CN105998032B - Application of oleanolic acid derivatives and pharmaceutical compositions thereof in medicine - Google Patents

Abstract

The invention discloses an oleanolic acid derivative, which is represented by formula (I), its stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt and its pharmaceutical combination The application of the compound in medicine specifically discloses a compound of the formula (I) or a pharmaceutical composition of the compound of the formula (I) to prepare for preventing or treating the following diseases, alleviating the symptoms of the following diseases or delaying the following diseases The use of medicines for the development or onset, wherein said disease is type II diabetes, hyperlipidemia: The present invention also discloses the compound represented by formula (I), or its stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt in protein tyrosine phosphatase (PTP-1B) , TGR5, or AMPK, or a combination thereof, in mediating diseases, primarily type II diabetes.

Description

Application of oleanolic acid derivatives and pharmaceutical compositions thereof in medicine

field of invention

The present invention relates to oleanolic acid derivatives and pharmaceutical compositions thereof, and also relates to the application of said derivatives and pharmaceutical compositions in reducing blood sugar, blood fat, antitumor, antiinfection, inflammatory diseases and the like.

Background of the invention

Diabetes mellitus (DM) is a systemic chronic secretory and metabolic disease associated with genetic factors. It is a metabolic disorder of sugar, fat, and protein caused by absolute or relative insufficiency of insulin secretion in the body. Its main features are hyperglycemia and urine sugar, often accompanied by atherosclerotic cardiovascular and cerebrovascular diseases, diabetic nephropathy, nervous system lesions and eye lesions such as cataracts, retinopathy and other complications in clinical practice. With the continuous improvement of living standards, the prevalence of diabetes is rising rapidly, and it has become the third major chronic disease that endangers human health. And China has become the country with the largest number of diabetic patients in the world. In 2013, the number of diabetic patients in China was as high as 114 million, and nearly 10 out of every 100 people were diabetics. In 2010, the global diabetes drug market was as high as US$34.43 billion, with a compound growth rate of 12.7% in the past five years, significantly higher than the growth rate of other disease drug markets over the same period. In 2013, the market size of China's diabetes drugs reached 17.33 billion yuan, and it is expected that the market size of diabetes drugs will reach 34.14 billion yuan in 2018. Therefore, the prevention and treatment of diabetes is a major research topic in the international diabetes community, and it is urgent to find effective methods and means for treating diabetes and its complications.

Diabetes is clinically divided into type 1 and type 2, of which type 2 diabetes accounts for more than 90% of all diabetic patients. Insulin resistance is an important etiology and distinctive feature of type 2 diabetes. Improving insulin resistance or increasing insulin sensitivity is one of the effective means to treat type 2 diabetes.

PTP1B (protein tyrosine phosphatase 1B) belongs to the protein tyrosine phosphatase family, which negatively regulates insulin signal transduction by dephosphorylating the tyrosine residues on the insulin receptor or its substrate, so that The inability of the insulin receptors to bind insulin leads to insulin resistance, which eventually leads to type 2 diabetes. It is recognized as a novel therapeutic target for diabetes and obesity (PTP1B as adrug target:recent developments in PTP1B inhibitor discovery[J].Drug discovery today,12(9-10):373-381.Natural and semisyntheticprotein tyrosine phosphatase 1B( PTP1B) inhibitors as anti-diabetic agents[J].RSC Advances,5(60):48822-48834.). In both in vivo and in vitro pharmacological experiments, PTP1B inhibitors can promote the improvement of insulin resistance and abnormal fat metabolism, which is another important research direction of insulin sensitizers.

Bile acids activate the mitogen-activated protease pathway, are ligands for the G-protein coupled receptor (GPCR) TGR5, and activate nuclear hormone receptors such as farnesoid X receptor alpha (FXR-alpha). By activating these distinct signaling pathways, bile acids not only regulate their own enterohepatic circulation, but also triglyceride, cholesterol, energy, and glucose homeostasis. Therefore, bile acids (BAs), which control signal transduction pathways, hold promise as new drug targets for the treatment of common metabolic diseases such as obesity, type II diabetes, hyperlipidemia, and atherosclerosis. Houten et al., TheEMBO Journal, 2006, 25, 1419-1425; Watanabe et al., Nature, 2006, 439(7075), 484-489 found that administration of bile acids to mice increased energy expenditure in brown fat tissue and could prevent obesity and insulin resistance. This new metabolism of bile acids is highly dependent on the induction of cyclic AMP-dependent thyroid hormone activating enzyme type II iodothyronine deiodinase (D2), which is absent in D2-/- mice middle. Treatment of brown adipocytes and human skeletal muscle cells with bile acids enhanced D2 activity and oxygen consumption. The above effects are not dependent on FXR-a, but are mediated by increased cAMP production resulting from the binding of bile acids to TGR5.

