WO2021093883A1 - 双受体重激动剂化合物及其药物组合物 - Google Patents

双受体重激动剂化合物及其药物组合物 Download PDF

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WO2021093883A1
WO2021093883A1 PCT/CN2020/129071 CN2020129071W WO2021093883A1 WO 2021093883 A1 WO2021093883 A1 WO 2021093883A1 CN 2020129071 W CN2020129071 W CN 2020129071W WO 2021093883 A1 WO2021093883 A1 WO 2021093883A1
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amino acid
acid residue
lys
ala
glu
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PCT/CN2020/129071
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English (en)
French (fr)
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花海清
孙运栋
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江苏豪森药业集团有限公司
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Priority to CN202080006382.2A priority Critical patent/CN113383014A/zh
Publication of WO2021093883A1 publication Critical patent/WO2021093883A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones

Definitions

  • the present invention belongs to the field of biomedicine, and specifically relates to a compound with agonist effect on human glucagon-like peptide-1 (GLP-1) receptor and human blood glucose-dependent insulinotropic polypeptide (GIP) receptor or its medicament
  • GLP-1 human glucagon-like peptide-1
  • GIP human blood glucose-dependent insulinotropic polypeptide
  • 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 imbalanced 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 ⁇ -cell function and long-term insulin resistance. Its main feature is the lack of insulin levels in the body and the 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 many other diseases.
  • BMI body mass index
  • diabetes drugs that have been approved for marketing mainly include chemically synthesized small-molecule oral hypoglycemic drugs, such as biguanides, sulfonyls, insulin sensitizers, ⁇ -glycosides, and injections of recombinant insulin and its derivatives produced by biosynthesis.
  • chemically synthesized small-molecule oral hypoglycemic drugs such as biguanides, sulfonyls, insulin sensitizers, ⁇ -glycosides, and injections of recombinant insulin and its derivatives produced by biosynthesis.
  • Class hypoglycemic drugs are chemically synthesized small-molecule oral hypoglycemic drugs, such as biguanides, sulfonyls, insulin sensitizers, ⁇ -glycosides, and injections of recombinant insulin and its derivatives produced by biosynthesis.
  • GLP-1 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 nutrient absorption 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.
  • GLP-1 controls blood glucose levels in the body is mainly to activate its GLP-1 receptors distributed in pancreatic ⁇ cells to promote insulin biosynthesis and secretion.
  • GLP-1 polypeptides can inhibit pancreatic hypertension in the case of high blood glucose levels in the body.
  • the secretion of glucagon, gastric emptying and food intake and through specific nervous system effects enhance the degradation of glucose in the body.
  • 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.
  • 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 ⁇ cell apoptosis. GLP-1 polypeptide also has the potential to inhibit gastrin and gastric acid secretion stimulated by eating. These characteristics 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 medicine for treating non-insulin-dependent diabetes and obesity diabetes.
  • GLP-1 polypeptide in controlling blood sugar and reducing body weight have brought hope for the treatment of non-insulin-dependent diabetes/obesity diabetes.
  • the human body's natural GLP-1 has poor druggability, and it is easy to be dipeptide-based in the body.
  • Peptidase-IV DPP-IV is degraded so that its half-life in the human body is only 1-2 minutes.
  • long-acting GLP-1 analogues by carrying out site-directed mutations of amino acids at enzyme cleavage sites, fatty acid modification of the polypeptide backbone, and the combination of GLP-1 polypeptides and a variety of protein/polymer polymers to construct long-acting GLP-1 analogs 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.
  • 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 subjects Accelerated heartbeat and under certain circumstances can increase the risk of pancreatitis in patients. 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 full-effect blood glucose control and weight loss in patients.
  • GIP Glucose-dependent Insulinotropic Polypeptide
  • GLP-1 polypeptide belong to 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 ⁇ cells, adipose tissue and central nervous system. Similar to GLP-1 polypeptide, GIP polypeptide can stimulate pancreatic ⁇ -cells to secrete insulin to reduce blood glucose concentration in plasma and protect pancreatic ⁇ -cells to control glucose metabolism in the body.
  • GIP polypeptide also includes activating its GIP receptor in adipose tissue to promote fat metabolism.
  • 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.
  • the inhibitory properties of the GIP polypeptides produced by these diabetic patients will be greatly reduced when the blood sugar level returns to normal.
  • 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 effects.
  • 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.
  • certain compounds of the present invention have extremely high plasma stability and have pharmacokinetic characteristics that support administration by subcutaneous injection once a week 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
  • Said 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 the amino acid residues of Ser or Ile Residue;
  • 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 the amino acid residue of Glu, Ile or Gln;
  • X 18 is selected from Ala , Aib or His amino acid residue;
  • X 19 is selected from the amino acid residue of Ala, Aib or 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 amino acid residues of Ala
  • 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 as described above is connected at its two ends 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
  • R 1 is H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu;
  • R 2 is -NH 2 or -OH.
  • the GLP-1 analog or pharmaceutically acceptable salt thereof as described above, 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 of Tyr Residue; X 12 is an amino acid residue of Ile; X 15 is selected from an amino acid residue of Asp or Glu; X 16 is selected from an amino acid residue of Lys or Aib; X 17 is an amino acid residue of Glu or Ile; X 18 Amino acid residues selected from Ala or Aib; X 19 is selected from amino acid residues of Ala or Gln; X 20 is selected from amino acid residues of Gln, Lys or Y1; X 23 is an amino acid residue of Val; X 24 is selected from Asn Or Gln amino acid residues; X 27 is selected from Leu amino acid residues; X 28 is selected from Ala amino acid residues; X 29 is selected from Gly or Gln amino acid residues;
  • the GLP-1 analog or pharmaceutically acceptable salt thereof as described above, 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 of Tyr Residue; X 12 is an amino acid residue of Ile; X 15 is selected from an amino acid residue of Asp or Glu; X 16 is selected from an amino acid residue of Lys or Aib; X 17 is an amino acid residue of Glu or Ile; X 18 Amino acid residues selected from Ala or Aib; X 19 is selected from amino acid residues of Ala or Gln; X 20 is selected from amino acid residues of Gln, Lys or Y1; X 23 is an amino acid residue of Val; X 24 is selected from Asn Or Gln amino acid residues; X 27 is selected from Leu amino acid residues; X 28 is selected from Ala amino acid residues; X 29 is selected from Gly or Gln amino acid residues;
  • the GLP-1 analog or pharmaceutically acceptable salt thereof as described above, 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 of Tyr Residues; 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 the amino acid residue of Gly, Lys or Y1; X 40 is selected from the amino acid residue of the amino acid residue of
  • the GLP-1 analog or pharmaceutically acceptable salt thereof as described above, 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 of Tyr Residues; 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 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 the amino acid residue of Gly, Lys or Y1; X 40 is selected from the amino acid residue of the amino acid residue of
  • the GLP-1 analog or pharmaceutically acceptable salt thereof as described above, 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 of Tyr Residues; 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 the amino acid residue of Gly, Lys or Y1; X 40 is selected from the amino acid residue of Ly
  • the GLP-1 analog or pharmaceutically acceptable salt thereof as described above, 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 of Tyr Residues; 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 the amino acid residue of Gly, Lys or Y1; X 40 is selected from the amino acid residue of the amino acid residue of
  • the GLP-1 analog or pharmaceutically acceptable salt thereof as described above, 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 of Tyr Residues; X 12 is an amino acid residue of Ile; X 15 is an amino acid residue of Glu; X 16 is an amino acid residue of Lys; X 17 is an amino acid residue selected from Glu or Ile; X 18 is selected from Ala or Aib Amino acid residues; 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 the amino acid residues of Gly, Lys or Y1; X 40 is selected from the amino acid residues of
  • 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).
  • 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).
  • the GLP-1 analog or pharmaceutically acceptable salt thereof as described above wherein Y1 is covalently linked to the fatty acid via the ⁇ amino group of the C-terminal Lys through an amide bond.
  • the aforementioned GLP-1 analog or pharmaceutically acceptable salt thereof is selected from the following compounds:
  • the present invention provides a pharmaceutical composition
  • 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
  • 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
  • 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 amino acid or Unnatural amino acids or peptides composed of them;
  • X 40 is selected from any natural amino acid or unnatural amino acid or a peptide consisting of it, or X 40 does not exist.
  • 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 in the following manner connection:
  • 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
  • R 1 is H, alkyl, acetyl, formyl, benzoyl, 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 amino acid or Unnatural amino acids or peptides composed of them;
  • X 40 is selected from any natural amino acid or unnatural amino acid or a peptide consisting of it, or X 40 does not exist.
  • the pharmaceutical composition of the GLP-1 analog or pharmaceutically acceptable salt thereof as described above wherein the GLP-1 analog represented by the general formula (I) or the 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 amino acid residues of Asp or Glu; X 16 is selected from amino acid residues of Glu, Gly, Lys or Aib; X 17 is selected from amino acid residues of Glu, Ile or Gln; X 18 is selected from Ala, The amino acid residue of Aib or His; X 19 is selected from the amino acid residue of Ala, Aib or Gln; X 20 is selected from the amino acid residue of Gln, Glu, Lys or Y1; X 23 is selected from the
  • Y1 is where the side chain is substituted with the formula ⁇ [2-(2-amino-ethoxy)-ethoxy]-acetyl ⁇ a -(y-Glu) b -CO-(CH 2 ) c -COOH Lys, Orn, Dap, Dab or Cys residues coupled to the base;
  • a is an integer between 1-3;
  • b is an integer between 1-2;
  • c is an integer between 10-30.
  • the pharmaceutical composition of the GLP-1 analog or pharmaceutically acceptable salt thereof as described above wherein the GLP-1 analog represented by the general formula (I) or the 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 amino acid residues of Asp or Glu; X 16 is selected from amino acid residues of Glu, Gly, Lys or Aib; X 17 is selected from amino acid residues of Glu, Ile or Gln; X 18 is selected from Ala, The amino acid residue of Aib or His; X 19 is selected from the amino acid residue of Ala, Aib or Gln; X 20 is selected from the amino acid residue of Gln, Glu, Lys or Y1; X 23 is selected from the
  • the pharmaceutical composition of the GLP-1 analog or pharmaceutically acceptable salt thereof as described above wherein the GLP-1 analog represented by the general formula (I) or the pharmaceutically acceptable salt thereof X 1 of the salt 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; X 12 is an amino acid residue of Ile; X 15 is an amino acid residue selected from Asp or Glu; X 16 is selected from the amino acid residues of Lys or Aib; X 17 is selected from the amino acid residues of Glu or Ile; X 18 is selected from the amino acid residues of Ala or Aib; X 19 is selected from the amino acid residues of Ala or Gln; X 20 Amino acid residues selected from Gln, Lys or Y1; X 23 is an amino acid residue of Val; X 24 is selected from an amino acid residue of Asn or Gln; X 27 is selected from an amino acid residue of Le
  • the pharmaceutical composition of the GLP-1 analog or pharmaceutically acceptable salt thereof as described above wherein the GLP-1 analog 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 the amino acid residue of Glu; X 16 is 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; X 20 is 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 amino acid residue or Y1
  • the pharmaceutical composition of the GLP-1 analog or pharmaceutically acceptable salt thereof as described above wherein the GLP-1 analog 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 the amino acid residue of Glu; X 16 is Amino acid residues of Lys; X 17 is selected from the amino acid residues of Glu or Ile; X 18 is selected from the amino acid residues 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 selected from G
  • the pharmaceutical composition of GLP-1 analogue or pharmaceutically acceptable salt thereof as described above wherein the GLP-1 analogue or pharmaceutically acceptable salt thereof as represented by general formula (I)
  • 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 the amino acid residue of Glu or 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 Y1
  • X 23 is the amino acid residue of Val
  • X 24 is an amino acid residue of Asn
  • X 27 is an amino acid residue of Leu
  • X 28 is an amino acid residue of Ala
  • X 29 is an amino acid residue of Gly
  • X 30 is an amino acid residue selected from
  • the pharmaceutical composition of GLP-1 analogue or pharmaceutically acceptable salt thereof as described above wherein the GLP-1 analogue or pharmaceutically acceptable salt thereof as represented by general formula (I)
  • 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 the amino acid residue of Glu or 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 Gln
  • X 23 is the amino acid residue of Val
  • X 24 is an amino acid residue of Asn
  • X 27 is an amino acid residue of Leu
  • X 28 is an amino acid residue of Ala
  • X 29 is an amino acid residue of Gly
  • X 30 is an amino acid residue selected from
  • the pharmaceutical composition of GLP-1 analog or its pharmaceutically acceptable salt as described above, wherein X 27 of GLP-1 analog or its pharmaceutically acceptable salt can also be selected from Ile Amino acid residues.
