Application of GLP-1R agonist and metformin in preparation of medicine for treating diabetes mellitus and complications of diabetes mellitus

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to application of a GLP-1R agonist compound and metformin in preparation of drugs for preventing and / or treating diseases such as diabetes and complications thereof.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to the use of a GLP-1R agonist compound and metformin in the preparation of a drug for preventing and / or treating diseases such as diabetes and its complications. Background Art

[0002] Diabetes affects millions of people worldwide and is considered one of the leading threats to human mortality in the 21st century. Over time, uncontrolled diabetes can damage body systems, including the heart, blood vessels, eyes, kidneys, and nerves. The socioeconomic burden of diabetes is high worldwide.

[0003] There are two main types of diabetes, named type I and type II, of which type II diabetes (T2DM) accounts for more than 90% of all diabetes worldwide. Type I diabetes is characterized by insulin deficiency, mainly caused by autoimmune-mediated destruction of pancreatic β cells, and type II diabetes is characterized by abnormal insulin secretion and subsequent insulin resistance. To prevent ketoacidosis, patients with type I diabetes must take exogenous insulin to survive. Although patients with type II diabetes are not as dependent on exogenous insulin as patients with type I diabetes, they may need exogenous insulin to control blood sugar levels.

[0004] Biguanides can improve the sensitivity of peripheral tissues and liver to insulin, reduce intestinal absorption of glucose, inhibit liver gluconeogenesis, and increase peripheral tissue utilization of glucose. Therefore, they are particularly suitable for obese patients with type 2 diabetes. Biguanides include phenformin, metformin, and buformin. Phenformin has been discontinued in Europe and the United States due to its high incidence of lactic acidosis, and has been phased out in my country. Buformin is rarely used in China. Metformin has become one of the most widely used hypoglycemic drugs. Metformin has the effect of improving blood sugar tolerance in patients with type 2 diabetes and reducing basal and postprandial blood sugar. Metformin does not stimulate insulin secretion, but mainly acts on the peripheral tissues of the pancreas, increases the sensitivity of peripheral tissues to insulin, increases the uptake and utilization of glucose, inhibits the absorption of glucose by the intestinal wall, and helps reduce postprandial blood sugar.

[0005] Glucagon-like peptide-1 (GLP-1) is a type of incretin secreted by intestinal epithelial L cells and exerts physiological effects by binding to its receptor. The GLP-1 receptor (GLP-1R) belongs to the G protein-coupled receptor subfamily. When GLP-1 binds to the GLP-1 receptor, it triggers a series of biological effects. Studies have shown that GLP-1 promotes insulin secretion in a glucose-dependent manner, that is, when the blood glucose concentration in the human body increases, GLP-1 stimulates pancreatic cells, increases insulin secretion, and lowers blood sugar. GLP-1 receptor agonists are a new type of hypoglycemic drug that can effectively control blood sugar levels without causing hypoglycemia; they can also effectively reduce body weight by increasing satiety, delaying gastric emptying, suppressing appetite, and reducing fat accumulation, thereby achieving the purpose of weight loss.

[0006] The applicant applied for a GLP-1R agonist compound represented by the following formula (I) (hereinafter referred to as "Compound A") in the previous application PCT / CN2021 / 133447:

[0007] Summary of the invention

[0008] The object of the present invention is to provide a use of a GLP-1R agonist compound in combination with metformin and / or its salt in the preparation of a medicament for preventing and / or treating diseases such as diabetes and its complications.

[0009] Specifically, the present invention provides a use of a glucagon-like peptide-1 receptor (GLP-1R) agonist and / or a salt thereof of a compound represented by formula (I) in combination with metformin and / or a salt thereof in the preparation of a drug for preventing and / or treating diabetes and its complications, and its structural formula is shown below:

[0010]

[0011] As a preferred technical solution of the present invention, the diabetic complications include obesity, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, fatty liver, cirrhosis, hepatic diabetes, cirrhosis combined with diabetes, diabetic fatty liver, diabetic liver disease or other diabetes-related diseases.

[0012] As a preferred technical solution of the present invention, the glucagon-like peptide-1 (GLP-1) receptor agonist is selected from:

[0013]

[0014] As a preferred technical solution of the present invention, the salt of the glucagon-like peptide-1 (GLP-1) receptor agonist is selected from at least one of lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, iron salt, zinc salt or ammonium salt; or the salt is selected from hydrochloride, methylamine salt, dimethylamine salt, trimethylamine salt, ethylamine salt, diethylamine salt, triethylamine salt, isopropylamine salt, 2-ethylaminoethanol salt, pyridine salt, methylpyridine salt, ethanolamine salt, diethanolamine salt, ammonium salt , tetramethylammonium salt, tetraethylammonium salt, triethanolamine salt, piperidine salt, piperazine salt, morpholine salt, lysine salt, L-lysine salt, arginine salt, L-arginine salt, histidine salt, L-histidine salt, meglumine salt, dimethylglucamine salt, ethylglucamine salt, dicyclohexylamine salt, 1,6-hexanediamine salt, glucosamine salt, sarcosine salt, serinol salt, trishydroxymethylaminomethane salt, aminopropanediol salt, ornithine salt or choline salt.

[0015] As a preferred technical solution of the present invention, the salt of the glucagon-like peptide-1 (GLP-1) receptor agonist is selected from sodium salt, potassium salt, trishydroxymethylaminomethane salt, calcium salt and magnesium salt.

[0016] As a preferred technical solution of the present invention, the salt of the glucagon-like peptide-1 (GLP-1) receptor agonist is selected from:

[0017]

[0018] As a preferred technical solution of the present invention, the salt of metformin is selected from hydrochloride.

