TW202120535A - Dual agonists compounds and pharmaceutical composition thereof - Google Patents

Abstract

A kind of dual GLP1/GIP agonists compounds and pharmaceutical composition thereof. The invention provides a series of peptides dual agonists compounds, pharmaceutically salts and pharmaceutical compositions thereof, which have dual agonist effect on glucagon-like peptide-1 (GLP-1) receptor and glucose-dependent insulinotropic polypeptide (GIP) receptor and can be used in the treatment of non-insulin-dependent diabetes mellitus, insulin-dependent diabetes mellitus, obesity and related diseases.

Description

Receptor dual agonist compound and its medical composition

The present invention belongs to the field of biomedicine, and specifically relates to a compound having an agonist effect on human glucagon-like peptide-1 (GLP-1) receptor and human blood glucose-dependent insulinotropic polypeptide (GIP) receptor, or its medicinal use The salt and its pharmaceutical composition can be used for the treatment of metabolic diseases such as non-insulin-dependent diabetes, insulin-dependent diabetes and obesity-related diseases.

Diabetes is a metabolic disease in which the body's glucose, protein and lipid metabolism is unregulated due to insufficient insulin secretion in the body. According to the difference of its pathological mechanism, diabetes is mainly divided into insulin-dependent diabetes (type I diabetes) and non-insulin-dependent diabetes (type II diabetes). Among them, 90-95% of diabetic patients worldwide have non-insulin-dependent diabetes. Non-insulin-dependent diabetes mellitus is a long-term, chronic metabolic disease caused by impaired pancreatic β-cell function and long-term insulin resistance. Its main feature is the lack of insulin levels in the body and high blood glucose concentration in plasma. Studies have shown that non-insulin-dependent diabetes mellitus is associated with a variety of high-risk diseases in patients, and it often leads to cardiovascular disease, kidney failure, blindness, amputation and other diseases.

Obesity is the main cause of non-insulin-dependent diabetes. Obesity is defined as excessive or abnormal fat accumulation in the body that damages human health. According to the body mass of the person Body mass index (BMI), obesity can also be defined as when a person’s BMI index is greater than or equal to 30kg/m2. The emergence of obesity will significantly increase the risk of cardiovascular disease, diabetes, musculoskeletal diseases and certain cancers. In addition, an increase in human body mass index will also increase the risk of certain non-communicable diseases.

Due to the huge number of patients caused by diabetes and its disease and the significant economic burden it causes, the development of safe and effective drugs for the treatment of diabetes has always been one of the focus areas of many research institutions and pharmaceutical companies. At present, diabetes drugs that have been approved for marketing mainly include chemically synthesized small-molecule oral hypoglycemic drugs, such as biguanides, sulfonamides, insulin sensitizers, α-glycosides, and injections of recombinant insulin and its derivatives produced by biosynthesis. Class hypoglycemic drugs. Although the above-mentioned drugs can effectively control the blood glucose level in the plasma of diabetic patients, their long-term use is often accompanied by adverse reactions such as weight gain of the patients, which in turn leads to an increase in the risk of potential cardiovascular disease and a decrease in patient compliance. Taking into account the potential pathological relationship between diabetes and obesity and the potential risk of disease caused by obesity, the development of a drug that can effectively control blood sugar while appropriately reducing the weight of diabetic patients is an effective treatment for diabetes and the potential risk of disease The reduction has multiple meanings, so it is a more excellent clinical research direction.

Glucagon like peptide-1 (GLP-1) is a gastrointestinal regulatory polypeptide containing 30 or 31 amino acid residues. The secretion of GLP-1 is mainly regulated by L-cells in the small intestine according to the absorption of nutrients and fluctuating blood glucose levels in the body. After food intake, the L-cells of the small intestine secrete a large amount of GLP-1 to enhance the endocrine function of the pancreas. GLP-1 polypeptide mainly completes its physiological functions of controlling blood sugar and reducing appetite in the body by activating GLP-1 receptors distributed on the surface of cell membranes. The mechanism by which GLP-1 controls blood glucose levels in the body is mainly to activate its GLP-1 receptors distributed in pancreatic β cells to promote insulin biosynthesis and secretion. At the same time, GLP-1 polypeptides can inhibit pancreatic hypertension in the case of high blood glucose levels in the body. Glucagon secretion, gastric excretion The intake of air and food enhances the degradation of glucose in the body through specific nervous system effects. It is worth noting that the physiological function of GLP-1 polypeptide to promote insulin secretion is highly controlled by plasma glucose concentration. Therefore, compared with other diabetes treatment drugs, GLP-1 polypeptide does not cause severe and lasting hypoglycemia. In addition, it is reported in the literature that GLP-1 polypeptide and its analogues can directly promote the growth, differentiation and proliferation of beta cells in experimental animals, indicating that GLP-1 polypeptide and its analogues can protect pancreatic islets and delay the progression of diabetes. Physiological function and inhibit β cell apoptosis. GLP-1 polypeptide also has the potential to inhibit gastrin and gastric acid secretion stimulated by eating. These features mean that GLP-1 polypeptide also has a physiological role in preventing peptic ulcers. GLP-1 polypeptide can also activate its GLP-1 receptors distributed in the central nervous system of the brain to enhance satiety, reduce food intake and achieve the physiological effect of maintaining or reducing body weight. Therefore, the extensive mechanism of action and physiological functions of GLP-1 polypeptide and its analogs mean that GLP-1 polypeptide is an ideal drug for the treatment of non-insulin-dependent diabetes and obesity diabetes.

The physiological functions of GLP-1 polypeptide in controlling blood sugar and reducing weight bring hope to the treatment of non-insulin-dependent diabetes/obesity diabetes, but the human body's natural GLP-1 is poorly formulated, and it is easy to be used by dipeptidyl peptides in the body. Enzyme-IV (DPP-IV) is degraded so that its half-life in the human body is only 1-2 minutes. Faced with this difficulty, the pharmaceutical industry has constructed long-acting GLP-1 similarity by carrying out site-directed amino acid mutations at the restriction site, fatty acid modification of the polypeptide backbone, and the combination of GLP-1 polypeptides and various protein/polymer polymers.物 and its derivatives. The long-acting GLP-1 analogs that have been on the market and are widely used in clinical practice include enastrotide administered by subcutaneous injection twice a day, liraglutide administered by subcutaneous injection once a day, and subcutaneous injection administered once a week. The dulaglutide and semaglutide and so on.

Clinically, the side effects of GLP-1 polypeptide and its derivatives are mainly manifested in nausea, vomiting and diarrhea caused by the gastrointestinal tract; in addition, it has been found that GLP-1 polypeptide and its derivatives can also cause heartbeat in subjects. Accelerate and under certain circumstances increase the risk of pancreatitis in patients risk. Therefore, the dosage of GLP-1 polypeptide and its derivatives is limited by the side effects caused by it, so its clinical use cannot achieve complete blood glucose control and weight loss in patients.

Glucose-dependent insulin-releasing peptide (Glucose-dependent Insulinotropic Polypeptide, GIP) and GLP-1 polypeptide are a kind of incretin, which play a key physiologically relevant role in the metabolism of blood glucose in the body. GIP is mainly composed of 42 amino acid residues in the body and is secreted by K cells in the duodenum and adjacent jejunum according to the level of glucose in the plasma. GIP polypeptide exerts its physiological effects by binding to GIP receptors distributed in pancreatic β cells, adipose tissue and central nervous system. Similar to GLP-1 polypeptide, GIP polypeptide can stimulate pancreatic β-cells to secrete insulin to reduce blood glucose concentration in plasma and protect pancreatic β-cells to control glucose metabolism in the body. In addition, the physiological function of GIP polypeptide also includes activating its GIP receptor in adipose tissue to promote fat metabolism. Interestingly, intraventricular injection of GIP polypeptides in mice can reduce the food intake and weight of the test animals, which seems to indicate that GIP polypeptides also have certain physiological functions in reducing body weight. Studies have shown that the incretin function of GIP polypeptide in patients with non-insulin-dependent diabetes mellitus is greatly reduced, which leads to lack or loss of incretin effects in patients. Studies have shown that the inhibitory properties of the GIP polypeptides produced by these diabetic patients will be greatly reduced when the blood sugar level returns to normal.

Therefore, there is a clinical need for a method of using GIP polypeptides to treat non-insulin-dependent diabetes mellitus and a clinically effective hypoglycemic agent to restore the tolerance of non-insulin-dependent diabetic patients to GIP polypeptides, and further combine the intestines of GIP polypeptides Insulin-stimulating effect thus obtains a stronger clinical hypoglycemic effect. Therefore, compared with many GLP-1 receptor agonist polypeptides in the art, the purpose of the present invention is to provide a derivative of GLP-1 analogues with agonist activity at the human GIP receptor, which is effective against human GLP- 1 receptor and human GIP receptor have Dual agonist effect. In addition, certain compounds of the present invention have a stronger effect on lowering blood sugar and reducing body weight than GLP-1 receptor agonists in the art. Finally, certain compounds of the present invention have extremely high plasma stability and have pharmacokinetic characteristics that support once-a-week subcutaneous administration in humans.

The purpose of the present invention is to provide a GLP-1 analogue with general formula (I), or its usable salt form:

X ₁ -X ₂ -Glu-Gly-Thr-Phe-Thr-Ser-Asp-X ₁₀ -Ser-X ₁₂ -Tyr-Leu-X ₁₅ -X ₁₆ -X ₁₇ -X ₁₈ -X ₁₉ -X _20- Glu-Phe-X ₂₃ -X ₂₄ -Trp-Leu-X ₂₇ -X ₂₈ -X ₂₉ -X ₃₀ -Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-X ₄₀ (I)

among them:

X _{1 is} selected from the amino acid residues of Tyr or His; X _{2 is} selected from the amino acid residues of Aib or D-Ala; X _{10 is} selected from the amino acid residues of Val or Tyr; X _{12 is} selected from Ser Or the amino acid residue of Ile; X _{15 is} selected from the amino acid residue of Asp or Glu; X _{16 is} selected from the amino acid residue of Glu, Gly, Lys or Aib; X _{17 is} selected from Glu, Ile or Gln _{X 18 is} selected from the amino acid residue of Ala, Aib or His; X _{19 is} selected from the amino acid residue of Ala, Aib or Gln; X _{20 is} selected from the amine of Gln, Glu, Lys X _{23 is} selected from the amino acid residue of Ile or Val; X _{24 is} selected from the amino acid residue of Ala, Asn or Gln; X _{27 is} selected from the amino acid residue of Val or Leu X _{28 is} selected from the amino acid residue of Arg or Ala; X _{29 is} selected from the amino acid residue of Gly or Gln; X _{30 is} selected from the amino acid residue of Gly, Lys or Y1; X _{40 is} selected from Lys The amino acid residue of, Y1 or does not exist;

Y1 is K(-OEG-OEG-yGlu-C20-OH), and this group has the chemical formula of the following structure:

In a preferred embodiment of the present invention, the GLP-1 analogue or its pharmaceutically acceptable salt as described above has its two ends connected in the following way:

R ₁ -X ₁ -X ₂ -Glu-Gly-Thr-Phe-Thr-Ser-Asp-X ₁₀ -Ser-X ₁₂ -Tyr-Leu-X ₁₅ -X ₁₆ -X ₁₇ -X ₁₈ -X _19- X ₂₀ -Glu-Phe-X ₂₃ -X ₂₄ -Trp-Leu-X ₂₇ -X ₂₈ -X ₂₉ -X ₃₀ -Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-X _40- R ₂ (II)

among them:

R ₁ is H, alkyl, acetyl, formyl, benzyl, trifluoroacetyl or pGlu;

R ₂ is -NH ₂ or -OH.

In a preferred embodiment of the present invention, the GLP-1 analog or pharmaceutically acceptable salt thereof as described above, wherein X ₁ is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X ₁₀ is an amino acid residue of Tyr; X ₁₂ is an amino acid residue of Ile; X ₁₅ is an amino acid residue selected from Asp or Glu; X _{16 is} an amino acid residue selected from Lys or Aib; X _{17 is} selected from the amino acid residue of Glu or Ile; X _{18 is} selected from the amino acid residue of Ala or Aib; X _{19 is} selected from the amino acid residue of Ala or Gln; X _{20 is} selected from the amine of Gln and Lys X ₂₃ is the amino acid residue of Val; X _{24 is} selected from the amino acid residue of Asn or Gln; X _{27 is} selected from the amino acid residue of Leu; X _{28 is} selected from the amino acid residue of Ala Amino acid residue; X _{29 is} selected from the amino acid residue of Gly or Gln; X _{30 is} selected from the amino acid residue of Gly, Lys or Y1; X _{40 is} selected from the amino acid residue of Lys, Y1 or Not present, Y1 is as defined in general formula (I).

In a preferred embodiment of the present invention, the GLP-1 analog or pharmaceutically acceptable salt thereof as described above, wherein X ₁ is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X ₁₀ is an amino acid residue of Tyr; X ₁₂ is an amino acid residue of Ile; X ₁₅ is an amino acid residue selected from Asp or Glu; X _{16 is} an amino acid residue selected from Lys or Aib; X _{17 is} selected from the amino acid residue of Glu or Ile; X _{18 is} selected from the amino acid residue of Ala or Aib; X _{19 is} selected from the amino acid residue of Ala or Gln; X _{20 is} selected from the amine of Gln and Lys X ₂₃ is the amino acid residue of Val; X _{24 is} selected from the amino acid residue of Asn or Gln; X _{27 is} selected from the amino acid residue of Leu; X _{28 is} selected from the amino acid residue of Ala Amino acid residue; X _{29 is} selected from the amino acid residue of Gly or Gln; X _{30 is} selected from the amino acid residue of Gly, Lys or Y1; X _{40 is} selected from the amino acid residue of Lys, Y1 or Not present, Y1 is as defined in general formula (I).

