WO2016074566A1 - 一类葡萄糖苷衍生物及其药用组合物 - Google Patents

一类葡萄糖苷衍生物及其药用组合物 Download PDF

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WO2016074566A1
WO2016074566A1 PCT/CN2015/093089 CN2015093089W WO2016074566A1 WO 2016074566 A1 WO2016074566 A1 WO 2016074566A1 CN 2015093089 W CN2015093089 W CN 2015093089W WO 2016074566 A1 WO2016074566 A1 WO 2016074566A1
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methyl
compound
pyran
triol
tetrahydro
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French (fr)
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史东方
傅长金
刘伟
方飞
曹成跑
张长亮
承曦
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镇江新元素医药科技有限公司
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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D421/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings
    • C07D421/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

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  • the present invention relates to a glucoside derivative or a pharmaceutically acceptable salt or a stereoisomer thereof represented by the formula (I), and a pharmaceutical composition containing the same, and as a therapeutic agent, in particular Use as a sodium-glucose cotransporter 2 (SGLT2) inhibitor.
  • SGLT2 sodium-glucose cotransporter 2
  • sulfonylureas such as glimepiride
  • glucosidase inhibitors such as acarbose
  • oxazolidinone such as rosiglitazone
  • GLP-1 Glucagon-like peptide-1
  • GLP-1 agonists such as exenatide, PPAR ⁇ agonists such as motaghazole, DPP -IV inhibitors such as sitagliptin and the like.
  • GLP-1 is a peptide hormone secreted by intestinal L cells, which can increase the biosynthesis and secretion of insulin; stimulate the proliferation and differentiation of ⁇ cells, inhibit the apoptosis of ⁇ cells; inhibit the secretion of glucagon; suppress appetite And feeding, delaying the emptying of stomach contents, etc.
  • SGLT2 Sodium glucose co-transporter 2 (SGLT2) inhibitors are a hot area for the development of type 2 diabetes drugs in recent years.
  • SGLT2 consists of 672 amino acid residues with low affinity and 59% homology to sodium glucose co-transporter 1 (SGLT1) (SGLT1 has high affinity, high affinity ).
  • SGLT2 is mainly used in the proximal convoluted tubules of the kidney to complete the reabsorption of 90% glucose in the original urine (Neumiller JJ, White JR Jr, Campbell R K. Sodium-glucose co-transport inhibitors: progress and therapeutic potential in type 2diabetes mellitus [ J]. Drugs, 2010, 70(4): 377-385.) (Wright, EM.
  • kidney SGLT2 can promote urine sugar excretion and lower blood sugar in the body, providing a new method for treating diabetes.
  • hypoglycemic mechanism is not related to insulin, can be used for almost all diabetes including insulin resistance; (2) can improve insulin sensitivity of liver and peripheral tissues , improve ⁇ cell function, improve insulin resistance; (3) not easy to cause hypoglycemia; (4) can reduce the percentage of glycated hemoglobin; (5) have a certain weight loss and help improve cardiovascular and cerebrovascular diseases; (6) inhibit SGLT2 No significant effect on other tissues and organs (Wang Yuli, Wang Xiaoyan, Tang Lida et al. Development of anti-diabetic drugs for sodium-glucose cotransporter 2 inhibitors [J]. Modern Medicine and Clinical. 2012,27(3):138- 141).
  • SGLT2 inhibitors can also be used in combination with existing therapeutic agents such as sulfonamides, thiazolidinediones, metformin and insulin. Without affecting the efficacy of the drug, the dosage is reduced, thereby avoiding or alleviating the occurrence of adverse reactions and improving the patient's compliance with the treatment.
  • the stable isotope (Stable isotope) which exists in a certain proportion in nature has the characteristics of no radioactivity, stable physical properties and no harm to the human body.
  • hydrazine is a stable non-radioactive isotope of hydrogen and weighs 2.0144.
  • An important feature of hydrazine is that its shape and volume in the drug molecule are substantially the same as hydrogen. That is, if the hydrogen in the drug molecule is selectively replaced with hydrazine, the deuterated drug will generally retain its original biological activity and selectivity.
  • the carbon- ⁇ bond is more stable than the carbon-hydrogen bond.
  • the carbon- ⁇ bond formed by the neutron-carrying ruthenium and carbon vibrates at a lower frequency and is therefore stronger than the carbon-hydrogen bond.
  • This increase in strength can directly affect the absorption, distribution, metabolism and excretion of certain drugs, thereby improving the efficacy, safety and tolerability of the drug. Therefore, the theory is that if a specific carbon-hydrogen bond to be decomposed in a drug molecule is deuterated into a corresponding carbon- ⁇ bond, it will delay the decomposition process and make the deuterated drug act longer in the body. The effect is better than the original drug.
  • SGLT2 inhibitors have good prospects for development as a new type of diabetes treatment.
  • FDA US Food and Drug Administration
  • PMDA Japan Pharmaceutical and Medical Device Administration
  • Istriaflozin Astellas. It is still necessary to develop a compound with high efficacy, good pharmacokinetic properties and good safety for the treatment of diabetes and related metabolic disorders.
  • the present invention discloses compounds of the structure represented by the general formula (I), and has found that compounds having such structures exhibit Excellent SGLT2 inhibition and hypoglycemic effect.
  • An object of the present invention is to provide a glucoside derivative or a pharmaceutically acceptable salt or a stereoisomer thereof represented by the formula (I), and a pharmaceutical composition containing the same;
  • Another object of the present invention is to provide a use of the above-described class of glucoside derivatives and pharmaceutical compositions thereof as therapeutic agents, particularly as sodium-glucose cotransporter 2 inhibitors.
  • the object of the invention can be achieved by the following measures:
  • R 1 is independently selected from -CH 3 , -CH 2 CH 3 , halogen or -CN;
  • R 2 is independently selected from H, D, -OH, halogen, C 1-3 alkyl, C 1-3 substituted alkyl, C 1-3 alkoxy, C 1-3 substituted alkoxy or -CN;
  • R 3 , R 4 are independently selected from H or D;
  • R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from the group consisting of H, D, halogen, —CN, C 1-3 alkyl, C 1-3 substituted alkyl, C 1-4 alkoxy, a C 1-4 substituted alkoxy group, a C 1-4 alkylthio group or a C 1-4 substituted alkylthio group selected from D, halogen, C 1-4 alkoxy or C 1-4 alkane sulfur base;
  • At least one of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 must be D.
  • the compound of the present invention may further be a compound having the formula (II), a pharmaceutically acceptable salt thereof or a hydrolyzable prodrug thereof:
  • R 1 is independently selected from -CH 3 , F, Cl or -CN;
  • R 2 is independently selected from H, D, -OH, halogen, -OCH 3 , -OCH 2 CH 3 or -CN;
  • R 3 and R 4 are independently selected from H or D;
  • R 5 , R 6 , R 7 , R 8 , R 9 are independently selected from H, D, F, Cl, -CN, -CH 3 or -CH 2 CH 3 ; R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 must have at least one of D.
  • the compounds of the formula (I) may contain asymmetric carbon atoms and may therefore exist in the form of optically pure diastereomers, diastereomeric mixtures, diastereomeric racemates, mixtures of diastereomeric racemates. Or exist as a meso compound.
  • the invention includes all of these forms. Mixtures of diastereomeric mixtures, diastereomeric racemates or diastereomeric racemates can be separated by conventional methods, for example by column chromatography, thin layer chromatography and HPLC.
  • Preferred compounds of the formula (I) of the present invention include, but are not limited to:
  • the invention includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a pharmaceutically acceptable carrier.
  • the compound of the present invention a pharmaceutically acceptable salt thereof, a hydrolyzable prodrug ester thereof, or an isomer thereof, and a pharmaceutical composition thereof can be used for the preparation of the sodium-glucose cotransporter inhibitor 2.
  • the compound of the present invention a pharmaceutically acceptable salt thereof, a hydrolyzable prodrug ester thereof or an isomer thereof and a pharmaceutical composition thereof can be prepared for treating or delaying diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy , insulin resistance, hyperglycemia, hyperinsulinemia, elevated fatty acids or glycerol, hyperlipidemia, obesity, high glycerol Drugs for the development or onset of diseases such as esteremia, X syndrome, diabetic complications, atherosclerosis or hypertension.
  • diseases such as esteremia, X syndrome, diabetic complications, atherosclerosis or hypertension.
  • Haldrogen as used in the present invention means hydrazine (1H) which is the main stable isotope of hydrogen.
  • ⁇ refers to a stable morphological isotope of hydrogen, also known as heavy hydrogen, and its elemental symbol is D.
  • halogen atom as used in the present invention includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • alkyl refers to a straight or branched alkyl group derived from alkane having from 1 to 8 carbon atoms removed by a hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, n-Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1- Dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3- Dimethylbutyl, 1-ethyl, methylbut
  • alkoxy group as used in the present invention means an -O-(unsubstituted alkyl group) and an -O-(unsubstituted cycloalkyl) group, which further represents -O-(unsubstituted alkyl group).
  • alkyl group is as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and the like.
  • alkylthio group as used in the present invention means an -S-(unsubstituted alkyl group) and an -S-(unsubstituted cycloalkyl) group, which further represents -S-(unsubstituted alkyl group).
  • alkyl group is as described above. Non-limiting examples include methylthio, ethylthio, propylthio, and the like.
  • hydroxyl group as used in the present invention means an -OH group.
  • amino group as used in the present invention means an -NH 2 group.