  • the pharmaceutical composition of GLP-1 analogue or pharmaceutically acceptable salt thereof as described above wherein the GLP-1 analogue or pharmaceutically acceptable salt thereof as represented by general formula (I)
  • 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 Val or Tyr
  • X 12 is the amino acid residue of Ile
  • X 15 is the amino acid residue of Asp or Glu
  • 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 Gln, Amino acid residue of Lys or Y1
  • X 23 is selected from amino acid residues of Ile or Val
  • X 24 is selected from amino acid residues of Ala, Asn or Gln
  • X 27 is selected from amino acid residues of Ile or
  • 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
  • R 1 is H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu;
  • R 2 is -NH2 or -OH
  • the pharmaceutical composition of GLP-1 analogue or pharmaceutically acceptable salt thereof as described above wherein the GLP-1 analogue or pharmaceutically acceptable salt thereof as represented by 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 residue of Val
  • X 12 is an amino acid residue of Ile
  • X 15 is an amino acid residue of Asp or 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 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 G
  • the pharmaceutical composition of GLP-1 analogue or pharmaceutically acceptable salt thereof as described above wherein the GLP-1 analogue or pharmaceutically acceptable salt thereof as represented by 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 residue of Tyr
  • X 12 is an amino acid residue of Ile
  • X 15 is an amino acid residue of Glu
  • X 16 Amino acid residues selected from Glu and Lys
  • X 17 is selected from amino acid residues of Glu and Ile
  • X 18 is an amino acid residue of Ala
  • X 19 is an amino acid residue of Ala
  • X 20 is selected from amino acid residues of Gln and 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 Ile or Leu
  • X 28 is the amino acid residue
  • the pharmaceutical composition of GLP-1 analogue or pharmaceutically acceptable salt thereof as described above wherein the GLP-1 analogue or pharmaceutically acceptable salt thereof as represented by 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 residue of Tyr
  • X 12 is an amino acid residue of Ile
  • X 15 is an amino acid residue of Glu
  • X 16 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
  • 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
  • the pharmaceutical composition of GLP-1 analogue or pharmaceutically acceptable salt thereof as described above wherein the GLP-1 analogue or pharmaceutically acceptable salt thereof as represented by 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 residue of Tyr
  • X 12 is an amino acid residue of Ile
  • X 15 is an amino acid residue of Glu
  • X 16 X 17 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 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 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 pharmaceutical composition of GLP-1 analogue or pharmaceutically acceptable salt thereof as described above wherein the GLP-1 analogue or pharmaceutically acceptable salt thereof as represented by 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 residue of Tyr
  • X 12 is an amino acid residue of Ile
  • X 15 is an amino acid residue of Glu
  • X 16 X 17 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 X 24 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 the amino acid residue of Ile or Leu
  • X 28 is the amino acid residue of Ala
  • the pharmaceutical composition of GLP-1 analogue or pharmaceutically acceptable salt thereof as described above wherein the GLP-1 analogue or pharmaceutically acceptable salt thereof as represented by 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 residue of Tyr
  • X 12 is an amino acid residue of Ile
  • X 15 is an amino acid residue of Glu
  • X 16 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 Amino acid residues selected from Ile or Val
  • X 24 is selected from amino acid residues of Ala, Asn or Gln
  • X 27 is selected from amino acid residues of Leu
  • X 28 is amino acid residues of Ala
  • X 29 is amino acid residues of Gly
  • X 30
  • the pharmaceutical composition of GLP-1 analogue or pharmaceutically acceptable salt thereof as described above wherein the GLP-1 analogue or pharmaceutically acceptable salt thereof as represented by 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 residue of Tyr
  • X 12 is an amino acid residue of Ile
  • X 15 is an amino acid residue of Glu
  • X 16 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 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
  • the pharmaceutical composition of GLP-1 analogue or pharmaceutically acceptable salt thereof as described above wherein the GLP-1 analogue or pharmaceutically acceptable salt thereof as represented by general formula (I) , Wherein X 20 , X 30 and X 40 are each independently selected from Y1, and Y1 is as described above.
  • the pharmaceutical composition of GLP-1 analogue or pharmaceutically acceptable salt thereof as described above wherein the GLP-1 analogue or pharmaceutically acceptable salt thereof as represented by general formula (I) , Wherein X 40 is independently selected from Y1, and Y1 is as described above.
  • the pharmaceutical composition of GLP-1 analogue or pharmaceutically acceptable salt thereof as described above such as the GLP-1 analogue or pharmaceutically acceptable salt thereof represented by general formula (I), In the definition of Y1, a is 2, b is 1 or 2, and c is 16-20.
  • the pharmaceutical composition of GLP-1 analogue or pharmaceutically acceptable salt thereof as described above such as the GLP-1 analogue or pharmaceutically acceptable salt thereof represented by general formula (I),
  • a is 2
  • b is 1 or 2
  • c is 16, 18 or 20.
  • the Y1 is K (-OEG-OEG-yGlu-C 18 -OH) or K (-OEG-OEG-yGlu-C 20 -OH).
  • the Y1 is covalently linked to the fatty acid through the amide bond of the epsilon amino group of the C-terminal Lys.
  • the Y1 has the chemical formula of the following structure:
  • the pharmaceutical composition of GLP-1 analogue or a pharmaceutically acceptable salt thereof as described above is an injection, preferably a lyophilized injection or an injection, more preferably
  • the solution type injection, suspension type injection or emulsion type injection is more preferably a solution type injection, and even more preferably an aqueous solution type injection.
  • the pharmaceutical composition of the GLP-1 analog or pharmaceutically acceptable salt thereof as described above wherein the concentration of the GLP-1 analog or pharmaceutically acceptable salt thereof 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.
  • 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: 20mg, 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.
  • the injection contains an isotonic agent.
  • the isotonic 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.
  • 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.
  • the GLP-1 analog of formula (I) or its pharmaceutically acceptable salt and its pharmaceutical composition are combined with metformin, thiazolidinediones, guanylureas, and two
  • the peptidyl peptidase inhibitor and one or more reagents of sodium-glucose transporter are used in combination separately or sequentially.
  • the polypeptide dual agonist compounds and their derivatives provided by the present invention belong to amphoteric compounds.
  • Those skilled in the art can use acidic or basic compounds to react with them to form salts through known techniques.
  • the acid commonly used to form acid addition salts is: 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, coke Sulfate, trifluoroacetate, sulfite, bisulfite, phosphate, hydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, bromide, iodide, acetic acid Salt, propionate, caprylate, acrylate,
  • Alkaline substances can also form salts with the polypeptide compounds and their derivatives provided by the present invention.
  • These alkaline substances include ammonium, hydroxides of alkali metals or alkaline earth metals, as well as carbonates and bicarbonates, typically hydroxides.
  • 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 can also be administered via a transdermal route, such as scalp administration via a patch, and an iontophoresis patch can be selected; or via a transmucosal route.
  • 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 ⁇ -amino group of the amino acid derivative used in the synthesis process is composed of the Fmoc group (fluorenyl carbonyl group).
  • the side chain of amino acid selects the following protecting groups according to different functional groups: cysteine side chain sulfhydryl group, glutamine side chain amino group, histidine side chain imidazole group is protected by Trt (trityl), refined
  • the amino acid side chain guanidine group is protected by Pbf (2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl), tryptophan side chain indolyl group, lysine side chain amino group It is protected by Boc (tert-butyloxycarbonyl), the side chain hydroxyl of threonine, phenolic side chain of tyrosine, and the hydroxyl group of serine side chain are protected by t-Bu (tert-butyl).
  • 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 an amide bond, and then used with 20% piperidine-containing nitrogen, nitrogen-dimethylformamide (DMF) )
  • the solution removes the Fmoc protecting group on the ⁇ -amino 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.
  • 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 reverse phase preparative chromatographic column to obtain the pure product of the polypeptide and its derivatives.
  • amino acid sequence of the present invention contains standard one-letter or three-letter codes for twenty amino acids. Unless explicitly stated otherwise, the preferred configuration of all amino acid residues in the present invention is L-shaped.
  • Aib is ⁇ -aminoisobutyric acid
  • D-Ala is D-alanine
  • agonist is defined as a substance that activates the type of receptor in question:
  • 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.
  • treatment includes inhibiting, slowing down, stopping or reversing the existing symptoms or the progress or severity of the disease.
  • Natural amino acids refer to 20 kinds of conventional amino acids (ie alanine (A), cysteine (C), aspartic acid (D), glutamic acid (E), phenylalanine (F)) , Glycine (G), Histidine (H), Isoleucine (I), Lysine (K), Leucine (L), Methionine (M), Asparagine (N), Proline (P), Glutamine (Q), Arginine (R), Serine (S), Threonine (T), Valine (V), Tryptophan (W) and Tyrosine (Y).
  • Unnatural amino acid refers to an amino acid that is not naturally encoded or found in the genetic code of any organism. They may be purely synthetic compounds, for example. Examples of unnatural amino acids include, but are not limited to, hydroxyproline, ⁇ -carboxyglutamic acid, O-phosphoserine, azetidine carboxylic acid, 2-aminoadipate, 3-aminoadipate, ⁇ -Alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-amino Pimelic acid, tert-butylglycine, 2,4-diaminoisobutyric acid (Dap), desmosine, 2,2′-diaminopimelic acid, 2,3-diaminopropionic acid (Dab) , N-ethylglycine
  • 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 carbon atoms
  • the alkyl group is most preferably an alkyl group of 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-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-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms More preferred are lower alkyl groups containing 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl.
  • Alkyl groups may be substituted or unsubstituted.
  • substituents When substituted, 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, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, the present invention is preferably methyl, ethyl, isopropyl, tert-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
  • 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.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but need not 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 up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, 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 amino 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 components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus 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.
  • the amount of amino acid derivatives and condensation reagents and their condensation methods are the same as coupling Fmoc-L-Lys(Boc)-OH to Rink-amide ChemMatrix resin.
  • amino acid residues used in the synthesis process are: 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.
  • 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.
  • 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 then separated with a WATERS Prep150LC reversed-phase high performance liquid chromatography system.
  • the buffer was A (0.1% trifluoroacetic acid).
  • Acetic acid, 10% acetonitrile, aqueous solution) and B (0.1% trifluoroacetic acid, 90% acetonitrile, aqueous solution).
  • the chromatographic column is an X-SELECT OBD C-18 (WATERS) reversed-phase chromatographic column.
  • 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 1 with a yield of 20%.
  • the purity and compound identity of the pure peptides are determined by analytical high performance liquid chromatography and liquid chromatography/mass spectrometry. The purity is 95.38%, and the molecular weight of the compound is 4218.4.
  • 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.
  • the reaction was carried out at room temperature and constructed with 1 mmol of amino acids, 1 mmol of DEPBT and 2 mmol of DIEA were reacted in DMF for 4 hours
  • 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.
  • the crude peptide was dissolved in a mixed solvent containing 0.1% trifluoroacetic acid, 20% acetonitrile/water, filtered through a 0.22um membrane, and separated by WATERS Prep150LC reversed-phase high performance liquid chromatography system.
  • the buffer was A (0.1% trifluoroacetic acid).
  • Acetic acid, 10% acetonitrile, aqueous solution) and B (0.1% trifluoroacetic acid, 90% acetonitrile, aqueous solution).
  • the chromatographic column is an X-SELECT OBD C-18 reversed-phase chromatographic column.
  • 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. 25, with a yield of 18%.
  • the purity of the pure polypeptide product is 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 is 96.23%, and the molecular weight of the compound is 5008.6.
  • the compound 25 experimental program was used to synthesize the polypeptide compounds of the present invention with compound numbers 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:
  • 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.
  • the reaction was carried out at room temperature and constructed with 1 mmol of amino acids, 1 mmol of DEPBT and 2 mmol of DIEA were reacted in DMF for 4 hours.
  • 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.
  • the crude peptide was dissolved in a mixed solvent containing 0.1% trifluoroacetic acid, 20% acetonitrile/water, filtered through a 0.22um membrane, and separated by WATERS Prep150LC reversed-phase high performance liquid chromatography system.
  • the buffer was A (0.1% trifluoroacetic acid).
  • Acetic acid, 10% acetonitrile, aqueous solution) and B (0.1% trifluoroacetic acid, 90% acetonitrile, aqueous solution).
  • the chromatographic column is an X-SELECT OBD C-18 reversed-phase chromatographic column.
  • 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 polypeptide is 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 is 95.14% and the molecular weight of the compound is 5020.6.
  • 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:
  • the preparation method is as follows: Take compound 74 as an example, weigh 5 g of compound 74, add 4.5 g of NaCl solid, optionally add 25 mL of 20 mM citric acid buffer, make up to 500 mL of water for injection, stir, filter, and prepare an injection of compound 74 liquid.
  • 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)
  • the cells were washed once, and resuspended in DMEM/F12 medium containing 0.1% casein (Sigma Cat#C3400) in the experimental buffer, adjusted the cell density with the experimental buffer, and plated at a density of 2500 cells/5 ⁇ L/well In a 384-well plate (Sigma Cat#CLS4514), then add 2.5 ⁇ L of buffer solution to each well of IBMX working solution (Sigma Cat#I7018), the final concentration of IBMX is 0.5mM, and 2.5 ⁇ L of the polypeptide sample with gradient dilution, centrifuged at 1000rpm for 1min , Shake for 30 seconds to mix, and incubate at room temperature for 30 minutes.
  • IBMX working solution Sigma Cat#I7018
  • Cisbio cAMP-Gs Dynamic kit (Cisbio Cat#62AM4PEC) for detection. Dilute cAMP-d2 and Anti-cAMP-Eu 3+ -Cryptate 20 times with cAMP Lysis&Detection Buffer and mix well. Add 5 ⁇ L of diluted cAMP-d2 solution to each well, and then add 5 ⁇ L 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.