In a preferred embodiment of the present invention, the GLP-1 analog or pharmaceutically acceptable salt thereof as described above, wherein X ₁ is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X ₁₀ is the amino acid residue of Tyr; X ₁₂ is the amino acid residue of Ile; X ₁₅ is the amino acid residue of Glu; X ₁₆ is the amino acid residue of Lys; X ₁₇ is the amino acid residue of Glu Acid residue; X ₁₈ is the amino acid residue of Ala or Aib; X ₁₉ is the amino acid residue of Ala; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X ₂₃ is the amine of Val X ₂₄ is the amino acid residue of Asn; X ₂₇ is the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from the amino acid residue of Gly and Lys or Y1; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, and Y1 is as defined in the general formula (I).

In a preferred embodiment of the present invention, the GLP-1 analog or pharmaceutically acceptable salt thereof as described above, wherein X ₁ is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X ₁₀ is the amino acid residue of Tyr; X ₁₂ is the amino acid residue of Ile; X ₁₅ is the amino acid residue of Glu; X ₁₆ is the amino acid residue of Lys; X ₁₇ is the amino acid residue of Ile Acid residue; X _{18 is} selected from the amino acid residue of Ala or Aib; X ₁₉ is the amino acid residue of Ala; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X ₂₃ is the amino acid residue of Val Amino acid residue; X ₂₄ is the amino acid residue of Asn; X ₂₇ is the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from the amino acid residue of Gly, Lys or Y1; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, and Y1 is as defined in the general formula (I).

In a preferred embodiment of the present invention, the GLP-1 analog or pharmaceutically acceptable salt thereof as described above, wherein X ₁ is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X ₁₀ is the amino acid residue of Tyr; X ₁₂ is the amino acid residue of Ile; X ₁₅ is the amino acid residue of Glu; X ₁₆ is the amino acid residue of Lys; X _{17 is} selected from Glu or Ile X ₁₈ is the amino acid residue of Ala; X ₁₉ is the amino acid residue of Ala; X _{20 is} selected from Gln, Lys amino acid residues or Y1; X ₂₃ is Val Amino acid residue; X ₂₄ is the amino acid residue of Asn; X ₂₇ is the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from the amino acid residue of Gly, Lys or Y1; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, and Y1 is as defined in the general formula (I).

In a preferred embodiment of the present invention, the GLP-1 analog or pharmaceutically acceptable salt thereof as described above, wherein X ₁ is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X ₁₀ is the amino acid residue of Tyr; X ₁₂ is the amino acid residue of Ile; X ₁₅ is the amino acid residue of Glu; X ₁₆ is the amino acid residue of Lys; X _{17 is} selected from Glu or Ile X ₁₈ is the amino acid residue of Aib; X ₁₉ is the amino acid residue of Ala; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X ₂₃ is the amino acid residue of Val Amino acid residue; X ₂₄ is the amino acid residue of Asn; X ₂₇ is the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from the amino acid residue of Gly, Lys or Y1; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, and Y1 is as defined in the general formula (I).

In a preferred embodiment of the present invention, the GLP-1 analog or pharmaceutically acceptable salt thereof as described above, wherein X ₁ is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X ₁₀ is the amino acid residue of Tyr; X ₁₂ is the amino acid residue of Ile; X ₁₅ is the amino acid residue of Glu; X ₁₆ is the amino acid residue of Lys; X _{17 is} selected from Glu or Ile X _{18 is} the amino acid residue of Ala or Aib; X ₁₉ is the amino acid residue of Ala; X ₂₀ is the amino acid residue of Gln; X ₂₃ is the amino acid residue of Val Acid residue; X ₂₄ is the amino acid residue of Asn; X ₂₇ is the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X ₃₀ An amino acid residue selected from Gly, Lys or Y1; X _{40 is} selected from an amino acid residue of Lys, Y1 or not present, and Y1 is as defined in the general formula (I).

In a preferred embodiment of the present invention, X ₁ is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X ₁₀ is the amino acid residue of Tyr; X ₁₂ is the amino acid of Ile Residue; X ₁₅ is the amino acid residue of Glu; X ₁₆ is the amino acid residue of Lys; X _{17 is} the amino acid residue of Glu or Ile; X _{18 is} the amino acid of Ala or Aib Residue; X ₁₉ is the amino acid residue of Ala; X ₂₀ is Y1; X ₂₃ is the amino acid residue of Val; X ₂₄ is the amino acid residue of Asn; X ₂₇ is the amino acid residue of Leu X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from the amino acid residue of Gly, Lys or Y1; X _{40 is} the amino acid residue of Lys Base, Y1 or not exist.

In a preferred embodiment of the present invention, the GLP-1 analog or pharmaceutically acceptable salt thereof as described above, wherein X ₂₀ and X ₄₀ are each independently selected from Y1, and Y1 is as defined in the general formula (I).

In a preferred embodiment of the present invention, the GLP-1 analog or pharmaceutically acceptable salt thereof as described above, wherein X _{40 is} independently selected from Y1, and Y1 is as defined in the general formula (I).

In a preferred embodiment of the present invention, the GLP-1 analog or pharmaceutically acceptable salt thereof as described above, wherein Y1 is covalently linked to the fatty acid via the epsilon amine group of the C-terminal Lys via the amide bond.

In the most preferred embodiment of the present invention, the aforementioned GLP-1 analog or pharmaceutically acceptable salt thereof is selected from the following compounds:

In another aspect, the present invention provides a pharmaceutical composition comprising a GLP-1 analog or a pharmaceutically acceptable salt thereof represented by the general formula (I), wherein the GLP-1 analog or a pharmaceutically acceptable salt thereof is such as The general formula (I) is as follows:

X ₁ -X ₂ -Glu-Gly-Thr-Phe-Thr-Ser-Asp-X ₁₀ -Ser-X ₁₂ -Tyr-Leu-X ₁₅ -X ₁₆ -X ₁₇ -X ₁₈ -X ₁₉ -X _20- Glu-Phe-X ₂₃ -X ₂₄ -Trp-Leu-X ₂₇ -X ₂₈ -X ₂₉ -X ₃₀ -Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-X ₄₀ (I)

among them:

X ₁ , X ₂ , X ₁₀ , X ₁₂ , X ₁₅ , X ₁₆ , X ₁₇ , X ₁₈ , X ₁₉ , X ₂₀ , X ₂₇ , X ₂₈ , X ₂₉ and X _{30 are} independently selected from any natural amine group Acids or unnatural amino acids or peptides composed of them;

X _{40 is} selected from any natural amino acid or non-natural amino acid or a peptide composed of it, or X ₄₀ does not exist.

In a preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analog or its pharmaceutically acceptable salt as described above, wherein the two ends of the GLP-1 analog or its pharmaceutically acceptable salt are as follows: Way to connect:

R ₁ -X ₁ -X ₂ -Glu-Gly-Thr-Phe-Thr-Ser-Asp-X ₁₀ -Ser-X ₁₂ -Tyr-Leu-X ₁₅ -X ₁₆ -X ₁₇ -X ₁₈ -X _19- X ₂₀ -Glu-Phe-X ₂₃ -X ₂₄ -Trp-Leu-X ₂₇ -X ₂₈ -X ₂₉ -X ₃₀ -Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-X _40- R ₂ (II)

among them:

R ₁ is H, alkyl, acetyl, formyl, benzyl, trifluoroacetyl or pGlu;

R ₂ is -NH ₂ or -OH;

X ₁ , X ₂ , X ₁₀ , X ₁₂ , X ₁₅ , X ₁₆ , X ₁₇ , X ₁₈ , X ₁₉ , X ₂₀ , X ₂₇ , X ₂₈ , X ₂₉ and X _{30 are} independently selected from any natural amine group Acids or unnatural amino acids or peptides composed of them;

X _{40 is} selected from any natural amino acid or non-natural amino acid or a peptide composed of it, or X ₄₀ does not exist.

In a preferred embodiment of the present invention, the pharmaceutical composition of a GLP-1 analog or a pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analog represented by the general formula (I) or a pharmaceutically acceptable salt thereof _{X 1 of the} salt is selected from the amino acid residue of Tyr or His; X _{2 is} selected from the amino acid residue of Aib or D-Ala; X _{10 is} selected from the amino acid residue of Val or Tyr; X _{12 is} selected from The amino acid residue of Ser or Ile; X _{15 is} selected from the amino acid residue of Asp or Glu; X _{16 is} selected from the amino acid residue of Glu, Gly, Lys or Aib; X _{17 is} selected from Glu, Ile or The amino acid residue of Gln; X _{18 is} selected from the amino acid residue of Ala, Aib or His; X _{19 is} selected from the amino acid residue of Ala, Aib or Gln; X _{20 is} selected from Gln, Glu, Lys Amino acid residue or Y1; X _{23 is} selected from the amino acid residue of Ile or Val; X _{24 is} selected from the amino acid residue of Ala, Asn or Gln; X _{27 is} selected from the amino acid residue of Val or Leu X _{28 is} selected from the amino acid residue of Arg or Ala; X _{29 is} selected from the amino acid residue of Gly or Gln; X _{30 is} selected from the amino acid residue of Gly, Lys or Y1; X _{40 is} selected from The amino acid residue of Lys, Y1 or not exist,

Y1 is where the side chain has the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} _a -(y-Glu) _b -CO-(CH ₂ ) _c -COOH Lys, Orn, Dap, Dab or Cys residues to which the substituents are coupled;

a is an integer between 1-3;

b is an integer between 1-2;

c is an integer between 10-30.

In a preferred embodiment of the present invention, the pharmaceutical composition of a GLP-1 analog or a pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analog represented by the general formula (I) or a pharmaceutically acceptable salt thereof _{X 1 of the} salt is selected from the amino acid residue of Tyr or His; X _{2 is} selected from the amino acid residue of Aib or D-Ala; X _{10 is} selected from the amino acid residue of Val or Tyr; X _{12 is} selected from The amino acid residue of Ser or Ile; X _{15 is} selected from the amino acid residue of Asp or Glu; X _{16 is} selected from the amino acid residue of Glu, Gly, Lys or Aib; X _{17 is} selected from Glu, Ile or The amino acid residue of Gln; X _{18 is} selected from the amino acid residue of Ala, Aib or His; X _{19 is} selected from the amino acid residue of Ala, Aib or Gln; X _{20 is} selected from Gln, Glu, Lys Amino acid residue or Y1; X _{23 is} selected from the amino acid residue of Ile or Val; X _{24 is} selected from the amino acid residue of Ala, Asn or Gln; X _{27 is} selected from the amino acid of Val, Ile or Leu Acid residue; X _{28 is} selected from the amino acid residue of Arg or Ala; X _{29 is} selected from the amino acid residue of Gly or Gln; X _{30 is} selected from the amino acid residue of Gly, Lys or Y1; X ₄₀ An amino acid residue selected from Lys, Y1 or not present, Y1 is as described above.

In a preferred embodiment of the present invention, the pharmaceutical composition of a GLP-1 analog or a pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analog represented by the general formula (I) or a pharmaceutically acceptable salt thereof X ₁ of the salt is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X ₁₀ is the amino acid residue of Tyr; X ₁₂ is the amino acid residue of Ile; X _{15 is} selected from The amino acid residue of Asp or Glu; X _{16 is} selected from the amino acid residue of Lys or Aib; X _{17 is} selected from the amino acid residue of Glu or Ile; X _{18 is} selected from the amino acid residue of Ala or Aib X _{19 is} selected from the amino acid residue of Ala or Gln; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X ₂₃ is the amino acid residue of Val; X _{24 is} selected from Asn or Gln X _{27 is} selected from the amino acid residue of Leu; X _{28 is} selected from the amino acid residue of Ala; X _{29 is} selected from the amino acid residue of Gly or Gln; X _{30 is} selected from Gly , The amino acid residue of Lys or Y1; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, Y1 is as described above.

In a preferred embodiment of the present invention, the pharmaceutical composition of a GLP-1 analog or a pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analog represented by the general formula (I) or a pharmaceutically acceptable salt thereof X ₁ of the salt is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X ₁₀ is the amino acid residue of Tyr; X ₁₂ is the amino acid residue of Ile; X ₁₅ is Glu X ₁₆ is the amino acid residue of Lys; X ₁₇ is the amino acid residue of Glu; X ₁₈ is the amino acid residue of Ala or Aib; X ₁₉ is the amino acid of Ala Residue; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X ₂₃ is the amino acid residue of Val; X ₂₄ is the amino acid residue of Asn; X ₂₇ is the amino acid residue of Leu X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from the amino acid residue of Gly, Lys or Y1; X _{40 is} the amino acid residue of Lys Base, Y1 or not exist, Y1 as mentioned above.

In a preferred embodiment of the present invention, the pharmaceutical composition of a GLP-1 analog or a pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analog represented by the general formula (I) or a pharmaceutically acceptable salt thereof X ₁ of the salt is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X ₁₀ is the amino acid residue of Tyr; X ₁₂ is the amino acid residue of Ile; X ₁₅ is Glu X ₁₆ is the amino acid residue of Lys; X ₁₇ is the amino acid residue of Ile; X _{18 is} the amino acid residue of Ala or Aib; X ₁₉ is the amino acid residue of Ala Acid residue; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X ₂₃ is the amino acid residue of Val; X ₂₄ is the amino acid residue of Asn; X ₂₇ is the amino acid of Leu Residue; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from Gly, Lys amino acid residue or Y1; X _{40 is} selected from Lys amino acid Residue, Y1 or absent, Y1 is as before.