In recent years, in order to find drugs for the treatment of type 2 diabetes with novel mechanism of action and high safety, researchers continue to explore new targets. Among them, adenylate-activated protein kinase (AMPK) is one of the most concerned and potential targets. AMPK is a serine/threonine protein kinase and an important energy sensor in cells. It is widely distributed in various tissues and can regulate the energy metabolism state of the body. Its structure is a heterotrimer, composed of a catalytic subunit α and two regulatory subunits β and γ. Different AMPK subtypes in the body are encoded by different genes and thus have different physiological functions. The activation of AMPK is completed under the cooperation of many factors. Among them, the phosphorylation of the N-terminal amino acid residue Thr172 of the α subunit is necessary for the activation of AMPK. After being activated, AMPK exerts various physiological functions by phosphorylating various downstream substrates. In terms of glucose metabolism, AMPK activation can inhibit excessive hepatic glucose production and reduce blood drug concentration; at the same time, it can also induce the translocation of glucose transporter (GLUT) to the cell membrane and phosphorylate transcription factors to turn on the expression of GLUT gene to promote the development of peripheral tissues. uptake of glucose. In addition, studies have shown that activated AMPK can increase glucose transport, promote intracellular mitochondrial biosynthesis, promote energy metabolism, increase insulin sensitivity in related tissues, and improve insulin resistance. In terms of lipid metabolism, activated AMPK phosphorylates hydroxymethylglutaryl-CoA reductase (HMGR), causing a decrease in the synthesis of cholesterol; activating AMPK can also phosphorylate acetyl-CoA carboxylase (ACC) to hinder acetylation The conversion of coenzyme A to malonyl coenzyme A promotes the oxidative metabolism of fatty acids in the mitochondria and inhibits the synthesis of fat. In conclusion, AMPK is closely related to the metabolism of sugar and fat. Activating AMPK can play an active role in glucose and lipid metabolism, which is of great significance to the treatment of diabetes.

In recent years, with the improvement of people's living environment, the three high-level diseases of affluence are also a major problem that plagues people, especially hyperlipidemia, which can cause a variety of concurrent diseases. At present, the mainstream treatment method is to take blood lipid-lowering drugs, such as HMGCoA reductase inhibitors (statin class) and appropriate exercise, in addition, like MTP inhibitors, squalene synthase inhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, ileal sodium ion / bile acid cotransporter Inhibitors, up-regulators of LDL receptor activity, nicotinic acid or its derivatives, bile acid chelates or drug combinations also have certain applications.

Oleanolic acid (Oleanolic acid, OA), also known as Qingsisu, pentacyclic triterpenoids, widely exists in a variety of plants in the form of free or combined glycosides, such as ginseng, licorice, clove, privet fruit, three Seven and so on. Oleanolic acid has a wide range of pharmacological effects and biological activities such as anti-HIV, antibacterial, anti-cancer, anti-ulcer, and treatment of osteoporosis. Currently, oleanolic acid is a very promising lead compound in the research on structural modification of anti-diabetic, anti-inflammatory and anti-tumor activities. In the anti-diabetic structural modification, oleanolic acid derivatives can delay the hydrolysis of disaccharides and oligosaccharides in carbohydrates into glucose by inhibiting α-glucosidase in the upper small intestine, reducing the absorption of glucose to lower blood sugar; By inhibiting glycogen phosphorylase and activating glycogen synthase, glucose is synthesized into glycogen to lower blood sugar; by inhibiting protein tyrosine phosphatase 1B (PTP1B), regulating insulin signal transduction, increasing the sensitivity of insulin target tissues to insulin, Reduces glucose utilization and lowers blood sugar. Among the structural modifications aimed at anti-inflammation, oleanolic acid derivatives inhibited the production of NO induced by γ-interferon, and the inhibition of NO in macrophages played an anti-inflammatory role. In addition to hypoglycemic and anti-inflammatory effects, oleanolic acid derivatives also have strong anti-tumor activity, which can inhibit the proliferation of various tumor cells, such as inhibiting the proliferation and invasion of human lung cancer cells, inhibiting chronic myelogenous leukemia K562 cells, Inhibit human cervical cancer Hela cells, human breast cancer MCF cells, liver cancer cell line HepG2, etc. However, due to the weak anti-diabetic, anti-inflammatory and anti-tumor activities of oleanolic acid, and there are defects such as pharmacokinetic indicators that do not meet clinical standards and poor water solubility, it affects its clinical application. Therefore, in order to improve the anti-diabetic, anti-inflammatory and anti-tumor activities and improve its pharmacokinetic properties, a lot of work has been done on the structural modification of oleanolic acid as the lead compound.

The compound shown in formula (I) was first disclosed in Otting-Walter, Drawert-Friedrich et al, Chemische Berichte, 1955,88,1469-78, but did not mention formula (I), (Ia) or (Ib) shown in The compound can be used for lowering blood sugar, lowering blood fat, anti-tumor, anti-infection, inflammatory diseases and the like. Later, there were also related literature reports on the application of oleanolic acid derivatives in hypoglycemic and as protein tyrosine phosphatase 1B (PTP1B) inhibitors, such as the literature J.J.Ramírez-Espinosa et al.European Journal of Medicinal Chemistry, 2014, 87,316-327, wherein it is mentioned that the compound shown in formula (2) has no inhibitory effect on protein tyrosine phosphatase 1B (PTP1B), indicating that there is no hypoglycemic effect, and the present invention surprisingly finds that formula (I), (Ia ) or compounds shown in (Ib) have obvious hypoglycemic and hypolipidemic effects. Other relevant documents also do not mention that the compounds shown in formula (I), (Ia) or (Ib) can be used for the treatment of diabetes and hyperlipidemia, and it is impossible to predict formula (I), (Ia) or (Ib) through existing documents. ) strong hypoglycemic and lipid-lowering effects of the compound shown.

The present invention refers to the literature Shaojing Liu, Yannan Peng, Synlett, 2012, 23, 1501-1504 and Chinese patent CN 201410745230, synthesized a kind of oleanolic acid derivative, which is shown in the compound of formula (I), and determined its The effect of reducing blood sugar in mice in vivo and in vitro, and the effect of reducing blood lipids in mice in vitro and in vivo, the result is surprisingly found that the compound shown in formula (I) consumes 67.7% of glucose in 24h of human liver HepG2 cells, which is significantly higher than Oleanolic acid and metformin; and the compound of formula (I) of the present invention has a significantly lower blood sugar percentage than oleanolic acid in db/db diabetic mice, and is also equivalent to metformin. The compound of the formula (I) of the present invention has a high exposure amount in mice and a high bioavailability of 40.06%. The lipid-lowering effect of the compound of formula (I) is also obviously better than oleanolic acid and metformin, and can effectively reduce the contents of plasma triglyceride and total cholesterol in mice. Therefore, the compound of the formula (I), (Ia) or (Ib) of the present invention can act as a PTP1B (protein tyrosine phosphatase 1B) inhibitor, a TGR5 agonist, or an AMPK agonist or have an effect on it at the same time, with a significant decrease in Sugar and lipid-lowering effects can be effectively used in the treatment of type II diabetes patients and hyperlipidemia patients, and unexpected effects have been achieved.