  • hGIPR plasmid Fugene HD (Promega Cat#E2311), OptiMEM (Gibco Cat#31985070), mix and let stand at room temperature for 15 minutes, add 100 ⁇ L to the corresponding cell well, transfect for 24h to make CHO-K1 cells Overexpress hGIPR on the surface.
  • Cisbio cAMP-Gs Dynamic kit (Cisbio Cat#62 AM4PEC) for detection, the cAMP -d2 and Anti-cAMP-Eu3+-Cryptate were diluted 20 times with cAMP Lysis&Detection Buffer and mixed well. Add 5 ⁇ L of diluted cAMP-d2 solution to each well, then add 5 ⁇ L of diluted Anti-cAMP-Eu3+-Cryptate solution, shake for 30 Mix well in seconds, and incubate for 1 hour at room temperature in the dark.
  • the polypeptide skeleton with stronger agonist activity has better treatment of metabolic diseases. potential.
  • the present invention has found through research that the activity changes of different polypeptide skeletons after coupling fatty acids are not the same, and the polypeptide skeleton of the present invention can still maintain good activity on GLP-1 and GIP receptors after being modified by coupling fatty acids.
  • 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.
  • this experiment is to test the stability of the numbered compound in plasma.
  • 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.
  • the method of LC-MS detection of compounds is to prepare 5% acetonitrile solution as solution A and 95% acetonitrile solution as solution B.
  • the time and solution ratio shown in the following table form a solution gradient , Inject 15 microliters of sample, and use Raptor Biphenyl 2.7 micron detection column to detect the content of the compound.
  • 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.
  • the compound 74 of the present invention is more stable in plasma (relative content >90%) at the 4 hour time point than compound 75 and the prior art compound H89.
  • Plasma stability is one of the factors that affect the pharmacokinetics of peptide drugs.
  • the pharmacokinetics of peptide drugs in the body are also affected by factors such as their absorption and clearance in the body.
  • mice 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).
  • PK parameters unit Compound 28 Compound 74 T 1/2 h 4.7 19.5 AUCInf h*ng/mL 9500 30698
  • the compound of the present invention has good pharmacokinetic characteristics in mice, indicating that it has advantages in the treatment of diseases.
  • SD rats were used as test animals in this experiment to study the pharmacokinetic behavior of the numbered compounds in rats (plasma) after a single subcutaneous injection.
  • PK parameters unit Compound 74 T 1/2 h 15.9 AUCInf h*ng/mL 17673
  • the compound of the present invention has good pharmacokinetic characteristics in mice, indicating that it has advantages in the treatment of diseases.
  • mice with a body weight of 35-55 grams and 10-12 weeks of age induced by high-fat diet were purchased from Shanghai Jiesjie Experimental Animal Co., Ltd.
  • C57BL/6 mice with diet-induced obesity were injected subcutaneously with the numbered compound (3 nanomole/kg body weight) and fasted without water. After 18 hours, the concentration was 0.2 g/ml by intraperitoneal injection at a dose of 2 g/kg body weight.
  • 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.
  • 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.
  • the blood glucose AUC is significantly different.
  • mice with a body weight of 35-55 grams and 18 weeks of age induced by high-fat diet were purchased from Shanghai Jiesjie Experimental Animal Co., Ltd.
  • C57BL/6 mice with diet-induced obesity were given placebo or semaglutide (10 nmol/kg body weight) or compound 74 (10 nmol/kg body weight) by subcutaneous injection every 3 days.
  • the compound of the present invention showed a significant weight reduction 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.

Abstract

提供了一系列多肽双重激动剂化合物及其可药用盐及其药物组合物，其对人类胰高血糖素样肽-1(Glucagon-like peptide-1，GLP-1)受体和人类血糖依赖性促胰岛素多肽(Glucose-dependent insulinotropic poly peptide，GIP)受体具有双重激动剂作用，并可以用于非胰岛素依赖性糖尿病、胰岛素依赖性糖尿病和肥胖症等相关疾病的治疗。

Description

双受体重激动剂化合物及其药物组合物 技术领域
本发明属于生物医药领域，具体涉及一种人类胰高血糖素样肽-1(GLP-1)受体和人类血糖依赖性促胰岛素多肽(GIP)受体具有激动剂作用的化合物或其可药用盐及其药物组合物，并可用于代谢性疾病例如非胰岛素依赖性糖尿病，胰岛素依赖性糖尿病和肥胖相关疾病的治疗。
背景技术
糖尿病是由于体内分泌的胰岛素不足进而引发的人体葡萄糖，蛋白质和脂质代谢失调的代谢性疾病。根据其病理机制的差异，糖尿病主要划分为胰岛素依赖性糖尿病(I型糖尿病)和非胰岛素依赖性糖尿病(II型糖尿病)。其中，全球范围内90-95％的糖尿病患者为非胰岛素依赖性糖尿病。非胰岛素依赖性糖尿病是一种由胰岛β细胞功能受损和长期胰岛素抗性导致的长期，慢性代谢性疾病，其最主要特征是体内胰岛素水平的缺乏和血浆中的高血糖浓度。研究表明非胰岛素依赖性糖尿病与病人的多种高危险性病发症相关，并且会其往往会导致病人罹患心血管疾病、肾脏衰竭、失明、截肢以及其它多种病发症。
引发非胰岛素依赖性糖尿病的一类主要原因是肥胖。肥胖的定义为损害人体健康的体内过多或异常的脂肪堆积。根据人的身体质量指数(Body mass index,BMI)，肥胖也可以定义为当人的BMI指数大于或等于30kg/m2。肥胖的出现会显著增加人类罹患心血管疾病，糖尿病，肌肉骨骼疾患和某些癌症的风险。除此之外，人身体质量指数的升高也会提高某些非传染性疾病的患病风险。
由于糖尿病及其病发症所带来的巨大患者数目和其造成的显著经济负担，开发安全，有效的治疗糖尿病药物向来是众多研究机构和制药企业关注的焦点领域之一。目前，已经批准上市的糖尿病药物主要包括化学合成小分子口服降糖药物，例如双胍类，磺酰类，胰岛素增敏剂，α-糖苷类以及由生物合成生产的重组胰岛素及其衍生物等注射类降糖药物。虽然上述药物临床上可以有效控制糖尿病患者血浆中的血糖水平，其长期使用往往伴随着患者体重增加等不良反应，继而导致潜在心血管疾病风险的升高以及患者使用依从性的降低。考虑到糖尿病和肥胖之间的潜在病理关系以及肥胖所导致的潜在病发症风险，开发一种既能够有效控制血糖同时也可以适当降低糖尿病患者体重的药物对于糖尿病的有效治疗和潜在病发症风险的降低具有多重意义，因此是临床上一个更加优良的研发方向。
胰高血糖素样肽-1(Glucagon like peptide-1，GLP-1)是一个含有30或31个氨基酸残基的胃肠道调节多肽。GLP-1的分泌主要由小肠上的L-细胞根据营养的吸收和体内波动的血糖水平进行调节。在食物摄入后，小肠的L-细胞分泌大量的 GLP-1以增强胰腺的内分泌功能。GLP-1多肽主要通过激活分布在细胞膜表面的GLP-1受体来完成其在体内控制血糖和降低食欲的生理功能。GLP-1控制体内血糖水平的机制主要为激活其分布在胰岛β细胞的GLP-1受体从而促进胰岛素的生物合成及分泌，同时GLP-1多肽可在体内高血糖水平的情况下抑制胰高血糖素的分泌，胃排空和食物摄入并通过特定的神经系统作用增强体内对葡萄糖的降解。值得注意的是，GLP-1多肽促进胰岛素分泌的生理功能是受到血浆葡萄糖浓度的高度控制的，因此与其它糖尿病治疗药物相比，GLP-1多肽不会引发严重和持久的低血糖。除此之外，文献中报导了GLP-1多肽及其类似物对实验动物β细胞的生长，分化和增殖具有直接的促进作用，表明GLP-1多肽及其类似物可以保护胰岛和延缓糖尿病进展的生理功能并抑制β细胞的凋亡。GLP-1多肽还具有潜在的抑制胃泌素和进食刺激的胃酸分泌作用，这些特征意味着GLP-1多肽还具有防止消化道溃疡的生理作用。GLP-1多肽还可以激活其在大脑中枢神经系统中分布的GLP-1受体从而增强饱腹感，降低食物摄入并达到保持或降低体重的生理效果。因此，GLP-1多肽及其类似物广泛的作用机制及其生理功能意味着GLP-1多肽是一种理想的治疗非胰岛素依赖性糖尿病以及肥胖型糖尿病的药物。
GLP-1多肽在控制血糖和降低体重等方面的生理功能为治疗非胰岛素依赖性糖尿病/肥胖型糖尿病带来了希望，但是人体天然GLP-1成药性较差，其在体内易被二肽基肽酶-IV(DPP-IV)降解以至于其在人体内的半衰期仅为1-2分钟。面对这种困难，医药工业界通过进行酶切位点氨基酸定点突变，多肽骨架的脂肪酸修饰以及GLP-1多肽和多种蛋白/高分子多聚物结合来构造长效GLP-1类似物及其衍生物。现阶段已经上市并在临床上广泛应用的长效GLP-1类似物包括一天两次皮下注射给药的艾那赛肽，一天一次皮下注射给药的利拉鲁肽以及一周一次皮下注射给药的杜拉鲁肽和索马鲁肽等等。
临床上，GLP-1多肽及其衍生物的副作用主要表现在由胃肠道所引发的恶心，呕吐以及腹泻；除此之外，已经发现GLP-1多肽及其衍生物还会引发受试者心跳加速和并在特定情况下会增加患者胰腺炎的风险。因此，GLP-1多肽及其衍生物的给药剂量受到其引发的副作用的限制，故而其临床使用无法实现患者的全效血糖控制和体重减轻。
葡萄糖依赖性胰岛素释放肽(Glucose-dependent Insulinotropic Polypeptide,GIP)和GLP-1多肽都属于肠降血糖素的一种，其对体内血糖的新陈代谢起到关键的生理相关作用。GIP在体内主要由42个氨基酸残基组成并由十二指肠和临近空肠K细胞根据血浆中的葡萄糖水平进行分泌。GIP多肽通过与其分布在胰岛β细胞，脂肪组织和中枢神经系统中的GIP受体相结合从而发挥其生理作用。与GLP-1多肽相似，GIP多肽可以刺激胰岛β细胞分泌胰岛素从而降低血浆中的血糖浓度并可以保护胰岛β细胞从而控制体内葡萄糖的新陈代谢。除此之外，GIP多肽的生理功能还包括激活其在脂肪组织中的GIP受体从而促进脂肪的新陈代谢。 有趣的是，对小鼠进行脑室注射的GIP多肽可以降低受试动物的食物摄入并降低体重，这似乎预示着GIP多肽在降低体重方面也具有某些特定的生理功能。研究表面，在非胰岛素依赖性糖尿病患者体内GIP多肽的肠促胰岛素功能大大降低从而导致患者缺乏或丧失了肠促胰岛素效应。研究表明，这些糖尿病患者所产生的GIP多肽的抑制性会在血糖水平恢复正常的同时大大减弱。
因此，临床上需要一种利用GIP多肽治疗非胰岛素依赖性糖尿病的方法和一种临床上有效的降糖药配合来恢复非胰岛素依赖性糖尿病患者对GIP多肽的耐受性，并进一步结合GIP多肽的肠促胰岛素功效从而得到更强的临床上的降糖效果。因此，与本领域内的许多GLP-1受体激动剂多肽相比，本发明的目的在于提供一种在人类GIP受体具有激动剂活性的GLP-1类似物的衍生物，其对人类GLP-1受体和人类GIP受体具有双重激动剂作用。此外，本发明的某些化合物与本领域内的GLP-1受体激动剂相比具有更强的降低血糖和减轻体重的疗效。最后，本发明的某些化合物具有极高的血浆稳定性并具有支持在人身上一周一次皮下注射给药的药代动力学特征。
发明内容
本发明的目的在于提供一种具有通式(I)所示的GLP-1类似物，或其可用药盐形式：
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)
其中：
所述的X 1选自Tyr或His的氨基酸残基；X 2选自Aib或D-Ala的氨基酸残基；X 10选自Val或Tyr的氨基酸残基；X 12选自Ser或Ile的氨基酸残基；X 15选自Asp或Glu的氨基酸残基；X 16选自Glu、Gly、Lys或Aib的氨基酸残基；X 17选自Glu、Ile或Gln的氨基酸残基；X 18选自Ala、Aib或His的氨基酸残基；X 19选自Ala、Aib或Gln的氨基酸残基；X 20选自Gln、Glu、Lys的氨基酸残基或Y1；X 23选自Ile或Val的氨基酸残基；X 24选自Ala、Asn或Gln的氨基酸残基；X 27选自Val或Leu的氨基酸残基；X 28选自Arg或Ala的氨基酸残基；X 29选自Gly或Gln的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或者不存在；
Y1为K(-OEG-OEG-yGlu-C20-OH)，该基团具有下列结构的化学式：。
Figure PCTCN2020129071-appb-000001
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐，其两端通过如下的方式连接：
