WO2014146606A1

WO2014146606A1 - C-triaryl glucoside sglt-2 inhibitors

Info

Publication number: WO2014146606A1
Application number: PCT/CN2014/073864
Authority: WO
Inventors: 赵军岭; 胡文辉; 徐登峰; 丁宇洋; 杨玲; 徐宏江
Original assignee: 正大天晴药业集团股份有限公司
Priority date: 2013-03-22
Filing date: 2014-03-21
Publication date: 2014-09-25
Also published as: CN104059042B; CN104059042A

Abstract

The present invention relates to a C-triaryl glucoside SGLT-2 inhibitor shown as formula (I), preparation methods therefor, pharmaceutical compositions thereof and uses thereof for treating diseases that benefit from inhibiting SGLT-2. Such diseases are diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood level of fatty acids, elevated blood level of glycerol, hyperlipidemia, obesity, hypertriglyceridemia, Syndrome X, atherosclerosis or hypertension. The compounds of the present invention have strong inhibition activity against SGLT-2, higher selectivity, improved drug metabolism properties in oral treatment, and good druggability.

Description

C-三芳基葡萄糖苷类 SGLT-2抑制剂技术领域 C-triaryl glucosides SGLT-2 inhibitors

本发明属于医药领域，具体地涉及一种 C-三芳基葡萄糖苷类 SGLT-2 (钠依赖性葡萄糖转运蛋白 -2)抑制剂及其制备方法，还涉及包含该 SGLT-2抑制剂的药物组合物及其用于治疗受益于 SGLT-2抑制的疾病的用途。背景技术 The invention belongs to the field of medicine, in particular to a C-triarylglucoside SGLT-2 (sodium-dependent glucose transporter-2) inhibitor and a preparation method thereof, and to a pharmaceutical composition comprising the SGLT-2 inhibitor And its use for treating diseases that benefit from inhibition of SGLT-2. Background technique

糖尿病主要分为 I型糖尿病与 Π型糖尿病。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，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。糖尿病患者中约 90-95%属于 II型糖尿病。目前常见的治疗 II型糖尿病的药物包括胰岛素增敏剂 (例如双胍类)、胰岛素促分泌剂 (例如磺酰脲类)和近年上市使用的 DPP-IV抑制剂等。然而，这些抗糖尿病药物均具有各自的局限性。例如双胍类化合物易引起乳酸性酸中毒，磺酰脲类会导致低血糖， DPP-IV抑制剂易使体重增加、耐受性不佳等。鉴于上述情况，人们迫切需要开发一种更为安全有效的新型降糖药物。 Diabetes is mainly divided into type I diabetes and type 2 diabetes. The former is caused by the insufficiency of insulin in the pancreatic islet β cells (absolute insulin deficiency), which is caused by insufficient insulin secretion or insulin resistance (relative lack of insulin). About 90-95% of people with diabetes are type 2 diabetes. Currently commonly used drugs for the treatment of type 2 diabetes include insulin sensitizers (such as biguanides), insulin secretagogues (such as sulfonylureas), and DPP-IV inhibitors used in recent years. However, these antidiabetic drugs have their own limitations. For example, biguanide compounds are prone to lactic acidosis, sulfonylureas cause hypoglycemia, and DPP-IV inhibitors tend to cause weight gain and poor tolerance. In view of the above, there is an urgent need to develop a new safer and more effective hypoglycemic agent.

研究发现，健康人体中超过 99%的血糖通过肾小球过滤后重新吸收回血液，不到 1%的血糖被***到尿中，该过程借助钠依赖性葡萄糖转运蛋白 SGLT-1 和 SGLT-2来完成。 SGLT-1 主要分布在胃、小肠、心脏和肾脏，完成 10%的尿糖重吸收； SGLT-2主要分布在肾脏，完成 90%的尿糖重吸收。选择性的 SGLT-2抑制剂阻止肾小球的血糖重吸收，可使多余的血糖*** 在尿中，从而降低糖尿病人的血糖，缓解高血糖对器官的损害。研究表明， SGLT-2抑制剂降糖的同时不会增加体重，因不会影响正常的血糖吸收过程所以不会引发低血糖，也不会造成对动物肾脏不良影响和引发血桨电解质浓度不平衡。因此，选择性 SGLT-2抑制剂成为潜在的理想抗糖尿病药物。 The study found that more than 99% of blood sugar in healthy humans is reabsorbed back into the bloodstream through glomerular filtration, and less than 1% of blood glucose is excreted into the urine, using the sodium-dependent glucose transporters SGLT-1 and SGLT-2. To be done. SGLT-1 is mainly distributed in the stomach, small intestine, heart and kidney, and completes 10% of urine glucose reabsorption; SGLT-2 is mainly distributed in the kidneys, and 90% of urine sugar reabsorption is completed. Selective SGLT-2 inhibitors prevent glomerular blood glucose reabsorption, allowing excess blood sugar to be excreted in the urine, thereby reducing blood sugar in diabetics and alleviating organ damage caused by hyperglycemia. Studies have shown that SGLT-2 inhibitors do not increase body weight while not affecting normal blood glucose absorption process, so it does not cause hypoglycemia, nor does it cause adverse effects on animal kidneys and cause imbalance of blood electrolyte concentration. . Therefore, selective SGLT-2 inhibitors are potentially ideal anti-diabetic drugs.