Contents of the invention

The present invention prepares an oleanolic acid derivative, such as the structure shown in formula (I), (Ia) or (Ib), or its stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable Accepted salt, and pharmaceutical composition thereof, and described compound has been carried out pharmacological action active screening, the result surprisingly finds, the compound shown in formula (I) consumes 67.7% to human liver HepG2 cell 24h glucose, obviously high in oleanolic acid and metformin; and the compound of formula (I) of the present invention has a significantly lower blood sugar percentage in db/db diabetic mice than oleanolic acid, and is also equivalent to metformin. The compound of the formula (I) of the present invention has a high exposure amount in mice and a high bioavailability of 40.06%. The lipid-lowering effect of the compound of formula (I) is also obviously better than oleanolic acid and metformin, and can effectively reduce the contents of plasma triglyceride and total cholesterol in mice. Therefore, the compound of formula (I) of the present invention can be used as a PTP1B (protein tyrosine phosphatase 1B) inhibitor, a TGR5 agonist, or an AMPK agonist or have an effect on it at the same time, have significant hypoglycemic and lipid-lowering effects, and may have It is effective in the treatment of patients with type II diabetes and hyperlipidemia, and has achieved unexpected results. The compounds represented by the formula (I), (Ia) or (Ib) of the present invention and their pharmaceutical compositions have very positive application prospects in reducing blood sugar, blood fat, anti-tumor, anti-infection, inflammatory diseases, etc., and are type II Patients with diabetes or hyperlipidemia provide another effective treatment option.

In one aspect, the present invention relates to a pharmaceutical composition, comprising a compound represented by formula (I), or its stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, and pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or combination thereof,

In some embodiments, the pharmaceutical composition of the present invention, wherein the compound represented by formula (I) has the following structure:

In some embodiments, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent, wherein the additional therapeutic agent is selected from antidiabetic drugs of DPP-IV inhibitors, biguanide drugs, sulfonylureas Drugs, glucosidase inhibitors, PPAR agonists, αP2 inhibitors, TGR5 agonists, AMPK agonists, PPARα/γ dual activators, SGLT-2 inhibitors, glinides, insulin, glucagon-like Peptide-1 (GLP-1) inhibitors, PTP1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, antihyperglycemic agents, antiobesity agents, antihypertensive agents, antiplatelets Drugs, anti-atherosclerotic drugs, lipid-lowering drugs, anti-inflammatory drugs or a combination thereof.

In other embodiments, the pharmaceutical composition of the present invention, wherein the lipid-lowering drug is selected from MTP inhibitors, HMGCoA reductase inhibitors, squalene synthase inhibitors, fibric acid derivatives, ACAT inhibitors , lipoxygenase inhibitors, cholesterol absorption inhibitors, ileal sodium ion/bile acid cotransporter inhibitors, upregulators of LDL receptor activity, niacin or derivatives thereof, bile acid chelates, or combinations thereof.

In other embodiments, the pharmaceutical composition of the present invention, wherein the HMGCoA reductase inhibitor is selected from pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, Eta Vastatin, rosuvastatin, or a combination thereof.

In other embodiments, the pharmaceutical composition of the present invention, wherein the lipid-lowering drug is selected from pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, etavastatin, rosuvastatin or a combination thereof.

In another aspect, the present invention relates to a compound represented by formula (I), (Ia) or (Ib), or its stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt Or the pharmaceutical composition of the present invention is prepared for the prevention or treatment of following diseases, the purposes of alleviating the following disease symptoms or delaying the development or onset of following diseases, wherein said diseases are diabetes, diabetic retinopathy, diabetes mellitus Neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol in the blood, hyperlipidemia, obesity, hypertriglyceridemia, Syndrome X, complications of diabetes disease, atherosclerosis, hypertension, acute anemia, neutropenia, Alzheimer's disease, depression, HIV, HBV, HCV, inflammatory disease or neoplastic disease,

In some embodiments, the use of the present invention, wherein the diabetes is type II diabetes.

In another aspect, the present invention relates to a compound represented by formula (I), (Ia) or (Ib), or its stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt Use in the preparation of medicines for treating diseases mediated by protein tyrosine phosphatase (PTP-1B), TGR5, or AMPK or a combination thereof.

In some embodiments, the use described in the present invention, wherein the disease mediated by protein tyrosine phosphatase (PTP-1B), TGR5, or AMPK or a combination thereof is type II diabetes.

In another aspect, the present invention relates to a preparation of a medicine for treating type II diabetes, comprising administering a therapeutically effective amount of a compound of formula (I), (Ia) or (Ib) to humans or mammals or comprising a therapeutically effective amount of a compound of formula ( Pharmaceutical compositions of I), (Ia) or (Ib) compounds.

In some embodiments, the use of the present invention includes administering the compound of formula (I), (Ia) or (Ib) to mice at a dosage of 100 mg/kg, twice a day, for 2 consecutive weeks or 3 weeks.

Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying test procedures. The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are included within the scope of the present invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including, but not limited to, defined terms, term usage, described techniques, etc.), this Application shall prevail.

It is further appreciated that certain features of the invention, which, for clarity, have been described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications referred to herein are hereby incorporated by reference in their entirety.

The term "treating" any disease or condition as used herein means, in some embodiments, ameliorating the disease or condition (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or condition either physically (eg, stabilizing a perceived symptom) or physiologically (eg, stabilizing a parameter of the body), or both. In other embodiments, "treating" refers to preventing or delaying the onset, development or worsening of a disease or condition.

As described in the present invention, the term "pharmaceutically acceptable carrier" includes any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (such as antibacterial agent, antifungal agent), isotonic agent, Salts, drug stabilizers, binders, excipients, dispersants, lubricants, sweeteners, flavoring agents, coloring agents, or combinations thereof, these carriers are known to those skilled in the art (such as Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp 1289-1329). Except where any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.

The term "subject" as used in the present invention refers to an animal. Typically the animal is a mammal. Subjects, for example, also refer to primates (such as humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to a human (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is an open expression, that is, it includes the content specified in the present invention, but does not exclude other content.

"Stereoisomers" refer to compounds that have the same chemical structure, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .

"Enantiomer" refers to two non-superimposable isomers of a compound that are mirror images of each other.

"Diastereoisomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting points, boiling points, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, eg HPLC.

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg, in solution), then a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol isomerization and imine-enol isomerization Amine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The "pharmaceutically acceptable salt" used in the present invention refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods such as ion exchange methods recorded in books and literature these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3 - Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates the quaternary ammonium salts of any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed as counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _{1 -8} sulfonates and aromatic sulfonates.

The following abbreviations are used throughout this disclosure:

CDC1 ₃ deuterated chloroform

DMF N,N'-Dimethylformamide

FBS fetal bovine serum

THF Tetrahydrofuran

m-CPBA 3-chloroperoxybenzoic acid

Py pyridine

hours

mL milliliter

mole mole

g grams

V volume

Compositions, Formulations and Administration of Compounds of the Invention

The pharmaceutical composition of the present invention includes the compound shown in formula (I), (Ia) or (Ib), the compound listed in the present invention, or its stereoisomer, geometric isomer, tautomer, external Racemates, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs, as well as pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles, or combinations thereof .

The compounds of the present invention exist in free form, or suitably, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other compounds that can be administered directly or indirectly according to the needs of patients. Adducts or derivatives, compounds described in other aspects of the present invention, their metabolites or their residues.

As described in the present invention, the pharmaceutically acceptable pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, diluent, adjuvant, or excipient, which, as used in the present invention, includes any solvent, diluent Agents or other liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for specific target dosage forms. As described in: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, summarizing the literature herein, shows that different carriers can be used in the formulation of pharmaceutically acceptable pharmaceutical compositions and their known methods of preparation. Except to the extent that any conventional carrier medium is incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions in a deleterious manner with any other components of the pharmaceutically acceptable pharmaceutical composition, Their use is also contemplated by the present invention.

Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, sorbic acid, Potassium phosphate, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl sodium cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive, corn, and soybean oils; glycols, such as propylene glycol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; seaweed acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffered solution, and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, Coatings, sweeteners, flavors and fragrances, preservatives and antioxidants.

The compounds of the present invention can be administered as the only pharmaceutical agent or in combination with one or more other additional therapeutic (pharmaceutical) agents, wherein the combination causes acceptable adverse reactions, which is important for diabetes, diabetic complications and other related diseases. The treatment of these diseases is of special significance, including, but not limited to, type I diabetes, type II diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia hyperlipidemia, obesity, hypertriglyceridemia, Syndrome X, diabetic complications, atherosclerosis, hypertension, etc. The "additional therapeutic agent" used in the present invention includes known antidiabetic drugs, antihyperglycemic drugs, antiobesity drugs, antihypertensive drugs, antiplatelet drugs, antiatherosclerotic drugs, lipid-lowering drugs or anti-inflammatory agents , or a combination thereof.

Wherein, the antidiabetic agent described in the present invention includes, but is not limited to biguanide drugs (such as phenformin, metformin (metformin)), sulfonylurea drugs (such as acesulfame, chlorpropamide (diabinese ), glibenclamide (glibenclamide, glibenclamide), glipizide (glipizide, pisulfuron), gliclazide (gliclazide, Dameikang), glimepiride (glimepiride), glipizide Glipentide, gliquidone, tolazamide and tolbutamide, meglitinide), meglitinides (such as repaglinide and nateglinide) , α-glucoside hydrolase inhibitors (such as acarbose (acarbose)), α-glucosidase inhibitors (such as esteridin, camiglibose (camiglibose), emiglitate (emiglitate), Miglitol, voglibose, pradimicin, and salbostatin), PPAR agonists (eg, balaglitazone, cyclamate ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, and troglitazone ), PPARα/γ dual activators (e.g. CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), DPP-IV Inhibitors (sitagliptin, vildagliptin, alogliptin, linagliptin, and saxagliptin), glucagon-like peptide -1 (GLP-1) agonist (exendin-3 (exendin-3) and exendin-4 (exendin-4)), protein tyrosine phosphatase-1B (PTP1B) inhibitor (qudukui Ming, Haitisol extract and compounds disclosed by Zhang, S. et al., Modern Drug Discovery, 12 (9/10), 373-381 (2007), TGR5 agonist, AMPK agonist, insulin, insulin Mimetics, glycogen phosphorylase inhibitors, VPAC2 receptor agonists, glucokinase activators, glycogen phosphorylase inhibitors, or glucose-6-phosphatase inhibitors; αP2 inhibitors, acetyl-CoA Carboxylase-2 (ACC -2) inhibitors, phosphodiesterase (PDE)-10 inhibitors, diacylglycerol acyltransferase (DGAT) 1 or 2 inhibitors, glucose transporter 4 (GLUT4) modulators, and glutamine-fructose-6 - Phosphate amidotransferase (GFAT) inhibitors, SGLT-2 inhibitors.