In a preferred embodiment of the present invention, the pharmaceutical composition of a GLP-1 analog or a pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analog represented by the general formula (I) or a pharmaceutically acceptable salt thereof X ₁ of the salt is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X ₁₀ is the amino acid residue of Tyr; X ₁₂ is the amino acid residue of Ile; X ₁₅ is Glu X ₁₆ is the amino acid residue of Lys; X _{17 is} the amino acid residue of Glu or Ile; X ₁₈ is the amino acid residue of Ala _{; X 19 is the amino acid residue of Ala} Acid residue; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X ₂₃ is the amino acid residue of Val; X ₂₄ is the amino acid residue of Asn; X ₂₇ is the amino acid of Leu Residue; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from Gly, Lys amino acid residue or Y1; X _{40 is} selected from Lys amino acid Residue, Y1 or absent, Y1 is as before.

In a preferred embodiment of the present invention, the pharmaceutical composition of a GLP-1 analog or a pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analog represented by the general formula (I) or a pharmaceutically acceptable salt thereof X ₁ of the salt is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X ₁₀ is the amino acid residue of Tyr; X ₁₂ is the amino acid residue of Ile; X ₁₅ is Glu X ₁₆ is the amino acid residue of Lys; X _{17 is} the amino acid residue of Glu or Ile; X ₁₈ is the amino acid residue of Aib; X ₁₉ is the amino acid residue of Ala Acid residue; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X ₂₃ is the amino acid residue of Val; X ₂₄ is the amino acid residue of Asn; X ₂₇ is the amino acid of Leu Residue; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from Gly, Lys amino acid residue or Y1; X _{40 is} selected from Lys amino acid Residue, Y1 or absent, Y1 is as before.

In a preferred embodiment of the present invention, the pharmaceutical composition of a GLP-1 analog or a pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analog represented by the general formula (I) or a pharmaceutically acceptable salt thereof X ₁ of the salt is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X ₁₀ is the amino acid residue of Tyr; X ₁₂ is the amino acid residue of Ile; X ₁₅ is Glu X ₁₆ is the amino acid residue of Lys; X _{17 is} the amino acid residue of Glu or Ile; X _{18 is} the amino acid residue of Ala or Aib; X ₁₉ is Ala X ₂₀ is the amino acid residue of Gln; X ₂₃ is the amino acid residue of Val; X ₂₄ is the amino acid residue of Asn; X ₂₇ is the amino acid residue of Leu ; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from the amino acid residue of Gly, Lys or Y1; X _{40 is} selected from the amino acid residue of Lys , Y1 or not present, Y1 is as before.

In a preferred embodiment of the present invention, the pharmaceutical composition of a GLP-1 analog or a pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analog represented by the general formula (I) or a pharmaceutically acceptable salt thereof X ₁ of the salt is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X ₁₀ is the amino acid residue of Tyr; X ₁₂ is the amino acid residue of Ile; X ₁₅ is Glu X ₁₆ is the amino acid residue of Lys; X _{17 is} the amino acid residue of Glu or Ile; X _{18 is} the amino acid residue of Ala or Aib; X ₁₉ is Ala X ₂₀ is the amino acid residue of Lys; X ₂₃ is the amino acid residue of Val; X ₂₄ is the amino acid residue of Asn; X ₂₇ is the amino acid residue of Leu ; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from the amino acid residue of Gly, Lys or Y1; X _{40 is} selected from the amino acid residue of Lys , Y1 or not present, Y1 is as before.

In a preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analogue or pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analogue represented by the general formula (I) or the pharmaceutically acceptable salt thereof X ₁ of the salt is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X ₁₀ is the amino acid residue of Tyr; X ₁₂ is the amino acid residue of Ile; X ₁₅ is Glu X ₁₆ is the amino acid residue of Lys; X _{17 is} the amino acid residue of Glu or Ile; X _{18 is} the amino acid residue of Ala or Aib; X ₁₉ is Ala X ₂₀ is Y1; X ₂₃ is the amino acid residue of Val; X ₂₄ is the amino acid residue of Asn; X ₂₇ is the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala Amino acid residue; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from Gly, the amino acid residue of Lys or Y1; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, Y1 is as before.

In a preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analogue or pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analogue represented by the general formula (I) or the pharmaceutically acceptable salt thereof X ₁ of the salt is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X ₁₀ is the amino acid residue of Tyr; X ₁₂ is the amino acid residue of Ile; X ₁₅ is Glu X ₁₆ is the amino acid residue of Lys; X _{17 is} the amino acid residue of Glu or Ile; X _{18 is} the amino acid residue of Ala or Aib; X ₁₉ is Ala X ₂₀ is Gln; X ₂₃ is the amino acid residue of Val; X ₂₄ is the amino acid residue of Asn; X ₂₇ is the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala Amino acid residue; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from Gly, the amino acid residue of Lys or Y1; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, Y1 is as before.

In a preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analog or its pharmaceutically acceptable salt as described above, wherein the X _{27 of the} GLP-1 analog or its pharmaceutically acceptable salt can also be selected from Ile The amino acid residues.

In a preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analogue or pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analogue represented by the general formula (I) or the pharmaceutically acceptable salt thereof X ₁ of the salt is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X _{10 is} selected from the amino acid residue of Val or Tyr; X ₁₂ is the amino acid residue of Ile; X _{15 is} selected from the amino acid residue of Asp or Glu; X _{16 is} selected from the amino acid residue of Glu and Lys; X _{17 is} selected from the amino acid residue of Glu and Ile; X ₁₈ is the amino acid residue of Ala X ₁₉ is the amino acid residue of Ala; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X _{23 is} selected from the amino acid residue of Ile or Val; X _{24 is} selected from Ala, Asn Or the amino acid residue of Gln; X _{27 is} selected from the amino acid residue of Ile or Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly _{; X 30 is the amino acid residue of Gly} Amino acid residue; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, Y1 is as described above.

In a preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analogue or pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analogue represented by the general formula (I) or the pharmaceutically acceptable salt thereof Salt, its two ends are connected in the following way:

R ₁ -X ₁ -X ₂ -Glu-Gly-Thr-Phe-Thr-Ser-Asp-X ₁₀ -Ser-X ₁₂ -Tyr-Leu-X ₁₅ -X ₁₆ -X ₁₇ -X ₁₈ -X _19- X ₂₀ -Glu-Phe-X ₂₃ -X ₂₄ -Trp-Leu-X ₂₇ -X ₂₈ -X ₂₉ -X ₃₀ -Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-X _40- R ₂ (II)

among them:

R ₁ is H, alkyl, acetyl, formyl, benzyl, trifluoroacetyl or pGlu;

R ₂ is -NH2 or -OH.

In a preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analogue or pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analogue represented by the general formula (I) or the pharmaceutically acceptable salt thereof X ₁ of the salt is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X _{10 is} selected from the amino acid residue of Val; X ₁₂ is the amino acid residue of Ile; X _{15 is} selected Amino acid residues from Asp or Glu; X _{16 is} selected from the amino acid residues of Lys; X _{17 is} selected from the amino acid residues of Ile; X ₁₈ is the amino acid residue of Ala _{; X 19 is Ala} X _{20 is} selected from the amino acid residue of Gln or Y1; X _{23 is} selected from the amino acid residue of Val; X _{24 is} selected from the amino acid residue of Asn; X _{27 is} selected from Leu X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue _{of Gly; X 30} is the amino acid residue of Gly; X _{40 is} the amino acid residue of Lys Base, Y1 or not exist, Y1 is as before.

In a preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analogue or pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analogue represented by the general formula (I) or the pharmaceutically acceptable salt thereof X ₁ of the salt is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X _{10 is} selected from the amino acid residue of Tyr; X ₁₂ is the amino acid residue of Ile; X _{15 is} selected X _{16 is} selected from the amino acid residues of Glu and Lys; X _{17 is} selected from the amino acid residues of Glu and Ile; X ₁₈ is the amino acid residue of Ala; X ₁₉ Is the amino acid residue of Ala; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X _{23 is} selected from the amino acid residue of Ile or Val; X _{24 is} selected from the amine of Ala, Asn or Gln X _{27 is} the amino acid residue of Ile or Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue _{of Gly; X 30} is the amino acid residue of Gly Group; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, Y1 is as described above.

In a preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analogue or pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analogue represented by the general formula (I) or the pharmaceutically acceptable salt thereof X ₁ of the salt is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X _{10 is} selected from the amino acid residue of Tyr; X ₁₂ is the amino acid residue of Ile; X _{15 is} selected From the amino acid residue of Glu; X _{16 is} selected from the amino acid residue of Glu; X _{17 is} selected from the amino acid residue of Glu and Ile; X18 is the amino acid residue of Ala _{; X 19 is the amino acid residue of Ala} Amino acid residue; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X _{23 is} selected from the amino acid residue of Val; X _{24 is} selected from the amino acid residue of Asn; X _{27 is} selected from The amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue _{of Gly; X 30} is the amino acid residue of Gly; X ₄₀ is the amino acid residue of Lys Residue, Y1 or not present, Y1 is as before.

In a preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analogue or pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analogue represented by the general formula (I) or the pharmaceutically acceptable salt thereof X ₁ of the salt is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X _{10 is} selected from the amino acid residue of Tyr; X ₁₂ is the amino acid residue of Ile; X _{15 is} selected From the amino acid residue of Glu; X _{16 is} selected from the amino acid residue of Lys; X _{17 is} selected from the amino acid residue of Glu and Ile; X ₁₈ is the amino acid residue of Ala _{; X 19 is Ala} X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X _{23 is} selected from the amino acid residue of Ile or Val; X _{24 is} selected from the amino acid of Ala, Asn or Gln Residue; X _{27 is} selected from the amino acid residue of Ile or Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue _{of Gly; X 30} is the amino acid residue of Gly; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, and Y1 is as described above.

In a preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analogue or pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analogue represented by the general formula (I) or the pharmaceutically acceptable salt thereof X ₁ of the salt is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X _{10 is} selected from the amino acid residue of Tyr; X ₁₂ is the amino acid residue of Ile; X _{15 is} selected From the amino acid residue of Glu; X _{16 is} selected from the amino acid residue of Lys; X _{17 is} selected from the amino acid residue of Ile; X ₁₈ is the amino acid residue _{of Ala; X 19} is the amine of Ala X _{20 is} selected from the amino acid residue of Gln or Y1; X _{23 is} selected from the amino acid residue of Val; X _{24 is} selected from the amino acid residue of Asn or Gln; X _{27 is} selected from Ile Or the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue _{of Gly; X 30} is the amino acid residue of Gly; X ₄₀ is the amino acid residue of Lys Acid residue, Y1 or not present, Y1 is as before.

In a preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analogue or pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analogue represented by the general formula (I) or the pharmaceutically acceptable salt thereof X ₁ of the salt is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X _{10 is} selected from the amino acid residue of Tyr; X ₁₂ is the amino acid residue of Ile; X _{15 is} selected From the amino acid residue of Glu; X _{16 is} selected from the amino acid residue of Lys; X _{17 is} selected from the amino acid residue of Glu; X ₁₈ is the amino acid residue _{of Ala; X 19} is the amine of Ala X _{20 is} selected from the amino acid residue of Lys or Y1; X _{23 is} selected from the amino acid residue of Ile or Val; X _{24 is} selected from the amino acid residue of Ala, Asn or Gln; X _{27 is} selected from the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue _{of Gly; X 30} is the amino acid residue of Gly; X _{40 is} selected from Lys The amino acid residue, Y1 or not present, Y1 is as previously described.

In a preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analogue or pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analogue represented by the general formula (I) or the pharmaceutically acceptable salt thereof X ₁ of the salt is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X _{10 is} selected from the amino acid residue of Tyr; X ₁₂ is the amino acid residue of Ile; X _{15 is} selected From the amino acid residue of Glu; X _{16 is} selected from the amino acid residue of Lys; X _{17 is} selected from the amino acid residue of Glu; X ₁₈ is the amino acid residue _{of Ala; X 19} is the amine of Ala X _{20 is} selected from the amino acid residue of Lys or Y1; X _{23 is} selected from the amino acid residue of Ile or Val; X _{24 is} selected from the amino acid residue of Ala or Gln; X _{27 is} selected From the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue _{of Gly; X 30} is the amino acid residue of Gly; X ₄₀ is the amino acid residue of Lys Acid residue, Y1 or not present, Y1 is as before.

In a preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analogue or pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analogue represented by the general formula (I) or the pharmaceutically acceptable salt thereof Salts, wherein X ₂₀ , X ₃₀ and X ₄₀ are each independently selected from Y1, and Y1 is as described above.

In a preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analogue or pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analogue represented by the general formula (I) or the pharmaceutically acceptable salt thereof Salt, wherein X _{40 is} independently selected from Y1, and Y1 is as described above.

In a preferred embodiment of the present invention, the pharmaceutical composition of the aforementioned GLP-1 analog or its pharmaceutically acceptable salt, such as the GLP-1 analog or its pharmaceutically acceptable salt represented by the general formula (I) , Wherein in the definition of Y1, a is 2, b is 1 or 2, and c is 16-20.