[0019] As a preferred technical solution of the present invention, the mass ratio of the glucagon-like peptide-1 (GLP-1) receptor agonist and / or its salt to metformin and / or its salt is: 10-80:85-100 or 300:300; preferably, the mass ratio of the glucagon-like peptide-1 (GLP-1) receptor agonist and / or its salt to metformin and / or its salt is: 10-80:85 or 10-80:100 or 300:300; more preferably, the glucagon-like peptide-1 (GLP-1) receptor agonist and / or its salt to metformin and / or its salt is: 10-80:85 or 10-80:100 or 300:300. ) receptor agonist and / or its salt to metformin and / or its salt is: 20-60:85 or 20-60:100 or 300:300; most preferably, the mass ratio of the glucagon-like peptide-1 (GLP-1) receptor agonist and / or its salt to metformin and / or its salt is: 20:85, 30:85, 40:85, 50:85, 60:85, 20:100, 30:100, 40:100, 50:100, 60:100 or 300:300.

[0020] As a preferred technical solution of the present invention, the present invention also provides a pharmaceutical composition, characterized in that the pharmaceutical composition is composed of a glucagon-like peptide-1 receptor (GLP-1R) agonist and / or a salt thereof of a compound represented by formula (I), further preferably compound Aa or a salt thereof, and metformin and / or a salt thereof; wherein the structure of the compound Aa is: The weight ratio of the compound Aa and / or its salt to metformin and / or its salt is: 10-80:85-100 or 300:300; preferably, the weight ratio of the compound Aa and / or its salt to metformin and / or its salt is: 10-80:85 or 10-80:100 or 300:300.

[0021] As a preferred technical solution of the present invention, the weight ratio of the compound Aa and / or its salt to metformin and / or its salt is: 20-60:85, 20-60:100 or 300:300; preferably, the weight ratio of the compound Aa and / or its salt to metformin and / or its salt is: 20:85, 30:85, 40:85, 50:85, 60:85, 20:100, 30:100, 40:100, 50:100, 60:100 or 300:300.

[0022] As a preferred technical solution of the present invention, the weight ratio of the tris salt of the compound Aa to metformin hydrochloride is: 10-80:85-100 or 300:300; preferably, the weight ratio of the tris salt of the compound Aa to metformin hydrochloride is: 10-80:85, 10-80:100 or 300:300; more preferably, the weight ratio of the tris salt of the compound Aa to metformin hydrochloride is: 20-60:85, 20-60:100 or 300:300; most preferably, the weight ratio of the tris salt of the compound Aa to metformin hydrochloride is: 20:85, 30:85, 40:85, 50:85, 60:85, 20:100, 30:100, 40:100, 50:100, 60:100, 300:300.

[0023] As a preferred technical solution of the present invention, the human daily dosage of the compound Aa and / or its salt is 200-1600 mg, and the human daily dosage of metformin and / or its salt is 1000-2000 mg; preferably, the human daily dosage of the compound Aa and / or its salt is 200 mg, 400 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg or 1600 mg; the human daily dosage of metformin and / or its salt is 1000 mg, 1700 mg or 2000 mg.

[0024] As a preferred technical solution of the present invention, the pharmaceutical composition is packaged according to the clinical dosage and prepared into dosage units of specific specifications, and the dosage unit contains 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg or 800 mg of compound Aa and / or its salt, and contains 500 mg, 850 mg or 1000 mg of metformin and / or its salt.

[0025] As a preferred technical solution of the present invention, when the specific content of compound Aa and / or its salt in the dosage unit is 200 mg, 400 mg or 600 mg, the specific content of metformin and / or its salt is 850 mg or 1000 mg.

[0026] As a preferred technical solution of the present invention, the salt of the glucagon-like peptide-1 (GLP-1) receptor agonist is selected from at least one of lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, aluminum salts, iron salts, zinc salts or ammonium salts; or the salt is selected from hydrochloride, methylamine salt, dimethylamine salt, trimethylamine salt, ethylamine salt, diethylamine salt, triethylamine salt, isopropylamine salt, 2-ethylaminoethanol salt, pyridine salt, methylpyridine salt, ethanolamine salt, diethanolamine salt, ammonium salt, tetramethylammonium salt, tetraethylammonium salt, triethanolamine At least one of salts, piperidine salts, piperazine salts, morpholine salts, lysine salts, L-lysine salts, arginine salts, L-arginine salts, histidine salts, L-histidine salts, meglumine salts, dimethylglucosamine salts, ethylglucosamine salts, dicyclohexylamine salts, 1,6-hexanediamine salts, glucosamine salts, sarcosinate salts, serinol salts, trishydroxymethylaminomethane salts, aminopropanediol salts, ornithine salts or choline salts; preferably, the salt is selected from: sodium salt, potassium salt, trishydroxymethylaminomethane salt, calcium salt, magnesium salt;

[0027] The salt of metformin is selected from hydrochloride.

[0028] As a preferred technical solution of the present invention, the dosage of the glucagon-like peptide-1 (GLP-1) receptor agonist and / or its salt is calculated as glucagon-like peptide-1 (GLP-1) receptor agonist; the dosage of the metformin salt is calculated as metformin hydrochloride.

[0029] As a preferred technical solution of the present invention, the pharmaceutical composition is selected from: tablets, capsules, oral solutions, pills, granules, pellets, sustained-release agents or other oral dosage forms; preferably, the pharmaceutical composition is selected from: tablets or capsules.

