Dual agonist compound

Abstract

Provided is a GCG-GLP-1 dual agonist compound. The GCG-GLP-1 dual agonist compound is used for preparing 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, strokes, inflammatory bowel syndrome and / or dyspepsia or gastric ulcers, hepatic fibrosis disease and pulmonary fibrosis disease.

Description

A dual 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 202311462761.4 and invention name “A Dual Agonist Compound”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present invention relates to a GLP-1 / GCG dual agonist compound and its use. The compound is a dual agonist compound of glucagon (GCG) receptor and glucagon-like peptide-1 (GLP-1) receptor. Background Art

[0003] 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. GLP-1 is known as an incretin; incretin receptor signaling plays a key physiological role in glucose homeostasis. In normal physiology, GLP-1 is secreted from the intestine after a meal. These incretins enhance physiological responses to food, including satiety, insulin secretion, and nutrient disposition.

[0004] The most common side effects of GLP-1 analogs are the inability to achieve full glycemic control and weight loss, while GCG alone has very modest glucose-lowering potential in patients with type 2 diabetes. Native GLP-1 is rapidly inactivated by the ubiquitous protease DPP IV and can therefore only be used for short-term metabolic control.

[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 / GCG receptor dual agonist compounds not only have better blood sugar control, but also have the effect 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 / GCG dual agonist compound and its use, which is a class of dual agonist compounds of glucagon-like peptide-1 (GLP-1) receptor and glucagon (GCG) receptor.

[0009] In one aspect, the present invention provides a compound shown in structure I:

[0010] His-Aib-Gln-Gly-Thr-AA1-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Lys-Ala-Lys((CO(CH2) n1 PEG n2 ) n3 -(AA2) n4 -CO(CH2) n5 -COOH)-Glu-Phe-Val-Glu-Trp-Leu-Leu-Glu-(5-Ava)-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AA3

[0011] Structure I

[0012] in:

[0013] AA1 is selected from any one of Phe, 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 / GCG dual agonist compound, AA1 is selected as Phe, 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, and n5=10-30; preferably, AA1 is selected as Phe, AA2 is selected as γGlu, AA3 is selected as amino, n1=1, n2=5, n3=1, n4=1, and n5=18;

[0018] Optionally, in the GLP-1 / GCG dual 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, and n5=10-30; preferably, AA1 is selected as αMePhe, AA2 is selected as γGlu, AA3 is selected as amino, n1=1, n2=5, n3=1, n4=1, and n5=18;

[0019] Optionally, in the GLP-1 / GCG dual 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, and n5=10-30; preferably, AA1 is selected as αMePhe, AA2 is selected as δAad, AA3 is selected as amino, n1=1, n2=5, n3=1, n4=1, and n5=18;

[0020] Optionally, in the GLP-1 / GCG dual 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=5, n3=1, n4=1, n5=18;

[0021] Optionally, in the GLP-1 / GCG dual 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=5, n3=1, n4=1, n5=18.

[0022] In some specific embodiments of the present invention, the GLP-1 / GCG dual agonist compound has:

[0023] (I) the amino acid sequence shown in any one of SEQ ID Nos. 2 to 16;

[0024] (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

[0025] (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).

[0026] Optionally, the above-mentioned GLP-1 / GCG dual 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 above forms.

[0027] A second aspect of the embodiments of the present invention provides a use of the GLP-1 / GCG dual agonist compound as described in any one of the first aspects above in preparing a pharmaceutical composition for treating a disease.

[0028] Optionally, the pharmaceutical composition for treating a disease is characterized in that the pharmaceutical composition is used in the preparation of a medicament for treating at least one of the following diseases, the 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 dyspepsia or gastric ulcer, liver fibrosis and pulmonary fibrosis.

[0029] Preferably, the pharmaceutical composition is used in the preparation of a drug for treating type II diabetes with delayed efficacy and / or preventing the worsening of type II diabetes.