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)
其中：
R 1是H、烷基、乙酰基、甲酰基、苯甲酰基、三氟乙酰基或pGlu；
R 2是-NH 2或-OH。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐，其中X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15选自Asp或Glu的氨基酸残基；X 16选自Lys或Aib的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18选自Ala或Aib的氨基酸残基；X 19选自Ala或Gln的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23为Val的氨基酸残基；X 24选自Asn或Gln的氨基酸残基；X 27选自Leu的氨基酸残基；X 28选自Ala的氨基酸残基；X 29选自Gly或Gln的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或者不存在，Y1如通式(I)中所定义。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐，其中X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15选自Asp或Glu的氨基酸残基；X 16选自Lys或Aib的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18选自Ala或Aib的氨基酸残基；X 19选自Ala或Gln的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23为Val的氨基酸残基；X 24选自Asn或Gln的氨基酸残基；X 27选自Leu的氨基酸残基；X 28选自Ala的氨基酸残基；X 29选自Gly或Gln的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或者不存在，Y1如通式(I)中所定义。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐，其中X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17为Glu的氨基酸残基；X 18为Ala或Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在，Y1如通式(I)中所定义。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐，其中X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17为Ile的氨基酸残基；X 18选自Ala或Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在，Y1如通式(I)中所定义。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐，其中X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18为Ala的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在，Y1如通式(I)中所定义。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐，其中X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18为Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在，Y1如通式(I)中所定义。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐，其中X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18选自Ala或Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20为Gln的氨基酸残基；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在，Y1如通式(I)中所定义。
在本发明优选的方案中，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18选自Ala或Aib 的氨基酸残基；X 19为Ala的氨基酸残基；X 20为Y1；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐，其中X 20和X 40各自独立的选自Y1，Y1如通式(I)中所定义。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐，其中X 40独立的选自Y1，Y1如通式(I)中所定义。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐，其中Y1由C端Lys的ε氨基通过酰胺键与脂肪酸共价连接。
在本发明最优选的方案中，如前所述的GLP-1类似物或其可药用盐，其选自如下化物：
Figure PCTCN2020129071-appb-000002
另一方面，本发明提供了一种包含通式(I)所示的GLP-1类似物或其可药用盐的药物组合物，其中所述GLP-1类似物或其可药用盐如通式(I)所示：
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)
其中：
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和X 30独立的选自任意天然的氨基酸或非天然氨基酸或由其组成的肽段；
X 40选自任意天然的氨基酸或非天然氨基酸或由其组成的肽段，或者X 40不存在。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中所述GLP-1类似物或其可药用盐的两端通过如下的方式连接：
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)
其中：
R 1是H、烷基、乙酰基、甲酰基、苯甲酰基、三氟乙酰基或pGlu；
R 2是-NH 2或-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和X 30独立的选自任意天然的氨基酸或非天然氨基酸或由其组成的肽段；
X 40选自任意天然的氨基酸或非天然氨基酸或由其组成的肽段，或者X 40不存在。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中所述通式(I)所示的GLP-1类似物或其可药用盐的X 1选自Tyr或His的氨基酸残基；X 2选自Aib或D-Ala的氨基酸残基；X 10选自Val或Tyr的氨基酸残基；X 12选自Ser或Ile的氨基酸残基；X 15选自Asp或Glu的氨基酸残基；X 16选自Glu、Gly、Lys或Aib的氨基酸残基；X 17选自Glu、Ile或Gln的氨基酸残基；X 18选自Ala、Aib或His的氨基酸残基；X 19选自Ala、Aib或Gln的氨基酸残基；X 20选自Gln、Glu、Lys的氨基酸残基或Y1；X 23选自Ile或Val的氨基酸残基；X 24选自Ala、Asn或Gln的氨基酸残基；X 27选自Val或Leu的氨基酸残基；X 28选自Arg或Ala的氨基酸残基；X 29选自Gly或Gln的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或者不存在，
Y1是其中侧链与具有式{[2-(2-氨基-乙氧基)-乙氧基]-乙酰基} a-(y-Glu) b-CO-(CH 2) c-COOH之取代基耦合的Lys、Orn、Dap、Dab或Cys残 基；
a为1-3之间的整数；
b为1-2之间的整数；
c为10-30之间的整数。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中所述通式(I)所示的GLP-1类似物或其可药用盐的X 1选自Tyr或His的氨基酸残基；X 2选自Aib或D-Ala的氨基酸残基；X 10选自Val或Tyr的氨基酸残基；X 12选自Ser或Ile的氨基酸残基；X 15选自Asp或Glu的氨基酸残基；X 16选自Glu、Gly、Lys或Aib的氨基酸残基；X 17选自Glu、Ile或Gln的氨基酸残基；X 18选自Ala、Aib或His的氨基酸残基；X 19选自Ala、Aib或Gln的氨基酸残基；X 20选自Gln、Glu、Lys的氨基酸残基或Y1；X 23选自Ile或Val的氨基酸残基；X 24选自Ala、Asn或Gln的氨基酸残基；X 27选自Val、Ile或Leu的氨基酸残基；X 28选自Arg或Ala的氨基酸残基；X 29选自Gly或Gln的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或者不存在，Y1如前所述。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中所述通式(I)所示的GLP-1类似物或其可药用盐的X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15选自Asp或Glu的氨基酸残基；X 16选自Lys或Aib的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18选自Ala或Aib的氨基酸残基；X 19选自Ala或Gln的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23为Val的氨基酸残基；X 24选自Asn或Gln的氨基酸残基；X 27选自Leu的氨基酸残基；X 28选自Ala的氨基酸残基；X 29选自Gly或Gln的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或者不存在，Y1如前所述。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中所述通式(I)所示的GLP-1类似物或其可药用盐的X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17为Glu的氨基酸残基；X 18为Ala或Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存，Y1如前所述。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中所述通式(I)所示的GLP-1类似物或其可药用盐的X 1为Tyr的氨基酸 残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17为Ile的氨基酸残基；X 18选自Ala或Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在，Y1如前所述。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中所述通式(I)所示的GLP-1类似物或其可药用盐的X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18为Ala的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在，Y1如前所述。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中所述通式(I)所示的GLP-1类似物或其可药用盐的X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18为Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在，Y1如前所述。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中所述通式(I)所示的GLP-1类似物或其可药用盐的X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18选自Ala或Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20为Gln的氨基酸残基；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在，Y1如前所述。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组 合物，其中所述通式(I)所示的GLP-1类似物或其可药用盐的X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18选自Ala或Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20为Lys的氨基酸残基；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在，Y1如前所述。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中如通式(I)所示的GLP-1类似物或其可药用盐的X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18选自Ala或Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20为Y1；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在，Y1如前所述。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中如通式(I)所示的GLP-1类似物或其可药用盐的X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18选自Ala或Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20为Gln；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在，Y1如前所述。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中GLP-1类似物或其可药用盐的X 27还可以选自Ile的氨基酸残基。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中如通式(I)所示的GLP-1类似物或其可药用盐的X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10选自Val或Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15选自Asp或Glu的氨基酸残基；X 16选自Glu、Lys的氨基酸残基；X 17选自Glu、Ile的氨基酸残基；X 18为Ala的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23选自Ile或Val的氨基酸残基；X 24选自Ala、Asn或Gln的氨基酸残基；X 27选自Ile或Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30为Gly的氨基酸残基；X 40选自Lys的氨基酸残基、Y1或者不存在，Y1如前所述。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中如通式(I)所示的GLP-1类似物或其可药用盐，其两端通过如下的方式连接：
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)
其中：
R 1是H、烷基、乙酰基、甲酰基、苯甲酰基、三氟乙酰基或pGlu；
R 2是-NH2或-OH；
