WO2018127194A1 - 一种碳糖苷类钠葡萄糖转运蛋白体2抑制剂 - Google Patents

一种碳糖苷类钠葡萄糖转运蛋白体2抑制剂 Download PDF

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WO2018127194A1
WO2018127194A1 PCT/CN2018/071848 CN2018071848W WO2018127194A1 WO 2018127194 A1 WO2018127194 A1 WO 2018127194A1 CN 2018071848 W CN2018071848 W CN 2018071848W WO 2018127194 A1 WO2018127194 A1 WO 2018127194A1
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acid
group
glucose transporter
inhibitor
salt
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PCT/CN2018/071848
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French (fr)
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王国成
汪国松
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江苏天士力帝益药业有限公司
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • the present invention relates to the field of chemical drugs related to diabetes, and in particular to a type 2 sodium-glucose transporter (SGLT-2) inhibitor of a carbohydrate sodium glucose transporter structure.
  • SGLT-2 type 2 sodium-glucose transporter
  • the invention also discloses a preparation method and use thereof.
  • Diabetes is a metabolic disorder characterized by hyperglycemia caused by defects in insulin secretion and/or insulin deficiency. It is classified into type 1 (T1DM) and type 2 (T2DM). The former is due to islet ⁇ . - Cells can not produce enough insulin (absolute insulin deficiency), mostly in adolescents, the latter is caused by insufficient insulin secretion or insulin resistance (relative lack of insulin), more common in middle and old.
  • SGLTs Sodium-dependent glucose transporters
  • SGLT2 is a low-affinity, high-capacity specialized transporter of glucose on the surface of renal epithelial cells, whereas SGLT1 is expressed not only in the kidney but also in the intestine and other tissues.
  • S1 and S2 segments proximal end of the proximal convoluted tubule
  • S3 segment distal end of the proximal tubule
  • SGLT1 In the absence of SGLT2, SGLT1 is capable of absorbing approximately 70% of the glucose filtered.
  • SGLT2 inhibitors reduce glucose reabsorption in renal proximal convoluted tubules and achieve a negative balance of energy by increasing urinary glucose excretion. Since these inhibitors are not dependent on insulin action, they can be used at any stage of diabetes development, even in the case of ⁇ -cell deterioration and insulin resistance, to continuously and effectively lower blood sugar, which makes SGLT2 inhibitors the only treatment for diabetes. select.
  • SGLT2 inhibitors are mainly classified into oxyglycosides, carbosides, aglycones, and non-glycoside SGLT2 inhibitors. Because oxygen glycosides are sensitive to glycosidase, easy to hydrolyze, and poor pharmacokinetic tests, the development of the final oxygen glycoside has stopped, people turn the research direction to the design and development of C-glycoside drugs, C-glycoside drugs By directly changing the O in the glycosidic bond to C, it greatly enhances the hydrolytic stability without affecting the pharmacodynamics and pharmacokinetic properties, and is a very promising drug. It is also a class of sodium glucose transporter 2 inhibitors that are currently on the market and have been studied more. The following compounds circumvent the problem of sensitivity to glycosidase by removing anomeric glycosides.
  • the present invention has been modified on related groups, and it has been unexpectedly found that the compound of the present invention has stronger hypoglycemic effect, prolonged action time and reduced side effects.
  • the invention discloses a C-glycoside SGLT2 inhibitor compound having the general formula (I),
  • n 0, 1, 2 or 3;
  • X is selected from a C3 to C6 alkyl group, a C3 to C6 alkenyl group, a C3 to C6 alkynyl group, or a substituted phenyl group as shown in the formula (II).
  • R 1 , R 2 and R 3 are independently selected from the group consisting of -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -OH, -CH 2 OH, -CH 2 CH 2 OH;
  • R 4 , R 5 and R 6 are independently selected from the group consisting of -H, -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -OH, -CH 2 OH, -NH 2 , - NHCOCH 3 ;
  • n 0, 1 or 2;
  • X is selected from substituted phenyl groups as shown in formula (II),
  • R 1 , R 2 and R 3 are independently selected from -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 ;
  • R 4 , R 5 and R 6 are independently selected from -H, -CH 3 and -CH 2 CH 3 ;
  • the C-glycoside SGLT2 inhibitor compound of the present invention is the following specific compound:
  • the C-glycoside SGLT2 inhibitor compound of the present invention is the following specific compound:
  • C-glycoside SGLT2 inhibitor compounds of the invention are the following specific compounds:
  • the invention further provides a process for the preparation of a compound of the invention, which can be carried out using the following route:
  • 5-bromo-2-chlorobenzoic acid acylation, condensation and reduction
  • 5-bromo-2-chloro-4'-methoxydiphenylmethane 4 is obtained, and compound 4 is tribrominated.
  • the phenolic hydroxyl group is protected to obtain 6
  • the compound 6 and the gluconolactone (9) are condensed, the anomeric carbon hydroxy ether is etherified, and the methoxy group is reacted to obtain the key intermediate 1-chloro 4-( ⁇ -D-glucopyran-1-yl)-2-(4-hydroxy-benzyl)-benzene 10.
  • the compound of the formula (I) of the present invention can also form stable salts, esters, solvates and the like as needed.
  • salts with inorganic acids such as hydrochloric acid, sulfuric acid, and organic acids such as acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid a salt formed from benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid or malic acid, and a salt formed by an amino acid such as alanine, aspartic acid or lysine or with a sulfonic acid such as methanesulfonic acid.
  • a pharmaceutically acceptable salt may be formed with a basic substance such as an alkali metal salt, an alkaline earth metal salt, a silver salt, a barium salt or the like.
  • the compounds of the formula (I) of the present invention may also exist in the form of solvates (e.g., hydrates), and therefore, such solvates (e.g., hydrates) are also included in the compounds of the present invention.
