WO2018166494A1 - 苦参碱衍生物在治疗糖尿病中的用途 - Google Patents

苦参碱衍生物在治疗糖尿病中的用途 Download PDF

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WO2018166494A1
WO2018166494A1 PCT/CN2018/079099 CN2018079099W WO2018166494A1 WO 2018166494 A1 WO2018166494 A1 WO 2018166494A1 CN 2018079099 W CN2018079099 W CN 2018079099W WO 2018166494 A1 WO2018166494 A1 WO 2018166494A1
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group
diabetic
compound
butyl
formula
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PCT/CN2018/079099
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English (en)
French (fr)
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宋丹青
蒋建东
唐胜
孔维佳
汪燕翔
王灿
李迎红
李玉环
张靖浦
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中国医学科学院医药生物技术研究所
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine

Definitions

  • the present disclosure relates to novel uses of matrine derivatives, in particular to the use of matrine derivatives as insulin sensitizers, and to the preparation of matrine derivatives for the treatment or prevention of diabetes or diabetic complications. use.
  • Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia, classified into type 1 and type 2 diabetes. Long-term blood sugar, large blood vessels, microvascular damage and endanger the heart, brain, kidney, peripheral nerves, eyes, feet, etc., will lead to a series of complications such as diabetic nephropathy, diabetic eye disease, diabetic cardiovascular complications, diabetic neuropathy . Once the complications have occurred, drug treatment is difficult to reverse, so it is important to prevent diabetes complications as soon as possible.
  • the drugs currently used to treat diabetes mainly include insulin and its analogues, oral hypoglycemic agents, and the like.
  • Oral hypoglycemic agents mainly include sulfonylurea insulin secretagogues, non-sulfonylurea insulin secretagogues, thiazolidinediones, biguanides, glucagon-like peptide 1 analogues, DPP-4 inhibitors. , ⁇ -glucosidase inhibitors, and the like.
  • These oral hypoglycemic agents commonly used in clinical practice have certain side effects. For example, it has been reported that the use of sulfonylurea hypoglycemic agents may cause side effects such as hypoglycemia, major adverse cardiovascular events, and gastrointestinal damage.
  • Non-sulfonylurea-like insulin secretagogues may cause gastrointestinal side effects such as nausea, abdominal pain, and diarrhea.
  • Thiazolidinediones have been reported to be involved in the development of atherosclerosis, rosiglitazone may cause cardiovascular risk, and pioglitazone may cause bladder cancer.
  • the clinical adverse reactions of biguanide drugs are mainly gastrointestinal symptoms, such as diarrhea, bloating, nausea, loss of appetite, upper abdominal discomfort, and other adverse reactions such as lactic acidosis.
  • Diabetic patients with severe liver, kidney, heart and lung dysfunction should not use biguanide drugs.
  • DPP-4 inhibitors may produce hypoglycemic reactions.
  • Alpha-glucosidase inhibitors may cause side effects such as flatulence.
  • matrine derivatives can reduce fasting blood glucose, improve oral glucose tolerance, improve insulin tolerance, and improve urine-related indicators in mice by in vitro screening and pharmacological validation in animals. Increase serum ALT levels, while reducing liver coefficient, reducing liver triglyceride levels, and reducing liver AGEs. This indicates that the matrine derivative can be used as an insulin sensitizer, and/or for preventing and/or treating diabetes or diabetic complications such as diabetic nephropathy.
  • the present disclosure has been completed based on the above findings.
  • the present disclosure relates to the use of a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of diabetes.
  • the present disclosure also relates to the use of a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention and/or treatment of diabetic complications.
  • the present disclosure also relates to the use of a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament as an insulin sensitizer.
  • the present disclosure also relates to the use of a pharmaceutical composition for the preparation of a medicament for the treatment of diabetes, or for the preparation of a medicament for preventing or treating a diabetic complication, or for the preparation of a medicament as an insulin sensitizer Use, wherein the pharmaceutical composition comprises a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present disclosure also relates to compounds of formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof, for use in the treatment of diabetes.
  • the present disclosure also relates to compounds of formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof, for use in the prevention and/or treatment of diabetic complications.
  • the present disclosure also relates to compounds of formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof, which are useful as insulin sensitizers.
  • the present disclosure also relates to a pharmaceutical composition for treating diabetes, wherein the pharmaceutical composition comprises a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present disclosure also relates to a pharmaceutical composition for preventing and/or treating diabetic complications, wherein the pharmaceutical composition comprises a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof An acceptable carrier or excipient.
  • the present disclosure also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an insulin sensitizer, wherein the pharmaceutical composition comprises a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier Or an excipient.
  • the present invention provides a method of treating diabetes comprising administering to a subject in need thereof an effective amount of a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a subject in need thereof.
  • the test subject is administered an effective amount of a pharmaceutical composition comprising a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present disclosure also relates to a method of preventing and/or treating a diabetic complication comprising administering to a subject in need thereof an effective amount of a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof Or administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present disclosure also relates to a method of enhancing insulin sensitivity in a human comprising administering to a subject in need thereof an effective amount of a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or A subject in need thereof is administered an effective amount of a pharmaceutical composition comprising a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • R 1 represents an aryl group or a heterocyclic group, an aryl group or a heterocyclic group optionally substituted with mono- or polysubstituted by R 4,
  • R 4 is selected from: C 1-4 alkanoyl, cyano, C 1-4 alkyl Oxy, halo C 1-4 alkoxy, carboxy, sulfonic acid, C 1-4 alkoxycarbonyl, C 1-4 alkanoylamino, nitro, halogen, hydroxy, decyl, amino, C 1-4 An alkylsulfonyl group, a C 1-4 alkyl group, and a halogenated C 1-4 alkyl group;
  • R 2 represents -(CH 2 ) n R 3 ;
  • n 0, 1, 2, 3 or 4;
  • R 3 is selected from the group consisting of hydrogen, amino, mercapto, halogen, and C 1-6 alkoxy.
  • the heterocyclic group is a 5-6 membered monoheteroaryl group.
  • the heterocyclic group is selected from the group consisting of imidazolyl, thiazolyl, pyridyl, and thienyl.
  • the heterocyclic group is an imidazolyl group.
  • the heterocyclic group is a thiazolyl group.
  • the heterocyclic group is pyridyl.
  • the heterocyclic group is a thienyl group.
  • the aryl group is a phenyl group.
  • R 4 is selected from the group consisting of halomethoxy, haloethoxy, halopropoxy, acetyl, halo , haloethyl, halopropyl, cyano, methoxy, ethoxy, propoxy, carboxy, methoxycarbonyl, acetylamino, nitro, amino, methylsulfonyl, methyl, ethyl , n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
  • R 4 is selected from the group consisting of trifluoromethoxy, trifluoromethyl, cyano, methoxy, carboxyl, nitro, amino, methylsulfonyl, methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl, sec-butyl and tert-butyl. Further preferably, R 4 is a trifluoromethyl group.
  • R 4 is halomethoxy
  • R 4 is haloethoxy
  • R 4 is halopropoxy
  • R 4 is acetyl
  • R 4 is halomethyl
  • R 4 is haloethyl
  • R 4 is halopropyl
  • R 4 is cyano
  • R 4 is methoxy
  • R 4 is ethoxy
  • R 4 is propoxy
  • R 4 is a carboxyl group.
  • R 4 is methoxycarbonyl
  • R 4 is acetylamino
  • R 4 is a nitro group.
  • R 4 is an amino group.
  • R 4 is methylsulfonyl
  • R 4 is methyl
  • R 4 is ethyl
  • R 4 is n-propyl
  • R 4 is isopropyl
  • R 4 is n-butyl
  • R 4 is isobutyl
  • R 4 is a sec-butyl group.
  • R 4 is t-butyl
  • R 4 is trifluoromethoxy
  • R 2 represents -(CH 2 ) n R 3 , wherein R 3 is hydrogen.
  • R 2 represents -(CH 2 ) n R 3 , wherein R 3 is an amino group.
  • R 2 represents -(CH 2 ) n R 3 , wherein R 3 is methoxy.
  • R 2 represents -(CH 2 ) n R 3 , wherein R 3 is ethoxy.
  • R 2 represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl Or tert-butyl.
  • R 2 represents methyl, ethyl, n-propyl or isopropyl.
  • R 2 represents a methyl group.
  • R 2 represents an ethyl group.
  • R 2 represents n-propyl
  • R 2 represents an isopropyl group.
  • R 2 represents n-butyl
  • R 2 represents an isobutyl group.
  • R 2 represents a sec-butyl group.
  • R 2 represents a tert-butyl group.
  • the compound of Formula I described in the present disclosure is selected from the group consisting of:
  • the diabetes described in the present disclosure is type 1 diabetes or type 2 diabetes.
  • diabetic complications described in the present disclosure are diabetic nephropathy, diabetic ophthalmopathy, diabetic cardiovascular complications or diabetic neuropathy, preferably diabetic nephropathy.
  • insulin sensitizer described in the present disclosure is also called “insulin sensitizing factor", which is a kind of substance which can enhance insulin sensitivity in human body and promote full utilization of insulin.
  • aryl refers to a monocyclic or bicyclic aromatic system comprising at least one unsaturated aromatic ring, preferably an aryl group having from 6 to 10, ie 6, 7, 8, 9, or 10 carbon atoms. Specific examples include, but are not limited to, phenyl, naphthyl, and the like.
  • heterocyclyl refers to a monocyclic or bicyclic saturated, partially saturated or unsaturated aromatic which is optionally substituted with at least one and up to four independent heteroatoms selected from N, O or S. Or an aliphatic ring system, preferably a monoheterocyclic group having 4 to 7 atoms (including 4, 5, 6 or 7 atoms) or 7 to 11 atoms (containing 7, 8, 9, 10 or 11 atoms)
  • a biheterocyclyl group for example a 5-6 membered monoheteroaryl group, a 7-11 membered biheteroaryl group, a nitrogen heterocycle or a 4-6 membered aliphatic nitrogen heterocycle. Specific examples include, but are not limited to, imidazolyl, thiazolyl, pyridyl, thienyl.
  • C 1-4 alkyl refers to a straight or branched alkyl group having from 1 to 4 carbon atoms, such as 1, 2, 3 or 4 carbon atoms. Specific examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • C1-6 alkoxy as used in the present disclosure means a group obtained by linking a carbon atom on the C1-6 alkyl group to the oxygen atom as described above, preferably a " C1-4 alkoxy group”. Specific examples include, but are not limited to, methoxy, ethoxy or propoxy.
  • C 1-4 alkanoyl as used in the present disclosure means a group obtained by linking one end of a carbonyl carbon atom to the C 1-4 alkyl group defined above, and specific examples include, but are not limited to, formyl group, acetyl group, Propionyl and the like.