[0030] As a preferred technical solution of the present invention, the present invention also provides an application of the pharmaceutical composition of the present invention in the preparation of a drug for preventing and / or treating diabetes and its complications; preferably, the diabetic complications include obesity, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, fatty liver, cirrhosis, hepatic diabetes, cirrhosis combined with diabetes, diabetic fatty liver, diabetic liver disease or other diabetes-related diseases.

[0031] As a preferred technical solution of the present invention, the present invention also provides a method for preparing the pharmaceutical composition of the present invention, wherein the method is a wet granulation method, a dry granulation method or a powder direct compression method.

[0032] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood in accordance with the ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" used here refers to those compounds, materials, compositions and / or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0033] The salts of the glucagon-like peptide-1 (GLP-1) receptor agonist compounds of the present invention refer to "pharmaceutically acceptable salts" prepared from the compounds with specific substituents found in the present invention and pharmaceutically acceptable acids or bases.

[0034] The salts of the glucagon-like peptide-1 (GLP-1) receptor agonist compounds of the present invention may exist in unsolvated or solvated forms, including hydrate forms. Generally speaking, the solvated forms are equivalent to the unsolvated forms and are all included in the scope of the present invention.

[0035] The glucagon-like peptide-1 (GLP-1) receptor agonist compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present invention.

[0036] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (for example, a carbamate is generated from an amine).

[0037] The atoms of the glucagon-like peptide-1 (GLP-1) receptor agonist compound molecules of the present invention are isotopes, and isotope derivatization can generally prolong half-life, reduce clearance rate, stabilize metabolism, and improve in vivo activity. In addition, an embodiment is included in which at least one atom is replaced by an atom with the same atomic number (proton number) and a different mass number (proton and neutron sum). Examples of isotopes included in the compounds of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, which respectively include 2 H. 3 H. 13 C. 14 C. 15 N. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl. In particular, radioactive isotopes such as 3H or 14C that emit radiation as they decay can be used in pharmaceutical preparations or local anatomical examinations of compounds in vivo. Stable isotopes neither decay nor change with their amount nor are they radioactive, so they can be used safely. When the atoms constituting the molecules of the compounds of the invention are isotopes, the isotopes can be converted according to general methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0038] The glucagon-like peptide-1 (GLP-1) receptor agonist compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound may be labeled with a radioactive isotope, such as deuterium ( 2 H), iodine-125( 125 I) or C-14( 14C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0039] Furthermore, the glucagon-like peptide-1 (GLP-1) receptor agonist compounds of the present invention have one or more hydrogen atoms deuterated with isotopes ( 2 After deuteration, the compounds of the present invention have the effects of extending half-life, reducing clearance rate, stabilizing metabolism and improving in vivo activity.

[0040] The preparation method of the isotopic derivative generally includes: a phase transfer catalytic method. For example, a preferred deuteration method uses a phase transfer catalyst (e.g., a tetraalkylammonium salt, NBu4HSO4). The use of a phase transfer catalyst to exchange the methylene protons of the diphenylmethane compound results in a higher deuterium introduction than reduction with deuterated silane (e.g., triethyldeuterated monosilane) or with a Lewis acid such as aluminum trichloride using sodium deuterated borate in the presence of an acid (e.g., methanesulfonic acid).

[0041] The term "therapeutic" refers to a chemical entity that is effective in treating a target disorder, disease or condition.

[0042] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0043] The compound of formula (I) of the present invention is prepared by referring to the method in PCT / CN2021 / 133447, and the relevant contents are cited in this text for illustration.

[0044] The beneficial effects of the present invention compared with the prior art include: the present invention provides a glucagon-like peptide-1 (GLP-1) receptor agonist combined with metformin in the prevention and / or treatment of diabetes drugs, which has a synergistic effect and can be used to prevent and / or treat diabetes and its complications, and is specifically beneficial for the treatment of diabetes, obesity, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, fatty liver, cirrhosis, hepatic diabetes, cirrhosis combined with diabetes, diabetic fatty liver, diabetic liver disease or other diabetes-related diseases. DETAILED DESCRIPTION

[0045] The present invention is further described in detail below with reference to examples, but the embodiments of the present invention are not limited thereto.

[0046] Example 1

[0047] Synthesis of 2-(1-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid - Compound A

[0048] Synthesis of 2-((S)-(1-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid - Compound Aa

[0049] Synthesis of 2-((R)-(1-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid - Compound Ab

[0050]

[0051] The specific synthetic route is as follows:

[0052] Step A: Synthesis of tert-butyl 4-(6-chloropyridin-2-yl)piperazine-1-carboxylate

[0053]

[0054] Dissolve tert-butyl piperazine-1-carboxylate (300.0 mg, 1.61 mmol) in 1,4-dioxane (12.0 ml), add 2,6-dichloropyridine (262.0 mg, 1.77 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (135.4 mg, 0.16 mmol) and cesium carbonate (788.5 mg, 2.42 mmol). Under nitrogen protection, heat to 100 degrees Celsius and stir to react for 5 hours. The solvent is dried and separated by column chromatography (ethyl acetate: n-hexane = 1:10) to obtain 150.0 mg of beige solid tert-butyl 4-(6-chloropyridin-2-yl)piperazine-1-carboxylate (yield: 31.3%). LC-MS: RT = 1.82 min, [M- t Bu+H] + =242.36.