Among them, the anti-hyperglycemic agents of the present invention include, but are not limited to, biguanide drugs (such as phenformin, metformin (metformin)), oleanolic acid and its derivatives, sulfonylurea drugs (such as acesulfame Cyclohexamide, chlorpropamide (diabinese), glibenclamide (glibenclamide, glibenclamide), glipizide (glipizide, sulfonyl urea), gliclazide (gliclazide, Dameikang), Glimepiride, glipentide, gliquidone, tolazamide and tolbutamide, meglitinide), meglitinides (such as repaglinide and nateglinide), α-glucoside hydrolase inhibitors (such as acarbose (acarbose)), α-glucosidase inhibitors (such as esteridins, camiglibose (camiglibose) ), emiglitate, miglitol, voglibose, pradimicin, and salbostatin), PPAR agonists (such as Balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone ( rosiglitazone) and troglitazone), PPARα/γ dual activators (such as CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK- 0767 and SB-219994), dipeptidyl peptidase IV (DPP-IV) (such as sitagliptin, vildagliptin, alogliptin, and saxagliptin )), glucagon-like peptide-1 (GLP-1) agonist (exendin-3 (exendin-3) and exendin-4 (exendin-4)), protein tyrosine phosphatase-1B (PTP1B) inhibitors (Traduquimin, Hetisol extract and compounds disclosed by Zhang, S. et al., Modern Drug Discovery, 12(9/10), 373-381(2007)), insulin, Insulin mimetics, glycogen phosphorylase inhibitors, VPAC2 receptor agonists, glucokinase activators, glycogen phosphorylase inhibitors, or glucose-6-phosphatase inhibitors; αP2 inhibitors, acetyl- CoA carboxylase-2 (ACC-2 inhibitor), phosphodiesterase (PDE )-10 inhibitors, TGR5 agonists, AMPK agonists, diacylglycerol acyltransferase (DGAT) 1 or 2 inhibitors, glucose transporter 4 (GLUT4) modulators, and glutamine-fructose-6-phosphate amidotransferase Enzyme (GFAT) inhibitors.

Among them, the lipid-lowering agents described in the present invention include, but are not limited to, MTP inhibitors, HMG CoA reductase inhibitors, squalene synthase inhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenase inhibitors , cholesterol absorption inhibitors, ileal sodium ion/bile acid cotransporter inhibitors, upregulators of LDL receptor activity, bile acid chelates or niacin and derivatives thereof. In some embodiments, the lipid-lowering agent is selected from pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, ertavastatin or rosuvastatin. Wherein, the anti-obesity agent is selected from CB-1 antagonists (such as rimonabant, taranabant, surinabant, otenabant, SLV319 and AVE1625), gut-selective MTP inhibitors (such as dirlotapide, mitratapide, and implitapide), CCKa agonists, 5HT2c agonists (such as loca lorcaserin), TGR5 agonists, AMPK agonists, MCR4 agonists, lipase inhibitors (such as Cetilistat), PYY _3-36 , opioid antagonists (such as naltrexone )), oleoyl-estrone, obinepitide, pramlintide, tesofensine, leptide, liraglutide, bromocriptide , orlistat (orlistat), exenatide (exenatide), AOD-9604 and sibutramine (sibutramide).

Among them, the suitable anti-inflammatory agents of the present invention include drugs for the prevention and treatment of reproductive tract/urethral infection, such as cranberry (Vaccinium macrocarpon) and cranberry derivatives, such as cranberry juice, cranberry extract or cranberry Vine flavonols. In addition, other suitable anti-inflammatory agents include, but are not limited to, aspirin, non-steroidal anti-inflammatory drugs, glucocorticoids, sulfasalazine, and cyclooxygenase II selective inhibitors, among others.

The pharmaceutical composition of the present invention can be administered orally, by injection, by spray inhalation, topically, rectally, nasally, buccally, vaginally or via an implantable kit. medicine. The term "injected" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial (cavity), intrasternal, intrathecal, intraocular, intrahepatic, focal Intracranial, and intracranial injection or infusion techniques. Preferred pharmaceutical compositions are administered orally, intraperitoneally or intravenously. The sterile injection form of the pharmaceutical composition of the present invention can be aqueous or oily suspension. These suspensions may be formulated according to the known art using suitable dispersing agents, wetting agents and suspending agents. Sterile injections can be sterile injection solutions or suspensions, which are non-toxic acceptable diluents or solvents for injection, such as 1,3-butanediol solution. Among the acceptable vehicles and solvents are water, Ringer's solution and isotonic sodium chloride solution. Furthermore, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

For this purpose any bland fixed oil may be a synthetic mono- or diglyceride. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially their polyoxyethylene derivatives. These oil solutions or suspensions may contain a long-chain alcohol diluent or dispersant, such as carboxymethylcellulose or similar dispersing agents, commonly used in pharmaceutical formulations of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifiers or enhancers of bioavailability, are generally used in pharmaceutically acceptable solid, liquid, or other dosage forms, and can be applied to target pharmaceutical preparations preparation.