  • solvates e.g., hydrates
  • the present invention also provides a hypoglycemic pharmaceutical composition
  • a hypoglycemic pharmaceutical composition comprising the compound of the formula (I) as defined above, or a pharmaceutically acceptable salt thereof, as an active ingredient.
  • the pharmaceutical composition sheet contains the active ingredient in the composition in a weight ratio of from 0.1 to 99.9%, and the pharmaceutically acceptable carrier in the composition in a weight ratio of from 0.1 to 99.9%.
  • the pharmaceutical compositions are in the form of a pharmaceutically acceptable preparation.
  • the medicinal preparations are preferably, for example, tablets, sugar-coated tablets, film-coated tablets, enteric coated tablets, sustained-release tablets, capsules, hard capsules, soft capsules, sustained release capsules, powders.
  • each dose means each preparation unit, such as each tablet of the tablet, each of the capsules Granules can also mean doses taken each time, such as 100 mg each time.
  • the pharmaceutical composition of the present invention can be used as a solid pharmaceutical preparation in the form of a powder, a tablet, a dispersible powder, a capsule or a cachet.
  • the solid carrier which can be used is preferably one or more selected from the group consisting of a diluent, a flavoring agent, a solubilizing agent, a lubricant, a suspending agent, a binder, a swelling agent and the like, or may be an encapsulating substance.
  • Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, cocoa butter, and the like. Because of their ease of administration, tablets, powders and capsules are the most suitable oral solid preparations.
  • the preferred dosage for a particular situation can be determined in a conventional manner. Generally, the amount of treatment initiated is lower than the optimal dose of the active ingredient, and then the dosage is gradually increased until the optimal therapeutic effect is achieved. For convenience, the total daily dose can be divided into several parts, administered in divided doses.
  • the present invention further provides the use of the SGLT2 inhibitor of the formula (I) of the present invention for the treatment of type 2 diabetes, and the present invention further provides the SGLT2 inhibitor of the formula (I) of the present invention and a pharmaceutical composition thereof for preparing a therapeutic type 2
  • the use of drugs for diabetes can improve glycemic control as an adjunct to diet and exercise in adults with type 2 diabetes.
  • the beneficial effects of the present invention are that, by comparative experiments, the compounds of the present invention, particularly the compound 13h, the compound 13i, 13j, have the characteristics of stronger hypoglycemic effect, prolonged action time and low side effects compared with the existing compounds of the same type.
  • FIG. 1 HNMR spectrum of 22.13h.
  • Figure 33.13c shows the hSGLT1 and hSGLT2 inhibitory activity profiles.
  • Figure 34.13d shows the hSGLT1 and hSGLT2 inhibitory activity profiles.
  • Figure 35.13e is a graph of hSGLT1 and hSGLT2 inhibitory activity.
  • FIG. 37 Graph of hSGLT1 and hSGLT2 inhibition activities of 13g.
  • Figure 38 Graph of hSGLT1 and hSGLT2 inhibition activities of 13h.
  • Figure 39 Graph of hSGLT1 and hSGLT2 inhibition activities of 13i.
  • Figure 40 Graph of hSGLT1 and hSGLT2 inhibition activities of 13j.
  • FIG. 41 Graph of hSGLT1 and hSGLT2 inhibitory activity of the control dapagliflozin.
  • reaction solution was slowly poured into 750 mL of ice water, stirred for 45 min, and the organic layer was separated, washed successively with 1 mol ⁇ L -1 aqueous sodium hydroxide solution, 2 mol ⁇ L -1 hydrochloric acid, saturated brine, and anhydrous sodium sulfate. The mixture was dried and evaporated to dryness. The purity by HPLC was 89.3%. MS-EI (m/z): 325.1 [M]+.
  • the reaction was stirred in a solution of 14.00 g (0.08 mol) of 1,5-gluconolactone, 80 mL of N-methylmorpholine-5 ° C in 120 mL of tetrahydrofuran, 50 mL (0.48 mol) of trimethylchlorosilane. Slowly add dropwise to the mixture, and control the dropping rate so that the reaction temperature does not exceed 5 ° C. After stirring for 1 h, the temperature is raised to 35 ° C and the reaction is continued for 15 h, then cooled to room temperature and stirred overnight, diluted with 100 mL of dichloromethane.
  • the present invention confirmed the mass spectrometry and nuclear magnetic resonance spectroscopy ( 1 H NMR) and carbon spectrum ( 13 C NMR and 13 CDEPT 135) of the 13 target compounds of 13c-13j, respectively.
  • the nuclear magnetic resonance spectrum data of 13c-13j target compound are shown in Table 1, the mass spectrometry data is shown in Table 2, and the spectrum is shown in Figures 1-32.
  • Human SGLT2 and SGLT1 were stably expressed in Chinese hamster ovary cells (CHO) and thus were used in this activity assay, incubated in 96-well plates at 37 ° C overnight.
  • the activity test of the target compound for inhibiting SGLT1 and SGLT2 was separately tested.
  • the substrate for SGLT uses the radiolabeled glucose analog alpha-methyl-D-glucopyranoside (AMG).
  • AMG radiolabeled glucose analog alpha-methyl-D-glucopyranoside
  • the ability of the inhibitor to inhibit the uptake of AMG is measured in buffer, which is a condition that mimics the low protein of glomerular filtration.
  • IC 50 half-inhibitory concentration
  • the phenethyl-substituted derivative 13h of the three aromatic ring-substituted derivatives (13f, 13g, 13h) has the same inhibitory activity against SGLT2 as compared with dapagliflozin (IC 50 is 0.9 nM), but the selectivity is better than Dagley was well cleaned (540 times and 373.4 times, respectively).