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中如通式(I)所示的GLP-1类似物或其可药用盐的X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10选自Val的氨基酸残基；X 12为Ile的氨基酸残基；X 15选自Asp或Glu的氨基酸残基；X 16选自Lys的氨基酸残基；X 17选自Ile的氨基酸残基；X 18为Ala的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln的氨基酸残基或Y1；X 23选自Val的氨基酸残基；X 24选自Asn的氨基酸残基；X 27选自Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30为Gly的氨基酸残基；X 40选自Lys的氨基酸残基、Y1或者不存在，Y1如前所述。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中如通式(I)所示的GLP-1类似物或其可药用盐的X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10选自Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15选自Glu的氨基酸残基；X 16选自Glu、Lys的氨基酸残基；X 17选自Glu、Ile的氨基酸残基；X 18为Ala的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23选自Ile或Val的氨基酸残基；X 24选自Ala、Asn或Gln的氨基酸残基；X 27选自Ile或Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30为Gly的氨基酸残基；X 40选自Lys的氨基酸残基、Y1或者不存在，Y1如前所述。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中如通式(I)所示的GLP-1类似物或其可药用盐的X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10选自Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15选自Glu的氨基酸残基；X 16选自Glu的氨基酸残基；X 17选自Glu、Ile的氨基酸残基；X18为Ala的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23选自Val的氨基酸残基；X 24选自Asn的氨基酸残基；X 27选自Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨 基酸残基；X 30为Gly的氨基酸残基；X 40选自Lys的氨基酸残基、Y1或者不存在，Y1如前所述。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中如通式(I)所示的GLP-1类似物或其可药用盐的X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10选自Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15选自Glu的氨基酸残基；X 16选自Lys的氨基酸残基；X 17选自Glu、Ile的氨基酸残基；X 18为Ala的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23选自Ile或Val的氨基酸残基；X 24选自Ala、Asn或Gln的氨基酸残基；X 27选自Ile或Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30为Gly的氨基酸残基；X 40选自Lys的氨基酸残基、Y1或者不存在，Y1如前所述。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中如通式(I)所示的GLP-1类似物或其可药用盐的X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10选自Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15选自Glu的氨基酸残基；X 16选自Lys的氨基酸残基；X 17选自Ile的氨基酸残基；X 18为Ala的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln的氨基酸残基或Y1；X 23选自Val的氨基酸残基；X 24选自Asn或Gln的氨基酸残基；X 27选自Ile或Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30为Gly的氨基酸残基；X 40选自Lys的氨基酸残基、Y1或者不存在，Y1如前所述。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中如通式(I)所示的GLP-1类似物或其可药用盐的X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10选自Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15选自Glu的氨基酸残基；X 16选自Lys的氨基酸残基；X 17选自Glu的氨基酸残基；X 18为Ala的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Lys的氨基酸残基或Y1；X 23选自Ile或Val的氨基酸残基；X 24选自Ala、Asn或Gln的氨基酸残基；X 27选自Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30为Gly的氨基酸残基；X 40选自Lys的氨基酸残基、Y1或者不存在，Y1如前所述。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中如通式(I)所示的GLP-1类似物或其可药用盐的X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10选自Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15选自Glu的氨基酸残基；X 16选自Lys的氨基酸残基；X 17选自Glu的氨基酸残基；X 18为Ala的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Lys的氨基酸残基或Y1；X 23选自Ile或Val的氨基酸残基；X 24选自Ala或Gln的氨基 酸残基；X 27选自Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30为Gly的氨基酸残基；X 40选自Lys的氨基酸残基、Y1或者不存在，Y1如前所述。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中如通式(I)所示的GLP-1类似物或其可药用盐，其中X 20、X 30和X 40各自独立的选自Y1，Y1如前所述。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中如通式(I)所示的GLP-1类似物或其可药用盐，其中X 40独立的选自Y1，Y1如前所述。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，如通式(I)所示的GLP-1类似物或其可药用盐，其中所述Y1的定义中a为2，b为1或2，c为16-20。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，如通式(I)所示的GLP-1类似物或其可药用盐，其中所述Y1的定义中a为2，b为1或2，c为16、18或20。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中如通式(I)所示的GLP-1类似物或其可药用盐，所述Y1为K(-OEG-OEG-yGlu-C 18-OH)或K(-OEG-OEG-yGlu-C 20-OH)。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中如通式(I)所示的GLP-1类似物或其可药用盐，所述Y1由C端Lys的ε氨基通过酰胺键与脂肪酸共价连接。
在本发明优选的方案中，如前所述的GLP-1类似物或其可药用盐的药物组合物，其中如通式(I)所示的GLP-1类似物或其可药用盐，所述Y1具有下列结构的化学式：
Figure PCTCN2020129071-appb-000003
在本发明优选的方案中，如前所述的GLP‐1类似物或其可药用盐的药物组合 物，其中所述的GLP‐1类似物或其可药用盐选自如下编号为1-83的化合物或其可药用盐：
Figure PCTCN2020129071-appb-000004
Figure PCTCN2020129071-appb-000005
Figure PCTCN2020129071-appb-000006
在本发明优选的方案中，如前所述的GLP‐1类似物或其可药用盐的药物组合物，所述所述药物组合物为注射剂，优选冻干注射剂或注射液，更优选为溶液型注射液、混悬型注射液或乳剂型注射液，进一步优选为溶液型注射液，更进一步优选为水溶液型注射液。
在本发明优选的方案中，如前所述的GLP‐1类似物或其可药用盐的药物组合物，其中所述GLP‐1类似物或其可药用盐的浓度为0.1mg/mL至200mg/mL。
在本发明更为优选的方案中，如前所述的GLP‐1类似物或其可药用盐的药物组合物，其中所述GLP‐1类似物或其可药用盐的浓度为0.1mg/mL至120mg/mL。
在本发明更为优选的方案中，如前所述的GLP‐1类似物或其可药用盐的药物组合物，其中所述GLP‐1类似物或其可药用盐的浓度为2mg/mL至50mg/mL。
在本发明更为优选的方案中，如前所述的GLP‐1类似物或其可药用盐的药物组合物，其中所述GLP‐1类似物或其可药用盐的浓度为5mg/mL至30mg/mL。
在本发明更为优选的方案中，如前所述的GLP‐1类似物或其可药用盐的药物组合物，其中所述GLP‐1类似物或其可药用盐的浓度为0.5mg/mL、1mg/mL、2mg/mL、2.5mg/mL、5mg/mL、8mg/mL、10mg/mL、15mg/mL、20mg/mL或30mg/mL。
在本发明更为优选的方案中，如前所述的GLP-1类似物或其可药用盐单位剂量为0.5mL：1mg至0.5mL：50mg，优选0.5mL：1mg至0.5mL：20mg，更 优选0.5mL：1mg、0.5mL：2mg、0.5mL：5mg、0.5mL：10mg、0.5mL：15mg或0.5mL：20mg。
在本发明更为优选的方案中，注射剂中包含等渗剂。所述等渗剂选自多元醇、氯化盐、磷酸盐、糖或其任意组合，优选氯化钙、氯化镁、氯化钾、磷酸二氢钾、氯化钠、磷酸钠、磷酸二氢钠、磷酸氢二钠、氯化钠、单糖、二糖或糖醇或其任意组合。
另一方面，本发明还提供了式(I)所示的GLP-1类似物或其可药用盐以及其药物组合物的药用用途，包括在制备用于治疗非胰岛素依赖性糖尿病、胰岛素依赖性糖尿病或肥胖症的药物中的应用；优选地，所述非胰岛素依赖性糖尿病为II型糖尿病。
在本发明更为优选的方案中，式(I)所示的GLP-1类似物或其可药用盐以及其药物组合物与选自二甲双胍、噻唑烷二酮类、璜酰脲类、二肽基肽酶抑制剂和钠葡萄糖转运蛋白的一种或多种试剂的同时，分开或相继组合使用。
本发明提供的多肽双重激动剂化合物及其衍生物属于两性化合物，所属领域技术人员通过公知技术可使用酸性或碱性化合物与之反应成盐，通常采用的形成酸加成盐的酸为：盐酸、氢溴酸、氢碘酸、硫酸、磷酸、对甲苯磺酸、甲磺酸、草酸、对溴苯基磺酸、碳酸、琥珀酸、柠檬酸、苯甲酸、乙酸；盐包括硫酸盐、焦硫酸盐、三氟乙酸盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、盐酸盐、溴化物、碘化物、乙酸盐、丙酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、己酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、丁二酸盐、辛二酸盐、富马酸盐、马来酸盐、丁炔－1，4－二酸盐、己炔－1，6－二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、苯乙酸盐、苯丙酸盐、苯丁酸盐、柠檬酸盐、乳酸盐、γ－羟基丁酸盐、甘醇酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、奈－1－磺酸盐、奈－2－磺酸盐、扁桃酸盐等，优选三氟乙酸盐。碱性物质也可以和本发明提供的多肽化合物及其衍生物成盐，这些碱性物质包括铵，碱金属或碱土金属的氢氧化物，以及碳酸盐、碳酸氢盐，典型的有氢氧化钠、氢氧化钾、氢氧化铵、碳酸钠、碳酸钾等。
根据本发明的含有多肽双重激动剂化合物的药物组合物可以通过胃肠外给药的方式用于治疗需要这种治疗的病人。胃肠外给药途径可选择皮下注射、肌肉注射或静脉注射。本发明的多肽双重激动剂化合物还可以选择透皮途径给药，如经贴剂头皮给药，可选择离子透入贴剂；或经透粘膜途径给药。
本发明提供的多肽化合物及其衍生物采用固相合成的方法，合成载体为Rink-amide ChemMatrix(Biotage)树脂，合成过程中使用的氨基酸衍生物的α-氨基由Fmoc基团(芴甲酰羰基)保护，氨基酸的侧链根据官能团的不同选取以下保护基团：半胱氨酸侧链巯基、谷胺酰胺侧链氨基、组氨酸侧链咪唑基由Trt(三 苯甲基)保护、精氨酸侧链胍基由Pbf(2,2,4,6,7-五甲基二氢化苯并呋喃－5－磺酰基)保护，色氨酸侧链吲哚基、赖氨酸侧链氨基由Boc(叔丁氧羰基)保护，苏氨酸侧链羟基、酪氨酸侧链苯酚基、丝氨酸侧链羟基由t-Bu(叔丁基)保护。合成过程中，首先将多肽C-末端氨基酸残基的羧基以酰胺键的形式缩合至高分子不溶性Rink-amide ChemMatrix树脂上，然后用含20％哌啶的氮,氮-二甲基甲酰胺(DMF)溶液脱去α-氨基上的Fmoc保护基团，接着该固相载体与序列中下一个氨基酸衍生物在过量情况下进行缩合形成酰胺键以接长肽链。重复缩合→洗涤→去保护→洗涤→下一轮氨基酸缩合的操作以达到所要合成的多肽链长度，最后用三氟乙酸：水：三异丙基硅烷(90：5：5，v：v：v)的混合溶液与树脂反应将多肽从固相载体上裂解下来，再由冷冻异丙醚沉降后得到多肽衍生物的固体粗品。多肽固体粗品由含0.1％三氟乙酸的乙腈/水的混合溶液溶解后由C-18反相制备色谱柱纯化分离后得到多肽及其衍生物的纯品。
发明的详细说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
本发明的氨基酸序列含有二十种氨基酸的标准单字母或三字母代码，除非明确说明，否则本发明中所有氨基酸残基优选构型为L-型。另外，Aib是α氨基异丁酸，D-Ala是D-型丙氨酸
术语激动剂定义为激活所讨论的受体类型的物质：
本发明上下文中使用的术语GLP-1/GIP双重激动剂指可以同时激活GLP-1受体和GIP受体的物质或配体。本发明中，术语治疗包括抑制，减缓，停止或逆转现有症状或病患的进展或严重程度。
“天然的氨基酸”是指20种常规氨基酸(即丙氨酸(A)，半胱氨酸(C)，天冬氨酸(D)，谷氨酸(E)，苯丙氨酸(F)，甘氨酸(G)，组氨酸(H)，异亮氨酸(I)，赖氨酸(K)，亮氨酸(L)，甲硫氨酸(M)，天冬酰胺(N)，脯氨酸(P)，谷氨酰胺(Q)，精氨酸(R)，丝氨酸(S)，苏氨酸(T)，缬氨酸(V)，色氨酸(W)和酪氨酸(Y)。
“非天然氨基酸”是指不是天然编码的或在任何生物体的遗传密码中发现的氨基酸。它们可以是例如纯合成的化合物。非天然氨基酸的实例包括但不限于，羟基脯氨酸，γ-羧基谷氨酸，O-磷酸丝氨酸，氮杂环丁烷羧酸，2-氨基己二酸，3-氨基己二酸，β-丙氨酸，氨基丙酸，2-氨基丁酸，4-氨基丁酸，6-氨基己酸，2-氨基庚酸，2-氨基异丁酸，3-氨基异丁酸，2-氨基庚二酸，叔丁基甘氨酸，2，4-二氨基异丁酸(Dap)，锁链素(desmosine)，2，2′-二氨基庚二酸，2，3-二氨基丙酸(Dab)，N-乙基甘氨酸，N-甲基甘氨酸，N-乙基天冬酰胺，高脯氨酸，羟基赖氨酸，别羟基赖氨酸(allo-hydroxylysine)，3-羟基脯氨酸，4-羟基脯氨酸，异锁链素(isodesmosine)，别异亮氨酸，N-甲基丙氨酸，N-甲基甘氨酸，N-甲基异亮氨酸，N-甲基戊基甘氨酸，N-甲基缬氨酸，萘基丙氨酸(naphthalanine)，正 缬氨酸，正亮氨酸，鸟氨酸(Orn)，D-鸟氨酸，D-精氨酸，对氨基苯丙氨酸，戊基甘氨酸，呱啶酸(pipecolic acid)和硫代脯氨酸。此外，还包括天然氨基酸或非天然氨基酸的C-末端羧基，N-末端氨基和/或其侧链官能团被化学修饰。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至8个碳原子的烷基，更优选1至6个碳原子的烷基，最更优选1至3个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基，本发明优选甲基、乙基、异丙基、叔丁基、卤代烷基、氘代烷基、烷氧基取代的烷基和羟基取代的烷基。
“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中的任意一种或几种。
本发明所述的氢原子均可被其同位素氘所取代，本发明涉及的实施例化合物中的任一氢原子也均可被氘原子取代。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基 团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
具体实施方式
为了更详细的说明本发明，本说明书提供了下列具体实施方案，但本发明的方案并非仅限于此。
1、实验试剂
Figure PCTCN2020129071-appb-000007