[0030] Preferably, the pharmaceutical composition is used in the preparation of a drug for reducing food intake, reducing β-cell apoptosis, increasing pancreatic β-cell function, increasing β-cell mass and / or restoring glucose sensitivity to β-cells.

[0031] In a third aspect, the present invention also provides a drug comprising the GLP-1 / GCG dual agonist compound.

[0032] In a fourth aspect, the present invention also provides a pharmaceutical composition comprising the GLP-1 / GCG dual agonist compound and any other active ingredients.

[0033] In a fifth aspect, the present invention also provides a method for treating a disease by administering the GLP-1 / GCG dual agonist compound, the drug or the pharmaceutical composition.

[0034] The present invention further provides a method for regulating blood sugar in a subject by administering the compound.

[0035] More details of the present invention are described in detail below, or some of them can also be understood in the embodiments of the present invention.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] The compound shown in structure I provided by the present invention is stable in nature and is not easily degraded by dipeptidyl peptidase IV (DPP-IV) in the body. It is a GCG / GLP-1 dual agonist analogue with significant blood sugar and body weight reduction effects. DETAILED DESCRIPTION

[0041] The present invention discloses a GCG / GLP-1 analog and its use. Those skilled in the art can refer to the content of this document and appropriately improve the process parameters to achieve the desired effect. It is particularly important to note that all similar substitutions and modifications that would be obvious to those skilled in the art 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 those skilled in the art can modify or appropriately alter 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.

[0042] The Chinese names corresponding to the English abbreviations involved in this invention are shown in the following table:

[0043] Example 1 Preparation of Compound

[0044] The preparation method comprises: using RinkAmide MBHA resin as the starting resin, preparing the 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] Preferably, the peptide resin is acid-lyzed to remove the resin and side chain protecting groups to obtain a crude product:

[0052] 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.

[0053] 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.

[0054] 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.

[0055] The time for cleavage using an acid hydrolyzing agent is 1 to 6 hours at room temperature, preferably 3 to 4 hours.

[0056] Furthermore, the crude product was purified by high performance liquid chromatography and freeze-dried to obtain a pure product.

[0057] 1. Synthesis of peptide resin

[0058] 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.

[0059] (1) Insert the first protected amino acid in the main chain

[0060] Take 3 mmol of the first protected amino acid and 3 mmol of HOBt and dissolve them in an appropriate amount of DMF; take another 3 mmol 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 for later use.

[0061] 1 mmol of Rink amide MBHA resin (substitution value of about 0.4 mmol / g) was deprotected using 20% ​​PIP / DMF solution for 25 minutes, and the resin was washed and filtered to obtain the Fmoc-free resin.

[0062] 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.

[0063] (2) Insertion of main chain protective amino acids

[0064] 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 polypeptide sequence to obtain a resin containing main chain amino acids.

[0065] (3) Insertion of the first protected amino acid in the side chain

[0066] 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.

[0067] 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.

[0068] 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.

[0069] (4) Insertion of side chain protected amino acids

[0070] 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.

[0071] 2. Preparation of crude product

[0072] 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.

[0073] 3. Preparation of pure product

[0074] 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.

[0075] 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.

[0076] 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 adopted, 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.

[0077] The following compounds were synthesized using the above method:

[0078] Example 2 Activity determination

[0079] 1. GLP-1 activity assay

[0080] 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.

[0081] 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.

[0082] 2. GCG activity determination method

[0083] 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.

[0084] 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.

[0085] 3. Measurement results

[0086] The experimental results show that while maintaining the CGC activity, the GLP-1 activity of the compounds in the examples is greatly improved.

[0087] Example 3 Determination of preliminary pharmacokinetic properties

[0088] 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.

[0089] 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:

[0090] The results of preliminary pharmacokinetic characterization experiments in crab-eating monkeys showed that the subcutaneous half-lives of compounds 6 and 10 were both greater than 100 hours, fully meeting the requirements of long-acting drug delivery.