  • the inhibitory activity of the adamantane-substituted derivative (13i, 13j) and the selectivity to SGLT1 were not as good as dapagliflozin.
  • a each IC 50 value represents the average value of two measurements.
  • the b selectivity value is calculated from the IC 50 value SGLT1/SGLT2, taking two averages.
  • the structure of the eight target compounds was confirmed by MS and 1H NMR, 13C NMR and DEPT spectra. It can be seen from the results of in vitro human SGLT1 inhibitory activity of the target compound that the phenethyl substituted derivative (13h) has a ratio of Glipepside has a better inhibitory activity, and the selectivity to SGLT1 is higher than that of dapagliflozin.
  • the compound (13d) substituted with n-hexyl is much more selective for SGLT2 than dapagliflozin.

Abstract

一种碳糖苷类钠葡萄糖转运蛋白体2抑制剂，其制备方法和用途，所述抑制剂具有通式（I）的结构。

Description

一种碳糖苷类钠葡萄糖转运蛋白体2抑制剂 技术领域
本发明涉及与糖尿病相关的化学药领域，具体涉及一种碳糖苷类钠葡萄糖转运蛋白体结构的2型钠-葡萄糖转运蛋白(SGLT-2)抑制剂。本发明还公开了其制备方法和用途。
背景技术
糖尿病是一种以胰岛素分泌缺陷和(或)胰岛素作用不足所致的以高血糖为特征的代谢紊乱综合征，分为1型(T1DM)和2型(T2DM)两种，前者是由于胰岛β-细胞不能产生足够的胰岛素(胰岛素绝对缺乏)所致，多发生于青少年，后者是由于胰岛素分泌不足或胰岛素抵抗(胰岛素相对缺乏)所致，多见于中、老年人。
钠依赖性葡萄糖转运蛋白(SGLTs)依靠钠的电化学电位离子将细胞外葡萄糖主动转运进入细胞质。SGLT2是低亲和力，高容量的专门转运位于肾上皮细胞表面的葡萄糖，而SGLT1不仅在肾脏表达，而且在肠内及其他组织也有表达。过滤后的葡萄糖大约90％的是通过SGLT2在近曲小管近端(S1和S2段)被重吸收，其余的是由SGLT1在近端小管远端(S3段)再吸收。在没有SGLT2的存在下，SGLT1是能吸收过滤约70％的葡萄糖。SGLT2抑制剂可在肾近曲小管减少葡萄糖的重吸收，通过增加尿葡萄糖的排泄达到一个能量的负平衡。由于该类抑制剂不依赖于胰岛素作用，因此可用于糖尿病发展的任何阶段，即使在β细胞恶化和胰岛素抵抗的情况下都可以持续有效的降低血糖，这就使得SGLT2抑制剂成为糖尿病治疗唯一的选择。
SGLT2抑制剂主要分为氧糖苷类、碳糖苷类、氮糖苷类、以及非糖苷类SGLT2抑制剂。因为氧糖苷类对糖苷酶很敏感，易水解，并且药代动力学试验较差，最终氧糖苷的发展已经停止，人们将研究方向转向C-糖苷类药物的设计研发上来，C-糖苷类药物，将苷键中的O直接换成C，在不影响药效、药代性质的同时极大的增强了水解稳定性，是一类非常有前途的药物。也是目前上市以及研究较多的一类钠葡萄糖转运蛋白2抑制剂。以下几种化合物就通过除去异头糖苷氧避开了对糖苷酶敏感性问题的。
Figure PCTCN2018071848-appb-000001
但现有化合物在增加药效，增强稳定性的同时也存在一些不足，如血浆半衰期短，降血糖作用时间不长，有呕吐，腹泻副作用等需要改进的地方。
发明内容
本发明在现有技术的基础上，对有关的基团进行了改造，意外的发现，本发明化合物降血糖作用更强，作用时间延长，副作用降低。
本发明公开了一种具有通式(Ⅰ)的C-糖苷类SGLT2抑制剂化合物，
Figure PCTCN2018071848-appb-000002
其中，
n＝0，1，2或3；
X选自C3～C6烷基，C3～C6烯基，C3～C6炔基，或如式(II)所示的取代苯基，
Figure PCTCN2018071848-appb-000003
或如式(III)所示的取代金刚烷基，
Figure PCTCN2018071848-appb-000004
其中，R 1、R 2、R 3独立的选自-H、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-OCH 3、-OCH 2CH 3、-OH、-CH 2OH、-CH 2CH 2OH；
其中，R 4、R 5、R 6独立的选自-H、-CH 3、-CH 2CH 3、-OCH 3、-OCH 2CH 3、-OH、-CH 2OH、-NH 2、-NHCOCH 3；
优选的，本发明通式(Ⅰ)的C-糖苷类SGLT2抑制剂化合物，其中，
n＝0，1或2；
X选自如式(II)所示的取代苯基，
Figure PCTCN2018071848-appb-000005
或如式(III)所示的取代金刚烷基，
Figure PCTCN2018071848-appb-000006
其中，
R 1、R 2、R 3独立的选自-H、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3；
R 4、R 5、R 6独立的选自-H、-CH 3、-CH 2CH 3；
更优选的，本发明的C-糖苷类SGLT2抑制剂化合物为如下具体化合物：
Figure PCTCN2018071848-appb-000007
Figure PCTCN2018071848-appb-000008
Figure PCTCN2018071848-appb-000009