  • C 1-4 alkoxycarbonyl as used in the present specification means a group obtained by linking one end of a carbonyl carbon atom to the C 1-4 alkoxy group defined above. Specific examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and the like.
  • C 1-4 alkanoylamino as used in the present disclosure means a group obtained by linking one end of an amino nitrogen atom to the C 1-4 alkanoyl group defined above. Specific examples include, but are not limited to, formylamino, acetylamino, and the like.
  • C 1-4 alkylsulfonyl group as used in the present specification means a group obtained by linking one end of a sulfonylsulfide atom to a C 1-4 alkyl group as defined above. Specific examples include, but are not limited to, a methylsulfonyl group, Ethylsulfonyl and the like.
  • halogen refers to fluorine, chlorine, bromine, iodine.
  • subject as used in this disclosure includes mammals and humans, preferably humans.
  • salts include: acid addition salts with inorganic acids or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; organic acids such as acetic acid, propionic acid, Caproic acid, cyclopentanoic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methylsulfonate Acid, ethanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid
  • compositions of the present disclosure comprise a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • the carrier includes, but is not limited to, an ion exchanger, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphate, glycerin, sorbic acid, potassium sorbate, saturated plant fatty acids.
  • Partial glyceride mixture water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose Substance, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, beeswax, lanolin.
  • the excipient refers to an addenda other than the main drug in the pharmaceutical preparation.
  • composition of the compound of the present disclosure can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, sheath Inside, intraventricular, intrasternal and intracranial injection or input, or by means of an explant reservoir.
  • oral administration, intraperitoneal or intravenous administration is preferred.
  • an effective amount refers to an amount sufficient to achieve or at least partially achieve a desired effect.
  • a prophylactically effective amount refers to an amount sufficient to prevent, arrest, or delay the onset of a disease
  • a therapeutically effective amount refers to an amount sufficient to cure or at least partially arrest the disease and its complications in a patient already suffering from the disease. Determination of such an effective amount is well within the capabilities of those skilled in the art.
  • the amount effective for therapeutic use will depend on the severity of the disease to be treated, the overall state of the patient's own immune system, the general condition of the patient such as age, weight and sex, the mode of administration of the drug, and other treatments administered simultaneously. and many more.
  • the amount of a compound of the present disclosure administered to a subject will depend on the type and severity of the disease or condition and the characteristics of the subject, such as general health, age, sex, weight, and tolerance to the drug, and also The type of preparation and the mode of administration of the drug, as well as factors such as the dosing cycle or time interval. Those skilled in the art will be able to determine the appropriate dosage based on these and other factors.
  • the compounds of the present disclosure may be used in a therapeutic daily dose of from about 1 to 800 mg, which may be administered once or in divided doses as appropriate.
  • the compounds of the present disclosure may be provided in dosage units in an amount of from 0.1 to 200 mg, for example from 1 to 100 mg, in a dosage unit.
  • the compounds of formula I described in the present disclosure are capable of reducing fasting blood glucose in type 2 diabetic mice, improving oral glucose tolerance, improving insulin tolerance, and improving urine-related indicators in mice, without increasing serum ALT levels, but also reducing The liver coefficient reduces liver triglyceride levels and reduces liver AGEs.
  • the compounds of formula I described herein may act as insulin sensitizers and/or for the prevention and/or treatment of diabetes or diabetic complications, such as diabetic nephropathy.
  • Figure 1 Histogram of sugar consumption in HepG2 cells, in which: base sugar consumption was compared with DMSO group, * represents P ⁇ 0.05, ** represents P ⁇ 0.01, *** represents P ⁇ 0.001; insulin stimulated sugar consumption When each administration group was compared with the DMSO group, # represents P ⁇ 0.05, ## represents P ⁇ 0.01, and ### represents P ⁇ 0.001.
  • FIG. 2 Histogram of glucose consumption in L6 cells, in which: base sugar consumption was compared with DMSO group, * represents P ⁇ 0.05, ** represents P ⁇ 0.01, *** represents P ⁇ 0.001; insulin stimulated sugar consumption When each administration group was compared with the DMSO group, # represents P ⁇ 0.05, ## represents P ⁇ 0.01, and ### represents P ⁇ 0.001.
  • Fig. 3 Bar graph of glucose consumption in 3T3-L2 cells, in which: base sugar consumption was compared with DMSO group, * represents P ⁇ 0.05, ** represents P ⁇ 0.01, *** represents P ⁇ 0.001; insulin stimulated Sugar consumption Each administration group was compared with the DMSO group, # represents P ⁇ 0.05, ## represents P ⁇ 0.01, and ### represents P ⁇ 0.001.
  • Fig. 4 is a histogram of the change of fasting blood glucose in mice, wherein: the time of each time point of the model control group is compared with the time of the normal control group, # represents P ⁇ 0.05, ## represents P ⁇ 0.01, ### represents P ⁇ 0.001; each gives The fasting blood glucose after drug administration was compared with that before administration, * represents P ⁇ 0.05, ** represents P ⁇ 0.01, and *** represents P ⁇ 0.001.
  • Fig. 6 Area histogram under OGTT curve, where: model group in the figure is compared with normal group, # represents P ⁇ 0.05, ## represents P ⁇ 0.01, ### represents P ⁇ 0.001; each drug group is compared with the model group. , * represents P ⁇ 0.05, ** represents P ⁇ 0.01, and *** represents P ⁇ 0.001.
  • Figure 8 is a histogram of the area under the ITT curve, where: the model group in the figure is compared with the normal group, # represents P ⁇ 0.05, ## represents P ⁇ 0.01, ### represents P ⁇ 0.001; each administration group is compared with the model group. , * represents P ⁇ 0.05, ** represents P ⁇ 0.01, and *** represents P ⁇ 0.001.
  • Fig. 9 is a histogram of changes in urine volume of mice 24 hours before administration and 49 days after administration, wherein: the time points of the model control group were compared with the corresponding time of the normal control group, # represents P ⁇ 0.05, ## represents P ⁇ 0.01, ### represents P ⁇ 0.001; fasting blood glucose was compared with each time before administration in each administration group, where * represents P ⁇ 0.05, ** represents P ⁇ 0.01, and *** represents P ⁇ 0.001.
  • Fig. 10 is a histogram of changes in urine glucose concentration before and after administration for 49 days, wherein: the time point of the model control group was compared with the time of the normal control group, # represents P ⁇ 0.05, ## represents P ⁇ 0.01, ### represents P ⁇ 0.001; fasting blood glucose was compared with each time before administration in each administration group, where * represents P ⁇ 0.05, ** represents P ⁇ 0.01, and *** represents P ⁇ 0.001.
  • Fig. 11 is a histogram of changes in the amount of microalbumin production in mice before administration and after 49 days of administration, wherein: the time points of the model control group were compared with the corresponding time of the normal control group, # represents P ⁇ 0.05, ## represents P ⁇ 0.01, ### represents P ⁇ 0.001; fasting blood glucose is compared with pre-dose after administration of each administration group, wherein * represents P ⁇ 0.05, ** represents P ⁇ 0.01, and *** represents P ⁇ 0.001.
  • Fig. 12 is a histogram of changes in total urine protein production before and after administration for 49 days, in which: the time of each time point of the model control group was compared with that of the normal control group, # represents P ⁇ 0.05, ## represents P ⁇ 0.01 ### represents P ⁇ 0.001; fasting blood glucose was compared after administration at different time points in each administration group, where * represents P ⁇ 0.05, ** represents P ⁇ 0.01, and *** represents P ⁇ 0.001.
  • Figure 13 is a bar graph of ALT content in mouse serum after day 50 of dosing.
  • Figure 14 is a bar graph of AST content in mouse serum after day 50 of dosing.
  • Figure 15 is a bar graph of CHO content in mouse serum after day 50 of administration.
  • Figure 16 is a bar graph of LDL-c content in mouse serum after day 50 of administration.
  • Figure 17 is a bar graph of TG content in mouse serum after day 50 of administration.
  • Figure 18 is a bar graph of insulin concentration in mouse serum after 50 days of administration.
  • Figure 19 is a bar graph of the content of advanced glycation end products in mouse serum after 50 days of administration.
  • Figure 20 is a bar graph of mouse liver coefficient after 50 days of administration.
  • Figure 21 is a bar graph of liver tissue triglyceride content after 50 days of administration.
  • Figure 22 is a bar graph of total cholesterol content of liver tissue after 50 days of administration.
  • Figure 23 is a bar graph of AGEs content in liver tissue after 50 days of administration.
  • Figure 24 is a bar graph of SOD activity of liver tissue after 50 days of administration.
  • Figure 25 is a bar graph of MDA content in liver tissue after 50 days of administration.
  • DB-1, 10 represents 10 ⁇ M of the compound DB-1
  • DB-1, 10+I represents 10 ⁇ M of the compound DB-1 + 0.05 nM insulin
  • DB- 1,20 represents 20 ⁇ M of the compound DB-1
  • DB-1, 20+I represents 20 ⁇ M of the compound DB-1 + 0.05 nM insulin
  • HepG2 cells, L6 cells, and 3T3-L1 cells were purchased from American type culture collection (ATCC).
  • DMEM medium EDTA-pancreatin, and fetal bovine serum FBS were purchased from Gibco, USA.
  • the glucose test kit (glucose oxidase method) was purchased from Lando Experimental Diagnostics Co., Ltd. (Randox).
  • Compounds DB-1 and DB-1-3 were synthesized by the Chemical Laboratory of the Institute of Medical Biotechnology, Chinese Academy of Medical Sciences (see Method 28 and Example 30 of CN106279167A for synthesis methods), and berberine (BBR) was firstly produced by Northeast Pharmaceutical Group in Shenyang. Provided by the pharmaceutical company, rosiglitazone (RGZ) was purchased from sigma.
  • Blood glucose meters and blood glucose test strips were purchased from Roche Diagnostics (Shanghai) Co., Ltd.
  • D-glucose, SOD kit, MDA kit, hexokinase kit, glycogen detection kit were purchased from sigma.
  • a 0.22 ⁇ m filter and a mouse insulin ELISA kit were purchased from Millpore.
  • Recombinant human insulin injection was purchased from Eli Lilly and Company.
  • the EDTA-K2 anticoagulated blood collection tube was purchased from BD Corporation of the United States.
  • the advanced glycation end product AGE content was purchased from Cell Biolabs using an ELISA kit.
  • the protein concentration assay kit was purchased from Thermo Corporation.
  • the RNA extraction kit was purchased from Qiagen.
  • the reverse transcription kit and the fluorescent quantitative PCR kit were purchased from Promega.
  • the concentration unit "M" used in the experiment below indicates mol/L.
  • HepG2 cells were cultured in 10% FBS + DMEM medium and cultured at 37 ° C in a 5% CO 2 cell culture incubator.