Figure PCTCN2020129071-appb-000008
2、实验仪器
序号 仪器 来源
1 H-CLASS分析型超高效液相色谱 WATERS
2 Xevo液相色谱/质谱联用 WATERS
3 Labconco多功能冻干机 Thermo-Fisher Scientific
4 Prep150制备型高效液相色谱 WATERS
5 多通道高速离心机 希格玛
3、具体实验方案
3.1多肽骨架化合物编号1的化学合成
3.1.1 Fmoc-L-Lys(Boc)-OH与Rink-amide ChemMatrix树脂的偶联
称取Rink-amide ChemMatrix树脂(Biotage，0.1mmol)置于一次性聚丙烯多肽合成固相反应管中，加入DMF(10mL)在氮气鼓泡下溶胀树脂10分钟，真空抽掉DMF，加入DMF(10mL)洗涤树脂，重复洗涤2次；称取Fmoc-L-Lys(Boc)-OH(1mmol)，3-(二乙氧基磷酰氧基)-1,2,3-苯并三嗪-4-酮(DEPBT)(1mmol)和二异丙基乙胺(DIEA，2mmol)，加入DMF(10mL)溶解后将上述溶液加入到溶胀后的Rink-amide ChemMatrix树脂中，在室温下振荡反应2小时，反应结束后用DMF，二氯甲烷(DCM)交替洗涤树脂2次，最后用DMF洗涤3次。
3.1.2 Fmoc-L-Lys(Boc)-Rink-amide树脂脱除Fmoc保护基团
向装有Fmoc-L-Lys(Boc)-Rink amide树脂的固相反应管加入哌啶/DMF(20％，10mL)，室温下振荡反应10分钟后抽除，再加入含有哌啶/DMF(20％，10mL)，室温下振荡反应10分钟后抽除。反应结束后用DMF(10mL)洗涤树脂4次。
3.1.3肽链序列的偶联
按照化合物编号1的肽链序列从氨基端到羧基端的顺序(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)，氨基酸衍生物和缩合试剂的用量及其缩合方法与偶联Fmoc-L-Lys(Boc)-OH至Rink-amide ChemMatrix树脂相同，合成过程中所使用的氨基酸残基分别是：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和Fmoc-L-Pro-OH。重复氨基酸衍生物的缩合和Fmoc脱保护最终得到含有化合物编号1的多肽序列的树脂肽。
3.1.4树脂肽的裂解
将第3步得到的树脂肽依次用DMF，DCM洗涤3次后进行真空干燥，后加入新鲜配制的裂解液10mL(三氟乙酸：三异丙基硅烷：水＝90：5：5，v：v：v)在室温下振荡反应2小时。反应结束后过滤，用三氟乙酸洗涤树脂2次，合并滤液后加入大量冷冻无水异丙醚析出固体，离心后除去上清液并得到化合物编号为1的多肽粗品。
3.1.5粗品肽的反相液相色谱纯化
将粗品肽溶于含有0.1％三氟乙酸，20％乙腈/水的混合溶剂中，经过0.22um膜过滤后用WATERS Prep150LC反相高效液相色谱系统进行分离，缓冲液为A(0.1％三氟乙酸，10％乙腈，水溶液)和B(0.1％三氟乙酸，90％乙腈，水溶液)。其中，色谱柱为X-SELECT OBD C-18(WATERS)反相色谱柱，纯化过程中色谱仪检测波长设定为220nm，流速为20mL/min。收集产物相关馏分冻干后得到化合物编号1的多肽纯品，收率20％。多肽纯品通过分析性高效液相色谱和液相色谱/质谱联用确定纯度及化合物身份，其中纯度为95.38％，化合物分子量为：4218.4。
3.2化合物编号2-24、34-48、63-73和78-80的化学合成
采用化合物1的实验方案合成本发明化合物编号2-24、34-48、63-73和78-80的多肽化合物，并用分析型超高效液相色谱和液相色谱/质谱联用确定纯度和化合物分子量，具体如下表1：
表1
化合物编号 纯度 分子量
2 95.06％ 4244.8
3 97.98％ 4369.6
4 96.34％ 4353.2
5 96.05％ 4178.0
6 95.29％ 4203.3
7 95.15％ 4227.6
8 95.05％ 4230.3
9 95.95％ 4293.2
10 95.56％ 4292.1
11 96.33％ 4350.0
12 95.60％ 4249.5
13 96.86％ 4277.4
14 95.58％ 4277.4
15 97.64％ 4333.8
16 95.07％ 4307.4
17 97.76％ 4307.4
18 96.53％ 4233.9
19 95.11％ 4278.6
20 96.79％ 4262.7
21 98.73％ 4276.8
22 96.87％ 4233.6
23 95.69％ 4434.4
24 96.72％ 4419.3
34 95.65％ 4233.6
35 96.56％ 4304.7
36 96.74％ 4176.6
37 96.65％ 4105.5
38 95.24％ 4162.5
39 95.14％ 4247.7
40 95.75％ 4191.6
41 95.56％ 4192.5
42 95.74％ 4120.4
43 96.84％ 4193.5
44 95.24％ 4121.4
45 96.54％ 4177.5
46 95.77％ 4192.5
47 97.55％ 4304.8
48 95.32％ 4162.6
63 97.14％ 4178.6
64 96.32％ 4178.6
65 95.47％ 4193.3
66 96.56％ 4122.5
67 98.87％ 4136.4
68 96.54％ 4085.2
69 95.24％ 4071.1
70 96.14％ 4150.5
71 96.78％ 4166.6
72 95.69％ 4150.4
73 96.32％ 4165.3
78 95.18％ 4162.6
79 96.22％ 4162.6
80 97.21％ 4148.5
3.3脂肪酸偶联化合物编号25的化学合成
3.3.1 Fmoc-L-Lys(Mtt)-OH与Rink-amide ChemMatrix树脂的偶联
称取Rink-amide ChemMatrix树脂(Biotage,0.1mmol)置于一次性聚丙烯多肽合成固相反应管中，加入DMF(10mL)在氮气鼓泡下溶胀树脂10分钟，真空抽掉DMF，加入DMF(10mL)洗涤树脂，重复洗涤2次；称取Fmoc-L-Lys(Mtt)-OH(1mmol)，3-(二乙氧基磷酰氧基)-1,2,3-苯并三嗪-4-酮(DEPBT)(1mmol)和二异丙基乙胺(DIEA，2mmol)，加入DMF(10mL)溶解后将上述溶液加入到溶胀后的Rink-amide ChemMatrix树脂中，在室温下振荡反应2小时，反应结束后用DMF，二氯甲烷(DCM)交替洗涤树脂2次，最后用DMF洗涤3次。
3.3.2 Fmoc脱保护和肽链的延长
Fmoc-L-Lys(Mtt)-Rink amide ChemMatrix树脂的Fmoc脱保护和之后肽链的延长采用与实施例一相同的合成方法得到含有化合物编号25的树脂肽，其中N-端氨基酸残基选用Boc-L-Tyr(t-Bu)-OH。
3.3.3树脂肽的Mtt脱保护及赖氨酸侧链的修饰
在完成上述肽-树脂的延伸后，加入六氟异丙醇/二氯甲烷混合溶液(30％，10mL)，室温下振荡反应45分钟后抽除，再加入六氟异丙醇/二氯甲烷的混合溶液(30％，10mL)，室温下振荡反应45分钟后抽除，反应结束后用DMF洗涤树脂6次。使用Fmoc/tBu固相合成策略以延伸赖氨酸侧链的额外偶联/脱保护循环涉及Fmoc-NH-PEG2-COOH，Fmoc-L-Glu-OtBu和HOOC-(CH 2) 16-COOt-Bu。在所有偶联中，反应在室温条件下进行并使用1mmol的氨基酸构建，1mmol的DEPBT和2mmol的DIEA在DMF中反应4个小时
3.3.4裂解及产物纯化
将上一步骤中得到的树脂肽依次用DMF，DCM洗涤2次后进行真空干燥，后加入新鲜配置的裂解液(三氟乙酸：三异丙基硅烷：水＝90：5：5，v：v：v)室温下振荡反应2小时。反应结束后过滤，用三氟乙酸洗涤树脂2次，合并滤液后加入大量冷冻无水异丙醚析出固体，离心后除去上清液并得到化合物编号为25的多肽粗品。
3.3.5化合物25的反相液色色谱纯化
将粗品肽溶于含0.1％三氟乙酸，20％乙腈/水的混合溶剂中，经过0.22um膜过滤后用WATERS Prep150LC反相高效液相色谱系统进行分离，缓冲液为A(0.1％三氟乙酸，10％乙腈，水溶液)和B(0.1％三氟乙酸，90％乙腈，水溶液)。其中，色谱柱为X-SELECT OBD C-18反相色谱柱，纯化过程中色谱仪检测波长设定为220nm，流速为20mL/min。收集产物相关馏分冻干后得到化合物编号25的多肽纯品，收率18％。多肽纯品通过分析性高效液相色谱和液相色谱/质谱联用确定纯度及化合物其纯度和化合物分子量，其中纯度为96.23％，化合物分子量为：5008.6。
3.4化合物编号26-33和49-62的化学合成
采用化合物25的实验方案合成本发明化合物编号26-33的多肽化合物，并用分析型高效液相色谱和液相色谱/质谱联用确定纯度和化合物分子量，具体如下表2：
表2
化合物编号 纯度 分子量
26 96.01％ 4951.6
27 95.04％ 4880.5
28 96.56％ 4992.6
29 96.36％ 4935.5
30 95.64％ 4864.4
31 95.45％ 5022.6
32 95.36％ 4965.6
33 95.41％ 4894.4
49 95.92％ 4864.4
50 96.31％ 4936.6
51 95.14％ 4992.6
52 96.58％ 4992.6
53 95.74％ 4921.5
54 97.63％ 4992.6
55 95.54％ 5049.7
56 97.24％ 4894.4
57 96.64％ 4965.6
58 95.27％ 5022.6
59 96.64％ 4850.4
60 95.65％ 4921.5
61 96.67％ 4978.6
62 95.32％ 4992.6
3.5化合物编号74的化学合成
3.5.1 Fmoc-L-Lys(Mtt)-OH与Rink-amide ChemMatrix树脂的偶联
称取Rink-amide ChemMatrix树脂(Biotage,0.1mmol)置于一次性聚丙烯多肽合成固相反应管中，加入DMF(10mL)在氮气鼓泡下溶胀树脂10分钟，真空抽掉DMF，加入DMF(10mL)洗涤树脂，重复洗涤2次；称取Fmoc-L-Lys(Mtt)-OH(1mmol)，3-(二乙氧基磷酰氧基)-1,2,3-苯并三嗪-4-酮(DEPBT)(1mmol)和二异丙基乙胺(DIEA，2mmol)，加入DMF(10mL)溶解后将上述溶液加入到溶胀后的Rink-amide ChemMatrix树脂中，在室温下振荡反应2小时，反应结束后用DMF，二氯甲烷(DCM)交替洗涤树脂2次，最后用DMF洗涤3次。
3.5.2 Fmoc脱保护和肽链的延长
Fmoc-L-Lys(Mtt)-Rink amide ChemMatrix树脂的Fmoc脱保护和之后肽链的延长采用与实施例一相同的合成方法得到含有化合物编号74的树脂肽，其中N-端氨基酸残基选用Boc-L-Tyr(t-Bu)-OH。
3.5.3树脂肽的Mtt脱保护及赖氨酸侧链的修饰
在完成上述肽-树脂的延伸后，加入六氟异丙醇/二氯甲烷混合溶液(30％，10mL)，室温下振荡反应45分钟后抽除，再加入六氟异丙醇/二氯甲烷的混合溶液(30％，10mL)，室温下振荡反应45分钟后抽除，反应结束后用DMF洗涤树脂6次。使用Fmoc/tBu固相合成策略以延伸赖氨酸侧链的额外偶联/脱保护循环涉及Fmoc-NH-PEG2-COOH，Fmoc-L-Glu-OtBu和HOOC-(CH 2) 18-COOt-Bu。在所有偶联中，反应在室温条件下进行并使用1mmol的氨基酸构建，1mmol的DEPBT和2mmol的DIEA在DMF中反应4个小时。
3.5.4裂解及产物纯化
将上一步骤中得到的树脂肽依次用DMF，DCM洗涤2次后进行真空干燥，后加入新鲜配置的裂解液(三氟乙酸：三异丙基硅烷：水＝90：5：5，v：v：v)室温下振荡反应2小时。反应结束后过滤，用三氟乙酸洗涤树脂2次，合并滤液后加入大量冷冻无水异丙醚析出固体，离心后除去上清液并得到化合物编号为74的多肽粗品。
3.5.5化合物74的反相液色色谱纯化
将粗品肽溶于含0.1％三氟乙酸，20％乙腈/水的混合溶剂中，经过0.22um膜过滤后用WATERS Prep150LC反相高效液相色谱系统进行分离，缓冲液为A(0.1％三氟乙酸，10％乙腈，水溶液)和B(0.1％三氟乙酸，90％乙腈，水溶液)。其中，色谱柱为X-SELECT OBD C-18反相色谱柱，纯化过程中色谱仪检测波长 设定为220nm，流速为20mL/min。收集产物相关馏分冻干后得到化合物编号74的多肽纯品，收率18％。多肽纯品通过分析性高效液相色谱和液相色谱/质谱联用确定纯度及化合物其纯度和化合物分子量，其中纯度为95.14％，化合物分子量为：5020.6。
3.6化合物编号75-77和81-83的化学合成
采用化合物74的实验方案合成本发明化合物编号75-77和81-83的多肽化合物，并用分析型高效液相色谱和液相色谱/质谱联用确定纯度和化合物分子量，具体如下表3：
表3
化合物编号 纯度 分子量
75 95.91％ 4892.5
76 96.25％ 5047.6
77 95.36％ 5035.6
81 96.31％ 5034.7
82 97.22％ 5034.7
83 95.61％ 5020.6
3.7注射液的制备
制备0.1、0.2、0.5、1.0、2.5、5、10、15、20、25或30mg/mL编号1-83化合物的液体制剂，可任选地加入20mM柠檬酸缓冲液。
Figure PCTCN2020129071-appb-000009
制备方法如下：以化合物74为例，称取5g的化合物74，加入NaCl固体4.5g，任选地加入20mM柠檬酸缓冲液25mL，注射用水至500mL，搅拌，滤过、制备得到化合物74的注射液。
生物学测试评价
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。
1、实验试剂
Figure PCTCN2020129071-appb-000010
Figure PCTCN2020129071-appb-000011
2、实验仪器
序号 仪器 来源
1 CO 2培养箱 Thermo 311
2 生物安全柜 上海博讯BSC-1300IIA2
3 冷冻离心机 Eppendorf 5702R
4 海尔双开门家用冰箱 海尔BCD-268TN
5 细胞计数器 Life Technologies Countess II
6 药品保存箱 海尔hyc-940
7 零下20度冰箱 海尔DW-25L262
8 冷冻离心机5810R Eppendorf 5810R
9 自动分液器(Multidrop) Thermo 5840300
10 酶标仪 BioTek H1MFD
11 CO 2细菌培养箱 上海博讯BC-J80S
12 活力型血糖仪 罗氏
3.测试例
3.1.评估受试化合物在胰高血糖素样肽-1受体(GLP-1R)的激动剂活性
3.1.1实验目的：
该测试例的目的是测量编号化合物对在胰高血糖素样肽-1受体(GLP-1R)的激动剂活性
3.1.2实验方法：
从液氮罐中取出冻存的CHO-K1/GLP-1R/CRE-luc稳转细胞株，放于37℃水浴锅中快速融化，用DMEM/F12培养基(Gibco Cat#11330032)重悬，离心后清洗一遍细胞，使用实验缓冲液即含0.1％酪蛋白(Sigma Cat#C3400)的DMEM/F12培养基重悬，使用实验缓冲液调整细胞密度，以2500个细胞/5μL/孔的密度铺于384孔板(Sigma Cat#CLS4514)，然后每孔加入2.5μL缓冲液配制的IBMX工作液(Sigma Cat#I7018)，IBMX终浓度为0.5mM，以及2.5μL梯度稀释的多肽样品，1000rpm离心1min，震荡30秒混匀，室温静置孵育30分钟。使用Cisbio cAMP-Gs Dynamic kit(Cisbio Cat#62AM4PEC)进行检测，将cAMP-d2和Anti-cAMP-Eu 3+-Cryptate分别用cAMP Lysis&Detection Buffer稀释20倍混匀。每孔加入5μL稀释后的cAMP-d2溶液，再加入5μL稀释后的Anti-cAMP-Eu 3+-Cryptate溶液，震荡30秒混匀，室温避光孵育1小时。
3.1.3实验数据处理方法：
使用Biotek Synergy H1酶标仪进行HTRF的信号读取，激发波长为320nm，发射波长为620nm和665nm。计算信号比值(665nm/620nm*10,000)，并在GraphPad Prism 6中将信号比值与样品浓度使用四参数方程进行非线性拟合，得出EC 50值，具体数据见下表4。
3.2.评估受试化合物在葡萄糖依赖性胰岛素释放肽受体(GIPR)的激动剂活性
3.2.1实验目的：
测试编号化合物在葡萄糖依赖性胰岛素释放肽受体(GIPR)的激动剂活性
3.2.2实验方法：