进一步优选的，本发明的C-糖苷类SGLT2抑制剂化合物为如下具体化合物：
Figure PCTCN2018071848-appb-000010
最优选的，本发明的C-糖苷类SGLT2抑制剂化合物为如下具体化合物：
Figure PCTCN2018071848-appb-000011
本发明进一步提供本发明化合物的制备方法，所述制备方法可以采用以下路线：
以5-溴-2-氯苯甲酸为起始原料，经酰化、缩合、还原反应，得到5-溴-2-氯-4’-甲氧基二苯甲烷4，化合物4经三溴化硼作用脱除醚甲基后，对酚羟基进行保护得到6,化合物6与葡萄糖酸内酯(9)经缩合、异头碳羟基醚化、脱甲氧基反应，得关键中间体1-氯-4-(β-D-吡喃葡萄糖-1-基)-2-(4-羟基-苄基)-苯10。
烷烃、烯烃、环烷烃、炔烃及芳烃的醇分别与对甲苯磺酰氯反应，得到相应醇的对甲苯磺酰酯12，化合物12与中间体10反应，得到各个目标化合物。合成总路线如下图。
Figure PCTCN2018071848-appb-000012
本发明的式(I)化合物根据需要还可以形成稳定的盐，酯，溶剂化物等衍生物。
如可以获得药学上可接受的非毒性的药用盐，包括与无机酸，如盐酸、硫酸形成的盐，与有机酸，如乙酸、三氟乙酸、柠檬酸、马来酸、草酸、琥珀酸、苯甲酸、酒石酸、富马酸、扁桃酸、抗坏血酸或苹果酸形成的盐，以及氨基酸，如丙氨酸、天冬氨酸、赖氨酸形成的盐或与磺酸，如甲磺酸、对甲苯磺酸形成的盐。
或根据需要，可以和碱性物质形成药用盐，如形成碱金属盐、碱土金属盐、银盐、钡盐等。
本发明的式(I)化合物也可以溶剂化物(如水合物)的形式存在，因此，这些溶剂化物(如水合物)也包括在本发明的化合物之内。
本发明还提供含有如上所定义的式(I)化合物，或其药用盐作为活性成分的降血糖药物组合物。药物组合物张含有的活性成分在组合物中的重量比为0.1～99.9％，药物可接受的载体在组合物中的重量比为0.1～99.9％。药物组合物以适合药用的制剂形式存在。药用的制剂优选的如：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、缓释片剂、胶囊剂、硬胶囊剂、软胶囊剂、缓释胶囊剂、散剂。
本发明的药物组合物，作为制剂形式，每剂中含有的本发明化合物的有效量为0.1～1000mg，所述每剂指的是，每一制剂单位，如片剂的每片，胶囊的每粒，也可指每次服用剂量，如每次服用100mg。
本发明的药物组合物在制备成粉剂、片剂、可分散粉剂、胶囊、扁囊剂形式的固体药物制剂时，可 使用固体载体。可使用的固体载体优选为选自稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂、膨胀剂等中的一种或多种物质，或可为包封物质。适宜的固体载体包括碳酸镁、硬脂酸镁、滑石粉、蔗糖、乳糖、果胶、糊精、淀粉、明胶、甲基纤维素、羧甲基纤维素钠、可可脂等。由于它们易于给药，片剂，粉剂和胶囊是最适合的口服固体制剂。
本领域技术人员可按常规方法确定适于某种情况的优选剂量。一般，开始治疗的量低于活性成分的最佳剂量，然后逐渐增加给药剂量，直到达到最佳治疗效果。为方便起见，总的日剂量可分为几部分，分数次给药。
本发明进一步提供使用本发明式(I)所示的SGLT2抑制剂治疗2型糖尿病，为此本发明进一步提供本发明式(I)所示的SGLT2抑制剂及其药物组合物在制备治疗2型糖尿病的药物中的应用，可在有2型糖尿病的成人中作为辅助饮食和运动改善血糖控制。
本发明的有益效果在于，经过对比实验发现，和现有同类化合物相比，本发明的化合物特别是化合物13h，化合物13i，13j，具有降血糖作用更强，作用时间延长，副作用低的特点。
附图说明
图1.13c的MS图谱。
图2.13c的 1HNMR图谱。
图3.13c的 13CNMR图谱。
图4.13c的DEPT图谱。
图5.13d的MS图谱。
图6.13d的 1HNMR图谱。
图7.13d的 13CNMR图谱。
图8.13d的DEPT图谱。
图9.13e的MS图谱。
图10.13e的 1HNMR图谱。
图11.13e的 13CNMR图谱。
图12.13e的DEPT图谱。
图13.13f的MS图谱。
图14.13f的 1HNMR图谱。
图15.13f的 13CNMR图谱。
图16.13f的DEPT图谱。
图17.13g的MS图谱。
图18.13g的 1HNMR图谱。
图19.13g的 13CNMR图谱。
图20.13g的DEPT图谱。
图21.13h的MS图谱。
图22.13h的 1HNMR图谱。
图23.13h的 13CNMR图谱。
图24.13h的DEPT图谱。
图25.13i的MS图谱。
图26.13i的 1HNMR图谱。
图27.13i的 13CNMR图谱。
图28.13i的DEPT图谱。
图29.13j的MS图谱。
图30.13j的 1HNMR图谱。
图31.13j的 13CNMR图谱。
图32.13j的DEPT图谱。
图33.13c的hSGLT1和hSGLT2抑制活性曲线图。
图34.13d的hSGLT1和hSGLT2抑制活性曲线图。
图35.13e的hSGLT1和hSGLT2抑制活性曲线图。
图36.13f的hSGLT1和hSGLT2抑制活性曲线图。
图37.13g的hSGLT1和hSGLT2抑制活性曲线图。
图38.13h的hSGLT1和hSGLT2抑制活性曲线图。
图39.13i的hSGLT1和hSGLT2抑制活性曲线图。
图40.13j的hSGLT1和hSGLT2抑制活性曲线图。
图41.对照物达格列净的hSGLT1和hSGLT2抑制活性曲线图。
具体实施方式
以下通过实施例进一步说明本发明，但不作为对本发明的限制。
实施例1
5-溴-2-氯苯甲酰氯(2)的合成
将60.00g(0.26mol)5-溴-2-氯苯甲酸(1)加入至200mL干燥的二氯甲烷中，滴加1.5mL(5.2mol)DMF，冰盐浴条件下分四次向反应液中缓慢滴32mL(0.39mmol)草酰氯，要求反应液温度在0～5℃之间，滴毕，将反应液缓慢升至室温反应12h。薄层色谱TLC监测反应，直至原料反应完毕，减压蒸除溶剂和草酰氯，并用二氯甲烷分三次蒸除草酰氯，冷却后得到乳白色固体253.5g，收率89.1％。MS-EI(m/z):255.1[M+H]+.