[0055] Step B: Synthesis of tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazine-1-carboxylate

[0056]

[0057] Dissolve tert-butyl 4-(6-chloropyridin-2-yl)piperazine-1-carboxylate (150.0 mg, 0.51 mmol) in 1,4-dioxane (5.0 ml), add 3-fluoro-4-(hydroxymethyl)benzonitrile (76.3 mg, 0.51 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (43.2 mg, 0.05 mmol) and cesium carbonate (246.8 mg, 0.76 mmol). Under nitrogen protection, heat to 100 degrees Celsius and stir to react for 15 hours. The solvent was dried and separated by column chromatography (ethyl acetate: n-hexane = 1:10) to obtain 102.0 mg of beige solid 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (yield: 49.1%). LC-MS: RT = 2.23 min, [M-tBu+H] + =357.23.

[0058] Step C: Synthesis of 3-fluoro-4-(((6-(piperazin-1-yl)pyridin-2-yl)oxy)methyl)benzonitrile

[0059]

[0060] Dissolve tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazine-1-carboxylate (102.0 mg, 0.25 mmol) in methanol (2.0 ml), add hydrochloric acid / 1,4-dioxane solution (0.5 ml, 2.0 mmol). Stir and react for 3 hours at room temperature. The solvent is dried to obtain 73.7 mg of white solid 3-fluoro-4-(((6-(piperazin-1-yl)pyridin-2-yl)oxy)methyl)benzonitrile (yield: 73.5%). LC-MS: RT = 1.68 min, [M+H] + = 313.25.

[0061] Step D: Synthesis of methyl 2-(1-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate

[0062]

[0063] To a solution of 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazine hydrochloride (652 mg, 2.09 mmol) in acetonitrile (8.0 ml) at 25°C, N,N-diisopropylethylamine (1.0 ml), potassium iodide (420 mg, 3.13 mmol) and potassium carbonate (577 mg, 4.18 mmol) were added to N,N-dimethylformamide (10.0 ml) and finally 2-((S)-1-chloroethyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (650 mg, 2.09 mmol) was added. The reaction was carried out at 60°C for 3.0 hours under N2 protection.

[0064] After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 ml x 2 times). The organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2 / 1). 690 mg of yellow solid 2-(1-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester was obtained (yield: 56.4%, dr = 66%). LC-MS: RT = 1.93 min, [M+H] + =586.26.

[0065] Step E: Synthesis of 2-1-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound A)

[0066]

[0067] To a mixed solution of compound 51-1 (690 mg, 1.18 mmol) in tetrahydrofuran (3 ml) and methanol (1 ml) was added dropwise an aqueous solution (1 ml) of lithium hydroxide (198 mg, 4.72 mmol) at 0 degrees Celsius, and the mixture was reacted at 25 degrees Celsius for 30 minutes.

[0068] After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 ml x 2 times). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10). 290 mg of 2-(1-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester was obtained as a white solid (yield: 43.0%). LC-MS: RT = 1.79 min, [M+H] + =572.30. 1 H NMR (400MHz, DMSO-d6) δ8.14(d,J=8.2Hz,1H),7.97(d,J=8.2Hz,1H),7.87(dd,J=10.0,1.5Hz,1H),7.69(d d,J=7.9,1.4Hz,1H),7.64(t,J=7.6Hz,1H),7.45(t,J=8.0Hz,1H),6.30(d,J=8.1Hz,1H),6.10(d,J=7.8Hz ,1H),5.38(s,2H),5.30–5.24(m,1H),4.82–4.70(m,2H),4.63–4.58(m,1H),4.44–4.39(m,1H),4.11–4.06 (m,1H),3.43–3.33(m,4H),2.64–2.58(m,1H),2.56–2.52(m,4H),2.39–2.30(m,1H),1.45(d,J=6.7Hz,3H).

[0069] Step F: Synthesis of 2-((S)-1-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound Aa) and 2-((R)-1-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound Ab)

[0070]

[0071] To a mixed solution of methyl 2-(1-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (690 mg, 1.18 mmol) in tetrahydrofuran (3 ml) and methanol (1 ml) was added dropwise an aqueous solution (1 ml) of lithium hydroxide (198 mg, 4.72 mmol) at 0°C, and the mixture was reacted at 25°C for 30 min.

[0072] After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 ml x 2 times). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10). 290 mg of 2-((S)-1-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[ 4,5-b]pyridine-5-carboxylic acid (Compound Aa) (yield: 43.0%) and 59 mg of white solid 2-((R)-1-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound Ab) (yield 8.7%). The crude product was purified by preparative high performance liquid chromatography. Separation conditions were as follows: Chromatographic column: Agilent 5Prep-C 18 100mm×30mm 5μM; mobile phase: water (containing 0.1% ammonia) and acetonitrile; flow rate: 20 ml / min; gradient: 21% acetonitrile eluted compound Aa and compound Ab at 10.12 minutes and 12.17 minutes respectively, detection wavelength: 254nm.

[0073] Compound Aa:HPLC:RT=10.12min. LC-MS:RT=1.79min,[M+H] + =572.30. 1H NMR (400MHz, DMSO-d6) δ8.14(d,J=8.2Hz,1H),7.97(d,J=8.2Hz,1H),7.87(dd,J=10.0,1.5Hz,1H),7.69(d d,J=7.9,1.4Hz,1H),7.64(t,J=7.6Hz,1H),7.45(t,J=8.0Hz,1H),6.30(d,J=8.1Hz,1H),6.10(d,J=7.8Hz ,1H),5.38(s,2H),5.30–5.24(m,1H),4.82–4.70(m,2H),4.63–4.58(m,1H),4.44–4.39(m,1H),4.11–4.06 (m,1H),3.43–3.33(m,4H),2.64–2.58(m,1H),2.56–2.52(m,4H),2.39–2.30(m,1H),1.45(d,J=6.7Hz,3H).