In a preferred embodiment of the present invention, the pharmaceutical composition of the aforementioned GLP-1 analog or its pharmaceutically acceptable salt, such as the GLP-1 analog or its pharmaceutically acceptable salt represented by the general formula (I) , Wherein in the definition of Y1, a is 2, b is 1 or 2, and c is 16, 18 or 20.

In a preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analogue or pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analogue represented by the general formula (I) or the pharmaceutically acceptable salt thereof Salt, the Y1 is K (-OEG-OEG-yGlu-C ₁₈ -OH) or K (-OEG-OEG-yGlu-C ₂₀ -OH).

In a preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analogue or pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analogue represented by the general formula (I) or the pharmaceutically acceptable salt thereof Salt, the Y1 is covalently linked to the fatty acid via the ε amine group of the C-terminal Lys through the amide bond.

In a preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analogue or pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analogue represented by the general formula (I) or the pharmaceutically acceptable salt thereof Salt, the Y1 has the chemical formula of the following structure:

In a preferred embodiment of the present invention, the pharmaceutical composition of GLP-1 analog or pharmaceutically acceptable salt thereof as described above, wherein the GLP-1 analog or pharmaceutically acceptable salt thereof is selected from the following numbered 1- 83 compound or its pharmaceutically acceptable salt:

In a preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analog or its pharmaceutically acceptable salt as described above, the pharmaceutical composition is an injection, preferably a lyophilized injection or an injection, more preferably a solution Type injection, suspension type injection or emulsion type injection, more preferably solution type injection, and still more preferably aqueous solution type injection.

In a preferred embodiment of the present invention, the pharmaceutical composition of a GLP-1 analog or a pharmaceutically acceptable salt thereof as described above, wherein the concentration of the GLP-1 analog or a pharmaceutically acceptable salt thereof is 0.1 mg/mL To 200mg/mL.

In a more preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analog or its pharmaceutically acceptable salt as described above, wherein the concentration of the GLP-1 analog or its pharmaceutically acceptable salt is 0.1 mg /mL to 120mg/mL.

In a more preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analog or its pharmaceutically acceptable salt as described above, wherein the concentration of the GLP-1 analog or its pharmaceutically acceptable salt is 2 mg/ mL to 50mg/mL.

In a more preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analog or its pharmaceutically acceptable salt as described above, wherein the concentration of the GLP-1 analog or its pharmaceutically acceptable salt is 5 mg/ mL to 30mg/mL.

In a more preferred embodiment of the present invention, the pharmaceutical composition of the GLP-1 analog or its pharmaceutically acceptable salt as described above, wherein the concentration of the GLP-1 analog or its pharmaceutically acceptable salt is 0.5 mg /mL, 1mg/mL, 2mg/mL, 2.5mg/mL, 5mg/mL, 8mg/mL, 10mg/mL, 15mg/mL, 20mg/mL or 30mg/mL.

In a more preferred embodiment of the present invention, the unit dose of the aforementioned GLP-1 analog or its pharmaceutically acceptable salt is 0.5mL: 1mg to 0.5mL: 50mg, preferably 0.5mL: 1mg to 0.5mL: 20 mg, more preferably 0.5 mL: 1 mg, 0.5 mL: 2 mg, 0.5 mL: 5 mg, 0.5 mL: 10 mg, 0.5 mL: 15 mg, or 0.5 mL: 20 mg.

In a more preferred embodiment of the present invention, the injection contains an isotonic agent. The isotonizing agent is selected from polyols, chlorides, phosphates, sugars or any combination thereof, preferably calcium chloride, magnesium chloride, potassium chloride, potassium dihydrogen phosphate, sodium chloride, sodium phosphate, sodium dihydrogen phosphate , Disodium hydrogen phosphate, sodium chloride, monosaccharide, disaccharide or sugar alcohol or any combination thereof.

On the other hand, the present invention also provides the medicinal use of the GLP-1 analogue represented by formula (I) or its pharmaceutically acceptable salt and its pharmaceutical composition, including preparation for the treatment of non-insulin-dependent diabetes, insulin Application in drugs for dependent diabetes or obesity; preferably, the non-insulin dependent diabetes is type II diabetes.

In a more preferred embodiment of the present invention, the GLP-1 analogue represented by formula (I) or its pharmaceutically acceptable salt and its pharmaceutical composition are selected from metformin, thiazolidinediones, sulfonylureas, The dipeptidyl peptidase inhibitor and one or more reagents of sodium-glucose transporter are used in combination simultaneously, separately or sequentially.

The polypeptide dual agonist compounds and their derivatives provided by the present invention are amphoteric compounds. Those skilled in the art can use acidic or basic compounds to react with them to form salts by known techniques. The commonly used acids to form acid addition salts are: Hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid; salts include sulfate, Pyrosulfate, trifluoroacetate, sulfite, bisulfite, phosphate, hydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, bromide, iodide, acetate , Propionate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberic acid Salt, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoic acid Salt, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyric acid Salt, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc., preferably trifluoroacetate. Alkaline substances can also form salts with the polypeptide compounds and their derivatives provided by the present invention. These alkaline substances include ammonium, alkali metal or alkaline earth metal hydroxides, as well as carbonates and bicarbonates, typically sodium hydroxide , Potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, etc.

The pharmaceutical composition containing the polypeptide dual agonist compound according to the present invention can be used for the treatment of patients in need of such treatment by way of parenteral administration. Parenteral administration can choose subcutaneous injection, intramuscular injection or intravenous injection. The polypeptide dual agonist compound of the present invention It is also possible to choose transdermal route of administration, such as scalp administration via patch, iontophoresis patch; or transmucosal route administration.

The polypeptide compound and its derivatives provided by the present invention adopt a solid-phase synthesis method. The synthesis carrier is Rink-amide ChemMatrix (Biotage) resin. The α-amine group of the amino acid derivative used in the synthesis process is composed of the Fmoc group (fluorene). Formaldehyde carbonyl group) protection, the side chain of amino acid selects the following protecting groups according to the different functional groups: cysteine side chain sulfhydryl group, glutamine side chain amino group, histidine side chain imidazole group by Trt(三Benzyl) protection, arginine side chain guanidine group is protected by Pbf (2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl), tryptophan side chain indole The side chain amine group of lysine and lysine are protected by Boc (third butoxycarbonyl), the side chain hydroxyl of threonine, the phenol side chain of tyrosine, and the side chain hydroxyl group of serine are protected by t-Bu (third butyl group). )protection. In the synthesis process, the carboxyl group of the C-terminal amino acid residue of the polypeptide is first condensed to the polymer insoluble Rink-amide ChemMatrix resin in the form of amide bond, and then used with 20% piperidine-containing nitrogen, nitrogen-dimethylformamide The amide (DMF) solution removes the Fmoc protective group on the α-amine group, and then the solid-phase carrier and the next amino acid derivative in the sequence are condensed in excess to form an amide bond to extend the peptide chain. Repeat the condensation→washing→deprotection→washing→the next round of amino acid condensation to reach the length of the polypeptide chain to be synthesized, and finally use trifluoroacetic acid: water: triisopropyl silane (90: 5: 5, v: v The mixed solution of v) is reacted with a resin to cleave the polypeptide from the solid phase carrier, and then settled with frozen isopropyl ether to obtain a solid crude product of the polypeptide derivative. The crude polypeptide solid product is dissolved in a mixed solution of acetonitrile/water containing 0.1% trifluoroacetic acid and purified and separated by a C-18 reversed-phase preparative chromatography column to obtain the pure product of the polypeptide and its derivatives.

[Detailed Description of the Invention]

Unless stated to the contrary, the terms used in the specification and the scope of the patent application have the following meanings.

The amino acid sequence of the present invention contains twenty kinds of standard one-letter or three-letter codes for amino acids. Unless explicitly stated otherwise, the preferred configuration of all amino acid residues in the present invention is L-shaped. In addition, Aib is α-aminoisobutyric acid, and D-Ala is D-type alanine.

The term agonist is defined as a substance that activates the type of receptor in question:

The term GLP-1/GIP dual agonist used in the context of the present invention refers to a substance or ligand that can activate both the GLP-1 receptor and the GIP receptor. In the present invention, the term treatment includes inhibiting, slowing down, stopping or reversing the existing symptoms or the progress or severity of the disease.

"Natural amino acids" refers to 20 kinds of conventional amino acids (ie alanine (A), cysteine (C), aspartic acid (D), glutamic acid (E), amphetamine (F) ), Glycine (G), Histidine (H), Isoleucine (I), Lysine (K), Leucine (L), Methionine (M), Aspartamide (N), Proline (P), Glutamine (Q), Arginine (R), Serine (S), Threonine (T), Valine (V), Tryptophan (W) and Tyrosine (Y)).

"Non-natural amino acid" refers to an amino acid that is not naturally encoded or found in the genetic code of any organism. They can be, for example, purely synthetic compounds. Examples of non-natural amino acids include, but are not limited to, hydroxyproline, γ-carboxyglutamate, O-phosphoserine, azetidine carboxylic acid, 2-aminoadipic acid, 3-amine Adipic acid, β-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid , 3-aminoisobutyric acid, 2-aminopimelic acid, tertiary butylglycine, 2,4-diaminoisobutyric acid (Dap), desmosine, 2,2 ' - Diaminopimelic acid, 2,3-diaminopropionic acid (Dab), N-ethylglycine, N-methylglycine, N-ethyl aspartame, homoproline, Hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, allo-isoleucine, N-methylalanine, N-methylglycine, N-methylisoleucine, N-methylpentylglycine, N-methylvaline, naphthalanine, orthovaline, positive light Amino acid, ornithine (Orn), D-ornithine, D-arginine, p-alanine, amylglycine, pipecolic acid and thioproline. In addition, it also includes the C-terminal carboxyl group of natural amino acid or non-natural amino acid, the N-terminal amino group and/or its side chain functional group is chemically modified.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbons An alkyl group having 1 to 3 carbon atoms is most preferred. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, second butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferably, it is a lower alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, and Dibutyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl Group, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2- Dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Butyl and so on. Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point. The substituents are preferably one or more of the following groups, which are independently selected from alkanes Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ring Alkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendant oxy, carboxyl or carboxylate group, preferred in the present invention is methyl, ethyl, isopropyl, tertiary butyl , Haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.

"X is selected from A, B, or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and other terms all express the same Meaning, which means that X can be any one or more of A, B, and C.

The hydrogen atoms described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

"Optional" or "optionally" means that the event or environment described later can but does not have to occur, and the description includes occasions where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may but does not have to be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably at most 5, and more preferably 1 to 3 hydrogen atoms are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amine group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other component examples Such as physiological/pharmaceutically acceptable carriers and excipients. The purpose of the medicinal composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

"Pharmaceutically acceptable salt" refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has due biological activity.

In order to explain the present invention in more detail, this specification provides the following specific embodiments, but the scheme of the present invention is not limited to this.

1. Experimental reagents

2. Experimental equipment

3. Specific experimental plan

3.1 Chemical synthesis of peptide backbone compound No. 1

3.1.1 Coupling of Fmoc-L-Lys(Boc)-OH and Rink-amide ChemMatrix resin

Weigh Rink-amide ChemMatrix resin (Biotage, 0.1mmol) into a disposable polypropylene peptide synthesis solid-phase reaction tube, add DMF (10mL) and swell the resin under nitrogen bubbling for 10 minutes, vacuum out DMF, add DMF( 10mL) Wash the resin and repeat the washing twice; Weigh Fmoc-L-Lys(Boc)-OH(1mmol), 3-(diethoxyphosphoroxy)-1,2,3-benzotriazine- 4-ketone (DEPBT) (1mmol) and diisopropylethylamine (DIEA, 2mmol), add DMF (10mL) to dissolve, add the above solution to the swollen Rink-amide ChemMatrix resin, shake and react at room temperature After 2 hours, the resin was washed alternately with DMF and dichloromethane (DCM) twice after the reaction, and finally washed with DMF three times.

3.1.2 Fmoc-L-Lys(Boc)-Rink-amide resin to remove Fmoc protecting group

Add piperidine/DMF (20%, 10mL) to the solid-phase reaction tube containing Fmoc-L-Lys(Boc)-Rink amide resin, shake the reaction at room temperature for 10 minutes, then remove, then add piperidine/DMF (20%, 10mL), shake and react for 10 minutes at room temperature and then aspirate. After the reaction, the resin was washed 4 times with DMF (10 mL).

3.1.3 Coupling of peptide chain sequence

According to the sequence of the peptide chain of compound number 1 from the amino end to the carboxyl end (H-His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Glu -Glu-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH ₂ ) The amount of amino acid derivative and condensation reagent and the condensation method are the same as those for coupling Fmoc-L-Lys(Boc)-OH to Rink-amide ChemMatrix resin. The amino acid residues used in the synthesis process are respectively Yes: Fmoc-L-His(Trt)-OH, Fmoc-Aib-OH, Fmoc-L-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-L-Thr(tBu)-OH, Fmoc-L -Phe-OH, Fmoc-L-Ser(tBu)-OH, Fmoc-L-Asp(OtBu)-OH, Fmoc-L-Val-OH, Fmoc-Tyr(tBu)-OH, Fmoc-L-Ala- OH, Fmoc-L-Lys(Boc)-OH, Fmoc-L-Ile-OH, Fmoc-L-Trp(Boc)-OH, Fmoc-L-Leu-OH, Fmoc-L-Arg(Pbf)-OH And Fmoc-L-Pro-OH. Repeat the condensation of amino acid derivatives and Fmoc deprotection to finally obtain the resin peptide containing the polypeptide sequence of compound number 1.