  • Cyano as used in the present invention means a -CN group
  • the "pharmaceutically acceptable salt” as used in the present invention means a salt of an alkali metal, an alkaline earth metal, ammonium, an alkylammonium or an inorganic or organic acid.
  • examples thereof may include sodium salt, potassium salt, calcium salt, ammonium salt, aluminum salt, triethylammonium salt, formate, acetate, propionate, butyrate, trifluoroacetate, maleic acid Salt, tartrate, citrate, stearate, succinate, ethyl succinate, lactobionate, gluconate, benzoate, methanesulfonate, ethanesulfonate, 2-hydroxyl a salt of ethanesulfonate, besylate, p-toluenesulfonate, lauryl sulfate, malate, aspartate, glutamate, adipate, cysteine, Salt of N-acetylcysteine, hydrochloride, hydrobro
  • a "pharmaceutical composition” as used in the present invention denotes a compound containing one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug or other chemical component thereof, as well as other components such as physiology. / pharmaceutically acceptable carrier or excipient.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • prodrug refers to a compound which has a pharmacological action after being transformed in vivo.
  • the prodrug itself has no biological activity or low activity, and becomes an active substance after metabolism in the body. The purpose of this process is to increase the bioavailability of the drug, enhance the targeting, and reduce the toxicity and side effects of the drug.
  • “Isomers” as used in the present invention include all epimeric, diastereomeric, and tautomeric forms. When a key is represented by a wedge, this indicates that the key will come out of the paper in three dimensions, and when a key is shaded, this indicates that the key will return to the paper in three dimensions.
  • the invention further claims a pharmaceutical composition
  • a pharmaceutical composition comprising any of the compounds described above, a pharmaceutically acceptable salt thereof, a readily hydrolyzable prodrug ester thereof, or an isomer thereof, and other pharmaceutically active ingredients.
  • the invention also includes any of the above compounds, pharmaceutically acceptable salts thereof, prolacable prodrug esters thereof or isomers thereof, which may be formulated clinically or pharmaceutically acceptable in a manner known in the art.
  • the dosage form is administered to a patient in need of such treatment by oral, parenteral, rectal or pulmonary administration.
  • it can be prepared into a conventional solid preparation such as a tablet, a capsule, a pill, a granule or the like; or an oral liquid preparation such as an oral solution, an oral suspension, a syrup or the like.
  • a suitable filler, a binder, a disintegrant, a lubricant, or the like may be added.
  • parenteral administration it can be prepared as an injection, including an injection, a sterile powder for injection, and a concentrated solution for injection.
  • the injection When the injection is prepared, it can be produced by a conventional method in the prior art, and when the injection is formulated, an additional agent may be added, or a suitable additive may be added depending on the nature of the drug.
  • an additional agent When used for rectal administration, it can be made into a suppository or the like.
  • pulmonary administration it can be prepared as an inhalant or a spray.
  • the present invention also provides a compound of the present invention, a pharmaceutically acceptable salt thereof, an easily hydrolyzable prodrug ester thereof, an isomer thereof or a pharmaceutical composition thereof, which is prepared for the treatment or prevention of inhibition by sodium-glucose cotransporter 2 The application of a disease or condition.
  • the invention further provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, a readily hydrolyzable prodrug ester thereof, an isomer thereof or a pharmaceutical composition thereof, for the preparation of a medicament for the treatment or prevention of a metabolic disease.
  • the present invention also provides a compound of the present invention, a pharmaceutically acceptable salt thereof, a hydrolyzable prodrug ester thereof, an isomer thereof or a pharmaceutical composition thereof for use in the preparation of a medicament for treating or delaying the development or onset of the following diseases Use, wherein the disease is selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevation of fatty acids or glycerol, hyperlipidemia, obesity, Hypertriglyceridemia, syndrome X, diabetic complications, or atherosclerosis or hypertension.
  • the invention further provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, a readily hydrolyzable prodrug ester thereof, an isomer thereof or a pharmaceutical composition thereof for the preparation of a sodium-glucose cotransporter 2 inhibitor.
  • the compound of the present invention has remarkable inhibitory effect on sodium-glucose cotransporter 2 and hypoglycemic action, and can be safely used for preventing and/or treating diabetes in various mammals (including humans) and each caused by diabetes. a disease.
  • the compound of the present invention exhibits good physicochemical properties, low toxicity, and small side effects.
  • Figure 1 shows the results of inhibition test of hSGLT2 transporting glucose in HEK293 transfected cell lines.
  • Step A D-gluconolactone (5.0 g, 28.1 mmol) and N-methylmorpholine (23.3 g, 222 mmol) were dissolved in THF (50 mL), and trimethylchlorosilane (18.3) was added dropwise in an ice water bath. g, 168 mmol). After the addition was completed, stirring was continued at this temperature for 1 hour, and then naturally warmed to room temperature and stirred overnight. Toluene (200 mL) was added, and ice water (200 mL) was added dropwise under an ice water bath to control the internal temperature not exceeding 10 °C. The layers were separated, the organic layer was collected, and aqueous layer was extracted with toluene (50mL).
  • Step B Dissolve selenophene (6.76 g, 28.7 mmol) in dichloromethane (75 mL), add hydrobromic acid (10 drops), then add NBS (5.08 g, 28.5 mmol) in portions over 40 min. ). After the addition, the temperature was naturally raised to room temperature and stirring was continued for 4 hours. Water (50 mL) was added and the layers evaporated. The combined organic layers were washed with water (20 mL? The solvent was evaporated under reduced pressure to give 2-bromoselole (2) (5.10 g). The yield was 83.7%.
  • Step C To a mixture of compound 2 (2.50 g, 11.9 mmol), 4-fluorophenylboronic acid (2.0 g, 14.3 mmol), toluene (100 mL) and water (20 mL), sodium carbonate (3.79 g, 35.8 mmol) And tetrakis(triphenylphosphine)palladium (250 mg, 0.216 mmol), and the mixture was stirred under nitrogen overnight. After cooling to room temperature, it was filtered through celite, and filtered cake was washed with ethyl ether. The organic layer in the filtrate was collected, and the aqueous layer was extracted with methyl tert-butyl ether (40 mL ⁇ 3). The combined organic layers were dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified (jjjjjjjjjj The yield was 67.2%.
  • Step D 2-Methyl-5-iodobenzoic acid (2.0 g, 7.63 mmol) was dissolved in methylene chloride (50 mL), chlorosulfoxide (10 mL) was added and the mixture was stirred for 1 hour under reflux. The solvent was evaporated under reduced pressure. anhydrous dichloromethane (50 mL) was evaporated and evaporated. Stir overnight. After adding water (30 mL), EtOAc (EtOAc)EtOAc.
  • Step F Compound 5 (370 mg, 0.784 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (0.5 mL) was then added in ice water, then triethylsilane (0.2 mL) was added dropwise, and the mixture was obtained at room temperature Stir under 0.5 hour. Water (20 mL) was added and the pH was adjusted to neutral with saturated aqueous sodium bicarbonate. The layers were separated, and the organic layer was evaporated.
  • Step G Compound 6 (310 mg, 0.680 mmol) and Compound 1 (412 mg, 0.883 mmol) were dissolved in anhydrous THF (4 mL), and 0.5 M (trimethylsilane) was added dropwise at -40 to -60 ° C under nitrogen. Lithium methylate (2.7 mL, 1.35 mmol) was added and stirring was continued for 2 hours. Then, a solution of methanesulfonic acid (0.26 mL) in methanol (4 mL) was added dropwise at this temperature and then warmed to room temperature overnight. Saturated brine (20 mL) was added, and ethyl acetate (15 mL) was evaporated.
  • Step H Compound 7 (140 mg, 0.268 mmol) was dissolved in dichloromethane (20 mL), then triethylsilane (93 mg, 0.780 mmol) was added at -30 to 40 ° C under nitrogen, Boron ether (115 mg, 0.810 mmol) was added and the mixture was warmed to room temperature overnight. The solvent was evaporated under reduced pressure. EtOAc (EtOAc)EtOAc.
  • Step I Compound 8 (100 mg, 0.203 mmol) was dissolved in THF (20 mL), N-methylmorpholine (411 mg, 4.06 mmol) and DMAP (2.5 mg, 0.0205 mmol) were added, then B was added dropwise in ice water bath The anhydride (414 mg, 4.06 mmol) was stirred for 0.5 h and then warmed to room temperature and stirred overnight. The solvent was evaporated under reduced pressure, and ethyl acetate (40 mL) was evaporated. EtOAc EtOAcjjjjjjjj .
  • Step J Compound 9 (100 mg, 0.151 mmol) was suspended in a mixture of THF (2 mL), methanol (3 mL) and water (1 mL), hydrated lithium hydroxide (10 mg, 0.238 mmol) was added and the mixture was stirred at room temperature 3 hours. After the addition of water (10 mL), EtOAc (EtOAc m.
  • Step A Compound 4 (300 mg, 0.639 mmol) was dissolved in anhydrous THF (10 mL), sodium borohydride (80 mg, 1.91 mmol) was added, and then boron trifluoride diethyl ether (364 mg, 2.56 mmol) was added dropwise in an ice water bath. ). After the addition was completed, stirring was continued at this temperature for 20 minutes, and then the temperature was raised to room temperature and stirred for 1 hour, and the mixture was further heated to reflux and stirred overnight. Saturated brine (20 mL) was added, and the mixture was evaporated.
  • Steps B, C, D, and E respectively, refer to steps G, H, I, and J in Example 1, to obtain (2S, 3R, 4R, 5S, 6R)-2- ⁇ 3- ⁇ diodes [5-( 4-fluorophenyl)selenophen-2-yl]methyl ⁇ -4-methylphenyl ⁇ -6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (15 ).