[0091] The above is a detailed introduction to a dual 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 GLP-1 / GCG dual agonist compound having structural formula I: His-Aib-Gln-Gly-Thr-AA1-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Lys-Ala-Lys((CO(CH2) n1 PEG n2 ) n3 -(AA2) n4 -CO(CH2) n5 -COOH)-Glu-Phe-Val-Glu-Trp-Leu-Leu-Glu-(5-Ava)-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AA3 Structure I in: AA1 is selected from any one of Phe, αMePhe, and αMePhe(2F); AA2 is selected from any one of γGlu, δAad, εApm, and ζAsu; AA3 is selected from any one of amino and hydroxyl groups; n1=1-5, n2=1-30, n3=0 or =1-5, n4=0 or =1-5, n5=10-30.

2. The GLP-1 / GCG dual agonist compound according to claim 1, characterized in that The AA1 is selected as Phe, 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.

3. The GLP-1 / GCG dual agonist compound according to claim 2, characterized in that: The AA1 is selected as Phe, AA2 is selected as γGlu, AA3 is selected as amino, n1=1, n2=5, n3=1, n4=1, and n5=18.

4. The GLP-1 / GCG dual agonist compound according to claim 1, characterized in that The 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.

5. The GLP-1 / GCG dual agonist compound according to claim 4, characterized in that: The AA1 is selected as αMePhe, AA2 is selected as γGlu, AA3 is selected as amino, n1=1, n2=5, n3=1, n4=1, and n5=18.

6. The GLP-1 / GCG dual agonist compound according to claim 1, characterized in that The 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.

7. The GLP-1 / GCG dual agonist compound according to claim 6, characterized in that: The AA1 is selected as αMePhe, AA2 is selected as δAad, AA3 is selected as amino, n1=1, n2=5, n3=1, n4=1, and n5=18.

8. The GLP-1 / GCG dual agonist compound according to claim 1, characterized in that: The 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.

9. The GLP-1 / GCG dual agonist compound according to claim 8, characterized in that: The AA1 is selected as αMePhe(2F), AA2 is selected as γGlu, AA3 is selected as amino, n1=1, n2=5, n3=1, n4=1, and n5=18.

10. The GLP-1 / GCG dual agonist compound according to claim 1, characterized in that: The 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.

11. The GLP-1 / GCG dual agonist compound according to claim 10, characterized in that: AA1 is selected as αMePhe(2F), AA2 is selected as δAad, AA3 is selected as amino, n1=1, n2=5, n3=1, n4=1, and n5=18.

12. The GLP-1 / GCG dual agonist compound according to any one of claims 1 to 11, characterized in that: It has: (I), the amino acid sequence shown in any one of SEQ ID No. 2 to 16; (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 (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).

13. The GLP-1 / GCG dual agonist compound according to any one of claims 1 to 12, comprising a pharmaceutically acceptable salt, solvate, chelate or non-covalent complex of the compound, a prodrug based on the compound, or any mixture of the above forms.

14. Use of the GLP-1 / GCG dual agonist compound according to any one of claims 1 to 13 in the preparation of a pharmaceutical composition for treating a disease.

15. The use according to claim 14, characterized in that: The pharmaceutical composition is used in the preparation of a medicament for treating at least one of the following diseases, the diseases comprising 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, liver fibrosis and pulmonary fibrosis.

16. A drug, characterized in that It includes the GLP-1 / GCG dual agonist compound as described in any one of claims 1-13.

17. A pharmaceutical composition, characterized in that It comprises the GLP-1 / GCG dual agonist compound as described in any one of claims 1 to 13 and any other effective ingredients.

18. A method for treating a disease, characterized in that Administering the GLP-1 / GCG dual agonist compound according to any one of claims 1 to 13, the medicament according to claim 16, or the pharmaceutical composition according to claim 17.

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