收集野生型CHO-K1细胞，将细胞悬液调整为合适的密度，铺于6孔板中，每孔2mL，放入37℃，5％的CO 2培养箱中贴壁过夜，将转染混合物(hGIPR质粒，Fugene HD(Promega Cat#E2311)，OptiMEM(Gibco Cat#31985070)混匀并于室温静置15分钟，以100μL的体积加入到相应的细胞孔中，转染24h使CHO-K1细胞表面过表达hGIPR。瞬转结束后收集6孔板内的细胞，用实验缓冲液即含0.1％酪蛋白(Sigma Cat#C3400)的DMEM/F12培养基(Gibco Cat#11330032)清洗一遍，使用实验缓冲液调整细胞密度，以5000个细胞/5μL/孔的密度铺于384孔板(Sigma Cat#CLS4514)，然后每孔加入2.5μL缓冲液配制的IBMX工作液(Sigma Cat#I7018)，IBMX终浓度为0.5mM，以及2.5μL梯度稀释的多肽样品，1000rpm离心1min，震荡30秒混匀，室温静置孵育30分钟。使用Cisbio cAMP-Gs Dynamic kit(Cisbio Cat#62 AM4PEC)进行检测，将cAMP-d2和Anti-cAMP-Eu3+-Cryptate分别用cAMP Lysis&Detection Buffer稀释20倍混匀。每孔加入5μL稀释后的cAMP-d2溶液，再加入5μL稀释后的Anti-cAMP-Eu3+-Cryptate溶液，震荡30秒混匀，室温避光孵育1小时。
3.2.3实验数据处理方法：
使用Biotek Synergy H1酶标仪进行HTRF的信号读取，激发波长为320nm，发射波长为620nm和665nm。计算信号比值(665nm/620nm*10,000)，并在GraphPad Prism 6中将信号比值与样品浓度使用四参数方程进行非线性拟合，得出EC 50值，具体数值见下表4。
多肽骨架化合物在人类GLP-1R和人类GIPR受体的激动剂活性
表4
Figure PCTCN2020129071-appb-000012
Figure PCTCN2020129071-appb-000013
实验结论：
本发明通过对多肽骨架的设计和研究，与本领域的许多GLP-1/GIP受体双激动剂多肽相比，具有较强的激动剂活性的多肽骨架，具有更好的治疗代谢类疾病的潜力。
偶联脂肪酸的多肽化合物在人类GLP-1R和人类GIPR受体的激动剂活性
表5
Figure PCTCN2020129071-appb-000014
实验结论：
本发明通过研究发现，不同的多肽骨架在偶联脂肪酸后的活性变化并不一样，本发明的多肽骨架经偶联脂肪酸修饰后仍可以保持对GLP-1和GIP受体良好的活性。
3.3多肽骨架、偶联脂肪酸的多肽化合物的稳定性
血浆中的稳定性对于治疗性多肽类药物是很重要的，因为多肽类药物很可能对与血浆中的多肽水解酶和蛋白水解酶敏感。在血浆中不稳定的多肽，其半衰期和疗效将受到影响。
3.3.1实验目的：
本实验的目的是测试编号化合物在血浆中的稳定性。为比较编号化合物与 现有技术中的化合物的稳定性，本实验同时测试了专利WO2012/167744中的优势多肽骨架化合物023(H23)与024(H24)以及优势修饰化合物089(H89)。
3.3.2实验方法：
将5微升浓度为20,50,100,200,500,1000,2000,5000,10000纳克/毫升的样品加入到45微升的SD大鼠血浆中，通过LC-MS的方法检测其中化合物的含量并形成标准曲线。将5微升浓度为1毫克/毫升的多肽溶液加入到45微升的SD大鼠血浆中。为每个待测化合物准备5个样品，并分别于0分钟、30分钟、60分钟、120分钟和240分钟取出1个样品通过LC-MS的方法检测其中保留的化合物含量，并以0分钟为标准(100％)，计算其他时间点样品的保留的化合物的相对含量。LC-MS检测化合物的方法为，配制5％的乙腈溶液作为溶液A，配置95％的乙腈溶液作为溶液B，以0.6毫升/分钟的流速，以下表所示的时间和溶液配比形成溶液梯度，注入15微升的样品，用Raptor Biphenyl 2.7微米检测柱检测化合物的含量。
时间(分钟) A(％) B(％)
0.20 95.0 5.00
1.70 5.00 95.0
2.00 5.00 95.0
2.01 95.0 5.00
2.50 95.0 5.00
3.3.3实验结果：
1)通过以上实验方法，多肽骨架在血浆中的稳定性数据如下表6：
表6
Figure PCTCN2020129071-appb-000015
3.3.4实验结论：
通过研究发现，本发明的化合物能够保持血浆含量的稳定(相对含量>95％)，表示本发明的化合物成药性良好，具有很好的治疗疾病的潜力。本发明的化合物的血浆稳定性优于现有技术中的化合物H23和H24。
2)通过以上实验方法，偶联脂肪酸的多肽的血浆稳定性数据如下表7：
表7
Figure PCTCN2020129071-appb-000016
实验结论：
通过研究发现，本发明的化合物74相比于化合物75和现有技术化合物H89在4小时的时间点在血浆中更能够保持稳定(相对含量>90％)。
3.4偶联脂肪酸的多肽在小鼠体内的药代动力学
血浆稳定性是影响多肽药物的药代动力学的因素之一。多肽药物在体内的药代动力学还受到其在体内的吸收和清除等因素的影响。
3.4.1实验目的：
本实验的目的是以Balb/c小鼠为受试动物，研究编号化合物单次静脉注射给药在小鼠体内(血浆)的药代动力学行为。
3.4.2实验方法：
体重18～30克周龄7-9周的雄性Balb/c小鼠采购自上海杰思捷实验动物有限公司。使用含有20mM柠檬酸缓冲液(pH＝7.0)配制编号化合物后，按照30纳摩尔每千克体重的剂量通过尾静脉注射编号化合物进入小鼠体内，在0小时、0.083小时、0.25小时、0.5小时、1小时、2小时、4小时、6小时、8小时、24小时和32小时时间点采血0.2毫升。在4℃的温度下将采集到的小鼠血通过6000rpm的速度离心6分钟分离血浆。采用测试例3.3的实验方法检测小鼠血浆中编号化合物的含量。
3.4.3实验结果：
通过以上实验方法，具体数据如下表8：
表8
PK参数 单位 化合物28 化合物74
T 1/2 h 4.7 19.5
AUCInf h*ng/mL 9500 30698
3.4.4实验结论：
通过研究发现，本发明的化合物在小鼠体内具有良好的药代动力学特征，表示其在治疗疾病方面具有优势。
3.5偶联脂肪酸的多肽在大鼠体内的药代动力学
3.5.1实验目的：
为进一步研究本发明化合物的药代动力学，本实验以SD大鼠为受试动物，研究编号化合物单次皮下注射给药在大鼠体内(血浆)的药代动力学行为。
3.5.2实验方法：
体重150～300克的雄性SD大鼠采购自上海杰思捷实验动物有限公司。使用含有20mM柠檬酸缓冲液(pH＝7.0)配制编号化合物后，按照50纳摩尔每千克体重的剂量通过皮下注射编号化合物进入大鼠体内，在0小时、0.5小时、1小时、2小时、4小时、6小时、8小时、24小时、32小时、48小时、72小时、96小时和120小时的时间点采血0.2毫升。在4℃的温度下将采集到的大鼠血通过6000rpm的速度离心6分钟分离血浆。采用测试例3.3的实验方法检测大鼠血浆中编号化合物的含量。
3.5.3实验结果：
通过以上实验方法，具体数据如下表9所示：
表9
PK参数 单位 化合物74
T 1/2 h 15.9
AUCInf h*ng/mL 17673
3.5.4实验结论：
通过研究发现，本发明的化合物在小鼠体内具有良好的药代动力学特征，表示其在治疗疾病方面具有优势。
3.6偶联脂肪酸的多肽的体内药效
3.6.1实验目的：
测试编号化合物皮下给药对饮食诱导肥胖小鼠血糖的调节作用
3.6.2实验方法：
经过高脂食物诱导肥胖的体重35-55克周龄10-12周的雄性C57BL/6小鼠采购自上海杰思捷实验动物有限公司。对饮食诱导肥胖的C57BL/6小鼠皮下注射给予编号化合物(3纳摩尔/千克体重)后禁食、不禁水，18小时后按照2克每公斤体重的剂量通过腹腔注射浓度为0.2克/毫升的葡萄糖溶液。根据实验设计，在0分钟、15分钟、30分钟、60分钟、120分钟的时间点通过小鼠尾部采血，测量血糖值。具体方法是用物理方法固定住小鼠，暴露出尾巴并将尾部剪去少许，挤压尾巴使其出血，弃去第1滴血后用罗氏活力型血糖仪检测血糖。根据各点结果计算血糖曲线下面积(AUC)。
3.6.3实验结果：
通过以上实验方法，具体数据如下表10所示：
表10
Figure PCTCN2020129071-appb-000017
***与化合物74的血糖AUC相比有显著差异，P＝0.0001。
**与化合物74的血糖AUC相比有显著差异，P＝0.002。
3.6.4实验结论：
在本实验中，在3纳摩尔/千克体重的剂量下，本发明化合物显示出显著的降糖作用，化合物74组的血糖曲线下面积与安慰剂相比下降超过80％。与现有技术中具有GLP-1活性的化合物H89和索马鲁肽相比，血糖AUC有显著差异。
3.7偶联脂肪酸的多肽的降体重
3.7.1实验目的：
测试编号化合物皮下给药对饮食诱导肥胖小鼠体重的调节作用
3.7.2实验方法：
经过高脂食物诱导肥胖的体重35-55克周龄18周的雄性C57BL/6小鼠，采购自上海杰思捷实验动物有限公司。对饮食诱导肥胖的C57BL/6小鼠每3天皮下注射给予安慰剂或索马鲁肽(10纳摩尔/千克体重)或编号化合物74(10纳摩尔/千克体重)。根据实验设计，在第5、7、10、13、16、19天称量小鼠的随机体重，并计算第19天体重降低百分比。计算公式为：第19天体重降低百分比(％)＝(第0天体重-第19天体重)/第0天体重*100
3.6.3实验结果：
通过以上实验方法，具体数据如下表11所示：
表11
Figure PCTCN2020129071-appb-000018
*与化合物74的体重降低百分比相比有显著差异，P＝0.01。
3.7.4实验结论：
在本实验中，在10纳摩尔/千克体重的剂量下，本发明化合物显示出显著的降体重作用，化合物74组的体重下降百分比超过5％。与现有技术中具有GLP-1活性的化合物索马鲁肽相比，降体重有显著差异。

Claims (43)

  1. 具有通式(I)的GLP-1类似物，或其可用药盐形式：
    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)
    其中：
    所述的X 1选自Tyr或His的氨基酸残基；X 2选自Aib或D-Ala的氨基酸残基；X 10选自Val或Tyr的氨基酸残基；X 12选自Ser或Ile的氨基酸残基；X 15选自Asp或Glu的氨基酸残基；X 16选自Glu、Gly、Lys或Aib的氨基酸残基；X 17选自Glu、Ile或Gln的氨基酸残基；X 18选自Ala、Aib或His的氨基酸残基；X 19选自Ala、Aib或Gln的氨基酸残基；X 20选自Gln、Glu、Lys的氨基酸残基或Y1；X 23选自Ile或Val的氨基酸残基；X 24选自Ala、Asn或Gln的氨基酸残基；X 27选自Val或Leu的氨基酸残基；X 28选自Arg或Ala的氨基酸残基；X 29选自Gly或Gln的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或者不存在；
    Y1为K(-OEG-OEG-yGlu-C20-OH)，该基团具有下列结构的化学式：
    Figure PCTCN2020129071-appb-100001
  2. 根据权利要求1所述的GLP-1类似物或其可药用盐，其特征在于，其两端通过如下的方式连接：
    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)
    其中：
    R 1是H、烷基、乙酰基、甲酰基、苯甲酰基、三氟乙酰基或pGlu；
    R 2是-NH 2或-OH。
  3. 根据权利要求1所述的GLP-1类似物或其可药用盐，其特征在于，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15选自Asp或Glu的氨基酸残基；X 16选自Lys或Aib的氨基 酸残基；X 17选自Glu或Ile的氨基酸残基；X 18选自Ala或Aib的氨基酸残基；X 19选自Ala或Gln的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23为Val的氨基酸残基；X 24选自Asn或Gln的氨基酸残基；X 27选自Leu的氨基酸残基；X 28选自Ala的氨基酸残基；X 29选自Gly或Gln的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或者不存在。
  4. 根据权利要求1所述的GLP-1类似物或其可药用盐，其特征在于，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15选自Asp或Glu的氨基酸残基；X 16选自Lys或Aib的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18选自Ala或Aib的氨基酸残基；X 19选自Ala或Gln的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23为Val的氨基酸残基；X 24选自Asn或Gln的氨基酸残基；X 27选自Leu的氨基酸残基；X 28选自Ala的氨基酸残基；X 29选自Gly或Gln的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或者不存在。
  5. 根据权利要求1所述的GLP-1类似物或其可药用盐，其特征在于，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17为Glu的氨基酸残基；X 18为Ala或Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在。
  6. 根据权利要求1所述的GLP-1类似物或其可药用盐，其特征在于，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17为Ile的氨基酸残基；X 18选自Ala或Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在。
  7. 根据权利要求1所述的GLP-1类似物或其可药用盐，其特征在于，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17选自Glu 或Ile的氨基酸残基；X 18为Ala的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在。
  8. 根据权利要求1所述的GLP-1类似物或其可药用盐，其特征在于，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18为Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在。
  9. 根据权利要求1所述的GLP-1类似物或其可药用盐，其特征在于，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18选自Ala或Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20为Gln的氨基酸残基；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在。
  10. 根据权利要求1所述的GLP-1类似物或其可药用盐，其特征在于，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18选自Ala或Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20为Y1；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在。
  11. 根据权利要求1-10任一项所述的GLP-1类似物或其可药用盐，其特征在于，Y1由C端Lys的ε氨基通过酰胺键与脂肪酸共价连接。
  12. 根据权利要求1或2所述的GLP-1类似物或其可药用盐，其特征在于， 选自如下化合物或其可药用盐：
    Figure PCTCN2020129071-appb-100002
  13. 一种药物组合物，其包含通式(I)所示的GLP-1类似物或其可药用盐以及药学上可接受的辅料，
    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)
    其中：
    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和X 30独立的选自任意天然的氨基酸或非天然氨基酸或由其组成的肽段；
    X 40选自任意天然的氨基酸或非天然氨基酸或由其组成的肽段，或者X 40不 存在。
  14. 根据权利要求13所述的药物组合物，其中所述GLP-1类似物或其可药用盐两端通过如下的方式连接：
    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)
    其中：
    R 1是H、烷基、乙酰基、甲酰基、苯甲酰基、三氟乙酰基或pGlu；
    R 2是-NH 2或-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和X 30独立的选自任意天然的氨基酸或非天然氨基酸或由其组成的肽段；
    X 40选自任意天然的氨基酸或非天然氨基酸或由其组成的肽段，或者X 40不存在。