The crude peptide was dissolved in a mixed solvent containing 0.1% trifluoroacetic acid and 20% acetonitrile/water, filtered through a 0.22um membrane, and separated by a WATERS Prep150 LC reverse-phase high performance liquid chromatography system. The buffer was A (0.1% trifluoroacetic acid). Fluoroacetic acid, 10% acetonitrile, aqueous solution) and B (0.1% trifluoroacetic acid, 90% acetonitrile, aqueous solution). Among them, the chromatographic column is X-SELECT OBD C- 18 (WATERS) reversed-phase chromatography column, the detection wavelength of the chromatograph is set to 220nm during the purification process, and the flow rate is 20mL/min. The relevant fractions of the product were collected and lyophilized to obtain the pure polypeptide of compound number 1 with a yield of 20%. The purity and compound identity of the pure peptides were determined by analytical high performance liquid chromatography and liquid chromatography/mass spectrometry. The purity was 95.38%, and the molecular weight of the compound was 4218.4.

3.1.4 Cleavage of resin peptides

The resin peptide obtained in step 3 was washed with DMF and DCM for 3 times and then vacuum dried, and then 10 mL of freshly prepared lysate (trifluoroacetic acid: triisopropyl silane: water = 90: 5: 5, v: v: v) The reaction was shaken at room temperature for 2 hours. After the reaction was completed, it was filtered and the resin was washed twice with trifluoroacetic acid. After the filtrate was combined, a large amount of frozen anhydrous isopropyl ether was added to precipitate a solid. After centrifugation, the supernatant was removed and the crude polypeptide of compound number 1 was obtained.

3.1.5 Reversed-phase liquid chromatography purification of crude peptide

3.2 Chemical synthesis of compound numbers 2-24, 34-48, 63-73 and 78-80

The experimental program of compound 1 was used to synthesize the polypeptide compounds of the present invention with compound numbers 2-24, 34-48, 63-73 and 78-80, and the purity and compound were determined by analytical ultra-high performance liquid chromatography and liquid chromatography/mass spectrometry. Molecular weight, as shown in Table 1:

3.3 Chemical synthesis of fatty acid coupling compound No. 25

3.3.1 Coupling of Fmoc-L-Lys(Mtt)-OH and Rink-amide ChemMatrix resin

Weigh Rink-amide ChemMatrix resin (Biotage, 0.1mmol) into a disposable polypropylene peptide synthesis solid-phase reaction tube, add DMF (10mL) and swell the resin under nitrogen bubbling for 10 minutes, vacuum out DMF, add DMF( 10mL) Wash the resin and repeat the washing twice; Weigh Fmoc-L-Lys(Mtt)-OH(1mmol), 3-(diethoxyphosphoroxy)-1,2,3-benzotriazine- 4-ketone (DEPBT) (1mmol) and diisopropylethylamine (DIEA, 2mmol), add DMF (10mL) to dissolve, add the above solution to the swollen Rink-amide ChemMatrix resin, shake and react at room temperature After 2 hours, the resin was washed alternately with DMF and dichloromethane (DCM) twice after the reaction, and finally washed with DMF three times.

3.3.2 Fmoc deprotection and peptide chain extension

Fmoc-L-Lys(Mtt)-Rink amide ChemMatrix resin Fmoc deprotection and subsequent peptide chain extension The resin peptide containing compound No. 25 was obtained by the same synthetic method as in Example 1, wherein the N-terminal amino acid residue Choose Boc-L-Tyr(t-Bu)-OH.

3.3.3 Mtt deprotection of resin peptide and modification of lysine side chain

After completing the extension of the above peptide-resin, add hexafluoroisopropanol/dichloromethane mixed solution (30%, 10mL), shake the reaction at room temperature for 45 minutes and then remove, then add hexafluoroisopropanol/dichloro The mixed solution of methane (30%, 10 mL) was shaken and reacted at room temperature for 45 minutes and then removed. After the reaction, the resin was washed with DMF 6 times. The additional coupling/deprotection cycle using Fmoc/tBu solid phase synthesis strategy to extend the side chain of lysine involves Fmoc-NH-PEG2-COOH, Fmoc-L-Glu-OtBu and HOOC-(CH ₂ ) ₁₆ -COOt- Bu. In all couplings, the reaction was carried out at room temperature and constructed with 1mmol of amino acid, 1mmol of DEPBT and 2mmol of DIEA were reacted in DMF for 4 hours

3.3.4 Cracking and product purification

The resin peptide obtained in the previous step was washed with DMF and DCM twice, then vacuum dried, and then freshly prepared lysate (trifluoroacetic acid: triisopropyl silane: water = 90: 5: 5, v: v: v) The reaction was shaken at room temperature for 2 hours. After the reaction, it was filtered and the resin was washed twice with trifluoroacetic acid. After the filtrate was combined, a large amount of frozen anhydrous isopropyl ether was added to precipitate a solid. After centrifugation, the supernatant was removed and the crude polypeptide of compound number 25 was obtained.

3.3.5 Reversed-phase liquid chromatography purification of compound 25

The crude peptide was dissolved in a mixed solvent containing 0.1% trifluoroacetic acid and 20% acetonitrile/water, filtered through a 0.22um membrane, and separated by a WATERS Prep150 LC reversed-phase high performance liquid chromatography system. The buffer was A (0.1% trifluoroacetic acid). Fluoroacetic acid, 10% acetonitrile, aqueous solution) and B (0.1% trifluoroacetic acid, 90% acetonitrile, aqueous solution). Among them, the chromatographic column is an X-SELECT OBD C-18 reversed-phase chromatographic column. During the purification process, the detection wavelength of the chromatograph is set to 220 nm, and the flow rate is 20 mL/min. The relevant fractions of the product were collected and lyophilized to obtain the pure polypeptide of compound number 25 with a yield of 18%. The purity of the pure peptide product was determined by analytical high performance liquid chromatography and liquid chromatography/mass spectrometry combined with the purity of the compound and the molecular weight of the compound. The purity was 96.23%, and the molecular weight of the compound was 5008.6.

3.4 Chemical synthesis of compound numbers 26-33 and 49-62

The compound 25 experimental program was used to synthesize the polypeptide compounds of the present invention No. 26-33, and the purity and molecular weight of the compound were determined by analytical high performance liquid chromatography and liquid chromatography/mass spectrometry, as shown in Table 2 below:

3.5 Chemical synthesis of compound number 74

3.5.1 Coupling of Fmoc-L-Lys(Mtt)-OH and Rink-amide ChemMatrix resin

Weigh Rink-amide ChemMatrix resin (Biotage, 0.1mmol) into a disposable polypropylene peptide synthesis solid-phase reaction tube, add DMF (10mL) and swell the resin under nitrogen bubbling for 10 minutes, vacuum out DMF, add DMF( 10mL) Wash the resin and repeat the washing twice; Weigh Fmoc-L-Lys(Mtt)-OH(1mmol), 3-(diethoxyphosphoroxy)-1,2,3-benzotriazine- 4-ketone (DEPBT) (1mmol) and diisopropylethylamine (DIEA, 2mmol), add DMF (10mL) to dissolve, add the above solution to the swollen Rink-amide ChemMatrix resin, shake and react at room temperature After 2 hours, the resin was washed alternately with DMF and dichloromethane (DCM) twice after the reaction, and finally washed with DMF three times.

3.5.2 Fmoc deprotection and peptide chain extension

Fmoc-L-Lys(Mtt)-Rink amide ChemMatrix resin Fmoc deprotection and subsequent peptide chain extension The resin peptide containing compound No. 74 was obtained by the same synthetic method as in Example 1, wherein the N-terminal amino acid residue Choose Boc-L-Tyr(t-Bu)-OH.

3.5.3 Mtt deprotection of resin peptide and modification of lysine side chain

After completing the extension of the above peptide-resin, add hexafluoroisopropanol/dichloromethane mixed solution (30%, 10mL), shake the reaction at room temperature for 45 minutes and then remove, then add hexafluoroisopropanol/dichloro The mixed solution of methane (30%, 10 mL) was shaken and reacted at room temperature for 45 minutes and then removed. After the reaction, the resin was washed with DMF 6 times. The additional coupling/deprotection cycle using Fmoc/tBu solid phase synthesis strategy to extend the side chain of lysine involves Fmoc-NH-PEG2-COOH, Fmoc-L-Glu-OtBu and HOOC-(CH ₂ ) ₁₈ -COOt- Bu. In all couplings, the reaction was carried out at room temperature and constructed with 1 mmol of amino acid, 1 mmol of DEPBT and 2 mmol of DIEA were reacted in DMF for 4 hours.

3.5.4 Cracking and product purification

The resin peptide obtained in the previous step was washed with DMF and DCM twice and then vacuum dried, and then freshly prepared lysate (trifluoroacetic acid: triisopropyl silane: water = 90: 5: 5, v: v: v) The reaction was shaken at room temperature for 2 hours. After the reaction was completed, it was filtered and the resin was washed twice with trifluoroacetic acid. After the filtrate was combined, a large amount of frozen anhydrous isopropyl ether was added to precipitate a solid. After centrifugation, the supernatant was removed and the crude polypeptide of compound No. 74 was obtained.

3.5.5 Reversed-phase liquid chromatography purification of compound 74

The crude peptide was dissolved in a mixed solvent containing 0.1% trifluoroacetic acid and 20% acetonitrile/water, filtered through a 0.22um membrane, and separated by a WATERS Prep150 LC reversed-phase high performance liquid chromatography system. The buffer was A (0.1% trifluoroacetic acid). Fluoroacetic acid, 10% acetonitrile, aqueous solution) and B (0.1% trifluoroacetic acid, 90% acetonitrile, aqueous solution). Among them, the chromatographic column is an X-SELECT OBD C-18 reversed-phase chromatographic column. During the purification process, the detection wavelength of the chromatograph is set to 220 nm, and the flow rate is 20 mL/min. The relevant fractions of the product were collected and lyophilized to obtain the pure polypeptide of compound No. 74, with a yield of 18%. The purity of the pure peptide product was determined by analytical high performance liquid chromatography and liquid chromatography/mass spectrometry. The purity was 95.14% and the molecular weight of the compound was 5020.6.

3.6 Chemical synthesis of compound numbers 75-77 and 81-83

The compound 74 experimental program was used to synthesize the polypeptide compounds of the present invention with compound numbers 75-77 and 81-83, and the purity and molecular weight of the compounds were determined by analytical high performance liquid chromatography and liquid chromatography/mass spectrometry, as shown in Table 3 below:

3.7 Preparation of injection

To prepare a liquid formulation of 0.1, 0.2, 0.5, 1.0, 2.5, 5, 10, 15, 20, 25 or 30 mg/mL of compound numbered 1-83, 20 mM citrate buffer can be optionally added.

The preparation method is as follows: Take compound 74 as an example, weigh 5g of compound 74, add 4.5g of NaCl solid, optionally add 25mL of 20mM citric acid buffer, make up to 500mL with water for injection, stir, filter, and prepare an injection of compound 74 .

Biological test evaluation

The following further describes and explains the present invention in conjunction with test examples, but these examples are not meant to limit the scope of the present invention.

1. Experimental reagents

2. Experimental equipment

3. Test case

3.1. Assess the agonist activity of the test compound at the glucagon-like peptide-1 receptor (GLP-1R)

3.1.1 The purpose of the experiment:

The purpose of this test case is to measure the agonist activity of the numbered compound on the glucagon-like peptide-1 receptor (GLP-1R)

3.1.2 Experimental method:

Take out the frozen CHO-K1/GLP-1R/CRE-luc cell line from the liquid nitrogen tank, put it in a 37℃ water bath to quickly thaw, resuspend it in DMEM/F12 medium (Gibco Cat# 11330032), and centrifuge Then wash the cells again, resuspend them in DMEM/F12 medium containing 0.1% casein (Sigma Cat# C3400) in the experimental buffer, adjust the cell density with the experimental buffer, and spread on 384 cells at a density of 2500 cells/5μL/well. Plate (Sigma Cat# CLS4514), and then add 2.5μL of buffer solution to each well of IBMX working solution (Sigma Cat# I7018), the final concentration of IBMX is 0.5mM, and 2.5μL of the polypeptide sample with gradient dilution, centrifuge at 1000rpm for 1min, shake Mix for 30 seconds and incubate at room temperature for 30 minutes. Use Cisbio cAMP-Gs Dynamic kit (Cisbio Cat# 62AM4PEC) for detection. ^{Dilute cAMP-d2 and Anti-cAMP-Eu 3+} -Cryptate respectively with cAMP Lysis & Detection Buffer 20 times and mix. Add 5 μL of diluted cAMP-d2 solution to each well, and then add 5 μL of diluted Anti-cAMP-Eu ³⁺ -Cryptate solution, shake for 30 seconds to mix, and incubate for 1 hour at room temperature in the dark.

3.1.3 Experimental data processing method:

Use Biotek Synergy H1 microplate reader to read HTRF signal, excitation wavelength is 320nm, emission wavelength is 620nm and 665nm. Calculate the signal ratio (665nm/620nm*10,000), and use a four-parameter equation to perform non-linear fitting between the signal ratio and the sample concentration in GraphPad Prism 6 to obtain the EC ₅₀ value. The specific data are shown in Table 4 below.