实施例2
5-溴-2-氯-4'-甲氧基二苯甲酮(3)的合成
将34.10g(0.26mol)无水三氯化铝在冰浴条件下分三批加入干燥的110mL二氯甲烷中，搅拌15min后向反应液中缓慢滴加23mL(0.22mol)苯甲醚，控制滴加速度使反应液温度在0～5℃，30min后向反应液中缓慢滴加中间体2(66g)的二氯甲烷(115mL)溶液，控制滴加速度使反应液温度保持在0～5℃，滴毕，冰浴反应4h。升至室温反应6h。反应完毕，将反应液缓慢倒入750mL冰水中，搅拌45min，分出有机层，依次用1mol·L -1氢氧化钠水溶液、2mol·L -1盐酸、饱和食盐水洗涤，并无水硫酸钠干燥，减压蒸除溶剂，残留物用乙醇重结晶得白色针状晶体358.11g，收率78.4％。HPLC法检测纯度为89.3％。MS-EI(m/z):325.1[M]+.
实施例3
5-溴-2-氯-4'-甲氧基二苯甲烷(4)的合成
搅拌条件下将5mL(0.31mol)的三乙基硅烷和5.5g的3(0.17mol)加入至20mL的1:2的二氯甲烷与乙腈混合液中反应，控制温度在10℃条件下缓慢加入2.5mL三氟化硼乙醚溶液，随着反应的进行控制反应温度不超过20℃。HPLC监测反应，若未反应完全，则过夜搅拌反应，补加0.5mL三乙基硅烷和0.3mL三氟化硼乙醚液随后将反应温度升至50℃搅拌反应4h。冷却后用5mL7N的KOH溶液停止反应，水相用二氯甲烷萃取(2×)，合并有机相，依次用2N的KOH、饱和食盐水洗(2×)，无水硫酸钠干燥，过滤，滤液减压蒸除溶剂，残留物用乙醇重结晶，得白色固体43.1g，产率65.0％。MS-EI(m/z):311.6[M] +,312.4[M+H] -.
实施例4
4-(5-溴-2-氯苄基)苯酚(5)的合成
搅拌条件下将20.0g(64mmol)的4溶于80mL二氯甲烷中，缓慢滴加6mL(70.4mmol)三溴化硼溶液，控制反应温度0～4℃，滴毕，将混合液缓慢升至室温搅拌反应3.5h后将反应液冷却至-78℃，并用100 mL甲醇溶液停止反应，将混合液倒入500mL冰水中搅拌反应30min。并用1N的氢氧化钠溶液调节PH7～8，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，减压蒸除溶剂，残留物乙醇重结晶，得化合物5灰白色固体19.62g，产率78.0％。MS-EI(m/z):298[M] +,321.4[M+Na] -.
实施例5
(4-(5-溴-2-氯苄基)苯氧基)(叔丁基)二甲基硅烷(6)的合成
将60.00g(0.2mol)的5及39mL(0.28mol)三乙胺溶于125mL二氯甲烷中，冰浴条件下缓慢加入叔丁基二甲基氯硅烷，加毕，将混合液缓慢升至室温，继续搅拌反应15h。薄层色谱TLC检测至反应完全，将反应液倒入200mL冰水中，继续搅拌反应20min，有固体析出，过滤，滤液用二氯甲烷萃取，有机相减压蒸除溶剂，残留物过硅胶柱(石油醚：乙酸乙酯＝10:1)，得到乳白色粘稠固体6，60.12g，产率97.7％。MS-EI(m/z):411[M] +.
实施例6
2,3,4,6-四-O-三甲基甲硅烷-β-D-葡糖酸内酯(9)的合成
将14.00g(0.08mol)的1,5-葡萄糖酸内酯，80mL的N-甲基吗啉-5℃的条件下在120mL四氢呋喃溶液中搅拌反应，将50mL(0.48mol)三甲基氯硅烷缓慢滴加到混合液中，并控制滴加速度，使反应温度不超过5℃，搅拌反应1h后，温度升高到35℃继续反应15h，随后冷却至室温搅拌过夜，用100mL二氯甲烷稀释后倒入冰水中，控制温度不超过10℃，搅拌反应25min，分出有机相，并依次用10％盐酸液，水，饱和食盐水洗，无水硫酸钠干燥过滤，滤液减压蒸除溶剂，得无色油状液体，残留物无水乙醇重结晶得化合物9，140.3g，产率92.4％。MS-EI(m/z):465[M-H] +,466[M] +.