  • Example 19 For the preparation method of the compound 19, refer to Example 1, wherein the 4-fluorophenylboronic acid in the step C of the embodiment 1 is replaced with 2,3,4,5,6-pentaphenylbenzeneboronic acid, the sodium borohydride in the step E of the embodiment 1. Replace with sodium borohydride.
  • Step B The crude compound 20 (3.66 g) was dissolved in methanol (73 mL), iodine (5.0 g, 19.7 mmol) and silver nitrate (5.14 g, 30.3 mmol) were added and the mixture was stirred at 30 ° C overnight. Insoluble material was removed by filtration, and the cake was washed with ethyl acetate (20mL). The filtrate was collected, and the solvent was evaporated, evaporated, evaporated, evaporated, evaporated.
  • Step C Compound 21 (2.4 g, 7.84 mmol) was dissolved in methanol (50 mL), THF (25mL) and 4M aqueous sodium hydroxide (25mL), and the mixture was stirred at room temperature for 5 hours. Most of the solvent was evaporated under reduced pressure. Water (50 mL) was evaporated, and the mixture was adjusted to pH 2-3 with 2M hydrochloric acid. The solvent was evaporated under reduced pressure to give 5-iodo-4-methoxy-2-methylbenzoic acid (22) (2.1 g). The yield was 91.7%.
  • Step D Compound 22 (1.26 g, 4.31 mmol).
  • Step E Compound 23 (500 mg, 1.0 mmol) was dissolved in methanol (10 mL) and dichloromethane (20 mL), and sodium borohydride (126 mg, 3.0 mmol) was added portionwise in an ice water bath. Stirring was continued for 1 hour. The reaction was quenched with water (2 mL). After the addition of water (30 mL), EtOAc (EtOAc m.
  • Step F Compound 24 (500 mg, 0.995 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (1 mL) was then added in ice water, then triethyl silane (0.5 mL) was added dropwise and the mixture was obtained at room temperature Stir for 1 hour. Water (20 mL) was added and the pH was taken to neutral with saturated aqueous sodium bicarbonate.
  • Step G Compound 25 (390 mg, 0.802 mmol) was dissolved in anhydrous dichloromethane (20 mL), and a solution of 4.0 M of boron tribromide in dichloromethane (0.6 mL) was added at -40 ° C, then warmed to -20 °C and stirring was continued for 2 hours. The reaction solution was poured into ice water, extracted with dichloromethane (15 mL ⁇ 3) and dried over anhydrous sodium sulfate.
  • Step I Compound 27 (260 mg, 0.504 mmol) and Compound 1 (305 mg, 0.653 mmol) were dissolved in anhydrous THF (3 mL), and 0.5 M (trimethylsilane) was added dropwise at -40 to -60 ° C under nitrogen. Lithium methylate (1.9 mL). After the addition was completed, stirring was continued for 2.5 hours, and the resulting mixture was added dropwise a solution of methanesulfonic acid (0.19 mL) in methanol (2 mL), and then warmed to room temperature overnight. Saturated brine (20 mL) was added, and ethyl acetate (15 mL ⁇ 3) was evaporated.
  • Step J Compound 28 (90 mg, 0.167 mmol) was dissolved in dichloromethane (2 mL), then triethylsilane (62 mg, 0.533 mmol) was added at -30 to -40 ° C under nitrogen, Boron ether (76 mg, 0.535 mmol). After the addition was completed, the temperature was naturally raised to room temperature and stirring was continued for 6 hours. After adding water (15 mL), EtOAc was evaporated.
  • Step K Compound 29 (55 mg, 0.108 mmol) was dissolved in THF (10 mL), N-methylmorpholine (219 mg, 2.16 mmol) and DMAP (1.32 mg, 0.011 mmol) were added, then B was added dropwise in ice water bath The anhydride (221 mg, 2.16 mmol) was stirred for 0.5 h and then warmed to room temperature and stirred overnight. The solvent was evaporated under reduced pressure, and ethyl acetate (30 mL) was evaporated and evaporated.
  • Step L Compound 30 (52 mg, 0.0724 mmol) was suspended in a mixture of THF (2 mL), methanol (2 mL) and water (1 mL), hydrated lithium hydroxide (5 mg, 0.119 mmol), and the mixture was stirred at room temperature 1 hour. Water (15 mL) was added, and the pH was adjusted to 2 to 3 with 2M hydrochloric acid, ethyl acetate (15 mL ⁇ 3), and dried over anhydrous sodium sulfate.
  • Step A Add NBS (5.89 g, 33.1 mmol) in portions to 2-methyl-5-nitrobenzoic acid (5.0) at 60 °C. A solution of g, 27.6 mmol) in concentrated sulfuric acid (20 mL) was stirred at this temperature for one hour. The reaction solution was poured into ice water, filtered and dried to give 3-bromo-2-methyl-5-nitrobenzoic acid (32) (6.3 g). The yield was 73.2%.
  • Step B Compound 32 (6.3 g, 24.2 mmol) was dissolved in methanol (50 mL) and concentrated sulfuric acid (5 mL). Most of the solvent was evaporated under reduced pressure. dichloromethane (dichloromethanol) (EtOAc) The solvent was evaporated under reduced pressure, and the product was purified (jjjjjjjj . The yield was 64.8%.
  • Step D Compound 34 (520 mg, 3.13 mmol) was dissolved in a mixture of sulfuric acid (1 mL) and water (10 mL), and a solution of sodium nitrite (227 mg, 3.29 mmol) in water (10 mL) was added dropwise at 0 to 5 °C Stirring was continued for 30 minutes after the addition was completed. Then, a solution of potassium iodide (1.56 g, 9.40 mmol) in water (10 mL) was added dropwise to the reaction mixture, and the mixture was stirred at 0 to 5 ° C for one hour. It was extracted with ethyl acetate (20 mL ⁇ 3) and dried over anhydrous sodium sulfate.
  • Step E Compound 35 (830 mg, 3.0 mmol) was dissolved in methanol (10 mL). The pH was adjusted to 2 to 3 with dilute hydrochloric acid, extracted with ethyl acetate (30 mL ⁇ 3) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 3-indane-5-iodo-2-benzoic acid (36) (800 mg). The yield was 100%.
  • Steps F, G, H, I, J, K, and L refer to steps D, E, F, G, H, I, and J in Example 7, respectively, to obtain (2S, 3R, 4R, 5S, 6R)-2.
  • the stably transfected cells HEK293-hSGLT2 were seeded in a 24-well plate at 2 ⁇ 10 5 cells/well, and cultured for 3 days in advance.
  • pre-treatment buffer (10 mM HEPES, 5 mM Tris, 140 mM choline chloride, 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , pH 7.4) and add appropriate pre-treatment buffer in the incubator. Incubate at °C for 20 minutes.
  • test compound pores (other conditions as described above) be added as positive control wells.
  • pretreatment buffer without Na +
  • transport buffer other conditions as described above
  • the synthesized partial compounds 10, 15, 16, 17, 18, 19, 31 and 43 were tested according to the above experimental procedures, and the results of inhibition test of hSGLT2 transporting glucose in HEK293 transfected cell lines at a concentration of 50 nM were obtained. 1. These compounds showed good inhibition of hSGLT2.