[0074] Compound Ab: HPLC: RT = 12.17 min. LC-MS: RT = 1.79 min, [M+H] + =572.30. 1 H NMR (400MHz, DMSO) δ8.09(d,J=8.2Hz,1H),7.95(d,J=8.2Hz,1H),7.87(dd,J=10.0,1 .4Hz,1H),7.69(dd,J=7.9,1.5Hz,1H),7.67–7.61(m,1H),7.46(t,J=8.0Hz,1H),6.31 (d,J=8.1Hz,1H),6.11(d,J=7.8Hz,1H),5.39(s,2H),5.07–5.00(m,2H),4.69–4.49(m ,4H),3.47–3.37(m,4H),2.79–2.70(m,1H),2.66–2.52(m,5H),1.42(d,J=6.8Hz,3H).

[0075] Example 2

[0076] Synthesis of 2-((S)-1-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid sodium salt

[0077]

[0078] 2-((S)-1-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (1 g, 1.75 mmol) was dissolved in 20 ml of water to obtain a suspension. An aqueous sodium hydroxide solution (0.175 mmol / ml, 10 ml, 1.75 mmol) was added dropwise under ice bath conditions. The solution became clear and stirring was continued for 1 hour while maintaining the ice bath conditions. The sample was directly lyophilized to obtain a sodium salt sample.

[0079] 1 HNMR(400MHz,DMSO-d6)δ7.96(d,J=8.2Hz,1H),7.91(d,J=8.2Hz,1H),7.88(dd,J=9.9,1.5Hz,1H),7.70(dd,J =7.9,1.5Hz,1H),7.64(t,J=7.5Hz,1H),7.45(t,J=8.0Hz,1H),6.30(d,J=8.1Hz,1H),6.11(d,J=7.8Hz,1H),5 .39(s,2H),5.22(tt,J=7.6,3.9Hz,1H),4.83–4.69(m,2H),4.52(q,J=6.7Hz,1H),4.41(td,J=8.0,5.7Hz,1H) ,4.07(dt,J=9.2,5.7Hz,1H),3.45–2.53(m,4H),2.58–2.53(m,5H),2.41–2.32(m,1H),1.44(d,J=6.7Hz,3H).

[0080] Example 3

[0081] Synthesis of 2-((S)-1-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid potassium salt

[0082]

[0083] 2-((S)-1-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (1 g, 1.75 mmol) was dissolved in 20 ml of water to obtain a suspension. A potassium hydroxide aqueous solution (0.175 mmol / ml, 10 ml, 1.75 mmol) was added dropwise under ice bath conditions. The solution became clear and stirring was continued for 1 hour while maintaining the ice bath conditions. The sample was directly freeze-dried to obtain a potassium salt sample.

[0084] 1 HNMR (400MHz, DMSO-d6) δ7.91(d,J=8.2Hz,1H),7.88(dd,J=10.0,1.5Hz,1H),7.84(d,J=8.2Hz,2H),7.70(dd,J=7.9, 1.5Hz,1H),7.65(t,J=7.5Hz,1H),7.45(t,J=8.0Hz,1H),6.30(d,J=8.2Hz,1H),6.10(d,J=7.8Hz,1H),5.39(s,2H),5. 29–5.23(m,1H),4.70(dd,J=15.0,4.1Hz,1H),4.69(dd,J=15.0,4.1Hz,1H),4.57(q,J=6.7Hz,1H),4.41(td,J=8.1,5. 8Hz,1H),4.06(dt,J=9.1,5.9Hz,1H),3.50–3.30(m,5H),2.61–2.50(m,4H),2.40–2.31(m,1H),1.44(d,J=6.7Hz,3H).

[0085] Example 4

[0086] Synthesis of 2-((S)-1-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid trishydroxymethylaminomethane salt

[0087]

[0088] 2-((S)-1-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (599.9 mg, 1.05 mmol) was dissolved in 10 ml of methanol to obtain a suspension, and tris(hydroxymethylaminomethane) aqueous solution (2 mmol / ml, 524.9 The solution became clear after stirring at room temperature for 10 minutes, and the stirring was continued for 2 hours at room temperature. The clarified sample was transferred to room temperature for vacuum drying, and 10 ml of methyl tert-butyl ether was added to the solid sample obtained by drying to obtain a suspension. The suspension was stirred for 24 hours under temperature cycle (50°C to 5°C, 0.1°C / min), and the suspension was centrifuged. The solid was dried in vacuum at 50°C to obtain a trishydroxymethylaminomethane salt (tris salt) sample.

[0089] 1 H NMR(400MHz,MeOD)δ8.10–8.02(m,2H),7.62(t,J=7.5Hz,1H),7.56–7.51(m,2H),7.42(t,J=8.0Hz,1H) ,6.25(d,J=8.1Hz,1H),6.12(d,J=7.8Hz,1H),5.42(s,2H),5.41–5.33(m,1H),4.97(dd,J=15.2,3.8Hz, 1H),4.87(dd,J=15.2,3.6Hz,1H),4.66(q,J=6.7Hz,1H),4.53(td,J=8.0,6.0Hz,1H),4.11(dt,J=9.3,5 .9Hz,1H),3.67(s,6H),3.51–3.37(m,4H),2.72–2.56(m,5H),2.44–2.32(m,1H),1.56(d,J=6.8Hz,3H).

[0090] Example 5

[0091] Study on the pharmacokinetic characteristics of the GLP-1R agonist of the present invention combined with metformin in SD rats

[0092] 1. Reagents and instruments

[0093] 1,1-Dimethylbiguanide (Aladdin, batch number G2327041), LC-MS / MS instrument (Shimadzu Nexera LC-40UPLC, SCIEXAB Sciex 5500+ triple quadrupole mass spectrometer).