  • L6 cells were cultured in 10% FBS+DMEM medium, cultured in a 5% CO 2 cell culture incubator at 37 ° C, and inoculated with L6 cells, the cells were continued to use 10% FBS + DMEM after the cell density was as long as 80%-90%. The medium was induced to differentiate for 5-7 days.
  • 3T3-L1 cells were cultured in 10% FBS + DMEM high glucose and grown at 37 ° C in a 5% CO 2 cell culture incubator. Then, the cells were induced to differentiate and culture at 37 ° C in a 5% CO 2 cell incubator.
  • the differentiation medium was: 10% FBS + DMEM high glucose medium, and 1 ⁇ M dexamethasone, 0.5 mM 3-isobutyl group was added. -1-methylxanthine (IBMX) and 1 ⁇ g/ml insulin.
  • test compounds were: compounds DB-1, DB-1-3, berberine (BBR) and rosiglitazone (RGZ), in which berberine and rosiglitazone were used as positive control drugs.
  • Each test compound was formulated into a solution using DMSO.
  • HepG2 cells, L6 cells, and 3T3-L1 cells were each inoculated into 96-well plates. among them:
  • HepG2 cells were inoculated 2*10 4 per well, and after 24 hours of culture, dosing treatment was performed to perform a sugar consumption experiment for basal sugar consumption and insulin stimulation;
  • L6 cells were inoculated 5*10 3 per well, cultured and induced to differentiate after dosing treatment, and the sugar consumption experiment of basic sugar consumption and insulin stimulation was performed;
  • the same 3T3-L1 cells were inoculated 2*10 3 per well, the growth medium was cultured for 48 hours, the fresh growth medium was replaced for 48 hours, and then the differentiation medium was changed to induce differentiation for 48 hours, followed by dosing treatment to carry out the base sugar. Consumption and insulin-stimulated sugar consumption experiments.
  • Insulin-stimulated sugar consumption experiments insulin and test compounds were added to the wells, and an insulin control group was set up.
  • the insulin control group added the same amount of insulin and DMSO to the wells.
  • the final concentration of the test compound in each well was set to 10 ⁇ M, 20 ⁇ M, 40 ⁇ M, respectively, and the final concentration of insulin was set to 0.05 nM.
  • a certain amount of the supernatant was aspirated to measure the residual amount of glucose in the medium, and the glucose consumption was calculated.
  • the experiment was repeated three times independently to obtain an average sugar consumption.
  • the histograms of sugar consumption of different cells are plotted separately, as shown in Figures 1 to 3.
  • the results showed that in the HepG2 cell line, the L6 cell line, and the 3T3-L1 cell line, under the same assay conditions, the compound DB-1 and the compound DB-1-3 promoted the cell-based level of sugar consumption and promoted insulin-stimulated cells.
  • Sugar consumption has comparable or more significant effects than the positive control berberine and rosiglitazone, indicating that compound DB-1 and compound DB-1-3 have better hypoglycemic effect at the cellular level and increase insulin sensitivity. The role.
  • the high-fat and high-sugar feed formula is: 16.46% protein, 45.65% fat, and 37.89% carbohydrate.
  • OGTT Oral glucose tolerance test: After 30 days of administration, fasting for 12 hours at 8:30 pm, OGTT experiment at 8:30 in the morning, weighing 4 g of glucose in 20 ml of water, filtering and sterilizing by 0.22 ⁇ m filter. Configured as 20% glucose solution, weighed, measured fasting blood glucose as 0 point blood glucose, intragastrically administered to mice 20% glucose solution, the final dose of glucose 2g / kg, and then measured blood glucose levels at 30min, 60min, 120min, 180min , blood glucose values were calculated, OGTT curves were plotted, and the area under the OGTT curve was calculated.
  • ITT 4Insulin tolerance test: After 35 days of administration, the mice were fasted for 6 hours at 8:30 in the morning, and the blood glucose level was measured as the 0 point blood glucose level of the ITT experiment after 6 hours of fasting, and the mice were fasted 6 After the hour's weight, the conventional recombinant human insulin injection was administered to the Lilly, and the intraperitoneal injection was given. The final insulin concentration was 0.5 U/kg body weight, and blood glucose was measured at 15 min, 30 min, 60 min, 90 min, and 120 min after insulin injection. The blood glucose level was 0, and the relative blood glucose concentration was calculated at the other time points. The ITT curve was plotted and the area under the ITT curve was calculated.
  • Urine collection and measurement The urine was collected in the metabolic cage for 24 hours before the administration of the mice and 49 days after the administration. The mice were placed in a metabolic cage separately, and the mice were given free access to drinking water, and each mouse was collected for 24 hours. The solution was centrifuged at 12000 rpm for 10 minutes at 4 ° C to remove impurities. The volume of urine was measured. The total protein concentration in urine, the concentration of microalbuminuria in urine, the concentration of glucose in urine, and the total protein in urine of mice were calculated according to the amount of urine. Urinary microalbumin production, the kit was purchased from Beijing Jiuqiang Biotechnology Co., Ltd.
  • mice were harvested from the eyeballs, allowed to stand at room temperature for 2 hours, and then centrifuged at 15 ° C, 3000 rpm for 10 min to separate the serum, using an automatic biochemical analyzer (Hitachi 7100) and a biochemical test kit (purchased from Zhongsheng). Beikong) Determination of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (CHO), low density lipoprotein cholesterol (LDL-C), urea (UREA).
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • TG triglyceride
  • CHO total cholesterol
  • LDL-C low density lipoprotein cholesterol
  • urea urea
  • Creatinine was manually measured using a full-wavelength microplate reader, and total bile acid (TBA), total bilirubin (T-Bil), and direct bilirubin (D-Bil) were determined using a full-wavelength microplate reader.
  • TAA total bile acid
  • T-Bil total bilirubin
  • D-Bil direct bilirubin
  • the kit used was purchased from Beijing Jiuqiang Bio.
  • Serum insulin content was determined using an ELISA kit (purchased from Merck Millipore).
  • Serum advanced glycation end products AGEs were obtained using an ELISA kit (purchased from cell biolabs).
  • liver triglyceride and total cholesterol cut about 50mg of liver tissue, add 20 ⁇ L of lysate per milligram of tissue in proportion, follow the instructions according to the instructions, determine tissue TG and CHO, the kit used was purchased from Beijing Pulilai Gene Technology Co., Ltd. the company.
  • liver AGE and SOD activity assay Cut about 30 mg of liver tissue, add 20 ⁇ L of T-PER tissue protein extraction reagent per milligram of tissue (purchased from thermo scientific), and then lyse with tissue homogenizer (purchased from Qiagen), 12000g, 4 The supernatant was centrifuged for 15 min at °C, and the AGE content of the advanced glycation end products of the liver was determined by the kit (the AGE assay kit was purchased from cell biolabs) and the SOD activity (SOD viability assay kit was purchased from sigma). Protein concentration calibration (protein concentration assay kit was purchased from Thermo).
  • MDA malondialdehyde
  • hexokinase activity determination of glycogen content: the same amount of liver tissue was cut into the lysate provided by the kit, and lysed by tissue homogenizer, the subsequent steps were carried out according to the kit instructions. The relevant results were all calibrated with protein concentration (protein concentration determination kit was purchased from Thermo).
  • the OGTT curve is shown in Figure 5, and the area under the OGTT curve is shown in Figure 6.
  • the results showed that in the KK/upj-Ay/J2 type diabetic mice, after 30 days of oral administration, the compound DB-1 administration group having a dose of 50 mg/kg and 100 mg/kg and the administration amount was 100 mg/
  • the oral glucose tolerance of the kg group of DB-1-3 was improved to varying degrees, and the DB-1 administration group of 100 mg/kg and the DB-1-3 administration group of 100 mg/kg improved the degree of oral glucose tolerance. 100 mg/kg berberine or 5 mg/kg rosiglitazone is equivalent.
  • the ITT curve is shown in Figure 7, and the area under the ITT curve is shown in Figure 8.
  • the results showed that in KK/upj-Ay/J 2 type diabetic mice, compound DB-1 and compound DB-1-3 were administered at a dose of 50 mg/kg and 100 mg/kg 35 days after oral administration.
  • the insulin tolerance has been improved to varying degrees.
  • the DB-1 administration group and the DB-1-3 administration group administered at a dose of 100 mg/kg improved the degree of insulin tolerance and the amount of berberine administered at a dose of 100 mg/kg or a dose of 5 mg/kg.
  • the glitazone is quite.
  • Figs. 9 to 12 The changes in 24-hour urine volume, urine glucose concentration, urinary microalbumin production, and total urinary protein production in each group before and after administration are shown in Figs. 9 to 12 .
  • the 24-hour urine volume, urine glucose concentration, urinary microalbumin production and total urine protein production were observed in each group before administration.
  • the amount was significantly higher than that of C57BL/6J mice.
  • the model group had different degrees of increase compared with before administration.
  • the serum insulin content of each group of animals was as shown in FIG.
  • the insulin content of the model group animals was significantly higher than that of the normal group animals, and there was a statistically significant difference.
  • Each drug-administered group had a different degree of reduction compared with the model group, and there was a statistically significant difference. This indicates that the compound DB-1 and the compound DB-1-3 can improve the insulin state in the animal and increase the sensitivity of insulin in the body, and it is expected to be prepared for the insulin sensitizer.
  • AGEs are a group of highly active end products that are formed by non-enzymatic glycosylation between the amino group of a protein, fatty acid or nucleic acid and the aldehyde group of a reducing sugar.
  • the accumulation of AGEs in the body will trigger Various complications such as diabetic nephropathy.
  • the results showed that the serum AGEs content of the model group was significantly higher than that of the normal group.
  • organ coefficient In an animal model of KK/upj-Ay/J type 2 diabetic mice, 50 days after administration, liver, kidney, pancreas, epididymal fat, and perirenal fat were weighed. The ratio of the weight of each organ to the weight of the animal is the organ coefficient.
  • the liver coefficient of each group of animals was shown in Figure 20 after 50 days of administration. The results showed that the liver coefficients of the animals in each group changed significantly. The liver coefficient of the model group was significantly higher than that of the control group. There was a statistically significant difference. The compounds DB-1, DB-1-3 and BBR were significant. Reduce liver coefficient and improve liver function. After administration of rosiglitazone, the liver coefficient was statistically different, and we speculated that this was caused by the side effects of rosiglitazone.
  • FIG. 21 and 22 A histogram of liver tissue triglyceride content and total cholesterol content after 50 days of administration is shown in Figs. 21 and 22. The results showed that the liver triglyceride content and total cholesterol content of the model group were significantly higher than those of the normal control group, and there was a statistically significant difference.
  • the compound DB-1 was administered at a dose of 100 mg/kg.
  • the BBR control group administered in an amount of 100 mg/kg can reduce the liver triglyceride content to a different extent, and the administration amount is 5 mg/kg.