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Abstract

本发明公开了一类通式（I）所示的化合物、其药学上可接受的盐、其易水解的前药酯或其异构体，以及包含这类化合物的药物组合物作为钠-葡萄糖协同转运蛋白2抑制剂，用于治疗或延缓糖尿病、糖尿病性视网膜病、糖尿病性神经病、糖尿病性肾病、胰岛素抗性等相关疾病。

Description

一类葡萄糖苷衍生物及其药用组合物 技术领域
本发明涉及一种通式(I)所示的一类葡萄糖苷衍生物或可药用的盐或其立体异构体，及其含有该衍生物的药物组合物，以及其作为治疗剂特别是作为钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂的用途。
背景技术
随着人们生活水平的提高和生活方式的改变，全球范围内糖尿病患者人数急剧增加，糖尿病已成为危害大众健康的主要问题之一。世界卫生组织(WHO)2013年公布的数字表明，全球约有3.82亿成年人患有糖尿病。到2035年，患者人数预计会上升至5.92亿。
早期的治疗糖尿病药物有双胍类(如二甲双胍)、磺酰尿类(如格列美脲)、葡萄糖苷酶抑制剂类(如阿卡波糖)、恶唑烷酮类(如罗格列酮)等。这些药物的靶器官集中在肝脏、小肠或是胰腺，其作用方式是通过降低葡萄糖的合成或小肠对葡萄糖的吸收而达到降低体内血糖。新型糖尿病治疗药物多集中在作用于胰高血糖素样肽-1(Glucagon-like peptide 1,GLP-1)，GLP-1激动剂如艾塞那肽、PPARγ激动剂如莫格他唑、DPP-IV抑制剂如西格列汀等。GLP-1是由肠道L细胞分泌的一种肽类激素，可增加胰岛素的生物合成和分泌；刺激β细胞的增殖和分化，抑制β细胞凋亡；抑制胰高血糖素的分泌；抑制食欲及摄食，延缓胃内容物排空等。从而降低餐后血糖并使血糖维持在合理水平(刘永贵，田红，解学星，沈雪砚，陈常青。治疗2型糖尿病的非胰岛素类药物的研究进展[J].现代药物与临床，2013,28(2)：108-113)。尽管有如此众多药物可供选择，但许多病人对药物的不敏感以及药物不良反应等问题，使得研发新的治疗糖尿病药物成为人们的迫切需求。
钠-葡萄糖协同转运蛋白2(sodium glucose co-transporter 2，SGLT2)抑制剂为近年来研发2型糖尿病药物的一个热门领域。SGLT2由672个氨基酸残基构成，其亲和力低(low affinity)，与钠-葡萄糖协同转运蛋白1(sodium glucose co-transporter 1，SGLT1)有59％的同源性(SGLT1具有高亲和力，high affinity)。SGLT2主要作用是在肾脏近曲小管，完成对原尿中90％葡萄糖的重吸收(Neumiller J J,White J R Jr,Campbell R K.Sodium-glucose co-transport inhibitors:progress and therapeutic potential in type 2diabetes mellitus[J].Drugs,2010,70(4):377-385.)(Wright,E.M..Renal Na+-glucose cotransporters.Am J Physiol Renal Physiol.2001，280,F10-F18.)。研究人员之前就发现苹果树中的根皮苷(phlorizin)可增加糖尿病犬的尿糖排出，并证明根皮苷降低糖尿病大鼠的血糖。随后的大量研究证明根皮苷 是SGLT2活性较高的抑制剂(Ehrenkranz JR,Lewis NG,Kahn CR,Roth J et al.Phlorizin:a review.Diabetes Metab Res Rev.2005，21(1):31-38.)。进一步的研究表明，特异性抑制SGLT2表达，可增加糖尿病大鼠尿糖排泄、降低血糖及糖化血红蛋白(HbA1c)(Wancewicz EV,Siwkowski A,Meibohm B et al.Long term safety and efficacy of ISIS-388626,an optimized SGLT2antisense inhibitor,in multiple diabetic and euglycemic species.Diabetes.2008,57(Suppl.1):A96.)。同时，SGLT1抑制剂也可降低血糖，但由于SGLT1在心脏、脑等多个重要脏器分布，抑制SGLT1可能会引起多种不良反应，而且抑制肠道的SGLT1会影响糖类的吸收而引起腹泻等胃肠道反应。因此，选择性地抑制肾脏SGLT2，可促进尿糖排出，降低体内血糖，为治疗糖尿病提供了新方法。
SGLT2抑制剂与其他抗糖尿病药物相比，其主要优势有：(1)降糖机理与胰岛素无关，可用于几乎所有的包括胰岛素抵抗的糖尿病；(2)可以改善肝脏和外周组织的胰岛素敏感性，改善β细胞功能，改进胰岛素抵抗；(3)不易引起低血糖；(4)可降低糖化血红蛋白的百分率；(5)有一定的减肥作用及有利于改善心脑血管疾病；(6)抑制SGLT2对其它组织、器官无显著影响(王玉丽，王小彦，汤立达等。钠-葡萄糖协同转运蛋白2抑制剂类抗糖尿病新药的研发概况[J]。现代药物与临床。2012,27(3):138-141)。
SGLT2抑制剂亦可与现有的治疗药物(如磺酰胺、噻唑烷二酮、二甲双胍和胰岛素等)联合使用。在不影响药效的情况下，降低用药剂量，从而避免或减轻不良反应的发生，提高了患者对治疗的顺应性。
在自然界中其中以一定比例存在的稳定性同位素(Stable isotope)具有无放射性，物理性质稳定，对人体无害的特点。其中氘是氢的一种稳定非放射性同位素，重量为2.0144。氘的重要特点是其在药物分子中的形状和体积与氢基本上相同。也就是说，如果药物分子中的氢被选择性的替换为氘，氘代药物一般还会保留原来的生物活性和选择性。
实验证明，碳-氘键的结合比碳-氢键更加稳定。携带中子的氘与碳形成的碳-氘键在较低的频率振动，因而强于碳-氢键。这一强度的增加，可直接影响某些药物的吸收、分布、代谢和排泄等属性，从而提高药物的疗效、安全性和耐受性。因此理论认为，如果药物分子中将被分解的某个特定的碳-氢键被氘代为相应的碳-氘键后，将会延缓其分解过程，使氘代药物在身体里作用的时间更长，效果更优于原来的药物。
SGLT2抑制剂作为新型的糖尿病治疗药物有着良好的开发前景。目前，美国食品与药物管理局(FDA)批准了强生的Canagliflozin和阿斯利康的Dapagliflozin上市；日本药品与医疗器械管理局(PMDA)批准了安斯泰来的Ipragliflozin上市。开发出疗效高、药代性质好，安全性佳的化合物用于糖尿病及相关代谢紊乱疾病的治疗仍然非常有必要。经过不断努力，本发明公开了通式(I)所示的结构的化合物，并发现具有此类结构的化合物表现 出优异的SGLT2抑制效果和降糖作用。
发明内容
本发明的目的是提供一种通式(I)所示的一类葡萄糖苷衍生物或可药用的盐或其立体异构体，及其含有该衍生物的药物组合物；
本发明的另一目的是提供了上述一类葡萄糖苷衍生物及其药用组合物作为治疗剂，特别是作为钠-葡萄糖协同转运蛋白2抑制剂的用途。
本发明的目的可以通过以下措施达到：
通式(I)所示的化合物、其药学上可接受的盐、其易水解的前药酯或其异构体：
Figure PCTCN2015093089-appb-000001
其中，
R1独立地选自-CH3、-CH2CH3、卤素或-CN；
R2独立地选自H、D、-OH、卤素、C1-3烷基、C1-3取代烷基、C1-3烷氧基、C1-3取代烷氧基或-CN；
R3、R4独立地选自H或D；
R5、R6、R7、R8、R9独立地选自H、D、卤素、-CN、C1-3烷基、C1-3取代烷基、C1-4烷氧基、C1-4取代烷氧基、C1-4烷硫基或C1-4取代烷硫基，所述取代基选自D、卤素、C1-4烷氧基或C1-4烷硫基；
R2、R3、R4、R5、R6、R7、R8或R9必须至少有一个为D。
在一种优选方案中，本发明的化合物可进一步为具有通式(II)所示的化合物、其可药用的盐或其易水解的前药酯：
在一种优选方案中，R1独立地选自-CH3、F、Cl或-CN；
在一种优选方案中，R2独立地选自H、D、-OH、卤素、-OCH3、-OCH2CH3或-CN；
在一种优选方案中，R3、R4独立地选自H或D；
在一种优选方案中，R5、R6、R7、R8、R9独立地选自H、D、F、Cl、-CN、-CH3或-CH2CH3；R2、R3、R4、R5、R6、R7、R8或R9必须至少有一个为D。
通式(I)化合物可以含有不对称碳原子，因此可以以旋光纯的非对映体、非对映体混合物、非对映体外消旋体、非对映外消旋体的混合物的形式存在或作为内消旋体化合物存在。本发明包括所有这些形式。非对映体混合物、非对映外消旋体或非对映外消旋体的混合物可以通过常规方法，例如通过柱色谱法、薄层色谱法和HPLC等来分离。
本发明通式(I)所示的优选化合物包括，但不限于：
(2S,3R,4R,5S,6R)-2-{3-{氘代[5-(4-氟苯基)硒吩-2-基]甲基}-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇
(2S,3R,4R,5S,6R)-2-{3-{二氘代[5-(4-氟苯基)硒吩-2-基]甲基}-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇
(2S,3R,4R,5S,6R)-2-{3-{氘代[5-(4-氟苯基)硒吩-2-基]甲基}-4-氯苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇
(2S,3R,4R,5S,6R)-2-{3-[氘代(5-苯基硒吩-2-基)甲基]-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇
(2S,3R,4R,5S,6R)-2-{3-{氘代[5-(五氘代苯基)硒吩-2-基]甲基}-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇
(2R,3S,4R,5R,6S)-2-(羟甲基)-6-{4-甲基-3-{[5-(五氘代苯基)硒吩-2-基]甲基}苯基}四氢-2H-吡喃-3,4,5-三醇
(2S,3R,4R,5S,6R)-2-{5-{氘代[5-(4-氟苯基)硒吩-2-基]甲基}-2-羟基-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇
(2S,3R,4R,5S,6R)-2-{3-氘代-5-{[5-(4-氟苯基)硒吩-2-基]甲基}-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇
或其可药用的盐或其所有的立体异构体。
本发明包括一种药物组合物，其包括本发明治疗有效剂量的化合物或其可药用的盐或其立体异构体或可药用的载体。
本发明的化合物、其药学上可接受的盐、其易水解的前药酯或其异构体及药物组合物可应用于制备钠-葡萄糖协同转运蛋白抑制剂2中的用途。
本发明的化合物、其药学上可接受的盐、其易水解的前药酯或其异构体及药物组合物可制备用于治疗或延缓糖尿病、糖尿病性视网膜病、糖尿病性神经病、糖尿病性肾病、胰岛素抗性、高血糖、高胰岛素血症、脂肪酸或甘油的升高、高脂血症、肥胖症、高甘油三 酯血症、X综合症、糖尿病并发症、动脉粥样硬化或高血压等疾病的发展或发作的药物。
发明的详细说明
除非有其他陈述，下列用在说明书和权利要求书中的术语具有下述含义。
本发明所述的“氢”，是指氕(1H)，它是氢元素的主要稳定同位素。
本发明所述的“氘”，是指氢的一种稳定形态同位素，也被称为重氢，其元素符号为D。
本发明所述的“卤素原子”包括氟原子、氯原子、溴原子、碘原子。
本发明所述的“烷基”指含有1-8个碳原子的烷烃部分去除一个氢原子衍生的直链或支链的烷基，如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基、新戊基、1-乙基丙基、正己基、异己基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,2-二甲基丁基、2,3-二甲基丁基、3,3-二甲基丁基、1-乙基丁基、2-乙基丁基、1,1,2-三甲基丙基、1,2,2-三甲基丙基、1-乙基-1-甲基丙基和1-乙基-2-甲基丙基等。术语“C1-4烷基”和“C1-3烷基”指上述实例中的含有1-4个和1-3个碳原子的具体实例。
本发明所述的“烷氧基”是指-O-(未取代的烷基)和-O-(未取代的环烷基)基团，其进一步表示-O-(未取代的烷基)，其中烷基的定义如上所述。非限制性实施例包含甲氧基、乙氧基、丙氧基等。
本发明所述的“烷硫基”是指-S-(未取代的烷基)和-S-(未取代的环烷基)基团，其进一步表示-S-(未取代的烷基)，其中烷基的定义如上所述。非限制性地实施例包含甲硫基、乙硫基、丙硫基等。
本发明所述的“羟基”是指-OH基团。
本发明所述的“氨基”是指-NH2基团
本发明所述的“氰基”是指-CN基团
本发明所述的“药学上可接受盐”是指碱金属、碱土金属的盐、铵、烷基铵、或无机或有机酸的盐。其实例可以包括钠盐、钾盐、钙盐、铵盐、铝盐、三乙基铵盐、甲酸盐、乙酸盐、丙酸盐、丁酸盐、三氟乙酸盐、马来酸盐、酒石酸盐、柠檬酸盐、硬脂酸盐、琥珀酸盐、乙基琥珀酸盐、乳糖酸盐、葡萄糖酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、2-羟基乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、十二烷基硫酸盐、苹果酸盐、天冬氨酸盐、谷氨酸盐、己二酸盐、半胱氨酸的盐、N-乙酰半胱氨酸的盐、盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、氢碘酸盐、盐酸盐、草酸盐、苦味酸盐、与丙烯酸酯聚合物形成的盐。
本发明上所述的“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物或其他化学组分的化合物，以及其他组分例如生理学/可药用的载体或 赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
本发明上所述的“前药”指的是在经过生物体内转化后才具有药理作用的化合物。前体药物本身没有生物活性或活性很低，经过体内代谢后变为有活性的物质，这一过程的目的在于增加药物的生物利用度，加强靶向性，降低药物的毒性和副作用。
本发明上所述的“异构体”包括所有差向立体异构、非对映异构及互变异构形式。当一个键用一个楔表示时，这表明在三维上该键将从纸面出来，而当一个键是阴影时，这表明在三维上该键将返入纸面中。
本发明进一步要求保护包括上面所述的任一化合物、其药学上可接受的盐、其易水解的前药酯或其异构体与其它药用活性成分的药物组合物。
本发明也包括上述任一化合物、其药学上可接受的盐、其易水解的前药酯或其异构体，可以用本领域已知的方式配制成临床上或药学上可接受的任一剂型，以口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者。用于口服给药时，可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时，可以制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中常规方法生产，配制注射剂时，可以不加入附加剂，也可以根据药物的性质加入适宜的附加剂。用于直肠给药时，可制成栓剂等。用于经肺给药时，可制成吸入剂或喷雾剂等。
本发明还提供了本发明化合物、其药学上可接受的盐、其易水解的前药酯、其异构体或药物组合物在制备治疗或预防因受钠-葡萄糖协同转运蛋白2抑制所影响的疾病或病症的应用。
本发明还提供了本发明化合物、其药学上可接受的盐、其易水解的前药酯、其异构体或药物组合物在制备适于治疗或预防代谢性疾病的应用。
本发明还提供了本发明化合物、其药学上可接受的盐、其易水解的前药酯、其异构体或药物组合物在制备用于治疗或延缓下列疾病的发展或发作的药物中的用途，其中所述疾病选自糖尿病、糖尿病性视网膜病、糖尿病性神经病、糖尿病性肾病、胰岛素抗性、高血糖、高胰岛素血症、脂肪酸或甘油的升高、高脂血症、肥胖症、高甘油三酯血症、X综合征、糖尿病并发症或动脉粥样硬化或高血压。
本发明还提供了本发明化合物、其药学上可接受的盐、其易水解的前药酯、其异构体或药物组合物在制备钠-葡萄糖协同转运蛋白2抑制剂的用途。
本发明化合物具有以下特点：
(1)本发明化合物对钠-葡萄糖协同转运蛋白2的抑制作用和降糖作用显著，能被安全的用于预防和/治疗各种哺乳动物(包括人类)的糖尿病以及由糖尿病所引起的各种疾病。
(2)本发明化合物显示较好的理化性质，毒性低，副作用小。
附图说明
以下结合附图来详细说明本发明的实施方案，其中：
图1为化合物对HEK293转染细胞株中hSGLT2转运葡萄糖的抑制试验结果。
具体实施方式
给出下列制备例和实施例，使本领域技术人员能够更清楚地理解和实施本发明。它们不应被解释为限制本发明的范围，仅仅是其例证和代表。
实施例1
(2S,3R,4R,5S,6R)-2-{3-{氘代[5-(4-氟苯基)硒吩-2-基]甲基}-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇(10)的合成
Figure PCTCN2015093089-appb-000003
步骤A：将D-葡萄糖酸内酯(5.0g，28.1mmol)和N-甲基吗啉(23.3g，222mmol)溶解于THF(50mL)，在冰水浴下滴加三甲基氯硅烷(18.3g，168mmol)。加完后在该温度下继续搅拌1小时，然后自然升温到室温搅拌过夜。加入甲苯(200mL)，在冰水浴下，控制内温不超过10℃滴加冰水(200mL)。分层，收集有机层，水层用甲苯(50mL)萃取。合并的有机层依次用饱和磷酸二氢钠水溶液(70mL×2)、水(50mL)、饱和食盐水(50mL)洗涤，无水硫酸钠干燥。减压蒸除溶剂，得2,3,4,6-四-O-三甲基硅基-D-葡萄糖酸内酯(1)(13.0g)。收率为99.2％。
步骤B：将硒吩(6.76g，28.7mmol)溶解于二氯甲烷(75mL)，加入氢溴酸(10滴)，然后在冰水浴下在40分钟内分批加入NBS(5.08g，28.5mmol)。加毕，自然升温到室温并继续搅拌4小时。加入水(50mL)，分层，收集有机层，水层再用二氯甲烷(50mL)萃取。合并的有机层用水(20mL×2)洗涤，无水硫酸钠干燥。减压蒸除溶剂，得2-溴硒吩(2)(5.10g)。收率为83.7％。
步骤C：向含有化合物2(2.50g，11.9mmol)、4-氟苯硼酸(2.0g，14.3mmol)、甲苯(100mL)和水(20mL)的混合物中加入碳酸钠(3.79g，35.8mmol)和四(三苯基磷)钯(250mg，0.216mmol)，所得混合物在氮气下回流搅拌过夜。冷却到室温，经硅藻土过滤，滤饼用少量甲基叔丁基醚洗涤。收集滤液中的有机层，水层用甲基叔丁基醚(40mL×3)萃取。合并的有机层用无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，石油醚洗脱)，得2-(4-氟苯基)硒吩(3)(1.80g)。收率为67.2％。
步骤D：将2-甲基-5-碘苯甲酸(2.0g，7.63mmol)溶解于无水二氯甲烷(50mL)，加入氯化亚砜(10mL)，所得混合物在回流下搅拌1小时。减压蒸除溶剂，加入无水二氯甲烷(50mL)，在冰水浴下依次加入无水氯化铝(1.22g，9.15mmol)和化合物3(1.80g，7.99mmol)，所得混合物在室温下搅拌过夜。加入水(30mL)，分层，收集有机层，水层用二氯甲烷(50mL)萃取，合并的有机层用无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，石油醚洗脱)，得[5-(4-氟苯基)硒吩-2-基](5-碘-2-甲基苯基)甲酮(4)(2.80g)。收率为74.7％。1H NMR(CDCl3，400MHz)δ7.77(d，J＝2.0Hz，1H)，7.74-7.71(m，1H)，7.64-7.58(m，3H)，7.46-7.45(m，1H)，7.16-7.12(m，2H)，7.08-7.06(m，1H)，2.35(s，3H)。
步骤E：将化合物4(469mg，1.0mmol)溶解于甲醇(10mL)，在冰水浴下分批加入硼氘化钠(250mg，5.98mmol)，所得混合物在该温度下继续搅拌1.5小时。用水(2mL)淬灭反应，减压蒸除大部分溶剂。加入水(30mL)，用二氯甲烷(15mL×3)萃取，合并的有机层用饱和食盐水(20mL)洗涤，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯:石油醚＝1:30～1:10洗脱)，得[5-(4-氟苯基)硒吩-2-基](5- 碘-2-甲基苯基)-氘代甲醇(5)(372mg)。收率为78.8％。