实施例7
(3R，4S，5S，6R)-2-(4-氯-3-(4-羟基苄基)苯基)-6-(羟甲基)-2-甲基四氢-2H-吡喃-3,4,5-三醇(7)的合成
在-78℃条件下将56.36g(0.13mol)的6在氮气保护下加入到300mL的四氢呋喃溶液中，并将2.3mL(0.18mol)的正丁基里己烷溶液缓慢滴加到混合液中，搅拌反应30min后，在氮气保护下将反应液滴加到预冷-78℃的3(80.10g，0.18mol)的甲苯溶液中，搅拌反应1.5h后加入甲磺酸的甲醇溶液(250mL，0.6mol/L),缓慢升至室温反应18h。加入65mL饱和碳酸氢钠溶液猝灭反应，乙酸乙酯溶液萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压蒸除溶剂，得7粗品，溶于热甲苯溶液中，缓慢加入己烷溶液中，析出黄色固体7，47.8g，收率84.8％。MS-EI(m/z):412[M+H] +,410[M] +.
实施例8
1-氯-4-(β-D-吡喃葡萄糖-1-基)-2-(4-羟基-苄基)-苯(10)的合成
将45.3g(0.11mol)的7溶于300mL二氯甲烷乙腈(1:1)混合液中,搅拌反应，冷至-10℃条件下缓慢加入29mL(0.17mol)三乙基硅烷至混合液中，随后缓慢滴加16mL(0.13mol)三氟化硼乙醚液，冰浴条件下反应5h，加入150mL饱和碳酸氢钠溶液猝灭反应，搅拌反应15min，分出有机相，减压蒸除溶剂，残留物用乙酸乙酯和水搅拌反应静置分层，分出有机相，水相用乙酸乙酯(2×)萃取，合并有机相，依次用水，饱和食盐水洗，有机相无水硫酸钠干燥，过滤，滤液减压蒸除溶剂，残留物无水乙醇重结晶，得化合物10，36.4g，收率87.1％。MS-EI(m/z):381[M+H] +,380[M] +.
实施例9
(3R,4R,5S,6R)-2-(3-(4-正丁氧基)苄基)-4-氯苯基)-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇(13c)的合成
在55℃油浴条件下将1.7g(4.5mmol)的10及2.1g(6.8mmol)碳酸铯加入9mLN,N-二甲基甲酰胺中搅拌反应13min，油浴60℃条件下加入1.35g(5.9mmol)的对甲苯磺酸正丁酯，搅拌反应15h，加入饱和 食盐水，乙酸乙酯萃取，有机层无水硫酸钠干燥，过滤，减压蒸除溶剂，残留物过硅胶柱层析(二氯甲烷:甲醇＝20:1)得2.08g无色粘稠固体13c，收率80.6％。
实施例10
(3R,4R,5S,6R)-2-(3-(4-正己氧基)苄基)-4-氯苯基)-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇(13d)的合成
在55℃油浴条件下将1.7g(4.5mmol)的10及2.1g(6.8mmol)碳酸铯加入9mLN,N-二甲基甲酰胺中搅拌反应13min，油浴60℃条件下加入1.51g(5.9mmol)对甲苯磺酸正己酯，搅拌反应15h，加入饱和食盐水，乙酸乙酯萃取，有机层无水硫酸钠干燥，过滤，减压蒸除溶剂，残留物过硅胶柱层析(二氯甲烷:甲醇＝20:1)得2.23g无色粘稠固体13d，收率81.3％。
实施例11
(3R,4R,5S,6R)-2-(3-(4-丙炔氧基)苄基)-4-氯苯基)-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇(13e)的合成
在55℃油浴条件下将1.7g(4.5mmol)的10及2.1g(6.8mmol)碳酸铯加入9mLN,N-二甲基甲酰胺中搅拌反应13min，油浴60℃条件下加入1.24g(5.9mmol)的对甲苯磺酸丙炔酯，搅拌反应15h，加入饱和食盐水，乙酸乙酯萃取，有机层无水硫酸钠干燥，过滤，减压蒸除溶剂，残留物过硅胶柱层析(二氯甲烷:甲醇＝20:1)得1.89g无色粘稠固体13e，收率76.4％。
实施例12
(3R,4R,5S,6R)-2-(3-(4-苯氧基)苄基)-4-氯苯基)-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇(13f)的合成
在55℃油浴条件下将1.7g(4.5mmol)的10及2.1g(6.8mmol)碳酸铯加入9mLN,N-二甲基甲酰胺中搅拌反应13min，油浴60℃条件下加入1.46g(5.9mmol)的对甲苯磺酸苯酯，搅拌反应15h，加入饱和食盐水，乙酸乙酯萃取，有机层无水硫酸钠干燥，过滤，减压蒸除溶剂，残留物过硅胶柱层析(二氯甲烷:甲醇＝20:1)得1.91g无色粘稠固体13f，收率70.7％。
实施例13
(3R,4R,5S,6R)-2-(3-(4-苄氧基)苄基)-4-氯苯基)-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇(13g)的合成
在冰浴条件下，将7.0g(37mmol)的对甲苯磺酰氯及5.0mL(37mmol)的三乙胺加入40mL的二氯甲烷溶液中，10min后将苯甲醇2.5mL(23mmol)缓慢加入到混合液中，控制温度不超过8℃，反应5h后，TLC检测(石油醚：乙酸乙酯＝25：1)至反应完全，加入10mL二氯甲烷，将反应液倒入冰水中(10mL×2)，搅拌反应15min，依次用10％盐酸溶液，饱和碳酸氢钠，饱和食盐水洗，有机相无水硫酸钠干燥，过滤，滤液减压蒸除溶剂，残留物过硅胶柱，得化合物苄基4-甲基苯磺酸酯(G13)，用于13g的制备。