  • liver tissue AGEs content 10 liver tissue AGEs content, SOD activity, MDA content determination results
  • liver tissue AGEs content After 50 days of administration, a histogram of liver tissue AGEs content, SOD activity, and MDA content is shown in Figs. 23 to 25.
  • the results of AGEs determination in liver tissue showed that the AGEs content in the liver of the model group was significantly higher than that in the normal control group, and there was a statistically significant difference.
  • the compounds DB-1, DB-1-3 and BBR were different.
  • the degree of liver AGEs was reduced, and rosiglitazone did not reduce liver AGEs content, indicating that compounds DB-1 and DB-1-3 are superior to rosiglitazone.
  • liver SOD activity and MDA content showed that the SOD activity was significantly decreased and the MDA content was significantly increased in the model group compared with the normal control group, while the SOD activity in the liver of each group was increased to some extent.
  • MDA The content decreased to varying degrees, indicating that compounds DB-1 and DB-1-3 can improve liver oxidative stress levels.
  • the compounds DB-1 and DB-1-3 of the present disclosure reduce fasting blood glucose, improve oral glucose tolerance, improve insulin tolerance, and improve mouse urine in KK/upj-Ay/J 2 type diabetic mice.
  • Good results in terms of relevant indicators 100 mg/kg of DB-1 and DB-1-3 were comparable to 100 mg/kg of BBR and 5 mg/kg of rosiglitazone, indicating that the two compounds of the present disclosure are useful for treatment Type 2 diabetes and prevention of diabetic nephropathy.

Abstract

本公开涉及式（I）所示化合物、其立体异构体、或其可药用盐在制备用于治疗糖尿病的药物中的用途，或在制备用于预防或治疗糖尿病并发症的药物中的用途，或在制备作为胰岛素增敏剂的药物中的用途。

Description

苦参碱衍生物在治疗糖尿病中的用途
本申请是以CN申请号为201710152735.X，申请日为2017年3月15日的申请为基础，并主张其优先权，该CN申请的公开内容在此作为整体引入本申请中。
技术领域
本公开涉及苦参碱衍生物的新用途，具体涉及苦参碱衍生物作为胰岛素增敏剂的用途，还涉及苦参碱衍生物在制备用于治疗或预防糖尿病或糖尿病并发症的药物中的用途。
背景技术
糖尿病(diabetes mellitus)是一组以高血糖为特征的代谢性疾病，分为1型和2型糖尿病。长期血糖增高，大血管、微血管受损并危及心、脑、肾、周围神经、眼睛、足等，将会引发如糖尿病肾病、糖尿病眼病、糖尿病心血管并发症、糖尿病神经病变等一系列并发症。并发症一旦产生，药物治疗很难逆转，因此强调尽早预防糖尿病并发症。
目前用于治疗糖尿病的药物主要有胰岛素及其类似物、口服降糖药等。口服降糖药主要包括了磺酰脲类促胰岛素分泌剂、非磺酰脲类促胰岛素分泌剂、噻唑烷二酮类、双胍类、胰高血糖素样肽1类似物、DPP-4抑制剂、α-葡萄糖苷酶抑制剂等。临床上常用的这些口服降糖药都存在一定得副作用。例如，有报道显示使用磺酰脲类降糖药可能产生低血糖，主要不良心血管事件，胃肠道损伤等副作用。非磺酰脲类促胰岛素分泌剂可能产生恶心，腹痛，腹泻等胃肠道不良反应。噻唑烷二酮类药物被报道可能与动脉粥样硬化的产生有关，罗格列酮可能导致心血管风险，匹格列酮可能导致膀胱癌的产生。双胍类药物临床不良反应主要为消化道症状，如腹泻、腹胀、恶心、食欲减退、上腹不适，另可见乳酸性酸中毒等不良反应。有严重肝、肾、心、肺功能不全的糖尿病患者不宜使用双胍类药物。DPP-4抑制剂可能产生低血糖反应。α-葡萄糖苷酶抑制剂可能产生胃肠胀气等副作用。
因此，研究开发更加安全有效的新型口服降糖药就显得至关重要。
发明内容
发明人通过体外筛选以及动物体内药学验证，意外地发现苦参碱衍生物能够降低2型糖尿病小鼠的空腹血糖，改善口服葡萄糖耐量，改善胰岛素耐量以及改善小鼠尿液相关指标，并且不会增加血清ALT含量，同时还降低了肝脏系数，降低肝脏甘油三脂 含量，降低肝脏AGEs含量。这表明苦参碱衍生物可以作为胰岛素增敏剂，和/或用于预防和/或治疗糖尿病或糖尿病并发症，例如糖尿病肾病。本公开基于上述发现而得以完成。
本公开涉及式I所示化合物、其立体异构体、或其可药用盐在制备用于治疗糖尿病的药物中的用途。
本公开还涉及式I所示化合物、其立体异构体、或其可药用盐在制备用于预防和/或治疗糖尿病并发症的药物中的用途。
本公开还涉及式I所示化合物、其立体异构体、或其可药用盐在制备作为胰岛素增敏剂的药物中的用途。
本公开还涉及一种药物组合物在制备用于治疗糖尿病的药物中的用途，或在制备用于预防或治疗糖尿病并发症的药物中的用途，或在制备作为胰岛素增敏剂的药物中的用途，其中所述药物组合物含有式I所示化合物、其立体异构体、或其可药用盐，以及药学上可接受的载体或赋形剂。
本公开还涉及式I所示化合物、其立体异构体、或其可药用盐，其用于治疗糖尿病。
本公开还涉及式I所示化合物、其立体异构体、或其可药用盐，其用于预防和/或治疗糖尿病并发症。
本公开还涉及式I所示化合物、其立体异构体、或其可药用盐，其作为胰岛素增敏剂。
本公开还涉及一种药物组合物，其用于治疗糖尿病，其中所述药物组合物含有式I所示化合物、其立体异构体、或其可药用盐，以及药学上可接受的载体或赋形剂。
本公开还涉及一种药物组合物，其用于预防和/或治疗糖尿病并发症，其中所述药物组合物含有式I所示化合物、其立体异构体、或其可药用盐，以及药学上可接受的载体或赋形剂。
本公开还涉及一种药物组合物，其作为胰岛素增敏剂，其中所述药物组合物含有式I所示化合物、其立体异构体、或其可药用盐，以及药学上可接受的载体或赋形剂。
本公开一种治疗糖尿病的方法，其包括，给有此需要的受试者施用有效量的式I所示化合物、其立体异构体、或其可药用盐，或者给有此需要的受试者施用有效量的含有式I所示化合物、其立体异构体、或其可药用盐，以及药学上可接受的载体或赋形剂的药物组合物。
本公开还涉及一种预防和/或治疗糖尿病并发症的方法，其包括，给有此需要的受试者施用有效量的式I所示化合物、其立体异构体、或其可药用盐，或者给有此需要的受试者施用有效量的含有式I所示化合物、其立体异构体、或其可药用盐，以及药学上可接受的载体或赋形剂的药物组合物。
本公开还涉及一种增强人体内胰岛素敏感性的方法，其包括，给有此需要的受试者施用有效量的式I所示化合物、其立体异构体、或其可药用盐，或者给有此需要的受试者施用有效量的含有式I所示化合物、其立体异构体、或其可药用盐，以及药学上可接受的载体或赋形剂的药物组合物。
本公开所述的式I所示化合物的结构如下：
Figure PCTCN2018079099-appb-000001
其中，
R 1代表芳基或杂环基，所述芳基或杂环基任选地被R 4单取代或多取代，R 4选自：C 1-4烷酰基、氰基、C 1-4烷氧基、卤代C 1-4烷氧基、羧基、磺酸基、C 1-4烷氧羰基、C 1-4烷酰氨基、硝基、卤素、羟基、巯基、氨基、C 1-4烷基磺酰基、C 1-4烷基和卤代C 1-4烷基；
R 2代表-(CH 2) nR 3；其中，
n＝0、1、2、3或4；
R 3选自氢、氨基、巯基、卤素和C 1-6烷氧基。
在一个实施方案中，本公开所述的式I所示化合物中，所述的杂环基为5-6元单杂芳基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，所述杂环基选自咪唑基、噻唑基、吡啶基、噻吩基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，所述杂环基为咪唑基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，所述杂环基为噻唑基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，所述杂环基为吡啶基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，所述杂环基为噻吩基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，所述芳基为苯基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4选自卤代甲氧基、卤代乙氧基、卤代丙氧基、乙酰基、卤代甲基、卤代乙基、卤代丙基、氰基、甲氧基、乙氧基、丙氧基、羧基、甲氧羰基、乙酰氨基、硝基、氨基、甲磺酰基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基。优选地，R 4选自三氟甲氧基、三氟甲基、氰基、甲氧基、羧基、硝基、氨基、甲磺酰基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基。