步骤F：将化合物5(370mg，0.784mmol)溶解于二氯甲烷(20mL)，在冰水浴下加入三氟乙酸(0.5mL)，然后滴加三乙基硅烷(0.2mL)，所得混合物在室温下搅拌0.5小时。加入水(20mL)，用饱和碳酸氢钠水溶液调节pH值到中性。分层，收集有机层，水层用二氯甲烷(20mL)萃取。合并的有机层用饱和食盐水(10mL)洗涤，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，石油醚洗脱)，得2-[氘代(5-碘-2-甲基苯基)甲基]-5-(4-氟苯基)硒吩(6)(310mg)。收率为86.7％。1H NMR(CDCl3，300MHz)δ7.56(s，1H)，7.50(d，J＝8.1Hz，1H)，7.45-7.40(m，2H)，7.17(d，J＝3.6Hz，1H)，7.04-6.98(m，2H)，6.91(d，J＝8.1Hz，1H)，6.85(d，J＝3.9Hz，1H)，4.08(s，1H)，2.27(s，3H)。
步骤G：将化合物6(310mg，0.680mmol)和化合物1(412mg，0.883mmol)溶解于无水THF(4mL)，在-40～-60℃及氮气下滴加0.5M(三甲基硅烷)甲基化锂(2.7mL，1.35mmol)，加完后，继续搅拌2小时。然后在该温度下滴加甲烷磺酸(0.26mL)的甲醇(4mL)溶液，自然升温到室温搅拌过夜。加入饱和食盐水(20mL)，用乙酸乙酯(15mL×3)萃取，合并的有机层用饱和食盐水(10mL)洗涤，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯:石油醚＝5:1洗脱)，得(3R,4S,5S,6R)-2-{3-{氘代[5-(4-氟苯基)硒吩-2-基]甲基}-4-甲基苯基}-6-羟甲基-2-甲氧基四氢-2H-吡喃-3,4,5-三醇(7)(140mg)。收率为39.4％。
步骤H：将化合物7(140mg，0.268mmol)溶解于二氯甲烷(20mL)，然后在-30～-40℃及氮气下加入三乙基硅烷(93mg，0.780mmol)，再滴加三氟化硼乙醚(115mg，0.810mmol)，加完后，自然升温到室温搅拌过夜。减压蒸除溶剂，加入水(15mL)，用二氯甲烷(15mL×3)萃取，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯:石油醚＝5:1洗脱)，得(3R,4R,5S,6R)-2-{3-{氘代[5-(4-氟苯基)硒吩-2-基]甲基}-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇(8)(100mg)。收率为75.7％。
步骤I：将化合物8(100mg，0.203mmol)溶解于THF(20mL)，加入N-甲基吗啉(411mg，4.06mmol)和DMAP(2.5mg，0.0205mmol)，然后在冰水浴下滴加乙酸酐(414mg，4.06mmol)，搅拌0.5小时后自然升温到室温搅拌过夜。减压蒸除溶剂，加入乙酸乙酯(40mL)，所得溶液依次用饱和碳酸氢钠水溶液(10mL)、饱和磷酸二氢钠水溶液(10mL)和饱和食盐水(5mL)洗涤，无水硫酸钠干燥。减压蒸除溶剂，真空干燥，得130mg类白色固体。将该固体用乙醇(4mL)重结晶，得(2R,3R,4R,5S,6S)-2-乙酰氧甲基-6-{3-{氘代[5-(4-氟苯基)硒吩-2-基]甲基}-4-甲基苯基}四氢-2H-吡喃-3,4,5-三乙酸酯(9)(100mg)。收率为74.6％。
步骤J：将化合物9(100mg，0.151mmol)悬浮在THF(2mL)、甲醇(3mL)和水(1mL)的混合物中，加入水合氢氧化锂(10mg，0.238mmol)，所得混合物在室温下搅拌3小时。加入水(10mL)，用乙酸乙酯(15mL×3)萃取，合并的有机层依次用饱和磷酸二氢钠水溶液(10mL)和饱和食盐水(10mL)洗涤，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯:石油醚＝5:1洗脱)，得(2S,3R,4R,5S,6R)-2-{3-{氘代[5-(4-氟苯基)硒吩-2-基]甲基}-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇(10)(69mg)。收率为92.8％。1H NMR(CD3OD，500MHz)δ7.48-7.45(m，2H)，7.31(s，1H)，7.24-7.22(m，2H)，7.16-7.14(m，1H)，7.05-7.02(m，2H)，6.88-6.87(m，1H)，4.18-4.16(m，1H)，4.11-4.10(m，1H)，3.89-3.86(m，1H)，3.71-3.68(m，1H)，3.48-3.35(m，4H)，2.30(s，3H)。MS(EI，m/z)：516.1[M+Na]+。
实施例2
(2S,3R,4R,5S,6R)-2-{3-{二氘代[5-(4-氟苯基)硒吩-2-基]甲基}-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇(15)的合成
Figure PCTCN2015093089-appb-000004
步骤A：将化合物4(300mg，0.639mmol)溶解于无水THF(10mL)，加入硼氘化钠(80mg，1.91mmol)，然后在冰水浴下滴加三氟化硼乙醚(364mg，2.56mmol)。加完后在该温度下继续搅拌20分钟，然后升温到室温搅拌1小时，再升温到回流搅拌过夜。加入饱和食盐水(20mL)，用二氯甲烷(15mL×3)萃取，合并的有机层依次用饱和碳酸氢钠水溶液(15mL)和饱和食盐水(10mL)洗涤，无水硫酸钠干燥。减压蒸除溶剂，产物 经柱层析纯化(200～300目硅胶，石油醚洗脱)，得2-[二氘代(5-碘-2-甲基苯基)甲基]-5-(4-氟苯基)硒吩(11)(220mg)。收率为75.3％。1H NMR(CDCl3，500MHz)δ7.57(s，1H)，7.51(d，J＝8.0Hz，1H)，7.45-7.42(m，2H)，7.18(d，J＝3.5Hz，1H)，7.04-7.01(m，2H)，6.92(d，J＝8.0Hz，1H)，6.86(d，J＝3.5Hz，1H)，2.28(s，3H)。
步骤B、C、D和E分别参见实施例1中的步骤G、H、I和J，得(2S,3R,4R,5S,6R)-2-{3-{二氘代[5-(4-氟苯基)硒吩-2-基]甲基}-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇(15)。1H NMR(CD3OD，300MHz)δ7.50-7.45(m，2H)，7.31(s，1H)，7.24-7.23(m，2H)，7.16-7.14(m，1H)，7.07-7.01(m，2H)，6.89-6.88(m，1H)，4.12-4.09(m，1H)，3.90-3.86(m，1H)，3.72-3.67(m，1H)，3.47-3.40(m，4H)，2.30(s，3H)。MS(EI，m/z)：517.1[M+Na]+。
实施例3
(2S,3R,4R,5S,6R)-2-{3-{氘代[5-(4-氟苯基)硒吩-2-基]甲基}-4-氯苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇(16)的合成
Figure PCTCN2015093089-appb-000005
化合物16的制备方法参见实施例1，其中实施例1步骤D中2-甲基-5-碘苯甲酸用2-氯-5-碘苯甲酸替代。1H NMR(CD3OD，300MHz)δ7.51-7.46(m，3H)，7.39-7.36(m，1H)，7.33-7.30(m，1H)，7.24-7.23(m，1H)，7.07-7.02(m，2H)，6.98-6.97(m，1H)，4.31-4.27(m，1H)，4.14-4.11(m，1H)，3.89-3.85(m，1H)，3.72-3.67(m，1H)，3.43-3.39(m，4H)。MS(EI，m/z)：536.1[M+Na]+。
实施例4
(2S,3R,4R,5S,6R)-2-{3-[氘代(5-苯基硒吩-2-基)甲基]-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇(17)的合成
Figure PCTCN2015093089-appb-000006
化合物17的制备方法参见实施例1，其中实施例1步骤C中4-氟苯硼酸用苯硼酸替代。1H NMR(CD3OD，500MHz)δ7.47-7.44(m，2H)，7.32-7.20(m，6H)，7.16-7.14(m，1H)， 6.88(d，J＝3.9Hz，1H)，4.19-4.16(m，1H)，4.12-4.09(m，1H)，3.89-3.86(m，1H)，3.68-3.66(m，1H)，3.47-3.37(m，4H)，2.30(s，3H)。MS(EI，m/z)：498.1[M+Na]+。
实施例5
(2S,3R,4R,5S,6R)-2-{3-{氘代[5-(五氘代苯基)硒吩-2-基]甲基}-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇(18)的合成
Figure PCTCN2015093089-appb-000007
化合物18的制备方法参见实施例1，其中实施例1步骤C中4-氟苯硼酸用2,3,4,5,6-五氘代苯硼酸替代。1H NMR(CD3OD，300MHz)δ7.32-7.22(m，3H)，7.16-7.14(m，1H)，6.89-6.88(m，1H)，4.19-4.16(m，1H)，4.12-4.09(m，1H)，3.90-3.86(m，1H)，3.70-3.67(m，1H)，3.47-3.37(m，4H)，2.30(s，3H)。MS(EI，m/z)：503.1[M+Na]+。
实施例6
(2R,3S,4R,5R,6S)-2-(羟甲基)-6-{4-甲基-3-{[5-(五氘代苯基)硒吩-2-基]甲基}苯基}四氢-2H-吡喃-3,4,5-三醇(19)的合成
Figure PCTCN2015093089-appb-000008