[0094] 2. Experimental Animals

[0095] Six male SD rats, weighing 200-250 g, were purchased from Guangdong Weitonglihua Experimental Animal Technology Co., Ltd.

[0096] 3. Preparation

[0097] 1,1-Dimethylbiguanide, Compound Aa of Example 1 and the corresponding compound prepared according to Example 4A-1 of CN201780086550.1 were accurately weighed in a mortar, and the solvent was 50% CMC-Na (0.5%) + 30% TPGS (14.3%) + 20% PEG 400, and ground evenly. Three groups of preparations were prepared: metformin, metformin + compound Aa, and metformin + Example 4A-1. The concentrations of metformin, compound Aa and Example 4A-1 were all 30 mg / mL.

[0098] 4. Blood sample collection and biological analysis

[0099] Six SD rats were randomly divided into three groups, with fixed rat numbers, and each rat was orally gavaged with the corresponding preparation at a volume of 10 mL / kg. Each rat was fasted for 12 hours before administration.

[0100] After oral administration to SD rats, about 200 μL of blood was collected from the tail vein using a scalp needle at 15 min, 30 min, 1 h, 2 h, 5 h, 7 h, and 24 h, respectively. The blood was placed in a blood collection tube containing EDTA-K2 anticoagulant, centrifuged at 4000 rpm, 2-8 °C for 10 min to separate plasma, and stored at -80 °C for testing.

[0101] Accurately weigh a certain amount of metformin and dissolve it in DMSO to 2 mg / mL as a stock solution. The stock solution was diluted with acetonitrile: water (1:1) to 300000, 100000, 50000, 30000, 10000, 5000, 3000, 1000, 500, 300, 1000, 500, 300, 100 ng / mL to obtain standard curve working solutions and 240000, 6000, 240 ng / mL quality control working solutions. Take 5 μL of the working solution and add it to 45 μL of blank SD rat plasma, vortex and mix, and prepare standard curve samples equivalent to plasma concentrations of 30000, 10000, 5000, 3000, 1000, 500, 300, 100, 50, 30, 10 ng / mL and quality control samples of 24000, 600, 24 ng / mL. Take 30 μL of the standard curve sample, quality control sample and collected plasma sample and add 200 μL of compound A-D8 acetonitrile methanol solution (internal standard is deuterated compound A, 50 ng / mL) to precipitate protein, vortex for 4 minutes, centrifuge at 4000 rpm and 4°C for 10 minutes, transfer 150 μL of supernatant to a new 96-well plate, add 150 μL of ultrapure water to mix, and inject for analysis. LC-MS / MS detection conditions are as follows:

[0102] Chromatographic column: YMC-Triart C18.50×2.1mm, S-3μm 12nm.

[0103] Mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile, flow rate: 0.5 mL / min, gradient elution:

[0104] Time (min) A(％) B(％) 0 90％ 10％ 0.6 90％ 10％ 1.5 10％ 90％ 2.5 10％ 90％ 2.51 90％ 10％ 3.2 90％ 10％

[0105] 5. Data processing

[0106] After LC-MS / MS detection of blood drug concentration, the non-compartmental model of WinNonlin 6.1 software was used to calculate the pharmacokinetic parameters of SD rats after administration. The results are shown in Table 1.

[0107] Table 1: Pharmacokinetic parameters of the GLP-1R agonist of the present invention combined with metformin in SD rats

[0108]

[0109] From the above results, it can be seen that the combination of compound Aa of the present invention and metformin can significantly increase the exposure of metformin in SD rats, while the combination of Example 4A-1 of CN201780086550.1 and metformin does not increase the exposure of metformin.

[0110] Example 6

[0111] Hypoglycemic effect of compound Aa combined with metformin hydrochloride in a transgenic mouse model of humanized GLP-1R gene

[0112] 1. Experimental Methods

[0113] 1.1 Drug preparation

[0114] Solvent (0.5% CMC-Na)

[0115] 1.2 Preparation method: (Take the preparation of 1L as an example): Weigh 5g CMC-Na into a suitable container, add ultrapure water to make up to 1L, and continue stirring until there are no solid particles. After preparation, store at 4℃ and use within one month.

[0116] 1.2.1 Preparation method of tris salt of compound Aa: Weigh the sample and grind it in a mortar. First, add a small amount of solvent and grind it until it is fine and free of particles. Then add the solvent several times to make up to the calculated volume and grind it evenly. Prepare the final concentration of compound Aa to 1, 2, 4, 5, 6, 8 mg / mL, which can be stored at 4°C for 7 days.

[0117] 1.2.2 Preparation of metformin hydrochloride: Weigh the sample and grind it in a mortar. First, add a small amount of solvent and grind it evenly. Then add the solvent several times to make up to the calculated volume and grind it evenly. Prepare 8.5 and 10 mg / mL working solution of metformin hydrochloride, which can be stored at 4°C for 7 days.

[0118] 1.2.3 Preparation method of tris salt of compound Aa and metformin hydrochloride compound: Weigh the sample and grind it in a mortar. First, add a small amount of solvent and grind it evenly. Then add the solvent several times to make up to the calculated volume and grind it evenly. According to compound Aa and metformin hydrochloride, prepare 1mg / mL+8.5mg / mL, 1mg / mL+10mg / mL, 2mg / mL+8.5mg / mL, 2mg / mL+10mg / mL, 4mg / mL+8.5mg / mL, 4mg / mL+10mg / mL, 5mg / mL+8.5mg / mL, 5mg / mL+10mg / mL, 6mg / mL+8.5mg / mL, 6mg / mL+10mg / mL, 8mg / mL+8.5mg / mL, 8mg / mL+10mg / mL working solution, which can be stored at 4℃ for 7 days.