进一步优选地，R 4为三氟甲基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为卤代甲氧基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为卤代乙氧基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为卤代丙氧基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为乙酰基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为卤代甲基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为卤代乙基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为卤代丙基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为氰基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为甲氧基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为乙氧基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为丙氧基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为羧基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为甲氧羰基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为乙酰氨基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为硝基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为氨基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为甲磺酰基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为甲基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为乙基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为正丙基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为异丙基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为正丁基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为异丁基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为仲丁基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为叔丁基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 4为三氟甲氧基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 2代表-(CH 2) nR 3，其中，n＝1、2或3；R 3选自氢、氨基、甲氧基、乙氧基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 2代表-(CH 2) nR 3，其中，n＝1。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 2代表-(CH 2) nR 3，其中，n＝2。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 2代表-(CH 2) nR 3，其中，n＝3。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 2代表-(CH 2) nR 3，其中，R 3为氢。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 2代表-(CH 2) nR 3，其中，R 3为氨基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 2代表-(CH 2) nR 3，其中，R 3为甲氧基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 2代表-(CH 2) nR 3，其中，R 3为乙氧基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 2代表甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 2代表甲基、乙基、正丙基或异丙基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 2代表甲基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 2代表乙基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 2代表正丙基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 2代表异丙基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 2代表正丁基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 2代表异丁基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 2代表仲丁基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物中，R 2代表叔丁基。
在本公开的任意一个实施方案中，本公开所述的式I所示化合物选自：
Figure PCTCN2018079099-appb-000002
本公开所述的式I所示化合物的合成方法可参见CN106279167A。
本公开使用的各种术语和短语具有本领域技术人员公知的一般含义，提及的术语和短语如有与公知含义不一致的，以本公开所表述的含义为准。
本公开所述的糖尿病为1型糖尿病或2型糖尿病。
本公开所述的糖尿病并发症为糖尿病肾病、糖尿病眼病、糖尿病心血管并发症或糖尿病神经病变，优选为糖尿病肾病。
本公开所述的胰岛素增敏剂又称“胰岛素增敏因子”，它是一类能增强人体内胰岛素敏感性，促进胰岛素充分利用的物质。
本公开中使用的术语“芳基”是指包含至少一个不饱和芳环的单环或双环芳香系统，优选具有6-10，即6，7，8，9或10个碳原子的芳基。具体的例子包括但不限于苯基、萘基等。
本公开中使用的术语“杂环基”是指任选地被至少一个和最多四个独立的选自N、O或S的杂原子取代的单环或双环饱和、部分饱和或不饱和的芳香或脂肪环状系统，优选具有4-7个原子(包含4、5、6或7个原子)的单杂环基或7-11个原子(包含7、8、9、10或11个原子)的双杂环基，例如5-6元单杂芳基、7-11元双杂芳基、氮杂环或4-6元脂肪氮杂环。具体的例子包括但不限于咪唑基、噻唑基、吡啶基、噻吩基。
本公开中使用的术语所述“C 1-4烷基”是指具有1-4个碳原子，如1、2、3或4个碳原子的直链或支链烷基。具体的例子包括但不限于甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
本公开中使用的术语“C 1-6烷氧基”是指如前述的C 1-6烷基上的碳原子与氧原子连接后得到的基团，优选为“C 1-4烷氧基”，具体的例子包括但不限于甲氧基、乙氧基或丙氧基等。
本公开中使用的术语“C 1-4烷酰基”是指羰基碳原子一端与前述定义的C 1-4烷基连接后得到的基团，具体的例子包括但不限于甲酰基、乙酰基、丙酰基等。
本公开中使用的术语“C 1-4烷氧羰基”是指羰基碳原子一端与前述定义的C 1-4烷氧基连接后得到的基团。具体的例子包括但不限于甲氧羰基、乙氧羰基等。
本公开中使用的术语“C 1-4烷酰氨基”是指氨基氮原子一端与前述定义的C 1-4烷酰基连接后得到的基团。具体的例子包括但不限于甲酰氨基、乙酰氨基等。
本公开中使用的术语C 1-4烷基磺酰基”是指磺酰基硫原子一端与前述定义的C 1-4烷基连接后得到的基团。具体的例子包括但不限于甲磺酰基、乙磺酰基等。
如本公开中所使用的术语“卤素”是指氟、氯、溴、碘。
本公开中使用的术语“受试者”包括哺乳动物和人，优选为人。
本公开中使用的术语“可药用盐”意指在制药上可接受的并且具有母体化合物的所需药理学活性的本公开化合物的盐。这类盐包括：与无机酸或与有机酸形成的酸加成的盐，所述的无机酸诸如盐酸，氢溴酸，硫酸，硝酸，磷酸等；所述的有机酸诸如乙酸，丙酸，己酸，环戊丙酸，乙醇酸，丙酮酸，乳酸，丙二酸，琥珀酸，苹果酸，马来酸，富马酸，酒石酸，柠檬酸，苯甲酸，肉桂酸，扁桃酸，甲磺酸，乙磺酸，苯磺酸，萘磺酸，樟脑磺酸，葡庚糖酸，葡糖酸，谷氨酸，羟基萘甲酸，水杨酸，硬脂酸，粘康酸等；或在母体化合物上存在的酸性质子被金属离子，例如碱金属离子或碱土金属离子取代时形成的盐；或与有机碱形成的配位化合物，所述的有机碱诸如乙醇胺，二乙醇胺，三乙醇胺，N-甲基葡糖胺等。
本公开所述的药物组合物中含有式I所示化合物、其立体异构体、或其可药用盐，以及药学上可接受的载体或赋形剂。所述的载体包括但不限于：离子交换剂，氧化铝，硬脂酸铝，卵磷脂，血清蛋白如人血白蛋白，缓冲物质如磷酸盐，甘油，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶态氧化硅，三硅酸镁，聚乙烯吡咯烷酮，纤维素物质，聚乙二醇，羧甲基纤维素钠，聚丙烯酸酯，蜂蜡，羊毛脂。所述赋形剂是指在药物制剂中除主药以外的附加物。其性质稳定，与主药无配伍禁忌，不产生副作用，不影响疗效，在常温下不易变形、干裂、霉变、虫蛀、对人体无害、无生理作用，不与主药产生化学或物理作用，不影响主药的含量测定等。如片剂中的黏合剂、填充剂、崩解剂、润滑剂；中药丸剂中的酒、醋、药汁等；半固体制剂软膏剂、霜剂中的基质部分；液体制剂中的防腐剂、抗氧剂、矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂等均可称为赋形剂，等等。
本公开化合物的药物组合物可以以下面的任意方式施用：口服，喷雾吸入，直肠用药，鼻腔用药，颊部用药，局部用药，非肠道用药，如皮下，静脉，肌内，腹膜内，鞘内，心室内，胸骨内和颅内注射或输入，或借助一种外植储器用药。其中优选口服、腹膜内或静脉内给药方式。
本公开中所使用的术语“有效量”是指，足以获得或至少部分获得期望的效果的量。例如，预防有效量是指，足以预防，阻止，或延迟疾病的发生的量；治疗有效量是指，足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。测定这样 的有效量完全在本领域技术人员的能力范围之内。例如，对于治疗用途有效的量将取决于待治疗的疾病的严重度，患者自己的免疫系统的总体状态，患者的一般情况例如年龄、体重和性别，药物的施用方式，以及同时施用的其他治疗等等。
对受试者给予的本公开化合物的量取决于所述疾病或病况的类型和严重程度以及受试者的特征，如一般健康状况、年龄、性别、体重和对药物的耐受度，还取决于制剂的类型和药物的给药方式，以及给药周期或时间间隔等因素。本领域技术人员能够根据这些因素和其它因素来确定适当的剂量。一般而言，本公开的化合物用于治疗日剂量可为大约1～800毫克，该日剂量可以视情况一次或分多次给予。本公开化合物可以在剂量单位中提供，在剂量单位中的含量可以为0.1～200毫克，例如1～100毫克。