Uses of the compounds and pharmaceutical compositions of the present invention

In one aspect, the compound represented by formula (I), (Ia) or (Ib) of the present invention, or its stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt or comprising formula (I ), the pharmaceutical composition of (Ia) or (Ib) compound can be used to prepare the purposes of the medicine that is used for preventing or treating following disease, alleviating following disease symptom or delaying the development or onset of following disease, wherein said disease is diabetes, Diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood fatty acid or glycerol levels, hyperlipidemia, obesity, hypertriglyceridemia, Syndrome X, diabetic complications, atherosclerosis, hypertension, acute anemia, neutropenia, Alzheimer's disease, depression, HIV, HBV, HCV, inflammatory disease or neoplastic disease. Wherein said diabetes is but not limited to type II diabetes.

On the other hand, the compounds represented by formula (I), (Ia) or (Ib) of the present invention, or their stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts can be used to prepare Use of medicines for treating diseases mediated by protein tyrosine phosphatase (PTP-1B), TGR5, or AMPK or a combination thereof. Wherein, the disease mediated by protein tyrosine phosphatase (PTP-1B), TGR5, or AMPK or a combination thereof is not limited to type II diabetes.

The purposes of the medicament for preparing the treatment type II diabetes described in the present invention, comprise administering the compound of formula (I), (Ia) or (Ib) of therapeutically effective amount to human or mammal or comprise the compound of formula (I), (Ia) of therapeutically effective amount ) or a pharmaceutical composition of (Ib) compound. It includes administering the compound of formula (I), (Ia) or (Ib) to mice at a dose of 100 mg/kg, twice a day, for 2 weeks or 3 weeks.

The compound of formula (I), (Ia) or (Ib) of the present invention can be used as PTP1B (protein tyrosine phosphatase 1B) inhibitor, TGR5 agonist, or AMPK agonist or have effect on it at the same time, have significant hypoglycemic and The lipid-lowering effect can be effectively used in the treatment of patients with type II diabetes and hyperlipidemia, and unexpected effects have been achieved.

The preparation of formula (I) compound

Step 1) 28-position carboxyl methyl esterification of oleanolic acid

Take 5 g (0.011 mol) of oleanolic acid, 1.824 g (1.2 equivalents) of K ₂ CO ₃ , add 80 ml of DMF and stir to dissolve, then add 4.7 ml (3 equivalents) of CH ₃ I to react for 10 hours; after the reaction is complete, extract with ethyl acetate , the organic layer was washed with 1N HCl, distilled water, and saturated NaCl solution, and dried over anhydrous Na ₂ SO ₄ ; distilled under reduced pressure to obtain a light yellow solid; recrystallized with methanol to obtain 4.656 g of pure product in the form of white powder, with a yield of 90% .

IR(KBr), ν, cm ^-1 : 3445(-OH), 2944(-CH ₂ -), 1727(-C=O), 1464(-CH ₃ ), 1388(-CH ₃ ), 1363, 1270 ,1184,1034,996,655.

Step 2) Acetylation of the 3-hydroxyl group of methyl oleanate

Dissolve 4.6g (0.01mol) of methyl oleanolic acid in 70ml of anhydrous pyridine, add 10.2ml (10 equivalents) of acetic anhydride under stirring, and stir at room temperature for reaction. TLC traces until the reaction is complete. React for 14h; extract with dichloromethane , washed with 1N HCl (10ml×3), washed with water, dried over anhydrous Na ₂ SO ₄ , evaporated to dryness under reduced pressure, and passed through a silica gel column (petroleum ether:ethyl acetate=10:1) to obtain 4.584g of pure product in the form of white powder , yield 92%.

IR(KBr), ν, cm ^-1 : 2937(-CH ₂ -), 1729(-C=O), 1726(-C=O), 1470(-CH ₃ ), 1363(-CH ₃ ), 1266 ,1239,1203,1123,1022.

Step 3) 12,13-double bond carbonylation of methyl 3-acetoxyoleanate

Take 4.5g (0.009mol) of oleanolic acid diester, add CHCl ₃ 80ml and stir to dissolve, cool down to 0°C in an ice bath, then add 6.213g (4 equivalents) of m-CPBA, stir for a while and move to room temperature for reaction, TLC tracking to 13h reaction At the end, CH ₂ Cl ₂ extraction, saturated NaHSO ₃ solution, saturated NaHCO ₃ , water, saturated NaCl water washing, anhydrous Na ₂ SO ₄ drying, at this time the epoxy generated by TLC detection is converted to 3-acetoxy-12 Oxygen-methyl oleanolic acid was concentrated under reduced pressure and passed through a silica gel column (petroleum ether: ethyl acetate = 35:2) to obtain 3.698 g of pure product in the form of white powder with a yield of 80%.

IR(KBr), ν, cm ^-1 : 2947(-CH ₂ -), 1725(-C=O), 1698(-C=O), 1466(-CH ₃ ), 1368(-CH ₃ ), 1243 , 1193, 1036.

ESI: M/Z = 529.38 [M+1].

Step 4) Reduction of 3-acetoxy-12-oxo-oleanolic acid methyl ester

Take 3.6g (0.0068mmol) of 3-acetoxy-12-oxo-oleanolic acid methyl ester, 100ml of diethylene glycol, 8.77g of KOH (23 equivalents), 35ml of hydrazine hydrate, stir and reflux at 125°C, and the suspension gradually Change the distillation device to gradually increase the temperature to distill out water and hydrazine hydrate, raise the temperature to 210°C and react for about 7 hours; then cool to room temperature, pour into ice water to precipitate a white solid, then adjust the pH to 3-4 with 1N HCl, and filter with suction , spin-dried under reduced pressure; through a silica gel column (dichloromethane:methanol=40:1) to obtain 1.881g of pure product in the form of white powder, with a yield of 60%.