化合物19的制备方法参见实施例1，其中实施例1步骤C中4-氟苯硼酸用2,3,4,5,6-五氘代苯硼酸替代，实施例1步骤E中硼氘化钠用硼氢化钠替代。1H NMR(CD3OD，300MHz)δ7.38(s，1H)，7.29-7.27(m，1H)，7.25-7.23(m，1H)，7.16-7.14(m，1H)，6.89-6.88(m，1H)，4.20(s，2H)，4.11(d，J＝9.3Hz，1H)，3.89-3.86(m，1H)，3.72-3.66(m，1H)，3.47-3.35(m，4H)，2.30(s，3H)。MS(EI，m/z)：502.1[M+Na]+。
实施例7
(2S,3R,4R,5S,6R)-2-{5-{氘代[5-(4-氟苯基)硒吩-2-基]甲基}-2-羟基-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇(31)的合成
Figure PCTCN2015093089-appb-000009
步骤A：将2-甲基-4-羟基苯甲酸(3.04g，20.0mmol)溶解于DMF(50mL)，加入碘甲烷(9.12g，64.2mmol)和碳酸钾(8.28g，60.0mmol)，所得混合物在50℃搅拌过夜。冷却到室温，加入水(200mL)，用甲基叔丁基醚(50mL×3)萃取。合并的有机层用水(30mL×3)洗涤，无水硫酸钠干燥。减压蒸除溶剂，得4-甲氧基-2-甲基苯甲酸甲酯(20)(3.89g)。该产物不经纯化直接用于下一步反应。
步骤B：将化合物20粗品(3.66g)溶解于甲醇(73mL)，加入碘(5.0g，19.7mmol)和硝酸银(5.14g，30.3mmol)，所得混合物在30℃下搅拌过夜。过滤除去不溶物，滤饼再用乙酸乙酯(20mL)洗涤。收集滤液，减压蒸除大部分溶剂，然后用乙酸乙酯(80mL)溶解，用水(20mL×2)洗涤，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200 ～300目硅胶，乙酸乙酯:石油醚＝1:25～1:10洗脱)，得5-碘-4-甲氧基-2-甲基苯甲酸甲酯(21)(5.7g)。步骤A和B两步反应总收率为99％。1H NMR(CDCl3，500MHz)δ8.37(s，1H)，6.64(s，1H)，3.92(s，3H)，3.86(s，3H)，2.60(s，3H)。
步骤C：将化合物21(2.4g，7.84mmol)溶解于甲醇(50mL)，加入THF(25mL)和4M氢氧化钠水溶液(25mL)，所得混合物在室温下搅拌5小时。减压蒸除大部分溶剂，加入水(50mL)，用2M盐酸调节pH值至2～3，用乙酸乙酯(40mL×3)萃取，无水硫酸钠干燥。减压蒸除溶剂，得5-碘-4-甲氧基-2-甲基苯甲酸(22)(2.1g)。收率为91.7％。
步骤D：将化合物22(1.26g，4.31mmol)溶解于无水二氯甲烷(50mL)，加入氯化亚砜(15mL)，所得混合物在回流下搅拌1小时。减压蒸除溶剂，然后加入无水二氯甲烷(50mL)，在冰水浴下依次加入无水氯化铝(750mg，5.62mmol)和化合物3(970mg，4.31mmol)。自然升温到室温，所得混合物在室温下搅拌过夜。加入水(30mL)，收集有机层，水层用二氯甲烷(50mL)萃取，合并的有机层用无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯:石油醚＝1:10～1:2洗脱)，得[5-(4-氟苯基)-硒吩-2-基]-(5-碘-4-甲氧基-2-甲基苯基)甲酮(23)(1.50g)。收率为69.7％。1H NMR(CDCl3，500MHz)δ7.92(s，1H)，7.61-7.58(m，3H)，7.43(d，J＝4.5Hz，1H)，7.13-7.09(m，2H)，6.73(s，1H)，3.94(s，3H)，2.42(s，3H)。
步骤E：将化合物23(500mg，1.0mmol)溶解于甲醇(10mL)和二氯甲烷(20mL)，在冰水浴下分批加入硼氘化钠(126mg，3.0mmol)，所得混合物在该温度下继续搅拌1小时。用水(2mL)淬灭反应，减压蒸除大部分溶剂。然后加入水(30mL)，用二氯甲烷(20mL×3)萃取，合并的有机层用饱和食盐水(15mL)洗涤，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯:石油醚＝1:5洗脱)，得氘代[5-(4-氟苯基)硒吩-2-基]-(5-碘-4-甲氧基-2-甲基苯基)甲醇(24)(500mg)。收率为99.5％。
步骤F：将化合物24(500mg，0.995mmol)溶解于二氯甲烷(20mL)，在冰水浴下加入三氟乙酸(1mL)，然后滴加三乙基硅烷(0.5mL)，所得混合物在室温下搅拌1小时。加入水(20mL)，用饱和碳酸氢钠水溶液调pH值到中性。分层，收集有机层，水层用二氯甲烷(50mL)萃取。合并的有机层用饱和食盐水(20mL)洗涤，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，石油醚洗脱)，得2-[氘代(5-碘-4-甲氧基-2-甲基苯基)甲基]-5-(4-氟苯基)硒吩(25)(390mg)。收率为80.6％。
步骤G：将化合物25(390mg，0.802mmol)溶解于无水二氯甲烷(20mL)，在-40℃下加入4.0M三溴化硼的二氯甲烷溶液(0.6mL)，然后升温到-20℃并继续搅拌2小时。将反应液倒入冰水中，用二氯甲烷(15mL×3)萃取，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯:石油醚＝1:30洗脱)，得4-{氘代[5-(4-氟 苯基)硒吩-2-基]甲基}-2-碘-5-甲基苯酚(26)(290mg)。收率为76.6％。
步骤H：将化合物26(300mg，0.635mmol)溶解于丙酮(20mL)，加入氯甲基甲醚(256mg，3.18mmol)和碳酸钾(439mg，3.18mmol)，所得混合物在室温下搅拌过夜。减压蒸除大部分溶剂，加入水(20mL)，用乙酸乙酯(15mL×3)萃取，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯:石油醚＝1:20洗脱)，得2-{氘代[5-碘-4-甲氧基甲氧基-2-甲基苯基]甲基}-5-(4-氟苯基)硒吩(27)(220mg)。收率为67.1％。
步骤I：将化合物27(260mg，0.504mmol)和化合物1(305mg，0.653mmol)溶解于无水THF(3mL)，在-40～-60℃及氮气下滴加0.5M(三甲基硅烷)甲基化锂(1.9mL)。加完后，继续搅拌2.5小时，所得混合物在该温度下滴加甲烷磺酸(0.19mL)的甲醇(2mL)溶液，然后自然升温到室温搅拌过夜。加入饱和食盐水(20mL)，用乙酸乙酯(15mL×3)萃取。合并的有机层用饱和食盐水(10mL)洗涤，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯洗脱)，得(3R,4S,5S,6R)-2-{5-{氘代[5-(4-氟苯基)硒吩-2-基]甲基}-2-羟基-4-甲基苯基}-6-羟甲基-2-甲氧基四氢-2H-吡喃-3,4,5-三醇(28)(90mg)。收率为33.2％。
步骤J：将化合物28(90mg，0.167mmol)溶解于二氯甲烷(2mL)，然后在-30～-40℃及氮气下加入三乙基硅烷(62mg，0.533mmol)，再滴加三氟化硼乙醚(76mg，0.535mmol)。加完后，自然升温到室温并继续搅拌6小时。加入水(15mL)，分层，收集有机层，水层用二氯甲烷(15mL×2)萃取，合并的有机层用无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯:石油醚＝1:1～5:1洗脱)，得(3R,4R,5S,6R)-2-{5-{氘代[5-(4-氟苯基)硒吩-2-基]甲基}-2-羟基-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇(29)(55mg)。收率为64.8％。
步骤K：将化合物29(55mg，0.108mmol)溶解于THF(10mL)，加入N-甲基吗啉(219mg，2.16mmol)和DMAP(1.32mg，0.011mmol)，然后在冰水浴下滴加乙酸酐(221mg，2.16mmol)，搅拌0.5小时后自然升温到室温搅拌过夜。减压蒸除溶剂，加入乙酸乙酯(30mL)，然后依次用10％柠檬酸(5mL)、饱和碳酸氢钠水溶液(5mL)和饱和食盐水(5mL)洗涤，无水硫酸钠干燥。减压蒸除溶剂，真空干燥，得72mg类白色固体。将该固体悬浮在乙醇(2mL)中，升温到回流并继续搅拌0.5小时，然后缓慢降温到室温，过滤，收集滤饼，得(2R,3R,4R,5S,6S)-2-乙酰氧甲基-6-{5-[氘代(5-(4-氟苯基)硒吩-2-基)甲基]-2-羟基-4-甲基苯基}四氢-2H-吡喃-3,4,5-三乙酸酯(30)(52mg)。收率为71.2％。
步骤L：将化合物30(52mg，0.0724mmol)悬浮在THF(2mL)、甲醇(2mL)和水(1mL)的混合物中，加入水合氢氧化锂(5mg，0.119mmol)，所得混合物在室温下搅 拌1小时。加入水(15mL)，用2M盐酸调pH值至2～3，乙酸乙酯(15mL×3)萃取，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯:石油醚＝10:1洗脱)，得(2S,3R,4R,5S,6R)-2-{5-{氘代[5-(4-氟苯基)硒吩-2-基]甲基}-2-羟基-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇(31)。1H NMR(CD3OD，300MHz)δ7.49-7.45(m，2H)，7.23-7.21(m，2H)，7.06-7.00(m，2H)，6.87-6.85(m，1H)，6.65(s，1H)，4.52(d，J＝9.3Hz，1H)，4.08-4.07(m，1H)，3.89-3.85(m，1H)，3.74-3.68(m，1H)，3.59-3.41(m，4H)，2.21(s，3H)。MS(EI，m/z)：532.0[M+Na]+。
实施例8
(2S,3R,4R,5S,6R)-2-{3-氘代-5-{[5-(4-氟苯基)硒吩-2-基]甲基}-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇(43)的合成
Figure PCTCN2015093089-appb-000010