本公开的有益技术效果
本公开所述的式I所示化合物能够降低2型糖尿病小鼠的空腹血糖，改善口服葡萄糖耐量，改善胰岛素耐量以及改善小鼠尿液相关指标，并且不会增加血清ALT含量，同时还降低了肝脏系数，降低肝脏甘油三脂含量，降低肝脏AGEs含量。本公开所述的式I所示化合物可以作为胰岛素增敏剂，和/或用于预防和/或治疗糖尿病或糖尿病并发症，例如糖尿病肾病。
附图说明
图1 HepG2细胞糖消耗情况柱状图，其中：基础糖消耗各给药组与DMSO组比较，*代表P<0.05，**代表P<0.01，***代表P<0.001；胰岛素刺激的糖消耗各给药组与DMSO组比较，#代表P<0.05，##代表P<0.01，###代表P<0.001。
图2 L6细胞糖消耗情况柱状图，其中：基础糖消耗各给药组与DMSO组比较，*代表P<0.05，**代表P<0.01，***代表P<0.001；胰岛素刺激的糖消耗各给药组与DMSO组比较，#代表P<0.05，##代表P<0.01，###代表P<0.001。
图3 3T3-L2细胞糖消耗情况柱状图，其中：基础糖消耗各给药组与DMSO组比较，*代表P<0.05，**代表P<0.01，***代表P<0.001；胰岛素刺激的糖消耗各给药组与DMSO组比较，#代表P<0.05，##代表P<0.01，###代表P<0.001。
图4小鼠空腹血糖变化情况柱状图，其中：模型对照组各时间点与正常对照组对应时间比较，#代表P<0.05，##代表P<0.01，###代表P<0.001；各给药组给药不同时 间后空腹血糖与给药前比较，*代表P<0.05，**代表P<0.01，***代表P<0.001。
图5口服葡萄糖耐量(OGTT)曲线。
图6 OGTT曲线下面积柱状图，其中：图中模型组与正常组比较，#代表P<0.05,##代表P<0.01，###代表P<0.001；各给药组与模型组相比，*代表P<0.05，**代表P<0.01，***代表P<0.001。
图7胰岛素耐量(ITT)曲线。
图8 ITT曲线下面积柱状图，其中：图中模型组与正常组比较，#代表P<0.05，##代表P<0.01，###代表P<0.001；各给药组与模型组相比，*代表P<0.05，**代表P<0.01，***代表P<0.001。
图9给药前和给药49天后，小鼠24小时尿量变化柱状图，其中：模型对照组各时间点与正常对照组对应时间比较，#代表P<0.05，##代表P<0.01，###代表P<0.001；各给药组给药不同时间后空腹血糖与给药前比较，其中*代表P<0.05，**代表P<0.01，***代表P<0.001。
图10给药前和给药49天后，小鼠尿液葡萄糖浓度变化柱状图，其中：模型对照组各时间点与正常对照组对应时间比较，#代表P<0.05，##代表P<0.01，###代表P<0.001；各给药组给药不同时间后空腹血糖与给药前比较，其中*代表P<0.05，**代表P<0.01，***代表P<0.001。
图11给药前和给药49天后，小鼠尿微量白蛋白产生量变化柱状图，其中：模型对照组各时间点与正常对照组对应时间比较，#代表P<0.05，##代表P<0.01，###代表P<0.001；各给药组给药不同时间后空腹血糖与给药前比较，其中*代表P<0.05，**代表P<0.01，***代表P<0.001。
图12给药前和给药49天后，小鼠尿总蛋白产生量变化柱状图，其中：模型对照组各时间点与正常对照组对应时间比较，#代表P<0.05，##代表P<0.01，###代表P<0.001；各给药组给药不同时间后空腹血糖与给药前比较，其中*代表P<0.05，**代表P<0.01，***代表P<0.001。
图13给药第50天后，小鼠血清中ALT含量柱状图。
图14给药第50天后，小鼠血清中AST含量柱状图。
图15给药第50天后，小鼠血清中CHO含量柱状图。
图16给药第50天后，小鼠血清中LDL-c含量柱状图。
图17给药第50天后，小鼠血清中TG含量柱状图。
图18给药50天后，小鼠血清中胰岛素浓度柱状图。
图19给药50天后，小鼠血清中晚期糖基化终末产物含量柱状图。
图20给药50天后，小鼠肝脏系数柱状图。
图21给药50天后，肝脏组织甘油三酯含量柱状图。
图22给药50天后，肝脏组织总胆固醇含量柱状图。
图23给药50天后，肝脏组织AGEs含量柱状图。
图24给药50天后，肝脏组织SOD活力柱状图。
图25给药50天后，肝脏组织MDA含量柱状图。
图1至图25中，横坐标标记，“DB-1,10”表示10μM的化合物DB-1，“DB-1,10+I”表示10μM的化合物DB-1+0.05nM胰岛素，“DB-1,20”表示20μM的化合物DB-1，“DB-1,20+I”表示20μM的化合物DB-1+0.05nM胰岛素，其他的横坐标标记的含义与之类似。
具体实施方式
下面将结合实施例对本公开的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本公开，而不应视为限定本公开的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
下面实施例中涉及的实验材料及试剂如下：
HepG2细胞、L6细胞、3T3-L1细胞购自美国模式培养物集存库(American type culture collection，ATCC)。
DMEM培养基、EDTA-胰酶、胎牛血清FBS购自美国gibco公司。
葡萄糖检测试剂盒(葡萄糖氧化酶法)购自朗道实验诊断有限公司(Randox)。
雄性C57BL/6J小鼠和雄性KK/upj-Ay/J小鼠，维持饲料，高脂高糖饲料购自北京华阜康生物科技股份有限公司。
化合物DB-1和DB-1-3由中国医学科学院医药生物技术研究所化学室合成(合成方法参见CN106279167A的实施例28和实施例30)，小檗碱(BBR)由东北制药集团沈阳第一制药厂提供，罗格列酮(RGZ)购自sigma公司。
血糖仪和血糖试纸购自罗氏诊断产品(上海)有限公司。
D-葡萄糖、SOD试剂盒、MDA试剂盒、己糖激酶试剂盒、糖原检测试剂盒购自sigma公司。
0.22μm滤膜、小鼠胰岛素ELISA试剂盒购自Millpore公司。
重组人胰岛素注射液购自礼来公司。
EDTA-K2抗凝采血管购自美国BD公司。
晚期糖基化终末产物AGE含量利用ELISA试剂盒购自cell biolabs公司。
蛋白浓度测定试剂盒购自Thermo公司。
RNA提取试剂盒购自Qiagen公司。
反转录试剂盒和荧光定量PCR试剂盒购自Promega公司。
下面实验中所用浓度单位“M”表示mol/L。
实施例1体外HepG2细胞系/L6细胞系/3T3-L1细胞系糖消耗及胰岛素刺激的糖消耗实验
1.1实验方法如下：
①细胞培养：HepG2细胞用10％FBS+DMEM培养基培养，于37℃，5％CO 2细胞培养箱培养。
L6细胞用10％FBS+DMEM培养基培养，于37℃，5％CO 2细胞培养箱培养，L6细胞接种培养板后，在细胞密度长至80％-90％后继续用10％FBS+DMEM培养基诱导分化5-7天。
3T3-L1细胞使用10％FBS+DMEM高糖培养，于37℃，5％CO 2细胞培养箱进行生长培养。然后置于37℃，5％CO 2细胞培养箱进行诱导分化培养，诱导分化培养基为：10％FBS+DMEM高糖培养基，其中添加了1μM地塞米松，0.5mM的3-异丁基-1-甲基黄嘌呤(IBMX)和1μg/ml胰岛素。
②糖消耗测定：
待测化合物为：化合物DB-1、DB-1-3、小檗碱(BBR)和罗格列酮(RGZ)，其中小檗碱和罗格列酮作为阳性对照药。各待测化合物均使用DMSO配制成溶液。
将HepG2细胞、L6细胞、3T3-L1细胞分别接种至96孔板中。其中：
HepG2细胞每孔接种2*10 4个，培养24小时后，进行加药处理，进行进行基础糖消耗和胰岛素刺激的糖消耗实验；
L6细胞每孔接种5*10 3个，培养和诱导分化后作加药处理，进行基础糖消耗和胰 岛素刺激的糖消耗实验；
同样的3T3-L1细胞每孔接种2*10 3个，生长培养基培养48小时，更换新鲜生长培养基继续培养48小时，然后更换分化培养基诱导分化48小时后进行加药处理，进行基础糖消耗和胰岛素刺激的糖消耗实验。
基础糖消耗实验，向孔中加入0.5％FBS+DMEM培养基和待测化合物，同时设置对照组。对照组向孔中加入相同量的0.5％FBS+DMEM培养基和DMSO。每孔中待测化合物的终浓度分别设置为10μM、20μM、40μM。加药后培养24小时，吸取一定量上清液测定培养基中葡萄糖剩余量，计算葡萄糖消耗量。其中葡萄糖消耗量＝培养基中葡萄糖初始含量－培养基中葡萄糖剩余含量。
胰岛素刺激的糖消耗实验，向孔中加入胰岛素和待测化合物，同时设置胰岛素对照组。胰岛素对照组向孔中加入相同量胰岛素和DMSO。每孔中待测化合物的终浓度分别设置为10μM、20μM、40μM，胰岛素的终浓度设置为0.05nM。加药后培养24小时，吸取一定量上清液测定培养基中葡萄糖剩余量，计算葡萄糖消耗量。
1.2实验结果
实验独立重复三次，得到平均糖消耗量。分别绘制不同细胞的糖消耗柱状图，如图1至图3所示。结果显示，在HepG2细胞系、L6细胞系、3T3-L1细胞系中，在相同测定条件下，化合物DB-1和化合物DB-1-3在促进细胞基础水平的糖消耗以及促进胰岛素刺激的细胞糖消耗方面具有与阳性对照药小檗碱和罗格列酮相当或更加显著的效果，表明化合物DB-1和化合物DB-1-3在细胞水平具有较好的降糖作用以及增加胰岛素敏感性的作用。
实施例2降低2型糖尿病小鼠空腹血糖、增加胰岛素敏感性以及治疗糖尿病肾病的药理作用实验
2.1实验方法
①动物实验：8只10周龄雄性C57BL/6J小鼠，63只10周龄雄性KK/upj-Ay/J小鼠，其中：C57BL/6J小鼠给予维持饲料，KK/upj-Ay/J小鼠给予高脂高糖饲料，饲养两周后测定空腹血糖，并随机分组。C57BL/6J小鼠作为正常对照组，KK/upj-Ay/J小鼠为5组，每组9只，其中1组为模型对照组，4组为给药组，给药量分别为DB-150mg/kg，DB-1 100mg/kg，BBR 100mg/kg，RZG 5mg/kg。
高脂高糖饲料配方为：蛋白质16.46％，脂肪45.65％，碳水化合物37.89％。
②空腹血糖测定：于给药前测定不禁食情况下体重作为初始值，给药之后每3天测定一次体重。测定初始空腹血糖之后，称取一定量饲料给予每只小鼠，每5天称量剩余食物量，重新给予一定量饲料，给药结束后计算每只小鼠每天进食量。于前一日晚8:30禁食12小时，次日早上8:30测定空腹血糖，剪尾尖，用罗氏血糖仪活力型测定，给药前测定空腹血糖作为初始值，给药之后每10天测定空腹血糖。绘制小鼠空腹血糖变化情况柱状图，如图4所示。
③口服葡萄糖耐量实验(OGTT)：给药30天后，晚8:30禁食12小时，次日早上8:30进行OGTT实验，称取4g葡萄糖溶于20ml水中，0.22μm滤膜过滤除菌，配置成20％葡萄糖溶液，称体重，测定空腹血糖作为0点血糖值，灌胃给予小鼠20％葡萄糖溶液，最终给予葡萄糖量2g/kg，然后在30min，60min，120min，180min分别测定血糖值，统计血糖值，绘制OGTT曲线，并计算OGTT曲线下面积。
④胰岛素耐量实验(ITT)：给药35天后，早上8:30小鼠禁食6小时，测定小鼠禁食6小时后血糖值作为ITT实验0点血糖值，同时称量小鼠禁食6小时后的体重，按体重给予礼来常规性重组人胰岛素注射液，腹腔注射给予，最终给予胰岛素浓度为0.5U/kg体重，分别在注射胰岛素后15min，30min，60min，90min，120min测定血糖，以0点血糖值为1，其余各时间点计算相对血糖浓度，绘制ITT曲线，并计算ITT曲线下面积。