[0119] Return to room temperature before daily administration, stir thoroughly, and mix the drug before withdrawing it.

[0120] 1.3 Group design

[0121] 1.3.1 Animal screening

[0122] After the animal quarantine and adaptation period, the mice were fasted overnight, and blood glucose was tested by tail vein blood sampling. Then, B-hGLP1R gene mice (purchased from Biocytogen Jiangsu Gene Biotechnology Co., Ltd., weighing 20.4 g to 25.0 g) were given a single dose of metformin hydrochloride (100 mg / kg, PO) or solvent. One hour after administration, the mice were given 2.5 g / kg glucose solution, and then the tail tip blood glucose value of the mice was measured using a handheld Roche blood glucose meter (Roche, Accu-chek). The blood glucose changes of animals within 2 hours after sugar administration were measured: the blood glucose measurement time points were: before sugar administration (0 point), 15, 30, 60 and 120 minutes after sugar administration. The area under the curve (AUC) of glucose was calculated. 0～120minGlu ) to assess glucose tolerance in mice.

[0123] The area under the glucose curve (AUC 0～120minGlu ), screened out the AUC after administration of metformin hydrochloride 0～120min The animals with a decline rate lower than 25% were subjected to the next experiment.

[0124] 1.3.2 Grouping

[0125] The area under the glucose curve (AUC 0～120minGlu ) and body weight, the mice were randomly divided into 21 groups, 6 mice in each group. The groups and dosing are shown in Table 2.

[0126] Table 2 Animal grouping and dosing schedule

[0127]

[0128] Note: The dosage volume is 10mL / kg; single oral administration

[0129] 1.3.3 Observation and testing indicators

[0130] 1.3.3.1 Clinical observation

[0131] Observe the animal's behavior and coat color, and record any abnormalities.

[0132] 1.3.3.2 Weight

[0133] The dosing volume was determined according to the animal's body weight.

[0134] 1.3.3.3 Blood glucose testing

[0135] After the animals were fasted overnight, the blood glucose of the mouse tail tip was measured using a handheld Roche blood glucose meter (Roche, Accu-chek). Note: The first drop of blood from the tail tip was discarded, and the blood glucose was measured twice in succession. If the difference was greater than 10%, a third test was required.

[0136] Oral glucose tolerance test (OGTT): After the animals were fasted overnight, 2.5 g / kg glucose solution was given by oral gavage. The blood glucose of the animals was tested at the following time points: before sugar administration (0 min), and 15, 30, 60, 90, and 120 min after sugar administration.

[0137] Note: Sugar should be given 1 hour after the medication is given in the morning. The calculation method is as follows:

[0138] AUC 0-120minGlu Decline rate = (AUC 0-120minGlu Blank control group – AUC 0-120minGlu Dosage group) / AUC 0-120minGlu Blank control group × 100%

[0139] Synergistic effect = AUC of combined drug 0-120minGlu Decline rate – (AUC of tris salt of compound Aa 0-120minGlu Decline rate + metformin hydrochloride AUC 0-120minGlu Decline rate)

[0140] 1.4 End of the experiment

[0141] Death from inhalation of excessive carbon dioxide.

[0142] 1.5 Statistical analysis

[0143] Measurement data were expressed as mean ± standard deviation (Mean ± SD), and the t test was used for comparison between the two groups, and P < 0.05 indicated that the difference was statistically significant. One-way ANOVA was used for comparison between multiple groups, and P < 0.05 was considered statistically significant.

[0144] 1.6 Experimental Results and Discussion

[0145] As shown in Tables 3 and 4, in B-hGLP1R gene mice, the area under the glucose curve (AUC 0～120minGlu ) decreased after administration. The inhibition rate of the tris salt of compound Aa alone was 28%-42%, and the inhibition rate of the metformin hydrochloride alone (85, 100 mg / kg) was 15% and 19%, respectively. The combination of the two can produce a synergistic effect when the dose of metformin hydrochloride is 85 mg / kg or 100 mg / kg and the dose of tris salt of compound Aa is 10, 20, 40, 50, 60 or 80 mg / kg. When the dose of metformin hydrochloride is 85 mg / kg or 100 mg / kg and the dose of the tris salt of compound Aa is 20, 40, 50 or 60 mg / kg, the synergistic effect is strong (≥9%). In addition, we also found that the synergistic effect of the above-mentioned compound is better than the synergistic effect of the compound of PF-06882961 and metformin at the same dose; when the dose of metformin hydrochloride is 100 mg / kg and the dose of the tris salt of compound Aa is 20, 40, 50 or 60 mg / kg, the synergistic effect is strong (≥10%). When the dose of metformin hydrochloride is 100 mg / kg and the dose of the tris salt of compound Aa is 40 mg / kg, the synergistic effect is the strongest (13%).

[0146] Table 3 Effects of different combinations on OGTT glucose AUC in mice 0～120minGlu Inhibition rate

[0147]

[0148] Table 4 Synergistic effect results

[0149]

[0150]

[0151] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. Use of a glucagon-like peptide-1 receptor (GLP-1R) agonist and / or its salt in combination with metformin and / or its salt in the preparation of a drug for preventing and / or treating diabetes and its complications, characterized in that: The glucagon-like peptide-1 (GLP-1) receptor agonist is a compound represented by formula I and / or a salt thereof, 2. The application according to claim 1, characterized in that: The diabetic complications include obesity, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, fatty liver, cirrhosis, hepatic diabetes, cirrhosis combined with diabetes, diabetic fatty liver and diabetic liver disease.