在55℃油浴条件下将1.7g(4.5mmol)的10及2.1g(6.8mmol)碳酸铯加入9mLN,N-二甲基甲酰胺中搅拌反应13min，油浴60℃条件下加入1.55g(5.9mmol)的(G13)，搅拌反应15h，加入饱和食盐水，乙酸乙酯萃取，有机层无水硫酸钠干燥，过滤，减压蒸除溶剂，残留物过硅胶柱层析(二氯甲烷:甲醇＝20:1)得2.16g无色粘稠固体13g，收率77.9％。
实施例14
(3R,4R,5S,6R)-2-(3-(4-苯乙氧基)苄基)-4-氯苯基)-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇(13h)的合成
在冰浴条件下，将7.0g(37mmol)的对甲苯磺酰氯及5.0mL(37mmol)的三乙胺加入40mL的二氯甲烷溶液中，10min后将苯乙醇2.35mL(23mmol)缓慢加入到混合液中，控制温度不超过8℃，反应5h后，TLC检测(石油醚：乙酸乙酯＝25：1)至反应完全，加入10mL二氯甲烷，将反应液倒入冰水中(10mL×2)，搅拌反应15min，依次用10％盐酸溶液，饱和碳酸氢钠，饱和食盐水洗，有机相无水硫酸钠干燥，过滤，滤液减压蒸除溶剂，残留物过硅胶柱，得化合物对甲基苯磺酸苯乙酯(H13)，用于13h的制备。
在55℃油浴条件下将1.7g(4.5mmol)的10及2.1g(6.8mmol)碳酸铯加入9mLN,N-二甲基甲酰胺中搅拌反应13min，油浴60℃条件下加入1.63g(5.9mmol)的(H13)，搅拌反应15h，加入饱和食盐水，乙酸乙酯萃取，有机层无水硫酸钠干燥，过滤，减压蒸除溶剂，残留物过硅胶柱层析(二氯甲烷:甲醇＝20:1)得2.24g无色粘稠固体13h，收率78.4％。
实施例15
(3R,4R,5S,6R)-2-(3-(4-金刚烷氧基)苄基)-4-氯苯基)-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇(13i)的合成
在冰浴条件下，将7.0g(37mmol)的对甲苯磺酰氯及5.0mL(37mmol)的三乙胺加入40mL的二氯甲烷溶液中，10min后将金刚烷醇3.50g(23mmol)缓慢加入到混合液中，控制温度不超过8℃，反应5h后，TLC检测(石油醚：乙酸乙酯＝25：1)至反应完全，加入10mL二氯甲烷，将反应液倒入冰水中(10mL×2)，搅拌反应15min，依次用10％盐酸溶液，饱和碳酸氢钠，饱和食盐水洗，有机相无水硫酸钠干燥，过滤，滤液减压蒸除溶剂，残留物过硅胶柱,得化合物对甲苯磺酸金刚烷酯(I13)，用于13i的制备。
在55℃油浴条件下将1.7g(4.5mmol)的10及2.1g(6.8mmol)碳酸铯加入9mLN,N-二甲基甲酰胺中搅拌反应13min，油浴60℃条件下加入1.81g(5.9mmol)的(I13)，搅拌反应15h，加入饱和食盐水，乙酸乙酯萃取，有机层无水硫酸钠干燥，过滤，减压蒸除溶剂，残留物过硅胶柱层析(二氯甲烷:甲醇＝20:1)得2.20g无色粘稠固体13i，收率72.5％。
实施例16
(3R,4R,5S,6R)-2-(3-(4-金刚烷乙氧基)苄基)-4-氯苯基)-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇(13j)的合成
在冰浴条件下，将7.0g(37mmol)的对甲苯磺酰氯及5.0mL(37mmol)的三乙胺加入40mL的二氯甲烷溶液中，10min后将金刚烷乙醇4.15g(23mmol)缓慢加入到混合液中，控制温度不超过8℃，反应5h后，TLC检测(石油醚：乙酸乙酯＝25：1)至反应完全，加入10mL二氯甲烷，将反应液倒入冰水中(10mL×2)，搅拌反应15min，依次用10％盐酸溶液，饱和碳酸氢钠，饱和食盐水洗，有机相无水硫酸钠干燥，过滤，滤液减压蒸除溶剂，残留物过硅胶柱，得化合物对甲苯磺酸金刚烷乙酯(J13)，用于13j的制备。
在55℃油浴条件下将1.7g(4.5mmol)的10及2.1g(6.8mmol)碳酸铯加入9mLN,N-二甲基甲酰胺中搅拌反应13min，油浴60℃条件下加入1.97g(5.9mmol)的(J13)，搅拌反应15h，加入饱和食盐水，乙酸乙酯萃取，有机层无水硫酸钠干燥，过滤，减压蒸除溶剂，残留物过硅胶柱层析(二氯甲烷:甲醇＝20:1)得2.34g无色粘稠固体13j，收率73.2％。
实施例17
本发明分别对13c-13j这8个目标化合物进行质谱和核磁共振氢谱( 1HNMR)、碳谱( 13CNMR和 13CDEPT 135)确证。
13c-13j目标化合物的核磁共振氢谱数据见表1，质谱数据见表2，谱图见附图1-32。
表1 目标化合物核磁共振氢谱数据
Figure PCTCN2018071848-appb-000013
Figure PCTCN2018071848-appb-000014
表2 目标化合物的质谱(MS)数据
Figure PCTCN2018071848-appb-000015
实施例18体外SGLT抑制活性筛选
实验方法
中国仓鼠卵巢细胞(CHO)中稳定表达人的SGLT2和SGLT1，因此被用于该活性检测试验中，在96孔板中培育，37℃，过夜。分别检测了目标化合物抑制SGLT1和SGLT2的活性试验。SGLT的底物采用放射性标记的葡萄糖类似物α-甲基-D-吡喃葡萄糖苷(AMG)。抑制剂的抑制摄取AMG的能力测定是在缓冲液中进行，缓冲液作用是模拟肾小球滤过的低蛋白的条件。每个化合物将在8个不同浓度下测定葡萄糖转运实验，响应曲线拟合到四参数模型，以确定在半数最大响应的抑制剂浓度，记为半抑制浓度(IC 50)。8个目标化合物及对照物的hSGLT1和hSGLT2抑制活性曲线图见图33-41。