  15. 根据权利要求13所述的药物组合物，其特征在于，通式(I)中，X 1选自Tyr或His的氨基酸残基；X 2选自Aib或D-Ala的氨基酸残基；X 10选自Val或Tyr的氨基酸残基；X 12选自Ser或Ile的氨基酸残基；X 15选自Asp或Glu的氨基酸残基；X 16选自Glu、Gly、Lys或Aib的氨基酸残基；X 17选自Glu、Ile或Gln的氨基酸残基；X 18选自Ala、Aib或His的氨基酸残基；X 19选自Ala、Aib或Gln的氨基酸残基；X 20选自Gln、Glu、Lys的氨基酸残基或Y1；X 23选自Ile或Val的氨基酸残基；X 24选自Ala、Asn或Gln的氨基酸残基；X 27选自Val或Leu的氨基酸残基；X 28选自Arg或Ala的氨基酸残基；X 29选自Gly或Gln的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或者不存在，
    Y1是其中侧链与具有式{[2-(2-氨基-乙氧基)-乙氧基]-乙酰基} a-(y-Glu) b-CO-(CH 2) c-COOH之取代基耦合的Lys、Orn、Dap、Dab或Cys残基；
    a为1-3之间的整数；
    b为1-2之间的整数；
    c为10-30之间的整数。
  16. 根据权利要求13所述的药物组合物，其特征在于，通式(I)中，X 1选自Tyr或His的氨基酸残基；X 2选自Aib或D-Ala的氨基酸残基；X 10选自Val或Tyr的氨基酸残基；X 12选自Ser或Ile的氨基酸残基；X 15选自Asp或Glu的氨 基酸残基；X 16选自Glu、Gly、Lys或Aib的氨基酸残基；X 17选自Glu、Ile或Gln的氨基酸残基；X 18选自Ala、Aib或His的氨基酸残基；X 19选自Ala、Aib或Gln的氨基酸残基；X 20选自Gln、Glu、Lys的氨基酸残基或Y1；X 23选自Ile或Val的氨基酸残基；X 24选自Ala、Asn或Gln的氨基酸残基；X 27选自Val、Ile或Leu的氨基酸残基；X 28选自Arg或Ala的氨基酸残基；X 29选自Gly或Gln的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或者不存在，Y1如权利要求15所定义。
  17. 根据权利要求13所述的药物组合物，其特征在于，通式(I)中，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15选自Asp或Glu的氨基酸残基；X 16选自Lys或Aib的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18选自Ala或Aib的氨基酸残基；X 19选自Ala或Gln的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23为Val的氨基酸残基；X 24选自Asn或Gln的氨基酸残基；X 27选自Leu的氨基酸残基；X 28选自Ala的氨基酸残基；X 29选自Gly或Gln的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或者不存在，Y1如权利要求15所定义。
  18. 根据权利要求13所述的药物组合物，其特征在于，通式(I)中，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17为Glu的氨基酸残基；X 18为Ala或Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存，Y1如权利要求15所定义。
  19. 根据权利要求13所述的药物组合物，其特征在于，通式(I)中，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17为Ile的氨基酸残基；X 18选自Ala或Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在，Y1如权利要求15所定义。
  20. 根据权利要求13所述的药物组合物，其特征在于，通式(I)中，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18为Ala的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在，Y1如权利要求15所定义。
  21. 根据权利要求13所述的药物组合物，其特征在于，通式(I)中，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18为Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在，Y1如权利要求15所定义。
  22. 根据权利要求13所述的药物组合物，其特征在于，所述通式(I)中，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18选自Ala或Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20为Gln的氨基酸残基；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在，Y1如权利要求15所定义。
  23. 根据权利要求13所述的药物组合物，其特征在于，通式(I)中，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18选自Ala或Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20为Lys的氨基酸残基；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或 不存在，Y1如权利要求15所定义。
  24. 根据权利要求13所述的药物组合物，其特征在于，通式(I)中，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18选自Ala或Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20为Y1；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在，Y1如权利要求15所定义。
  25. 根据权利要求13所述的药物组合物，其特征在于，通式(I)中，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10为Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15为Glu的氨基酸残基；X 16为Lys的氨基酸残基；X 17选自Glu或Ile的氨基酸残基；X 18选自Ala或Aib的氨基酸残基；X 19为Ala的氨基酸残基；X 20为Gln；X 23为Val的氨基酸残基；X 24为Asn的氨基酸残基；X 27为Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30选自Gly、Lys的氨基酸残基或Y1；X 40选自Lys的氨基酸残基、Y1或不存在，Y1如权利要求15所定义。
  26. 根据权利要求13所述的药物组合物，其特征在于，通式(I)中，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10选自Val或Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15选自Asp或Glu的氨基酸残基；X 16选自Glu、Lys的氨基酸残基；X 17选自Glu、Ile的氨基酸残基；X 18为Ala的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23选自Ile或Val的氨基酸残基；X 24选自Ala、Asn或Gln的氨基酸残基；X 27选自Ile或Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30为Gly的氨基酸残基；X 40选自Lys的氨基酸残基、Y1或者不存在，Y1如权利要求15所定义。
  27. 根据权利要求13所述的药物组合物，其特征在于，通式(I)中，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10选自Val的氨基酸残基；X 12为Ile的氨基酸残基；X 15选自Asp或Glu的氨基酸残基；X 16选自Lys的氨基酸残基；X 17选自Ile的氨基酸残基；X 18为Ala的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln的氨基酸残基或Y1；X 23选自Val的氨基酸残基；X 24选自Asn的氨基酸残基；X 27选自Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为 Gly的氨基酸残基；X 30为Gly的氨基酸残基；X 40选自Lys的氨基酸残基、Y1或者不存在，Y1如权利要求15所定义。
  28. 根据权利要求13所述的药物组合物，其特征在于，通式(I)中，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10选自Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15选自Glu的氨基酸残基；X 16选自Glu、Lys的氨基酸残基；X 17选自Glu、Ile的氨基酸残基；X 18为Ala的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23选自Ile或Val的氨基酸残基；X 24选自Ala、Asn或Gln的氨基酸残基；X 27选自Ile或Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30为Gly的氨基酸残基；X 40选自Lys的氨基酸残基、Y1或者不存在，Y1如权利要求15所定义。
  29. 根据权利要求13所述的药物组合物，其特征在于，通式(I)中，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10选自Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15选自Glu的氨基酸残基；X 16选自Glu的氨基酸残基；X 17选自Glu、Ile的氨基酸残基；X18为Ala的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln、Lys的氨基酸残基或Y1；X 23选自Val的氨基酸残基；X 24选自Asn的氨基酸残基；X 27选自Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30为Gly的氨基酸残基；X 40选自Lys的氨基酸残基、Y1或者不存在，Y1如权利要求15所定义。
  30. 根据权利要求13所述的药物组合物，其特征在于，通式(I)中，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10选自Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15选自Glu的氨基酸残基；X 16选自Lys的氨基酸残基；X 17选自Glu、Ile的氨基酸残基；X 18为Ala的氨基酸残基；X 19为Ala的氨基酸残基；
    X 20选自Gln、Lys的氨基酸残基或Y1；X 23选自Ile或Val的氨基酸残基；X 24选自Ala、Asn或Gln的氨基酸残基；X 27选自Ile或Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30为Gly的氨基酸残基；X 40选自Lys的氨基酸残基、Y1或者不存在，Y1如权利要求15所定义。
  31. 根据权利要求13所述的药物组合物，其特征在于，通式(I)中，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10选自Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15选自Glu的氨基酸残基；X 16选自Lys的氨基酸残基；X 17选自Ile的氨基酸残基；X 18为Ala的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Gln的氨基酸残基或Y1；X 23选自Val的氨基酸残基；X 24选自Asn或Gln 的氨基酸残基；X 27选自Ile或Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30为Gly的氨基酸残基；X 40选自Lys的氨基酸残基、Y1或者不存在，Y1如权利要求15所定义。
  32. 根据权利要求13所述的药物组合物，其特征在于，通式(I)中，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10选自Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15选自Glu的氨基酸残基；X 16选自Lys的氨基酸残基；X 17选自Glu的氨基酸残基；X 18为Ala的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Lys的氨基酸残基或Y1；X 23选自Ile或Val的氨基酸残基；X 24选自Ala、Asn或Gln的氨基酸残基；X 27选自Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30为Gly的氨基酸残基；X 40选自Lys的氨基酸残基、Y1或者不存在，Y1如权利要求15所定义。
  33. 根据权利要求13所述的药物组合物，其特征在于，通式(I)中，X 1为Tyr的氨基酸残基；X 2为Aib的氨基酸残基；X 10选自Tyr的氨基酸残基；X 12为Ile的氨基酸残基；X 15选自Glu的氨基酸残基；X 16选自Lys的氨基酸残基；X 17选自Glu的氨基酸残基；X 18为Ala的氨基酸残基；X 19为Ala的氨基酸残基；X 20选自Lys的氨基酸残基或Y1；X 23选自Ile或Val的氨基酸残基；X 24选自Ala或Gln的氨基酸残基；X 27选自Leu的氨基酸残基；X 28为Ala的氨基酸残基；X 29为Gly的氨基酸残基；X 30为Gly的氨基酸残基；X 40选自Lys的氨基酸残基、Y1或者不存在，Y1如权利要求15所定义。
  34. 根据权利要求13所述的药物组合物，其特征在于，通式(I)中，X 20、X 30和X 40各自独立的选自Y1，优选地，X 40选自选自Y1，Y1如权利要求15所定义。
  35. 根据权利要求15-34任一项所述的药物组合物，其特征在于，a为2，b为1或2，c为16-20，优选地，a为2，b为1或2，c为16、18或20。
  36. 根据权利要求15-34任一项所述的药物组合物，其特征在于，所述GLP-1类似物或其可药用盐的Y1是K(-OEG-OEG-yGlu-C 18-OH)或K(-OEG-OEG-yGlu-C 20-OH)，优选地，Y1由C端Lys的ε氨基通过酰胺键与脂肪酸共价连接；进一步优选地，Y1基团具有下列结构的化学式：
    Figure PCTCN2020129071-appb-100003
  37. 根据权利要求13或14所述的药物组合物，其特征在于，选自如下编号为1-83的化合物或其可药用盐：
    Figure PCTCN2020129071-appb-100004
    Figure PCTCN2020129071-appb-100005
    Figure PCTCN2020129071-appb-100006
  38. 根据权利要求13-37任一项所述的药物组合物，其特征在于，所述药物组合物为注射剂，优选冻干注射剂或注射液，更优选为溶液型注射液、混悬型注射液或乳剂型注射液，进一步优选为溶液型注射液，更进一步优选为水溶液型注 射液。
  39. 根据权利要求38所述的药物组合物，其特征在于，GLP-1类似物或其可药用盐单位剂量的浓度为0.1mg/mL至200mg/mL，优选为0.1mg/mL至120mg/mL，更优选为2mg/mL至50mg/mL，进一步优选为5-30mg/mL，最优选为1mg/mL、2mg/mL、10mg/mL、20mg/mL或30mg/mL。
  40. 根据权利要求38所述的药物组合物，其特征在于，GLP-1类似物或其可药用盐单位剂量为0.5mL：1mg至0.5mL：50mg，优选0.5mL：1mg至0.5mL：20mg，更优选0.5mL：1mg、0.5mL：5mg、0.5mL：10mg、0.5mL：15mg或0.5mL：20mg。
  41. 根据权利要求38所述的药物组合物，其特征在于，注射剂中包含等渗剂。
  42. 根据权利要求1-12所述的GLP-1类似物或其可药用盐，以及权利要求13-41所述的药物组合物，在制备用于治疗非胰岛素依赖性糖尿病、胰岛素依赖性糖尿病或肥胖症的药物中的用途；优选地，所述非胰岛素依赖性糖尿病为II型糖尿病。
  43. 根据权利要求1-12所述的GLP-1类似物或其可药用盐，以及权利要求13-41所述的药物组合物，与选自二甲双胍、噻唑烷二酮类、璜酰脲类、二肽基肽酶抑制剂和钠葡萄糖转运蛋白的一种或多种试剂的同时，分开或相继组合使用。
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