ESI: M/Z=939.7[2M+Na-1]; IR(KBr), ν, cm ^-1 : 3462(-OH,-CO-OH), 2943(-CH ₂ -), 1692(-C= O), 1456(-CH ₃ ), 1387(-CH ₃ ), 1265, 1029.

¹ H NMR (400MHz,) δ3.18 (dd, J = 11.3, 4.8Hz, 1H), 2.15 (dd, J = 9.1, 4.6Hz, 1H), 1.89-1.74 (m, 3H), 1.71-1.40 ( m,10H),1.40-1.13(m,12H),1.09-1.01(m,1H),0.95(s,6H),0.89(s,3H),0.84(s,6H),0.78(s,3H) , 0.72 (s, 3H), 0.65 (d, J=11.2Hz, 1H).

Step 5) 28-position carboxymethyl esterification of 12,13-dihydrooleanolic acid

Take 1.8g (0.004mol) of 12,13-dihydrooleanolic acid and 0.663g (1.2 equivalents) of K ₂ CO ₃ , add 20ml of DMF and stir to dissolve, then add 1.7ml (3 equivalents) of CH ₃ I to react for 12h; After complete extraction with ethyl acetate, the organic layer was washed with 1N HCl, distilled water, and saturated NaCl solution, and dried over anhydrous Na ₂ SO ₄ ; distilled under reduced pressure to obtain a light yellow solid; pass through a silica gel column (petroleum ether: ethyl acetate = 5: 1) 1.711 g of pure product was obtained in the form of white powder, with a yield of 92%.

¹ H NMR (400MHz, CDCl ₃ ) δ: 3.70(s, 3H), 3.24-3.16(m, 1H), 2.23-2.14(m, 1H), 1.85-1.74(m, 2H), 1.74-1.58(m ,7H),1.57-1.14(m,15H),1.08-1.01(m,1H),0.96(d,J=3.1Hz,6H),0.90(d,J=4.9Hz,4H),0.84(d, J=7.3Hz, 6H), 0.80(d, J=5.8Hz, 3H), 0.75(s, 3H).

¹³ C NMR (100MHz, CDCl ₃ ) δ: 158.7, 78.5, 59.5, 56.7, 55.9, 53.8, 48.8, 47.6, 46.6, 45.0, 44.5, 44.2, 43.0, 42.2, 41.9, 41.6, 39.7, 38.1, 37.8, 37.3 ,36.8,34.1,34.0,32.2,30.0,29.0,28.3,28.1,27.8.

Bioactivity assay

1. The effect of formula (I) compound on HepG ₂ cell glucose consumption

HepG2 cells are a hepatic embryonoma cell line that is very similar in phenotype to human hepatocytes. It basically retains the pancreatic metabolic response of normal hepatocytes and can fully simulate the uptake and consumption of glucose in the surrounding environment by hepatocytes. Hypoglycemic drugs can increase glucose consumption in HepG2 cells. Therefore, the test drug can be used to affect the glucose consumption ability of HepG2 cells and evaluate its insulin-sensitizing activity.

HepG2 cells were cultured in high-glucose DMEM containing 10% fetal bovine serum and incubated in a 37°C, 5% CO ₂ cell incubator, and replaced with fresh culture medium every other day, and passaged once every 2-3 days. During the experiment, HepG2 cells were seeded in 96-well plates, and blank control wells without cells were set. When the cells grew to 70-80% confluence, the original medium was discarded, washed twice with PBS buffer, replaced with serum-free 1640 medium containing 0.2% BSA and 1nM insulin, and drugs were added in groups. Set no test drug normal control group, metformin positive and oleanolic acid control group (final concentration is 10 μmol/L) and formula (I) compound control group, each group is set more than 3 duplicate wells. After acting for 24 hours, the glucose content in the culture solution of each well was measured by the glucose oxidase method.

After the determination of glucose content was completed, the cells were fixed with 10% trichloroacetic acid for 1 hour, washed with double distilled water and dried, and 100 μl of SRB solution (4 mg/mL) was added to each well, stained at room temperature for 20 minutes, and then washed with 1% acetic acid. dry. Add 100 μl of 10 mM Tris solution to each well to dissolve SRB. Use a microplate reader at 515nm to reflect the status of cell proliferation and correct the experimental error caused by comprehensive factors such as the number of cells inoculated and the toxicity of the compound. Finally, calculate the increase percentage of glucose consumption in each group compared with the blank control group, and then calculate the glucose consumption promoted by the sample to evaluate the hypoglycemic activity of the test compound.

Get the compound shown in table 1 to carry out HepG2 cell viability test, and compare with metformin and oleanolic acid, the result surprisingly finds, when metformin test concentration is 100 times of the compound of formula (I) of the present invention, the present invention The maximal effect of compounds of formula (I) on increasing glucose consumption was still significantly stronger than both metformin and oleanolic acid.

Table 1. Effects of compounds on 24h glucose consumption in human liver HepG2 cells ( n=4)

Note: The data are mean ± standard deviation Indicates that the t-test was used for comparison between groups, compared with the DMSO solvent control group, *P<0.05,

**P<0.01, Met means metformin, OA means oleanolic acid.

2. The hypoglycemic pharmacodynamic study of the compound of formula (I) on db/db diabetic mice

Select 8-10 week-old SPF grade db/db female mice with similar fasting blood glucose values, and after feeding for 3 weeks, the blood glucose of the mice is higher than 10.6mmol/L, and they are grouped according to random blood glucose levels (the number of mice and the number of groups are determined by the test compound. depending on the number), 5 in each group, respectively 0.5% CMC-Na solvent control group, pioglitazone positive control group and test product group. Animals in each group were administered orally. Before administration, 2h, 3h, and 5h after a single administration, the blood glucose was measured with a Johnson & Johnson Wenhao blood glucose meter, and the blood glucose reduction percentage compared with the solvent control group was calculated; after 1 week of administration, Before the administration, measure the blood glucose level 3h and 5h after administration and calculate the blood glucose reduction percentage compared with the solvent control group; The percent reduction in blood glucose compared to the vehicle control group was calculated.