3.2. Assess the agonist activity of the test compound at the glucose-dependent insulin releasing peptide receptor (GIPR)

3.2.1 The purpose of the experiment:

Test the agonist activity of the numbered compound at the glucose-dependent insulin releasing peptide receptor (GIPR)

3.2.2 Experimental method:

Collect wild-type CHO-K1 cells, adjust the cell suspension to an appropriate density, spread 2 mL per well in a 6-well plate, place it in a 37°C, 5% CO ₂ incubator to adhere to the wall overnight, and transfer the transfection mixture (hGIPR plasmid, Fugene HD (Promega Cat# E2311), OptiMEM (Gibco Cat# 31985070), mix and let stand at room temperature for 15 minutes, add 100μL to the corresponding cell well, and transfect for 24h to make CHO-K1 The cell surface overexpresses hGIPR. Collect the cells in the 6-well plate after the transient transition, and wash them with the experimental buffer, namely DMEM/F12 medium (Gibco Cat# 11330032) containing 0.1% casein (Sigma Cat# C3400), and use the experiment. Adjust the cell density with the buffer solution, spread on a 384-well plate (Sigma Cat# CLS4514) at a density of 5000 cells/5μL/well, then add 2.5μL of the buffer solution to each well of the IBMX working solution (Sigma Cat# I7018), IBMX final Concentration of 0.5mM, and 2.5μL of gradient dilution peptide samples, centrifuge at 1000rpm for 1min, shake for 30 seconds to mix, and incubate at room temperature for 30 minutes. Use Cisbio cAMP-Gs Dynamic kit (Cisbio Cat# 62 AM4PEC) for detection. cAMP-d2 and Anti-cAMP-Eu3+-Cryptate were diluted 20 times with cAMP Lysis & Detection Buffer and mixed well. Add 5μL of diluted cAMP-d2 solution to each well, then add 5μL of diluted Anti-cAMP-Eu3+-Cryptate solution , Shake for 30 seconds to mix, and incubate for 1 hour at room temperature in the dark.

3.2.3 Experimental data processing method:

Use Biotek Synergy H1 microplate reader to read HTRF signal, excitation wavelength is 320nm, emission wavelength is 620nm and 665nm. Calculate the signal ratio (665nm/620nm*10,000), and use a four-parameter equation to perform nonlinear fitting between the signal ratio and the sample concentration in GraphPad Prism 6 to obtain the EC ₅₀ value. The specific values are shown in Table 4 below.

Agonist activity of peptide backbone compounds at human GLP-1R and human GIPR receptors

Experimental results:

Based on the design and research of the polypeptide backbone, the present invention has stronger agonist activity compared with many GLP-1/GIP receptor dual agonist polypeptides in the art, and has better treatment of metabolic diseases. potential.

Agonist activity of fatty acid-coupled polypeptide compounds at human GLP-1R and human GIPR receptors

Experimental results:

The present invention found through research that the activity changes of different polypeptide backbones after coupling fatty acids are not the same, and the polypeptide backbone of the present invention can still maintain good activity on GLP-1 and GIP receptors after being modified by coupling fatty acids.

3.3 Stability of peptide backbone and peptide compound coupled with fatty acid

Stability in plasma is very important for therapeutic peptide drugs, because peptide drugs are likely to be sensitive to peptide hydrolase and proteolytic enzymes in plasma. Polypeptides that are unstable in plasma will have an impact on their half-life and efficacy.

3.3.1 The purpose of the experiment:

The purpose of this experiment is to test the stability of the numbered compound in plasma. In order to compare the stability of the numbered compound with the compounds in the prior art, this experiment also tested the advantageous polypeptide backbone compounds 023 (H23) and 024 (H24) and the advantageous modified compound 089 (H89) in the patent WO2012/167744.

3.3.2 Experimental method:

Add 5 microliters of samples with concentrations of 20, 50, 100, 200, 500, 1000, 2000, 5000, and 10000 ng/ml to 45 microliters of SD rat plasma, and measure the content of the compound by LC-MS and form a standard curve. 5 microliters of peptide solution with a concentration of 1 mg/ml was added to 45 microliters of SD rat plasma. Prepare 5 samples for each compound to be tested, and take out 1 sample at 0 minutes, 30 minutes, 60 minutes, 120 minutes, and 240 minutes. Detect the content of the remaining compounds by LC-MS method, and use 0 minutes As the standard (100%), calculate the relative content of the retained compound of the sample at other time points. The method of LC-MS detection of compounds is to prepare 5% acetonitrile solution as solution A and 95% acetonitrile solution as solution B. At a flow rate of 0.6 ml/min, the time and solution ratio shown in the following table form a solution gradient , Inject 15 microliters of sample, use Raptor Biphenyl 2.7 micron detection tube to detect the content of the compound.

3.3.3 Experimental results:

1) According to the above experimental methods, the stability data of the peptide backbone in plasma are shown in Table 6 below:

3.3.4 Experimental conclusion:

It is found through research that the compound of the present invention can maintain a stable plasma content (relative content>95%), which indicates that the compound of the present invention has good drug-making properties and has a good potential for treating diseases. The plasma stability of the compound of the present invention is better than that of the compounds H23 and H24 in the prior art.

2) Using the above experimental methods, the plasma stability data of the fatty acid-conjugated peptides are shown in Table 7 below:

Experimental results:

Through research, it is found that the compound 74 of the present invention is more stable (relative content>90%) in the plasma at the time of 4 hours compared to compound 75 and the prior art compound H89.

3.4 Pharmacokinetics of peptides coupled with fatty acids in mice

Plasma stability is one of the factors that affect the pharmacokinetics of peptide drugs. The pharmacokinetics of peptide drugs in the body is also affected by factors such as their absorption and clearance in the body.

3.4.1 The purpose of the experiment:

The purpose of this experiment is to use Balb/c mice as the test animals to study the pharmacokinetic behavior of the numbered compound administered by a single intravenous injection in mice (plasma).

3.4.2 Experimental method:

Male Balb/c mice weighing 18-30 grams and 7-9 weeks old were purchased from Shanghai Jiesjie Laboratory Animal Co., Ltd. After preparing the numbered compound with 20 mM citrate buffer (pH=7.0), the numbered compound is injected through the tail vein at a dose of 30 nanomoles per kilogram of body weight Into the mice, 0.2 ml of blood was collected at the time points of 0 hour, 0.083 hour, 0.25 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours and 32 hours. The collected mouse blood was centrifuged at 6000 rpm for 6 minutes to separate plasma at a temperature of 4°C. The experimental method of Test Example 3.3 was used to detect the content of the numbered compound in mouse plasma.

3.4.3 Experimental results:

With the above experimental methods, the specific data are as follows in Table 8:

3.4.4 Experimental conclusion:

Through research, it is found that the compound of the present invention has good pharmacokinetic characteristics in mice, indicating that it has advantages in the treatment of diseases.

3.5 Pharmacokinetics of peptides coupled with fatty acids in rats

3.5.1 The purpose of the experiment:

In order to further study the pharmacokinetics of the compound of the present invention, this experiment used SD rats as the test animal to study the pharmacokinetic behavior of the numbered compound administered in a single subcutaneous injection in rats (plasma).

3.5.2 Experimental method:

Male SD rats weighing 150-300 grams were purchased from Shanghai Jiesjie Laboratory Animal Co., Ltd. After preparing the numbered compound with 20mM citrate buffer (pH=7.0), According to the dose of 50 nanomole per kilogram of body weight, the numbered compound was injected into the rat body by subcutaneous injection at 0 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, 32 hours, 48 hours 0.2 ml of blood was collected at hours, 72 hours, 96 hours, and 120 hours. The collected rat blood was centrifuged at 6000 rpm for 6 minutes to separate plasma at a temperature of 4°C. The experimental method of Test Example 3.3 was used to detect the content of the numbered compound in rat plasma.

3.5.3 Experimental results:

With the above experimental methods, the specific data is shown in Table 9 below:

3.5.4 Experimental conclusion:

Through research, it is found that the compound of the present invention has good pharmacokinetic characteristics in mice, indicating that it has advantages in the treatment of diseases.

3.6 In vivo efficacy of peptides coupled with fatty acids

3.6.1 The purpose of the experiment:

Test numbered compound subcutaneous administration on the regulation of blood glucose in diet-induced obese mice

3.6.2 Experimental method:

Male C57BL/6 mice with a body weight of 35-55 grams and 10-12 weeks of age induced by high-fat food were purchased from Shanghai Jiesjie Experimental Animal Co., Ltd. C57BL/6 mice with diet-induced obesity were subcutaneously injected with the numbered compound (3 nanomole/kg body weight), and then fasted and water was not allowed. After 18 hours, the concentration was 0.2 g by intraperitoneal injection at a dose of 2 g/kg body weight. /Milli Liter of glucose solution. According to the experimental design, blood was collected from the tail of the mouse at time points of 0 minutes, 15 minutes, 30 minutes, 60 minutes, and 120 minutes to measure blood glucose levels. The specific method is to physically fix the mouse, expose the tail and cut off the tail a little, squeeze the tail to make it bleed, discard the first drop of blood, and use the Roche Vigor blood glucose meter to test the blood sugar. Calculate the area under the blood glucose curve (AUC) based on the results of each point.

3.6.3 Experimental results:

With the above experimental methods, the specific data is shown in Table 10 below:

3.6.4 Experimental conclusion:

In this experiment, at a dose of 3 nanomole/kg body weight, the compound of the present invention showed a significant hypoglycemic effect, and the area under the blood glucose curve of the compound 74 group decreased by more than 80% compared with placebo. Compared with the compound H89 and Semaglutide that have GLP-1 activity in the prior art, the blood glucose AUC has a significant difference.

3.7 Weight reduction of peptides coupled with fatty acids

3.7.1 The purpose of the experiment:

Test numbered compound subcutaneous administration on the regulation of body weight in diet-induced obese mice

3.7.2 Experimental method:

Male C57BL/6 mice with a weight of 35-55 grams and 18 weeks of age induced by high-fat food were purchased from Shanghai Jiesjie Experimental Animal Co., Ltd. C57BL/6 mice with diet-induced obesity were subcutaneously injected with placebo or semaglutide (10 nanomole/kg body weight) or compound 74 (10 nanomole/kg body weight) every 3 days. According to the experimental design, mice were weighed at random on days 5, 7, 10, 13, 16, and 19, and the weight loss percentage on day 19 was calculated.

The calculation formula is: weight loss percentage on day 19 (%) = (weight on day 0-weight on day 19)/weight on day 0 * 100

3.6.3 Experimental results:

With the above experimental methods, the specific data is shown in Table 11 below:

3.7.4 Experimental conclusion:

In this experiment, at a dose of 10 nanomolar/kg body weight, the compound of the present invention showed a significant weight-reducing effect, and the weight loss percentage of the compound 74 group exceeded 5%. Compared with the compound semaglutide with GLP-1 activity in the prior art, there is a significant difference in weight loss.

Claims (43)

A GLP-1 analog with general formula (I) or a usable salt thereof, X ₁ -X ₂ -Glu-Gly-Thr-Phe-Thr-Ser-Asp-X ₁₀ -Ser-X ₁₂ -Tyr-Leu-X ₁₅ -X ₁₆ -X ₁₇ -X ₁₈ -X ₁₉ -X _20- Glu-Phe-X ₂₃ -X ₂₄ -Trp-Leu-X ₂₇ -X ₂₈ -X ₂₉ -X ₃₀ -Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-X ₄₀ (I) among them: X _{1 is} selected from the amino acid residues of Tyr or His; X _{2 is} selected from the amino acid residues of Aib or D-Ala; X _{10 is} selected from the amino acid residues of Val or Tyr; X _{12 is} selected from Ser Or the amino acid residue of Ile; X _{15 is} selected from the amino acid residue of Asp or Glu; X _{16 is} selected from the amino acid residue of Glu, Gly, Lys or Aib; X _{17 is} selected from Glu, Ile or Gln _{X 18 is} selected from the amino acid residue of Ala, Aib or His; X _{19 is} selected from the amino acid residue of Ala, Aib or Gln; X _{20 is} selected from the amine of Gln, Glu, Lys X _{23 is} selected from the amino acid residue of Ile or Val; X _{24 is} selected from the amino acid residue of Ala, Asn or Gln; X _{27 is} selected from the amino acid residue of Val or Leu X _{28 is} selected from the amino acid residue of Arg or Ala; X _{29 is} selected from the amino acid residue of Gly or Gln; X _{30 is} selected from the amino acid residue of Gly, Lys or Y1; X _{40 is} selected from Lys The amino acid residue of, Y1 or does not exist; Y1 is K(-OEG-OEG-yGlu-C20-OH), and this group has the chemical formula of the following structure:

. The GLP-1 analog or pharmaceutically acceptable salt thereof according to claim 1, wherein the two ends are connected in the following manner: R ₁ -X ₁ -X ₂ -Glu-Gly-Thr-Phe-Thr-Ser-Asp-X ₁₀ -Ser-X ₁₂ -Tyr-Leu-X ₁₅ -X ₁₆ -X ₁₇ -X ₁₈ -X _19- X ₂₀ -Glu-Phe-X ₂₃ -X ₂₄ -Trp-Leu-X ₂₇ -X ₂₈ -X ₂₉ -X ₃₀ -Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-X _40- R ₂ (II) among them: R ₁ is H, alkyl, acetyl, formyl, benzyl, trifluoroacetyl or pGlu; R ₂ is -NH ₂ or -OH. The GLP-1 analog or a pharmaceutically acceptable salt thereof according to claim 1, wherein X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X ₁₀ is an amino acid residue of Tyr Acid residue; X ₁₂ is the amino acid residue of Ile; X _{15 is} selected from the amino acid residue of Asp or Glu; X _{16 is} selected from the amino acid residue of Lys or Aib; X _{17 is} selected from Glu or Ile X _{18 is} selected from the amino acid residue of Ala or Aib; X _{19 is} selected from the amino acid residue of Ala or Gln; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1 X ₂₃ is the amino acid residue of Val; X _{24 is} selected from the amino acid residue of Asn or Gln; X _{27 is} selected from the amino acid residue of Leu; X _{28 is} selected from the amino acid residue of Ala; X _{29 is} selected from the amino acid residue of Gly or Gln; X _{30 is} selected from the amino acid residue of Gly, Lys or Y1; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present. The GLP-1 analog or a pharmaceutically acceptable salt thereof according to claim 1, wherein X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X ₁₀ is an amino acid residue of Tyr Acid residue; X ₁₂ is the amino acid residue of Ile; X _{15 is} selected from the amino acid residue of Asp or Glu; X _{16 is} selected from the amino acid residue of Lys or Aib; X _{17 is} selected from Glu or Ile X _{18 is} selected from the amino acid residue of Ala or Aib; X _{19 is} selected from the amino acid residue of Ala or Gln; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1 X ₂₃ is the amino acid residue of Val; X _{24 is} selected from the amino acid residue of Asn or Gln; X _{27 is} selected from the amino acid residue of Leu; X _{28 is} selected from the amino acid residue of Ala; X _{29 is} selected from the amino acid residue of Gly or Gln; X _{30 is} selected from the amino acid residue of Gly, Lys or Y1; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present. The GLP-1 analog or a pharmaceutically acceptable salt thereof according to claim 1, wherein X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X ₁₀ is an amino acid residue of Tyr Acid residue; X ₁₂ is the amino acid residue of Ile; X ₁₅ is the amino acid residue of Glu; X ₁₆ is the amino acid residue of Lys; X ₁₇ is the amino acid residue of Glu; X ₁₈ X is the amino acid residue of Ala or Aib; X ₁₉ is the amino acid residue of Ala; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X ₂₃ is the amino acid residue of Val; X ₂₄ is the amino acid residue of Asn; X ₂₇ is the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from Gly, Lys _{X 40 is} selected from the amino acid residue of Lys or Y1; X 40 is selected from the amino acid residue of Lys, Y1 or not present. The GLP-1 analog or a pharmaceutically acceptable salt thereof according to claim 1, wherein X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X ₁₀ is an amino acid residue of Tyr Acid residue; X ₁₂ is the amino acid residue of Ile; X ₁₅ is the amino acid residue of Glu; X ₁₆ is the amino acid residue of Lys; X ₁₇ is the amino acid residue of Ile; X ₁₈ the amino acid selected from Ala or Aib residue; X ₁₉ the amino acid residue is Ala; X ₂₀ is selected from Gln, Lys, or the amino acid residues Y1; X ₂₃ is Val of amino acid residue; X ₂₄ is the amino acid residue of Asn; X ₂₇ is the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from Gly, The amino acid residue of Lys or Y1; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present. The GLP-1 analog or a pharmaceutically acceptable salt thereof according to claim 1, wherein X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X ₁₀ is an amino acid residue of Tyr Acid residue; X ₁₂ is the amino acid residue of Ile; X ₁₅ is the amino acid residue of Glu; X ₁₆ is the amino acid residue of Lys; X _{17 is} the amino acid residue of Glu or Ile X ₁₈ is the amino acid residue of Ala; X ₁₉ is the amino acid residue of Ala; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X ₂₃ is the amino acid residue of Val; X ₂₄ is the amino acid residue of Asn; X ₂₇ is the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from Gly, The amino acid residue of Lys or Y1; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present. The GLP-1 analog or a pharmaceutically acceptable salt thereof according to claim 1, wherein X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X ₁₀ is an amino acid residue of Tyr Acid residue; X ₁₂ is the amino acid residue of Ile; X ₁₅ is the amino acid residue of Glu; X ₁₆ is the amino acid residue of Lys; X _{17 is} the amino acid residue of Glu or Ile X ₁₈ is the amino acid residue of Aib; X ₁₉ is the amino acid residue of Ala; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X ₂₃ is the amino acid residue of Val; X ₂₄ is the amino acid residue of Asn; X ₂₇ is the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from Gly, The amino acid residue of Lys or Y1; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present. The GLP-1 analog or a pharmaceutically acceptable salt thereof according to claim 1, wherein X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X ₁₀ is an amino acid residue of Tyr Acid residue; X ₁₂ is the amino acid residue of Ile; X ₁₅ is the amino acid residue of Glu; X ₁₆ is the amino acid residue of Lys; X _{17 is} the amino acid residue of Glu or Ile X _{18 is} the amino acid residue of Ala or Aib; X ₁₉ is the amino acid residue of Ala; X ₂₀ is the amino acid residue of Gln; X ₂₃ is the amino acid residue of Val; X ₂₄ Is the amino acid residue of Asn; X ₂₇ is the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from Gly, Lys The amino acid residue or Y1; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present. The GLP-1 analog or a pharmaceutically acceptable salt thereof according to claim 1, wherein X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X ₁₀ is an amino acid residue of Tyr Acid residue; X ₁₂ is the amino acid residue of Ile; X ₁₅ is the amino acid residue of Glu; X ₁₆ is the amino acid residue of Lys; X _{17 is} the amino acid residue of Glu or Ile X _{18 is} the amino acid residue of Ala or Aib; X ₁₉ is the amino acid residue of Ala; X ₂₀ is Y1; X ₂₃ is the amino acid residue of Val; X ₂₄ is the amino acid of Asn Residue; X ₂₇ is the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} the amino acid residue of Gly, Lys or Y1; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present. The GLP-1 analog or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein Y1 is covalently linked to the fatty acid via the epsilon amine group of the C-terminal Lys via an amide bond. The GLP-1 analog or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the GLP-1 analog or pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

