addition of 1, 2, 3 or more amino acids in the amino acid sequence (I) and having the same function as the amino acid sequence (I); or (III) an amino acid sequence having 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or greater sequence identity to the amino acid sequence of (I) or (II).

11. A GLP-1 / GIP / MHC triple agonist compound according to any one of claims 1-10, wherein the triple agonist compound comprises a pharmaceutically acceptable salt, chelate, or non-covalent complex formed by the compound, a precursor of the compound, or any mixture thereof.

12. Use of a GLP-1 / GIP / MHC triple agonist compound according to any one of claims 1-11 in the manufacture of a pharmaceutical composition for the treatment of a disease.

13. The use according to claim 12, wherein the pharmaceutical composition is intended for the treatment of at least one disease selected from the group consisting of type II diabetes, impaired glucose tolerance, type I diabetes, obesity, arterial hypertension, metabolic syndrome, dyslipidemia, cognitive impairment, atherosclerosis, myocardial infarction, coronary heart disease, cardiovascular disease, stroke, inflammatory bowel syndrome and / or dyspepsia or gastric ulcer, liver fibrosis and pulmonary fibrosis.

14. A medicinal product comprising a GLP-1 / GIP / MHC triple agonist compound according to any one of claims 1-11.

15. A pharmaceutical composition comprising a triple GLP-1 / GIP / MHC agonist compound according to any one of claims 1-11 and any additional active ingredient.

16. A method for treating a disease, comprising administering a triple GLP-1 / GIP / MHC agonist compound according to any one of claims 1-11, a medicinal product according to claim 14, or a pharmaceutical composition according to claim 15.