体外抑制活性测试结果
从表3可以看出，以炔丙基取代的衍生物13e，IC 50值分别为1.1nM，对SGLT2抑制活性比达格列净对照稍高(IC 50＝0.9nM)，但对SGLT1的选择性比达格列净要高很多。三个芳环取代的衍生物(13f，13g，13h)中苯乙基取代的衍生物13h与达格列净相比对SGLT2抑制活性相同(IC 50均为0.9nM)，但选择性要比达格列净好(分别为540倍和373.4倍)。以金刚烷取代衍生物(13i，13j)的抑制活性以及对SGLT1的选择性均不如达格列净。
表3 体外hSGLT抑制实验数据
Figure PCTCN2018071848-appb-000016
Figure PCTCN2018071848-appb-000017
注：a每一个IC 50值代表两次测定的平均值b选择性值是通过IC 50值SGLT1/SGLT2计算而得，取两次平均值
结论
8个目标化合物结构均通过MS和1HNMR、13C NMR和DEPT谱进行了确证，通过对目标化合物的体外人的SGLT1抑制活性实验结果可以看出，以苯乙基取代衍生物(13h)具有比达格列净要好的抑制活性，且对SGLT1的选择性比达格列净要高，以正己基取代的化合物(13d)对SGLT2的选择性比达格列净高很多。

Claims (10)

  1. 一种碳糖苷类钠葡萄糖转运蛋白体2抑制剂，具有通式(Ⅰ)的结构
    Figure PCTCN2018071848-appb-100001
    其中，
    n＝0，1，2或3；
    X选自C3～C6烷基，C3～C6烯基，C3～C6炔基，或如式(II)所示的取代苯基，
    Figure PCTCN2018071848-appb-100002
    或如式(III)所示的取代金刚烷基，
    Figure PCTCN2018071848-appb-100003
    其中，R 1、R 2、R 3独立的选自-H、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-OCH 3、-OCH 2CH 3、-OH、-CH 2OH、-CH 2CH 2OH；
    其中，R 4、R 5、R 6独立的选自-H、-CH 3、-CH 2CH 3、-OCH 3、-OCH 2CH 3、-OH、-CH 2OH、-NH 2、-NHCOCH 3。
  2. 根据权利要求1所述的碳糖苷类钠葡萄糖转运蛋白体2抑制剂，其中，
    n＝0，1或2；
    X选自如式(II)所示的取代苯基，
    Figure PCTCN2018071848-appb-100004
    或如式(III)所示的取代金刚烷基，
    Figure PCTCN2018071848-appb-100005
    其中，
    R 1、R 2、R 3独立的选自-H、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3；
    R 4、R 5、R 6独立的选自-H、-CH 3、-CH 2CH 3。
  3. 根据权利要求1所述的碳糖苷类钠葡萄糖转运蛋白体2抑制剂，选自以下化合物：
    Figure PCTCN2018071848-appb-100006
    Figure PCTCN2018071848-appb-100007
  4. 根据权利要求1所述的碳糖苷类钠葡萄糖转运蛋白体2抑制剂，其根据需要还可以形成稳定的盐，酯，溶剂化物。
  5. 根据权利要求1所述的碳糖苷类钠葡萄糖转运蛋白体2抑制剂，所述稳定的盐是药学上可接受的非毒性的药用盐，包括与无机酸，如盐酸、硫酸形成的盐，与有机酸，如乙酸、三氟乙酸、柠檬酸、马来酸、 草酸、琥珀酸、苯甲酸、酒石酸、富马酸、扁桃酸、抗坏血酸或苹果酸形成的盐，以及氨基酸，如丙氨酸、天冬氨酸、赖氨酸形成的盐或与磺酸，如甲磺酸、对甲苯磺酸形成的盐；或根据需要，可以和碱性物质形成药用盐，如形成碱金属盐、碱土金属盐、银盐、钡盐。
  6. 含有权利要求1所述的碳糖苷类钠葡萄糖转运蛋白体2抑制剂的药物组合物。
  7. 根据权利要求6所述的药物组合物，其中含有的活性成分碳糖苷类钠葡萄糖转运蛋白体2抑制剂的量在组合物中的重量比为0.1～99.9％，药物可接受的载体在组合物中的重量比为0.1～99.9％。
  8. 根据权利要求6所述的药物组合物，以适合药用的制剂形式存在，选自片剂、胶囊剂、散剂。
  9. 权利要求1所述的碳糖苷类钠葡萄糖转运蛋白体2抑制剂的制备方法，步骤如下：
    以5-溴-2-氯苯甲酸为起始原料，经酰化、缩合、还原反应，得到5-溴-2-氯-4’-甲氧基二苯甲烷4，化合物4经三溴化硼作用脱除醚甲基后，对酚羟基进行保护得到6,化合物6与葡萄糖酸内酯(9)经缩合、异头碳羟基醚化、脱甲氧基反应，得关键中间体1-氯-4-(β-D-吡喃葡萄糖-1-基)-2-(4-羟基-苄基)-苯10；
    烷烃、烯烃、环烷烃、炔烃及芳烃的醇分别与对甲苯磺酰氯反应，得到相应醇的对甲苯磺酰酯12，化合物12与中间体10反应，得到目标化合物
    Figure PCTCN2018071848-appb-100008
  10. 权利要求1所述碳糖苷类钠葡萄糖转运蛋白体2抑制剂在制备治疗2型糖尿病的药物中的应用。
PCT/CN2018/071848 2017-01-09 2018-01-09 一种碳糖苷类钠葡萄糖转运蛋白体2抑制剂 WO2018127194A1 (zh)

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