A pharmaceutical composition comprising a GLP-1 analog represented by general formula (I) or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, X ₁ -X ₂ -Glu-Gly-Thr-Phe-Thr-Ser-Asp-X ₁₀ -Ser-X ₁₂ -Tyr-Leu-X ₁₅ -X ₁₆ -X ₁₇ -X ₁₈ -X ₁₉ -X _20- Glu-Phe-X ₂₃ -X ₂₄ -Trp-Leu-X ₂₇ -X ₂₈ -X ₂₉ -X ₃₀ -Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-X ₄₀ (I) among them: X ₁ , X ₂ , X ₁₀ , X ₁₂ , X ₁₅ , X ₁₆ , X ₁₇ , X ₁₈ , X ₁₉ , X ₂₀ , X ₂₇ , X ₂₈ , X ₂₉ and X _{30 are} independently selected from any natural amine group Acids or unnatural amino acids or peptides composed of them; X _{40 is} selected from any natural amino acid or non-natural amino acid or a peptide composed of it, or X ₄₀ does not exist. The pharmaceutical composition according to claim 13, wherein both ends of the GLP-1 analog or pharmaceutically acceptable salt thereof are connected in the following manner: R ₁ -X ₁ -X ₂ -Glu-Gly-Thr-Phe-Thr-Ser-Asp-X ₁₀ -Ser-X ₁₂ -Tyr-Leu-X ₁₅ -X ₁₆ -X ₁₇ -X ₁₈ -X _19- X ₂₀ -Glu-Phe-X ₂₃ -X ₂₄ -Trp-Leu-X ₂₇ -X ₂₈ -X ₂₉ -X ₃₀ -Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-X _40- R ₂ (II) among them: R ₁ is H, alkyl, acetyl, formyl, benzyl, trifluoroacetyl or pGlu; R ₂ is -NH ₂ or -OH; X ₁ , X ₂ , X ₁₀ , X ₁₂ , X ₁₅ , X ₁₆ , X ₁₇ , X ₁₈ , X ₁₉ , X ₂₀ , X ₂₇ , X ₂₈ , X ₂₉ and X _{30 are} independently selected from any natural amine group Acids or unnatural amino acids or peptides composed of them; X _{40 is} selected from any natural amino acid or non-natural amino acid or a peptide composed of it, or X ₄₀ does not exist. The pharmaceutical composition according to claim 13, wherein, in the general formula (I), X _{1 is} selected from the amino acid residue of Tyr or His; X _{2 is} selected from the amino acid residue of Aib or D-Ala; X _{10 is} selected from amino acid residues of Val or Tyr; X _{12 is} selected from amino acid residues of Ser or Ile; X _{15 is} selected from amino acid residues of Asp or Glu; X _{16 is} selected from Glu, Gly, The amino acid residue of Lys or Aib; X _{17 is} selected from the amino acid residue of Glu, Ile or Gln; X _{18 is} selected from the amino acid residue of Ala, Aib or His; X _{19 is} selected from Ala, Aib or The amino acid residue of Gln; X _{20 is} selected from the amino acid residue of Gln, Glu, Lys or Y1; X _{23 is} selected from the amino acid residue of Ile or Val; X _{24 is} selected from Ala, Asn or Gln Amino acid residue; X _{27 is} selected from the amino acid residue of Val or Leu; X _{28 is} selected from the amino acid residue of Arg or Ala; X _{29 is} selected from the amino acid residue of Gly or Gln; X ₃₀ An amino acid residue selected from Gly, Lys or Y1; X _{40 is} selected from an amino acid residue of Lys, Y1 or not present, Y1 is where the side chain has the formula {[2-(2-amino-ethoxy)-ethoxy]-acetyl} _a -(y-Glu) _b -CO-(CH ₂ ) _c -COOH Lys, Orn, Dap, Dab or Cys residues to which the substituents are coupled; a is an integer between 1-3; b is an integer between 1-2; c is an integer between 10-30. The pharmaceutical composition according to claim 13, wherein, in the general formula (I), X _{1 is} selected from the amino acid residue of Tyr or His; X _{2 is} selected from the amino acid residue of Aib or D-Ala; X _{10 is} selected from amino acid residues of Val or Tyr; X _{12 is} selected from amino acid residues of Ser or Ile; X _{15 is} selected from amino acid residues of Asp or Glu; X _{16 is} selected from Glu, Gly, The amino acid residue of Lys or Aib; X _{17 is} selected from the amino acid residue of Glu, Ile or Gln; X _{18 is} selected from the amino acid residue of Ala, Aib or His; X _{19 is} selected from Ala, Aib or The amino acid residue of Gln; X _{20 is} selected from the amino acid residue of Gln, Glu, Lys or Y1; X _{23 is} selected from the amino acid residue of Ile or Val; X _{24 is} selected from Ala, Asn or Gln Amino acid residue; X _{27 is} selected from the amino acid residue of Val, Ile or Leu; X _{28 is} selected from the amino acid residue of Arg or Ala; X _{29 is} selected from the amino acid residue of Gly or Gln; X _{30 is} selected from the amino acid residues of Gly and Lys or Y1; X _{40 is} selected from the amino acid residues of Lys, Y1 or not present, and Y1 is as defined in claim 15. The pharmaceutical composition according to claim 13, wherein, in the general formula (I), X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X ₁₀ is an amino acid of Tyr Residue; X ₁₂ is the amino acid residue of Ile; X _{15 is} selected from the amino acid residue of Asp or Glu; X _{16 is} selected from the amino acid residue of Lys or Aib; X _{17 is} selected from the amino acid residue of Glu or Ile Amino acid residue; X _{18 is} selected from the amino acid residue of Ala or Aib; X _{19 is} selected from the amino acid residue of Ala or Gln; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X ₂₃ is the amino acid residue of Val; X _{24 is} selected from the amino acid residue of Asn or Gln; X _{27 is} selected from the amino acid residue of Leu; X _{28 is} selected from the amino acid residue of Ala; X _{29 is} selected from the amino acid residue of Gly or Gln; X _{30 is} selected from the amino acid residue of Gly, Lys or Y1; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, Y1 is as claimed 15 defined. The pharmaceutical composition according to claim 13, wherein, in the general formula (I), X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X ₁₀ is an amino acid of Tyr Residue; X ₁₂ is the amino acid residue of Ile; X ₁₅ is the amino acid residue of Glu; X ₁₆ is the amino acid residue of Lys; X ₁₇ is the amino acid residue of Glu; X ₁₈ is The amino acid residue of Ala or Aib; X ₁₉ is the amino acid residue of Ala; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X ₂₃ is the amino acid residue of Val; X ₂₄ Is the amino acid residue of Asn; X ₂₇ is the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from Gly, Lys The amino acid residue or Y1; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, and Y1 is as defined in claim 15. The pharmaceutical composition according to claim 13, wherein, in the general formula (I), X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X ₁₀ is an amino acid of Tyr Residue; X ₁₂ is the amino acid residue of Ile; X ₁₅ is the amino acid residue of Glu; X ₁₆ is the amino acid residue of Lys; X ₁₇ is the amino acid residue of Ile; X _{18 is} selected From the amino acid residue of Ala or Aib; X ₁₉ is the amino acid residue of Ala; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X ₂₃ is the amino acid residue of Val; X ₂₄ is the amino acid residue of Asn; X ₂₇ is the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from Gly, Lys X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, and Y1 is as defined in claim 15. The pharmaceutical composition according to claim 13, wherein, in the general formula (I), X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X ₁₀ is an amino acid of Tyr Residue; X ₁₂ is the amino acid residue of Ile; X ₁₅ is the amino acid residue of Glu; X ₁₆ is the amino acid residue of Lys; X _{17 is} the amino acid residue of Glu or Ile; X ₁₈ is the amino acid residue of Ala; X ₁₉ is the amino acid residue of Ala; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X ₂₃ is the amino acid residue of Val; X ₂₄ is the amino acid residue of Asn; X ₂₇ is the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from Gly, Lys X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, and Y1 is as defined in claim 15. The pharmaceutical composition according to claim 13, wherein, in the general formula (I), X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X ₁₀ is an amino acid of Tyr Residue; X ₁₂ is the amino acid residue of Ile; X ₁₅ is the amino acid residue of Glu; X ₁₆ is the amino acid residue of Lys; X _{17 is} the amino acid residue of Glu or Ile; X ₁₈ is the amino acid residue of Aib; X ₁₉ is the amino acid residue of Ala; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X ₂₃ is the amino acid residue of Val; X ₂₄ is the amino acid residue of Asn; X ₂₇ is the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from Gly, Lys X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, and Y1 is as defined in claim 15. The pharmaceutical composition according to claim 13, wherein, in the general formula (I), X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X ₁₀ is an amine of Tyr X ₁₂ is the amino acid residue of Ile; X ₁₅ is the amino acid residue of Glu; X ₁₆ is the amino acid residue of Lys; X _{17 is} the amino acid residue of Glu or Ile X _{18 is} the amino acid residue of Ala or Aib; X ₁₉ is the amino acid residue of Ala; X ₂₀ is the amino acid residue of Gln; X ₂₃ is the amino acid residue of Val; X ₂₄ is the amino acid residue of Asn; X ₂₇ is the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} selected from Gly, Lys X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, and Y1 is as defined in claim 15. The pharmaceutical composition according to claim 13, wherein, in the general formula (I), X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X ₁₀ is an amino acid of Tyr Residue; X ₁₂ is the amino acid residue of Ile; X ₁₅ is the amino acid residue of Glu; X ₁₆ is the amino acid residue of Lys; X _{17 is} the amino acid residue of Glu or Ile; X _{18 is} the amino acid residue of Ala or Aib; X ₁₉ is the amino acid residue of Ala; X ₂₀ is the amino acid residue of Lys; X ₂₃ is the amino acid residue of Val; X ₂₄ is The amino acid residue of Asn; X ₂₇ is the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} the amine selected from Gly and Lys The base acid residue or Y1; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, and Y1 is as defined in claim 15. The pharmaceutical composition according to claim 13, wherein, in the general formula (I), X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X ₁₀ is an amino acid of Tyr Residue; X ₁₂ is the amino acid residue of Ile; X ₁₅ is the amino acid residue of Glu; X ₁₆ is the amino acid residue of Lys; X _{17 is} the amino acid residue of Glu or Ile; X _{18 is} the amino acid residue of Ala or Aib; X ₁₉ is the amino acid residue of Ala; X ₂₀ is Y1; X ₂₃ is the amino acid residue of Val; X ₂₄ is the amino acid residue of Asn X ₂₇ is the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} the amino acid residue of Gly, Lys or Y1 ; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, and Y1 is as defined in claim 15. The pharmaceutical composition according to claim 13, wherein, in the general formula (I), X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X ₁₀ is an amino acid of Tyr Residue; X ₁₂ is the amino acid residue of Ile; X ₁₅ is the amino acid residue of Glu; X ₁₆ is the amino acid residue of Lys; X _{17 is} the amino acid residue of Glu or Ile; X _{18 is} the amino acid residue of Ala or Aib; X ₁₉ is the amino acid residue of Ala; X ₂₀ is Gln; X ₂₃ is the amino acid residue of Val; X ₂₄ is the amino acid residue of Asn X ₂₇ is the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X _{30 is} the amino acid residue of Gly, Lys or Y1 ; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, Y1 is as defined in claim 15. The pharmaceutical composition according to claim 13, wherein, in the general formula (I), X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X _{10 is} selected from Val or Tyr Amino acid residue; X ₁₂ is an amino acid residue of Ile; X ₁₅ is an amino acid residue selected from Asp or Glu; X _{16 is} an amino acid residue selected from Glu and Lys; X _{17 is} selected from Glu , The amino acid residue of Ile; X ₁₈ is the amino acid residue of Ala; X ₁₉ is the amino acid residue of Ala; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X _{23 is} selected An amino acid residue from Ile or Val; X _{24 is} an amino acid residue selected from Ala, Asn or Gln; X _{27 is} an amino acid residue selected from Ile or Leu; X ₂₈ is an amino acid residue of Ala X ₂₉ is the amino acid residue of Gly; X ₃₀ is the amino acid residue of Gly; X _{40 is} selected from the amino acid residue of Lys, Y1 or absent, Y1 is defined in claim 15. The pharmaceutical composition according to claim 13, wherein, in the general formula (I), X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X _{10 is} selected from the amino acid residue of Val Acid residue; X ₁₂ is the amino acid residue of Ile; X _{15 is} selected from the amino acid residue of Asp or Glu; X _{16 is} selected from the amino acid residue of Lys; X _{17 is} the amino acid of Ile Residue; X ₁₈ is the amino acid residue of Ala; X ₁₉ is the amino acid residue of Ala; X _{20 is} selected from the amino acid residue of Gln or Y1; X _{23 is} selected from the amino acid residue of Val X _{24 is} selected from the amino acid residue of Asn; X _{27 is} selected from the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X ₃₀ is The amino acid residue of Gly; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, and Y1 is as defined in claim 15. The pharmaceutical composition according to claim 13, wherein, in the general formula (I), X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X _{10 is} selected from the amino acid residue of Tyr Acid residue; X ₁₂ is the amino acid residue of Ile; X _{15 is} selected from the amino acid residue of Glu; X _{16 is} selected from the amino acid residue of Glu and Lys; X _{17 is} selected from the amine of Glu and Ile X ₁₈ is the amino acid residue of Ala; X ₁₉ is the amino acid residue of Ala; X _{20 is} selected from Gln, Lys amino acid residue or Y1; X _{23 is} selected from Ile or Val _{X 24 is} selected from the amino acid residue of Ala, Asn or Gln; X _{27 is} selected from the amino acid residue of Ile or Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ X30 is the amino acid residue of Gly; X ₃₀ is the amino acid residue of Gly; X _{40 is} selected from the amino acid residue of Lys, Y1 or absent, and Y1 is as defined in claim 15. The pharmaceutical composition according to claim 13, wherein, in the general formula (I), X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X _{10 is} selected from the amino acid residue of Tyr Acid residue; X ₁₂ is the amino acid residue of Ile; X _{15 is} selected from the amino acid residue of Glu; X _{16 is} selected from the amino acid residue of Glu; X _{17 is} selected from the amino acid of Glu and Ile Residue; X18 is the amino acid residue of Ala; X ₁₉ is the amino acid residue of Ala; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X _{23 is} selected from the amino acid residue of Val X _{24 is} selected from the amino acid residue of Asn; X _{27 is} selected from the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X ₃₀ Is the amino acid residue of Gly; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, and Y1 is as defined in claim 15. The pharmaceutical composition according to claim 13, wherein, in the general formula (I), X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X _{10 is} selected from the amino acid residue of Tyr Acid residue; X ₁₂ is the amino acid residue of Ile; X _{15 is} selected from the amino acid residue of Glu; X _{16 is} selected from the amino acid residue of Lys; X _{17 is} selected from the amino acid of Glu and Ile Residue; X ₁₈ is the amino acid residue of Ala; X ₁₉ is the amino acid residue of Ala; X _{20 is} selected from the amino acid residue of Gln, Lys or Y1; X _{23 is} selected from the amine of Ile or Val X _{24 is} selected from the amino acid residue of Ala, Asn or Gln; X _{27 is} selected from the amino acid residue of Ile or Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is Gly X ₃₀ is the amino acid residue of Gly; X _{40 is} selected from the amino acid residue of Lys, Y1 or absent, Y1 is defined in claim 15. The pharmaceutical composition according to claim 13, wherein, in the general formula (I), X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X _{10 is} selected from the amino acid residue of Tyr Acid residue; X ₁₂ is the amino acid residue of Ile; X _{15 is} selected from the amino acid residue of Glu; X _{16 is} selected from the amino acid residue of Lys; X _{17 is} selected from the amino acid residue of Ile X ₁₈ is the amino acid residue of Ala; X ₁₉ is the amino acid residue of Ala; X _{20 is} selected from the amino acid residue of Gln or Y1; X _{23 is} selected from the amino acid residue of Val; X _{24 is} an amino acid residue selected from Asn or Gln; X _{27 is} an amino acid residue selected from Ile or Leu; X ₂₈ is an amino acid residue of Ala; X ₂₉ is an amino acid residue of Gly; X ₃₀ is the amino acid residue of Gly; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, and Y1 is as defined in claim 15. The pharmaceutical composition according to claim 13, wherein, in the general formula (I), X ₁ is the amino acid residue of Tyr; X ₂ is the amino acid residue of Aib; X _{10 is} selected from the amino acid residue of Tyr; X ₁₂ is the amino acid residue of Ile; X _{15 is} selected from Glu X _{16 is} selected from the amino acid residue of Lys; X _{17 is} selected from the amino acid residue of Glu; X ₁₈ is the amino acid residue _{of Ala; X 19} is the amino acid of Ala Residue; X _{20 is} selected from the amino acid residue of Lys or Y1; X _{23 is} selected from the amino acid residue of Ile or Val; X _{24 is} selected from the amino acid residue of Ala, Asn or Gln; X _{27 is} selected From the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue _{of Gly; X 30} is the amino acid residue of Gly; X ₄₀ is the amino acid residue of Lys Acid residue, Y1 or not present, Y1 is as defined in claim 15. The pharmaceutical composition according to claim 13, wherein, in the general formula (I), X ₁ is an amino acid residue of Tyr; X ₂ is an amino acid residue of Aib; X _{10 is} selected from the amino acid residue of Tyr Acid residue; X ₁₂ is the amino acid residue of Ile; X _{15 is} selected from the amino acid residue of Glu; X _{16 is} selected from the amino acid residue of Lys; X _{17 is} selected from the amino acid residue of Glu ; X ₁₈ is the amino acid residue of Ala; X ₁₉ is the amino acid residue of Ala; X _{20 is} selected from the amino acid residue of Lys or Y1; X _{23 is} selected from the amino acid residue of Ile or Val X _{24 is} selected from the amino acid residue of Ala or Gln; X _{27 is} selected from the amino acid residue of Leu; X ₂₈ is the amino acid residue of Ala; X ₂₉ is the amino acid residue of Gly; X ₃₀ is the amino acid residue of Gly; X _{40 is} selected from the amino acid residue of Lys, Y1 or not present, and Y1 is as defined in claim 15. The pharmaceutical composition according to claim 13, wherein, in the general formula (I), X ₂₀ , X ₃₀ and X ₄₀ are each independently selected from Y1, preferably, X _{40 is} selected from Y1, and Y1 is as claimed 15 defined. The pharmaceutical composition according to any one of claims 15-34, wherein a is 2, b is 1 or 2, c is 16-20, preferably, a is 2, b is 1 or 2, and c is 16, 18 or 20. The pharmaceutical composition according to any one of claims 15 to 34, wherein Y1 of the GLP-1 analog or a pharmaceutically acceptable salt thereof is K(-OEG-OEG-yGlu-C ₁₈ -OH) or K(-OEG-OEG-yGlu-C ₂₀ -OH), preferably, Y1 is covalently linked to the fatty acid via the epsilon amine group of the C-terminal Lys via an amide bond; further preferably, the Y1 group has the following structure The chemical formula:

The pharmaceutical composition according to claim 13 or 14, wherein it is selected from the following compounds numbered 1-83 or pharmaceutically acceptable salts thereof:

The medical composition according to any one of claims 13 to 37, wherein the medical composition is an injection, preferably a lyophilized injection or an injection, more preferably a solution injection, a suspension injection or an emulsion The type injection is more preferably a solution type injection, and even more preferably an aqueous solution type injection. The pharmaceutical composition according to claim 38, wherein the unit dose of the GLP-1 analog or its pharmaceutically acceptable salt has a concentration of 0.1 mg/mL to 200 mg/mL, preferably 0.1 mg/mL to 120 mg/mL, It is more preferably 2 mg/mL to 50 mg/mL, further preferably 5-30 mg/mL, most preferably 1 mg/mL, 2 mg/mL, 10 mg/mL, 20 mg/mL or 30 mg/mL. The pharmaceutical composition according to claim 38, wherein the unit dose of the GLP-1 analog or its pharmaceutically acceptable salt is 0.5 mL: 1 mg to 0.5 mL: 50 mg, preferably 0.5 mL: 1 mg To 0.5mL: 20mg, more preferably 0.5mL: 1mg, 0.5mL: 5mg, 0.5mL: 10mg, 0.5mL: 15mg or 0.5mL: 20mg. The medical composition according to claim 38, wherein the injection contains an isotonic agent. A GLP-1 analog or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, or a pharmaceutical composition according to any one of claims 13 to 41, in preparation for the treatment of non-insulin Use in drugs for dependent diabetes, insulin dependent diabetes or obesity; preferably, the non-insulin dependent diabetes is type II diabetes. A GLP-1 analogue according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of claims 13 to 41, and selected from metformin, thiazolidine One or more reagents of diketones, sulfonylureas, dipeptidyl peptidase inhibitors and sodium glucose transporter can be used separately or in combination at the same time.