⑤尿液收集和测定：用代谢笼分别收集小鼠给药前和给药49天后的24小时尿液，将小鼠单独放入代谢笼中，自由饮食饮水，收集每只小鼠24小时尿液，12000rpm，4℃离心10min去除杂质，测量尿液体积，用试剂盒测定尿液总蛋白浓度，尿液微量白蛋白浓度，尿液葡萄糖浓度，根据尿量计算小鼠24小时尿总蛋白，尿微量白蛋白产生量，试剂盒购自北京九强生物技术股份有限公司。
⑥血液指标测定：动物给药48天后，禁食12小时，断尾取全血于EDTA-K2抗凝采血管中(购自BD)，取10μL抗凝全血测定糖化血红蛋白浓度和血红蛋白浓度，二者比值作为糖化血红蛋白含量(试剂盒购自RNADOX)。
给药50天后，小鼠摘眼球取血，室温静置2小时后，于15℃，3000rpm，离心10min，分离血清，用全自动生化仪(日立7100)和生化检测试剂盒(购自中生北控)测定谷丙转氨酶(ALT)，谷草转氨酶(AST)，甘油三酯(TG)，总胆固醇(CHO)，低密度脂蛋白胆固醇(LDL-C)，尿素(UREA)。肌酐(CRE)利用全波长酶标仪 进行手工测定，利用全波长酶标仪测定总胆汁酸(TBA)，总胆红素(T-Bil)，直接胆红素(D-Bil)，手工测定所用试剂盒购自北京九强生物。血清胰岛素含量利用ELISA试剂盒(购自Merck Millipore)测定。血清晚期糖基化终末产物AGEs含量利用ELISA试剂盒(购自cell biolabs)。
⑦动物组织器官的处理：给药50天后处死动物。动物处理前禁食12小时，称量禁食后体重，取血后，脱颈椎处死动物，取肝脏，肾脏，胰腺，附睾脂肪，肾周脂肪分别称重。分别取肝脏大叶的一半，取小鼠左侧肾脏，胰腺一半用10％福尔马林溶液固定过夜，进行病理HE染色，剩余肝脏大叶，右侧肾脏，剩余胰腺即刻冻存于液氮中，以备后续处理。
⑧肝脏甘油三脂及总胆固醇测定：切取50mg左右肝脏组织，按比例每毫克组织加入20μL裂解液，后续步骤按照说明书进行，测定组织TG和CHO，所用试剂盒购自北京普利莱基因技术有限公司。
⑨肝脏AGE和SOD活力测定:切取约30mg肝脏组织，按每毫克组织加入20μL T-PER组织蛋白提取试剂(购自thermo scientific)，后用组织匀浆器(购自Qiagen)裂解，12000g，4℃，离心15min取上清，利用试剂盒测定肝脏晚期糖基化终末产物AGE含量(AGE测定试剂盒购自cell biolabs)和SOD活力(SOD活力测定试剂盒购自sigma)，测得结果用蛋白浓度校准(蛋白浓度测定试剂盒购自Thermo)。
⑩丙二醛(MDA)含量，己糖激酶活力，糖原含量测定：同样的切取一定量的肝脏组织加入试剂盒提供的裂解液，用组织匀浆器裂解，后续步骤均按照试剂盒说明书进行，相关结果均用蛋白浓度校准(蛋白浓度测定试剂盒购自Thermo)。
2.2实验结果
①空腹血糖变化情况
小鼠空腹血糖变化情况如图4所示。结果显示，在KK/upj-Ay/J 2型糖尿病小鼠体内，按体重50mg/kg、100mg/kg的给药量，化合物DB-1和化合物DB-1-3经口给药20天、30天、40天、48天后，给药组动物空腹血糖均出现显著性降低，且化合物DB-1和化合物DB-1-3的降糖效果与100mg/kg剂量的小檗碱以及5mg/kg的罗格列酮相当。
②口服葡萄糖耐量实验(OGTT)结果
OGTT曲线如图5所示，OGTT曲线下面积如图6所示。结果显示，在KK/upj-Ay/J2型糖尿病小鼠体内，经口给药30天后，给药量为50mg/kg、100mg/kg的化合物DB-1给药组以及给药量为100mg/kg的化合物DB-1-3给药组口服葡萄糖耐量具有不同程度的改善，100mg/kg的DB-1给药组以及100mg/kg的DB-1-3给药组改善口服葡萄糖耐量的程度与100mg/kg的小檗碱或5mg/kg的罗格列酮相当。
③胰岛素耐量实验(ITT)结果
ITT曲线如图7所示，ITT曲线下面积如图8所示。结果显示，在KK/upj-Ay/J 2型糖尿病小鼠体内，经口给予35天后，给药量为50mg/kg、100mg/kg的化合物DB-1、化合物DB-1-3给药组的胰岛素耐量均有不同程度的改善。给药量为100mg/kg的DB-1给药组以及DB-1-3给药组改善胰岛素耐量的程度与给药量为100mg/kg的小檗碱或给药量为5mg/kg的罗格列酮相当。
④尿液指标测定结果
给药前后，各组动物24小时尿量、尿液葡萄糖浓度、尿微量白蛋白产生量以及尿总蛋白产生量变化情况如图9至图12所示。从图中可以看出，在KK/upj-Ay/J 2型糖尿病动物模型中，给药前，各组动物24小时尿量、尿液葡萄糖浓度、尿微量白蛋白产生量以及尿总蛋白产生量与C57BL/6J小鼠比较具有极显著的升高，KK/upj-Ay/J小鼠各组之间没有统计学差异；给药后，模型组较给药前具有不同程度的升高，与正常对照组相比有极显著差异，而各给药组较模型组均有不同程度的降低，且有统计学差异。结果表明，给药量为50mg/kg以及100mg/kg的化合物DB-1、化合物DB-1-3均能抑制KK/upj-Ay/J 2型糖尿病小鼠糖尿病肾病的发展恶化，效果与给药量为100mg/kg的小檗碱以及给药量为5mg/kg的罗格列酮相当。结果预示着化合物DB-1和DB-1-3有望制备用于治疗糖尿病肾病。
⑤血清生化指标测定结果
给药50天后，各组动物血清生化指标如图13至17所示。从图中可以看出，在KK/upj-Ay/J 2型糖尿病小鼠动物模型中，给药50天后，模型组与正常对照组相比，ALT、AST、CHO、TG、LDL-c均有升高，有极显著差异。而各给药组与模型组相比，给药量为100mg/kg的化合物DB-1-3和给药量为100mg/kg的BBR均能降低血清 ALT，有统计学差异，而给药量为5mg/kg的罗格列酮导致血清ALT有统计学差异的升高，考虑是罗格列酮副作用所致；给药量为100mg/kg的化合物DB-1-3还能显著降低血清AST；给药量为100mg/kg的化合物DB-1能够显著降低血清CHO和LDL-c；给药量为100mg/kg的化合物DB-1，50mg/kg的化合物DB-1-3，100mg/kg的化合物DB-1-3，100mg/kg的BBR，5mg/kg的罗格列酮均能显著降低血清TG。
⑥血清胰岛素含量测定结果
给药50天后，各组动物血清胰岛素含量情况如图18所示。从图中可以看出，在KK/upj-Ay/J 2型糖尿病小鼠动物模型中，给药50天后，模型组动物与正常组动物相比胰岛素含量显著升高，有极显著统计学差异，各给药组与模型组相比均有不同程度的降低，有显著统计学差异。这说明，化合物DB-1和化合物DB-1-3能够改善动物体内高胰岛素状态，增加体内胰岛素的敏感性，有望制备用于胰岛素增敏剂。
⑦血清AGEs测定结果
给药50天后，各组动物血清中晚期糖基化终末产物含量情况如图19所示。在KK/upj-Ay/J 2型糖尿病小鼠动物模型中，给药50天后，取血测定血清中晚期糖基化终末产物(advanced glycation end products，AGEs)。AGEs是一组在蛋白质、脂肪酸或核酸的氨基基团与还原糖的醛基之间发生非酶糖基化反应所形成的一系列具有高度活性终产物的总称，AGEs在体内的积聚将会引发如糖尿病肾病等各种并发症。结果表明，模型组动物血清AGEs含量显著高于正常组动物，有极显著统计学差异，各给药组动物血清AGEs含量与模型组比均有不同程度的降低，有显著统计学差异。这说明，化合物DB-1和化合物DB-1-3均能够显著降低血清AGEs含量，从而达到预防如糖尿病肾病等糖尿病并发症。
⑧脏器系数测定结果
在KK/upj-Ay/J 2型糖尿病小鼠动物模型中，给药50天后，取动物肝脏，肾脏，胰腺，附睾脂肪，肾周脂肪称重。各脏器重量与动物体重的比值即为各脏器系数。
给药50天后，各组动物的肝脏系数情况如图20所示。结果表明，各组动物的肝脏系数均有明显的变化，模型组与对照组相比肝脏系数显著增高，有极显著统计学差异，化合物DB-1、化合物DB-1-3以及BBR均能显著降低肝脏系数，改善肝脏功能。 而给予罗格列酮后，肝脏系数却有统计学差异的升高，我们推测这是罗格列酮产生的副作用导致。
⑨肝脏组织甘油三酯和总胆固醇含量测定结果
给药50天后，肝脏组织甘油三酯含量，总胆固醇含量的柱状图如图21和图22所示。结果表明，模型组动物肝脏甘油三酯含量和总胆固醇含量相比正常对照组有显著升高，有极显著统计学差异，给药量为100mg/kg的化合物DB-1给药组，给药量为50mg/kg以及100mg/kg的化合物DB-1-3的给药组，给药量为100mg/kg的BBR对照组能不同程度的降低肝脏甘油三脂含量，而给药量为5mg/kg的罗格列酮对照组，肝脏甘油三酯含量反而有统计学差异的升高，推测是由罗格列酮产生的副作用导致。给予50mg/kg以及100mg/kg的化合物DB-1和DB-1-3，100mg/kg的BBR以及5mg/kg的罗格列酮均能不同程度降低肝脏总胆固醇含量。
⑩肝脏组织AGEs含量、SOD活力、MDA含量测定结果
肝脏中AGEs含量的升高将会导致肝脏损伤，肝脏中SOD活力和MDA含量反应了肝脏氧化应激水平。
给药50天后，肝脏组织AGEs含量，SOD活力，MDA含量的柱状图如图23至图25所示。肝脏组织中AGEs含量的测定结果表明，模型组动物相比正常对照组动物，肝脏AGEs含量有显著升高，有极显著统计学差异，化合物DB-1、DB-1-3和BBR均能不同程度的降低肝脏AGEs含量，而罗格列酮并不能降低肝脏AGEs含量，这表明化合物DB-1和DB-1-3相比罗格列酮具有优越性。肝脏SOD活力以及MDA含量的测定结果表明，模型组动物相比正常对照组动物，SOD活力显著降低，MDA含量显著升高，而各给药组动物肝脏SOD活力均有不同程度的升高，MDA含量均与不同程度的降低，表明化合物DB-1和DB-1-3能够改善肝脏氧化应激水平。
在结果①②③④中，本公开涉及的化合物DB-1和DB-1-3在降低KK/upj-Ay/J 2型糖尿病小鼠空腹血糖，改善口服葡萄糖耐量，改善胰岛素耐量以及改善小鼠尿液相关指标方面表现出良好效果，100mg/kg的DB-1以及DB-1-3与100mg/kg的BBR以及5mg/kg的罗格列酮效果相当，表明了本公开的两个化合物可用于治疗2型糖尿病以及预防糖尿病肾病。
在结果⑤⑧⑨⑩中，5mg/kg的罗格列酮表现出了一定的副作用，如显著增加了血清ALT含量，显著增加了肝脏系数，显著增加了肝脏组织的甘油三酯含量，而且不能降低肝脏AGEs含量，而本公开涉及的化合物DB-1以及DB-1-3并不会增加血清ALT含量，并且降低了肝脏系数，降低肝脏甘油三脂含量，同时能够降低肝脏AGEs含量，这些结果表明了本公开涉及的化合物DB-1,DB-1-3在制备用于治疗2型糖尿病，制备作为胰岛素增敏剂以及制备用于预防糖尿病肾病方面的优越性。

Claims (30)

  1. 式I所示化合物、其立体异构体、或其可药用盐在制备用于治疗糖尿病的药物中的用途，或
    在制备用于预防和/或治疗糖尿病并发症的药物中的用途，或
    在制备作为胰岛素增敏剂的药物中的用途，
    Figure PCTCN2018079099-appb-100001
    其中，
    R 1代表芳基或杂环基，所述芳基或杂环基任选地被R 4单取代或多取代，R 4选自：C 1-4烷酰基、氰基、C 1-4烷氧基、卤代C 1-4烷氧基、羧基、磺酸基、C 1-4烷氧羰基、C 1-4烷酰氨基、硝基、卤素、羟基、巯基、氨基、C 1-4烷基磺酰基、C 1-4烷基和卤代C 1-4烷基；
    R 2代表-(CH 2) nR 3；其中，
    n＝0、1、2、3或4；
    R 3选自氢、氨基、巯基、卤素和C 1-6烷氧基，
    优选地，其中所述的糖尿病为1型糖尿病或2型糖尿病；