3. The application according to claim 1, characterized in that: The glucagon-like peptide-1 (GLP-1) receptor agonist is selected from:

4. The use according to claim 1, characterized in that: The salt of the glucagon-like peptide-1 (GLP-1) receptor agonist is selected from at least one of lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, iron salt, zinc salt or ammonium salt; or the salt is selected from hydrochloride, methylamine salt, dimethylamine salt, trimethylamine salt, ethylamine salt, diethylamine salt, triethylamine salt, isopropylamine salt, 2-ethylaminoethanol salt, pyridine salt, methylpyridine salt, ethanolamine salt, diethanolamine salt, ammonium salt, tetramethylammonium salt, tetraethylammonium salt, triethanolamine salt, piperidine salt , piperazine salt, morpholine salt, lysine salt, L-lysine salt, arginine salt, L-arginine salt, histidine salt, L-histidine salt, meglumine salt, dimethylglucosamine salt, ethylglucosamine salt, dicyclohexylamine salt, 1,6-hexanediamine salt, glucosamine salt, sarcosine salt, serinol salt, trishydroxymethylaminomethane salt, aminopropanediol salt, ornithine salt or choline salt; further preferably sodium salt, potassium salt, trishydroxymethylaminomethane salt, calcium salt, magnesium salt; The salt of metformin is selected from hydrochloride.

5. The use according to claim 1, characterized in that: The mass ratio of the glucagon-like peptide-1 (GLP-1) receptor agonist and / or its salt to metformin and / or its salt is: 10-80:85-100 or 300:300; preferably, the mass ratio of the glucagon-like peptide-1 (GLP-1) receptor agonist and / or its salt to metformin and / or its salt is: 10-80:85 or 10-80:100 or 300:300; more preferably, the glucagon-like peptide-1 (GLP-1) receptor agonist and / or its salt to metformin and / or its salt is: 10-80:85 or 10-80:100 or 300:300 The mass ratio of the glucagon-like peptide-1 (GLP-1) receptor agonist and / or its salt to metformin and / or its salt is 20:85, 30:85, 40:85, 50:85, 60:85, 20:100, 30:100, 40:100, 50:100, 60:100 or 300:

300.

6. A pharmaceutical composition, characterized in that The pharmaceutical composition is composed of compound Aa and / or its salt and metformin and / or its salt; wherein the structure of compound Aa is: The weight ratio of the compound Aa and / or its salt to metformin and / or its salt is: 10-80:85-100 or 300:300; Preferably, the weight ratio of the compound Aa and / or its salt to metformin and / or its salt is: 10-80:85, 10-80:100 or 300:300; More preferably, the weight ratio of the compound Aa and / or its salt to metformin and / or its salt is: 20-60:85, 20-60:100 or 300:300; Most preferably, the weight ratio of compound Aa and / or its salt to metformin and / or its salt is 20:85, 30:85, 40:85, 50:85, 60:85, 20:100, 30:100, 40:100, 50:100, 60:100 or 300:

300.

7. The pharmaceutical composition according to claim 6, characterized in that The daily dosage of the compound Aa and / or its salt is 200-1600 mg, and the daily dosage of metformin and / or its salt is 1000-2000 mg.

8. The pharmaceutical composition according to claim 6, characterized in that The pharmaceutical composition is packaged according to the clinical dosage and prepared into dosage units of specific specifications, wherein the dosage unit contains compound Aa and / or its salt: 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg or 800 mg, and contains metformin and / or its salt: 500 mg, 850 mg or 1000 mg.

9. The pharmaceutical composition according to any one of claims 6 to 8, characterized in that The salt of the compound Aa is selected from at least one of lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, iron salt, zinc salt or ammonium salt; or the salt is selected from hydrochloride, methylamine salt, dimethylamine salt, trimethylamine salt, ethylamine salt, diethylamine salt, triethylamine salt, isopropylamine salt, 2-ethylaminoethanol salt, pyridine salt, methylpyridine salt, ethanolamine salt, diethanolamine salt, ammonium salt, tetramethylammonium salt, tetraethylammonium salt, triethanolamine salt, piperidine salt, piperazine salt, morpholine salt , lysine salt, L-lysine salt, arginine salt, L-arginine salt, histidine salt, L-histidine salt, meglumine salt, dimethylglucosamine salt, ethylglucosamine salt, dicyclohexylamine salt, 1,6-hexanediamine salt, glucosamine salt, sarcosine salt, serinol salt, trishydroxymethylaminomethane salt, aminopropanediol salt, ornithine salt or choline salt at least one; further preferably sodium salt, potassium salt, trishydroxymethylaminomethane salt, calcium salt, magnesium salt; The salt of metformin is selected from hydrochloride.

10. The pharmaceutical composition according to any one of claims 6 to 9, characterized in that The pharmaceutical composition is selected from the group consisting of tablets, capsules, oral solutions, pills, granules, pellets, sustained-release preparations or other oral dosage forms; preferably, the pharmaceutical composition is selected from the group consisting of tablets or capsules.

11. Use of the pharmaceutical composition according to any one of claims 6 to 10 in the preparation of a drug for preventing and / or treating diabetes and its complications; preferably, the diabetic complications include obesity, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, fatty liver, cirrhosis, hepatic diabetes, cirrhosis combined with diabetes, diabetic fatty liver and diabetic liver disease.

Images