Table 2 compound to the hypoglycemic pharmacodynamic research result of db/db diabetic mice

Note: P<0.05, Met means metformin, OA means oleanolic acid.

As can be seen from Table 2, formula (I) compound of the present invention is significantly higher than oleanolic acid to db/db diabetic mice hypoglycemic percentage rate, and

Also comparable to metformin.

3. Pharmacokinetic study of the compound of formula (I)

Four rats were taken, half male and half male, fasted for 12 hours before the experiment, and drank water normally. After the rats were weighed, they were given GY3 (2-methyl-1-(4-chlorobenzoyl)-5-benzyloxy-1H-indole-3-acetic acid) gavage solution by gavage according to the usual dose conversion. 10min, 15min, 20min, 30min, 45min, 60min, 1.5h, 2h, 4h, 6h, 8h, 10h after intragastric administration, 0.3mL of blood was collected from the tail and placed in a heparinized 1.5mL centrifuge tube In the middle, centrifuge at 4500r/min for 10min, process the sample according to the processing method of the plasma sample, and measure the blood drug concentration. SD rats marked by gavage were injected intravenously one week later at a dose of 5 mg/kg, and the tails were docked at 5min, 10min, 15min, 20min, 30min, 45min, 60min, 2h, 4h, 6h, 8h, and 10h after intravenous administration. Take 0.3mL of blood, put it in a heparinized 1.5mL centrifuge tube, centrifuge at 4500r/min for 10min, process the sample according to the processing method of plasma sample, and measure the blood drug concentration. DAS 2.0 pharmacokinetic software was used for fitting, and the pharmacokinetic parameters of the compound of formula (I) in rats and the absolute oral bioavailability of the compound of formula (I) were calculated. The results are shown in Table 3.

Two kinds of route of administration pharmacokinetic parameters of the compound of table 3 formula (I) (X ± SD, n=4)

Note: iv: intravenous injection; ig: gavage.

It can be seen from Table 3 that the compound of formula (I) of the present invention has a high exposure in mice and a high bioavailability of 40.06%.

4. Lipid-lowering effect test of the compound of formula (I)

45 db/db mice aged 8-10 weeks, the blood glucose of the mice was higher than 10.6mmol/L after feeding for 3 weeks (the blood glucose of 4 animals was less than 11.10 at the beginning of administration), and divided into 9 groups according to the random blood glucose level, 5 rats in each group, respectively 0.5% CMC-Na solvent control group, pioglitazone positive control group and test product group. Animals in each group were administered orally. Before administration, 2h, 3h, and 5h after a single administration, the blood glucose was measured with a Johnson & Johnson Wenhao blood glucose meter, and the blood glucose reduction percentage compared with the solvent control group was calculated; after 1 week of administration, Before administration, 3h and 5h after administration, the blood glucose was measured by Johnson & Johnson Wenhao blood glucose meter, and the blood glucose reduction percentage compared with the solvent control group was calculated; 2 weeks and 3 weeks after administration, before administration, administration, respectively After 3 hours, the blood glucose was measured with a Johnson & Johnson Wenhao blood glucose meter, and the blood glucose reduction percentage compared with the solvent control group was calculated. Before administration and 3 weeks after administration, the animals were fasted for 5 hours, blood was taken from the tail vein, plasma was separated, and the levels of plasma triglyceride and total cholesterol in mice were measured with a triglyceride kit and a total cholesterol kit. During the administration period, the body weight of the animals was weighed every week, and the body weight increase percentage compared with that before the administration was calculated, and the results are shown in Table 4 and Table 5 respectively. The data are mean ± standard deviation The t-test was used for comparison between groups.

Table 4 Comparison of triglyceride-lowering effects in db/db mice

Note: P<0.05, Met means metformin, OA means oleanolic acid.

Table 5 Comparison of total cholesterol-lowering effects in db/db mice

Note: P<0.05, Met means metformin, OA means oleanolic acid.

As can be seen from Table 4 and Table 5, the compound of formula (I) of the present invention can obviously reduce triglyceride content and total cholesterol content in db/db mice,

The effects are significantly better than metformin and oleanolic acid.

The above is only a preferred embodiment of the present invention, and does not limit the present invention in any form. Any simple modification, Equivalent changes and modifications still fall within the scope of the technical solution of the present invention.

Claims (5)

1. Use a compound represented by formula (I) or a pharmaceutically acceptable salt to prepare medicines for preventing or treating the following diseases, wherein said diseases are diabetes, diabetic retinopathy, diabetic neuropathy , diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, hyperlipidemia, obesity, hypertriglyceridemia, the compound of formula (I) is: 2. The use according to claim 1, wherein the diabetes is type II diabetes. 3. A compound of formula (I) or a pharmaceutically acceptable salt thereof is used in the preparation of a drug for treating protein tyrosine phosphatase (PTP-1B), TGR5, or AMPK or a combination thereof mediated type II diabetes purposes, the compound of formula (I) is: 4. A preparation of a medicine for the treatment of type II diabetes, comprising administering to humans or mammals a therapeutically effective dose of the compound of formula (I) or a pharmaceutical composition comprising a therapeutically effective dose of the compound of formula (I), said formula (I) ) compound is: 5. The use according to claim 4, wherein the compound of formula (I) is given to mice at a dosage of 100 mg/kg, twice a day, for 2 or 3 weeks.