步骤A：在60℃下将NBS(5.89g，33.1mmol)分批加入到2-甲基-5-硝基苯甲酸(5.0 g，27.6mmol)的浓硫酸(20mL)溶液中，加完后在该温度下继续搅拌1小时。将反应液倒入冰水中，过滤，干燥，得3-溴-2-甲基-5-硝基苯甲酸(32)(6.3g)。收率为73.2％。
步骤B：将化合物32(6.3g，24.2mmol)溶解于甲醇(50mL)，加入浓硫酸(5mL)，所得混合物在回流下搅拌过夜。减压蒸除大部分溶剂，加入二氯甲烷(200mL)，依次用水(50mL)、饱和碳酸氢钠溶液(50mL)和饱和食盐水(25mL)洗涤，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，石油醚洗脱)，得3-溴-2-甲基-5-硝基苯甲酸甲酯(33)(4.3g)。收率为64.8％。
步骤C：将化合物33(3.08g，11.2mmol)溶解于DMF(30mL)，加入重水(1mL)及5％钯碳(300mg)，所得混合物在氘气中60℃下常压氘化反应72小时。通过硅藻土过滤后，向滤液中加入水(120mL)，用乙酸乙酯(50mL×6)萃取，合并的有机层用饱和食盐水(30mL)洗涤，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯:石油醚＝1:40～1:30洗脱)，得5-氨基-3-氘-2-甲基苯甲酸甲酯(34)(570mg)。收率为30.6％。MS(EI，m/z)：167.1[M+H]+。
步骤D：将化合物34(520mg，3.13mmol)溶解于硫酸(1mL)和水(10mL)的混合物中，在0～5℃下滴加亚硝酸钠(227mg，3.29mmol)的水(10mL)溶液，滴加完后继续搅拌30分钟。然后向该反应液中滴加碘化钾(1.56g，9.40mmol)的水(10mL)溶液，滴加完后在0～5℃下继续搅拌1小时。用乙酸乙酯(20mL×3)萃取，无水硫酸钠干燥。减压蒸除溶剂，产物经柱层析纯化(200～300目硅胶，乙酸乙酯:石油醚＝1:50洗脱)，得3-氘-5-碘-2-苯甲酸甲酯(35)(830mg)。收率为95.7％。1H NMR(DMSO-d6，300MHz)δ8.09(s，1H)，7.82(s，1H)，3.82(s，3H)，2.50(s，3H)。
步骤E：将化合物35(830mg，3.0mmol)溶解于甲醇(10mL)，加入10％氢氧化钾溶液(45mL)，所得混合物在室温下搅拌6小时。用稀盐酸调节pH值到2～3，乙酸乙酯(30mL×3)萃取，无水硫酸钠干燥。减压蒸除溶剂，得3-氘-5-碘-2-苯甲酸(36)(800mg)。收率为100％。
步骤F、G、H、I、J、K和L分别参见实施例7中的步骤D、E、F、G、H、I和J，得(2S,3R,4R,5S,6R)-2-{3-氘代-5-{[5-(4-氟苯基)硒吩-2-基]甲基}-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇(43)。1H NMR(CD3OD，300MHz)δ7.49-7.45(m，2H)，7.31(s，1H)，7.23-7.22(m，2H)，7.07-7.01(m，2H)，6.88(d，J＝3.6Hz，1H)，4.19(s，2H)，4.12-4.09(m，1H)，3.90-3.86(m，1H)，3.72-3.66(m，1H)，3.44-3.34(m，4H)，2.30(s，3H)。MS(EI，m/z)：516.0[M+Na]+。
化合物对HEK293转染细胞株中hSGLT2转运葡萄糖的抑制试验
一、实验步骤
1.首先把稳转细胞HEK293-hSGLT2按2×105个/孔接种于24孔板中，预先培养3天。
2.再用预处理缓冲液(10mM HEPES,5mM Tris,140mM氯化胆碱,2mM KCl,1mM CaCl2,1mM MgCl2,pH 7.4)清洗细胞并加入适量预处理缓冲液，置孵箱中37℃孵育20分钟。
3.去除预处理缓冲液,使用转运缓冲液(10mM HEPES,5mM Tris,140mM NaCl,2mM KCl,1mM CaCl2,1mM MgCl2,pH 7.4)配置终浓度为20uM 14C-甲基α-D-葡萄糖苷(14C-AMG)和终浓度为50nM的待测化合物，然后加入相应孔中，作为待测化合物孔。
4.设不加待测化合物孔(其它条件同上所述)，为阳性对照孔。另外，设不加待测化合物且预处理缓冲液(不含Na+)替代转运缓冲液(其它条件同上所述)使用，做为阴性对照孔。置孵箱中37℃孵育2小时30分钟。
5.再用预冷的清洗缓冲液(含10mM AMG的预处理缓冲液)清洗细胞，最后加入0.2M NaOH溶解细胞，收集细胞碎片并加入适量闪烁液，充分混匀后上机检测同位素14C的放射强度(CPM值)。
6.计算公式如下：
Figure PCTCN2015093089-appb-000011
二、实验结果
将合成的部分化合物10、15、16、17、18、19、31和43按照上述实验步骤进行测试，得到化合物在浓度为50nM时对HEK293转染细胞株中hSGLT2转运葡萄糖的抑制试验结果见图1，这些化合物表现出对hSGLT2良好的抑制作用。

Claims (6)

  1. 通式(I)所示的化合物、其药学上可接受的盐、其易水解的前药酯或其异构体：
    Figure PCTCN2015093089-appb-100001
    其中，
    R1独立地选自-CH3、-CH2CH3、卤素或-CN；
    R2独立地选自H、D、-OH、卤素、C1-3烷基、C1-3取代烷基、C1-3烷氧基、C1-3取代烷氧基或-CN；
    R3、R4独立地选自H或D；
    R5、R6、R7、R8、R9独立地选自H、D、卤素、-CN、C1-3烷基、C1-3取代烷基、C1-4烷氧基、C1-4取代烷氧基、C1-4烷硫基或C1-4取代烷硫基，所述取代基选自D、卤素、C1-4烷氧基或C1-4烷硫基；
    R2、R3、R4、R5、R6、R7、R8或R9必须至少有一个为D。
  2. 根据权利要求1所述的通式(I)所示的化合物、其药学上可接受的盐、其易水解的前药酯或其异构体，其中包括通式(II)所示的化合物、其可药用的盐或其易水解的前药酯：
    Figure PCTCN2015093089-appb-100002
    R1独立地选自-CH3、F、Cl或-CN；
    R2独立地选自H、D、-OH、卤素、-OCH3、-OCH2CH3或-CN；
    R3、R4独立地选自H或D；
    R5、R6、R7、R8、R9独立地选自H、D、F、Cl、-CN、-CH3或-CH2CH3；
    R2、R3、R4、R5、R6、R7、R8或R9必须至少有一个为D。
  3. 根据权利要求1～2任何一项所述的化合物、其药学上可接受的盐、其易水解的前药酯 或其异构体，所述的化合物选自：
    (2S,3R,4R,5S,6R)-2-{3-{氘代[5-(4-氟苯基)硒吩-2-基]甲基}-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇
    (2S,3R,4R,5S,6R)-2-{3-{二氘代[5-(4-氟苯基)硒吩-2-基]甲基}-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇
    (2S,3R,4R,5S,6R)-2-{3-{氘代[5-(4-氟苯基)硒吩-2-基]甲基}-4-氯苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇
    (2S,3R,4R,5S,6R)-2-{3-[氘代(5-苯基硒吩-2-基)甲基]-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇
    (2S,3R,4R,5S,6R)-2-{3-{氘代[5-(五氘代苯基)硒吩-2-基]甲基}-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇
    (2R,3S,4R,5R,6S)-2-(羟甲基)-6-{4-甲基-3-{[5-(五氘代苯基)硒吩-2-基]甲基}苯基}四氢-2H-吡喃-3,4,5-三醇
    (2S,3R,4R,5S,6R)-2-{5-{氘代[5-(4-氟苯基)硒吩-2-基]甲基}-2-羟基-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇
    (2S,3R,4R,5S,6R)-2-{3-氘代-5-{[5-(4-氟苯基)硒吩-2-基]甲基}-4-甲基苯基}-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇
  4. 一种药物组合物，其包括治疗有效剂量的根据权利要求1～3任何一项所述的化合物或其可药用的盐或其立体异构体或可药用的载体。
  5. 根据权利要求1～3任何一项所述的通式(I)所示的化合物、其药学上可接受的盐、其易水解的前药酯或其异构体，或根据权利要求4所述的药物组合物在制备钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂中的用途。
  6. 根据权利要求1～3任何一项所述的化合物、其药学上可接受的盐、其易水解的前药酯或其异构体，或根据权利要求4所述的药物组合物在制备用于治疗或延缓下列疾病的发展或发作的药物中的用途，其中所述疾病选自糖尿病、糖尿病性视网膜病、糖尿病性神经病、糖尿病性肾病、胰岛素抗性、高血糖、高胰岛素血症、脂肪酸或甘油的升高、高脂血症、肥胖症、高甘油三酯血症、X综合症、糖尿病并发症、动脉粥样硬化或高血压。
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CN104817554A (zh) * 2014-11-10 2015-08-05 镇江新元素医药科技有限公司 一类葡萄糖苷衍生物及其药物组合物
CN110551088B (zh) * 2018-06-01 2022-10-21 北京惠之衡生物科技有限公司 氘修饰的苄基-4-氯苯基的c-糖苷衍生物
CN113248554A (zh) * 2021-06-25 2021-08-13 北京惠之衡生物科技有限公司 一种c-糖苷类衍生物的杂质的合成方法

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