    优选地，其中所述的糖尿病并发症为糖尿病肾病、糖尿病眼病、糖尿病心血管并发症或糖尿病神经病变，优选为糖尿病肾病。
  2. 一种药物组合物在制备用于治疗糖尿病的药物中的用途，或
    在制备用于预防或治疗糖尿病并发症的药物中的用途，或
    在制备作为胰岛素增敏剂的药物中的用途，
    其中所述药物组合物含有式I所示化合物、其立体异构体、或其可药用盐，以及药学上可接受的载体或赋形剂，
    Figure PCTCN2018079099-appb-100002
    其中，
    R 1代表芳基或杂环基，所述芳基或杂环基任选地被R 4单取代或多取代，R 4选自：C 1-4烷酰基、氰基、C 1-4烷氧基、卤代C 1-4烷氧基、羧基、磺酸基、C 1-4烷氧羰基、C 1-4烷酰氨基、硝基、卤素、羟基、巯基、氨基、C 1-4烷基磺酰基、C 1-4烷基和卤代C 1-4烷基；
    R 2代表-(CH 2) nR 3；其中，
    n＝0、1、2、3或4；
    R 3选自氢、氨基、巯基、卤素和C 1-6烷氧基，
    优选地，其中所述的糖尿病为1型糖尿病或2型糖尿病；
    优选地，其中所述的糖尿病并发症为糖尿病肾病、糖尿病眼病、糖尿病心血管并发症或糖尿病神经病变，优选为糖尿病肾病。
  3. 权利要求1或2所述的用途，其中，所述的杂环基为5-6元单杂芳基。
  4. 权利要求3所述的用途，其中，所述杂环基选自咪唑基、噻唑基、吡啶基、噻吩基。
  5. 权利要求1或2所述的用途，其中，所述芳基为苯基。
  6. 权利要求1至5任一项所述的用途，其中，R 4选自卤代甲氧基、卤代乙氧基、卤代丙氧基、乙酰基、卤代甲基、卤代乙基、卤代丙基、氰基、甲氧基、乙氧基、丙氧基、羧基、甲氧羰基、乙酰氨基、硝基、氨基、甲磺酰基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基，
    优选地，R 4选自三氟甲氧基、三氟甲基、氰基、甲氧基、羧基、硝基、氨基、甲磺酰基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基，
    进一步优选地，R 4为三氟甲基。
  7. 权利要求1至6任一项所述的用途，其中，R 2代表-(CH 2) nR 3，其中，n＝1、2或3；R 3选自氢、氨基、甲氧基、乙氧基。
  8. 权利要求1至7任一项所述的用途，其中，R 2代表甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
  9. 权利要求1至8任一项所述的用途，其中，R 2代表甲基、乙基、正丙基或异丙基。
  10. 权利要求1或2所述的用途，其中，所述的式I所示化合物选自：
    Figure PCTCN2018079099-appb-100003
  11. 式I所示化合物、其立体异构体、或其可药用盐，其用于治疗糖尿病、用于预防和/或治疗糖尿病并发症、或作为胰岛素增敏剂，
    Figure PCTCN2018079099-appb-100004
    其中，
    R 1代表芳基或杂环基，所述芳基或杂环基任选地被R 4单取代或多取代，R 4选自：C 1-4烷酰基、氰基、C 1-4烷氧基、卤代C 1-4烷氧基、羧基、磺酸基、C 1-4烷氧羰基、C 1-4烷酰氨基、硝基、卤素、羟基、巯基、氨基、C 1-4烷基磺酰基、C 1-4烷基和卤代C 1-4烷基；
    R 2代表-(CH 2) nR 3；其中，
    n＝0、1、2、3或4；
    R 3选自氢、氨基、巯基、卤素和C 1-6烷氧基，
    优选地，其中所述的糖尿病为1型糖尿病或2型糖尿病；
    优选地，其中所述的糖尿病并发症为糖尿病肾病、糖尿病眼病、糖尿病心血管并发症或糖尿病神经病变，优选为糖尿病肾病。
  12. 一种药物组合物，其用于治疗糖尿病，或
    用于预防或治疗糖尿病并发症的药物中的用途，或
    用作胰岛素增敏剂，
    其中所述药物组合物含有式I所示化合物、其立体异构体、或其可药用盐，以及药学上可接受的载体或赋形剂，
    Figure PCTCN2018079099-appb-100005
    其中，
    R 1代表芳基或杂环基，所述芳基或杂环基任选地被R 4单取代或多取代，R 4选自：C 1-4烷酰基、氰基、C 1-4烷氧基、卤代C 1-4烷氧基、羧基、磺酸基、C 1-4烷氧羰基、C 1-4烷酰氨基、硝基、卤素、羟基、巯基、氨基、C 1-4烷基磺酰基、C 1-4烷基和卤代C 1-4烷基；
    R 2代表-(CH 2) nR 3；其中，
    n＝0、1、2、3或4；
    R 3选自氢、氨基、巯基、卤素和C 1-6烷氧基，
    优选地，其中所述的糖尿病为1型糖尿病或2型糖尿病；
    优选地，其中所述的糖尿病并发症为糖尿病肾病、糖尿病眼病、糖尿病心血管并发症或糖尿病神经病变，优选为糖尿病肾病。
  13. 权利要求11所述的式I所示化合物、其立体异构体、或其可药用盐或权利要求12所述的药物组合物，其中，所述的杂环基为5-6元单杂芳基。
  14. 权利要求11所述的式I所示化合物、其立体异构体、或其可药用盐或权利要求12所述的药物组合物，其中，所述杂环基选自咪唑基、噻唑基、吡啶基、噻吩基。
  15. 权利要求11所述的式I所示化合物、其立体异构体、或其可药用盐或权利要求12所述的药物组合物，其中，所述芳基为苯基。
  16. 权利要求11所述的式I所示化合物、其立体异构体、或其可药用盐或权利要 求12所述的药物组合物，其中，R 4选自卤代甲氧基、卤代乙氧基、卤代丙氧基、乙酰基、卤代甲基、卤代乙基、卤代丙基、氰基、甲氧基、乙氧基、丙氧基、羧基、甲氧羰基、乙酰氨基、硝基、氨基、甲磺酰基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基，
    优选地，R 4选自三氟甲氧基、三氟甲基、氰基、甲氧基、羧基、硝基、氨基、甲磺酰基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基，
    进一步优选地，R 4为三氟甲基。
  17. 权利要求11所述的式I所示化合物、其立体异构体、或其可药用盐或权利要求12所述的药物组合物，其中，R 2代表-(CH 2) nR 3，其中，n＝1、2或3；R 3选自氢、氨基、甲氧基、乙氧基。
  18. 权利要求11所述的式I所示化合物、其立体异构体、或其可药用盐或权利要求12所述的药物组合物，其中，R 2代表甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
  19. 权利要求11所述的式I所示化合物、其立体异构体、或其可药用盐或权利要求12所述的药物组合物，其中，R 2代表甲基、乙基、正丙基或异丙基。
  20. 权利要求11所述的式I所示化合物、其立体异构体、或其可药用盐或权利要求12所述的药物组合物，其中，所述的式I所示化合物选自：
    Figure PCTCN2018079099-appb-100006
  21. 一种预防和/或治疗糖尿病或糖尿病并发症的方法，其包括，给有此需要的受 试者施用有效量的式I所示化合物、其立体异构体、或其可药用盐，或者给有此需要的受试者施用有效量的含有式I所示化合物、其立体异构体、或其可药用盐，以及药学上可接受的载体或赋形剂的药物组合物，
    Figure PCTCN2018079099-appb-100007
    其中，
    R 1代表芳基或杂环基，所述芳基或杂环基任选地被R 4单取代或多取代，R 4选自：C 1-4烷酰基、氰基、C 1-4烷氧基、卤代C 1-4烷氧基、羧基、磺酸基、C 1-4烷氧羰基、C 1-4烷酰氨基、硝基、卤素、羟基、巯基、氨基、C 1-4烷基磺酰基、C 1-4烷基和卤代C 1-4烷基；
    R 2代表-(CH 2) nR 3；其中，
    n＝0、1、2、3或4；
    R 3选自氢、氨基、巯基、卤素和C 1-6烷氧基，
    优选地，其中所述的糖尿病为1型糖尿病或2型糖尿病；
    优选地，其中所述的糖尿病并发症为糖尿病肾病、糖尿病眼病、糖尿病心血管并发症或糖尿病神经病变，优选为糖尿病肾病。
  22. 一种增强人体内胰岛素敏感性的方法，其包括，给有此需要的受试者施用有效量的式I所示化合物、其立体异构体、或其可药用盐，或者给有此需要的受试者施用有效量的含有式I所示化合物、其立体异构体、或其可药用盐，以及药学上可接受的载体或赋形剂的药物组合物，
    Figure PCTCN2018079099-appb-100008
    其中，
    R 1代表芳基或杂环基，所述芳基或杂环基任选地被R 4单取代或多取代，R 4选自：C 1-4烷酰基、氰基、C 1-4烷氧基、卤代C 1-4烷氧基、羧基、磺酸基、C 1-4烷氧羰基、C 1-4烷酰氨基、硝基、卤素、羟基、巯基、氨基、C 1-4烷基磺酰基、C 1-4烷基和卤代C 1-4烷基；
    R 2代表-(CH 2) nR 3；其中，
    n＝0、1、2、3或4；
    R 3选自氢、氨基、巯基、卤素和C 1-6烷氧基。
  23. 权利要求21所述的预防和/或治疗糖尿病或糖尿病并发症的方法或权利要求22所述的增强人体内胰岛素敏感性的方法，其中，所述的杂环基为5-6元单杂芳基。
  24. 权利要求21所述的预防和/或治疗糖尿病或糖尿病并发症的方法或权利要求22所述的增强人体内胰岛素敏感性的方法，其中，所述杂环基选自咪唑基、噻唑基、吡啶基、噻吩基。
  25. 权利要求21所述的预防和/或治疗糖尿病或糖尿病并发症的方法或权利要求22所述的增强人体内胰岛素敏感性的方法，其中，所述芳基为苯基。
  26. 权利要求21所述的预防和/或治疗糖尿病或糖尿病并发症的方法或权利要求22所述的增强人体内胰岛素敏感性的方法，其中，R 4选自卤代甲氧基、卤代乙氧基、卤代丙氧基、乙酰基、卤代甲基、卤代乙基、卤代丙基、氰基、甲氧基、乙氧基、丙氧基、羧基、甲氧羰基、乙酰氨基、硝基、氨基、甲磺酰基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基，
    优选地，R 4选自三氟甲氧基、三氟甲基、氰基、甲氧基、羧基、硝基、氨基、甲磺酰基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基，
    进一步优选地，R 4为三氟甲基。
  27. 权利要求21所述的预防和/或治疗糖尿病或糖尿病并发症的方法或权利要求22所述的增强人体内胰岛素敏感性的方法，其中，R 2代表-(CH 2) nR 3，其中，n＝1、2或3；R 3选自氢、氨基、甲氧基、乙氧基。
  28. 权利要求21所述的预防和/或治疗糖尿病或糖尿病并发症的方法或权利要求22所述的增强人体内胰岛素敏感性的方法，其中，R 2代表甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
  29. 权利要求21所述的预防和/或治疗糖尿病或糖尿病并发症的方法或权利要求 22所述的增强人体内胰岛素敏感性的方法，其中，R 2代表甲基、乙基、正丙基或异丙基。
  30. 权利要求21所述的预防和/或治疗糖尿病或糖尿病并发症的方法或权利要求22所述的增强人体内胰岛素敏感性的方法，其中，所述的式I所示化合物选自：
    Figure PCTCN2018079099-appb-100009
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