近几年，越来越多的研究者以 SGLT-2作为分子靶点，第一个被评价的 SGLT-2抑制剂是从苹果树的根皮中分离出来的根皮苷 (Phlorizin), 但由于其在小肠中容易被根皮苷水解酶水解导致生物利用度低而未被发展成为抗糖尿病药物。之后研究者以根皮苷结构为基础，相继研发了一批具有选择性的 O-芳香糖苷类 SGLT-2抑制剂，例如 T-1095、sergliflozin和 remogliflozin 等，但由于代谢稳定性和选择性问题而终止开发。为了提高糖苷的化学稳定性和代谢稳定性，研究人员在 O-芳香糖苷类 SGLT-2抑制剂的基础上，进一步设计了 C-芳基糖苷类抑制剂，其中由百时美施贵宝和阿斯利康共同开发的 Dapagliflozin是 SGLT-2抑制剂中的领先者，目前已在欧洲上市。发明内容 In recent years, more and more researchers have used SGLT-2 as a molecular target. The first SGLT-2 inhibitor to be evaluated is phlorizin (Phlorizin) isolated from the root bark of apple trees, but It is not developed into an anti-diabetic drug because it is easily hydrolyzed by phlorizin hydrolase in the small intestine resulting in low bioavailability. The researchers then developed a batch of selective O-aromatic glycoside SGLT-2 inhibitors based on the phlorizin structure, such as T-1095, sergliflozin and remogliflozin, but due to metabolic stability and selectivity issues. And terminate development. In order to improve the chemical stability and metabolic stability of glycosides, the researchers further designed C-aryl glycoside inhibitors based on O-aromatic glycoside SGLT-2 inhibitors, including Bristol-Myers Squibb and Aspen. Dapagliflozin, jointly developed by Likang, is a leader in SGLT-2 inhibitors and is currently available in Europe. Summary of the invention

本发明提供一种如式 I所示的 C-三芳基葡萄糖苷类化合物（简称式 I化合物）或其盐、前药或立体异构体， The present invention provides a C-triaryl glucoside compound (abbreviated as a compound of formula I) of the formula I or a salt, prodrug or stereoisomer thereof,

其中选自卤素、 d_₈焼基或 d_₈烷氧基， R₂选自氢、卤素、 d_₈烷基、 d_₈烷氧基、 CF₃、Wherein selected from halogen, d- ₈ fluorenyl or d- ₈ alkoxy, and R _{2 is} selected from the group consisting of hydrogen, halogen, d- ₈ alkyl, d- ₈ alkoxy, CF ₃ ,

OCF₃、羟基、 CM烯基、 CM炔基、 C_3-8环烷基、氰基、 -S(0)_MR₃、 -COR₃、 COOR₃、 N 3R4 或 CONR₃R4， m为 0至 2的整数，、各自独立地选自氢、 d.₈烷基或 C₃.₈环焼基。 OCF ₃ , hydroxy, CM alkenyl, CM alkynyl, C _3-8 cycloalkyl, cyano, -S(0) _M R ₃ , -COR ₃ , COOR ₃ , N 3R4 or CONR ₃ R4, m is 0 An integer of up to 2, each independently selected from hydrogen, d. ₈ alkyl or C _3. ₈ cyclodecyl.

在一些实施方案中，选自卤素、 C_M焼基或 C_M焼氧基；在另一些实施方案中，选自卤素、甲基、乙基、丙基、甲氧基、乙氧基或丙氧基；在另一些实施方案中，选自卤素、甲基或甲氧基；在另一些实施方案中，选自氟、氯、甲基、乙基、丙基、甲氧基、乙氧基或丙氧基；在另一些实施方案中，选自氟、氯、甲基或甲氧基。 In some embodiments, selected from halogen, C _M decyl or C _M decyloxy; in other embodiments, selected from halogen, methyl, ethyl, propyl, methoxy, ethoxy or propyl Oxyl; in other embodiments, selected from halogen, methyl or methoxy; in other embodiments, selected from the group consisting of fluorine, chlorine, methyl, ethyl, propyl, methoxy, ethoxy Or propoxy; in other embodiments, selected from fluoro, chloro, methyl or methoxy.

在一些实施方案中，选自氢、卤素、 CM焼基、 CM焼氧基、 CF₃、 OCF₃、羟基、 CM 烯基、 C_M炔基、 C_3-6环烷基、氰基、 -S(0)_mR₃、 -COR₃、 COOR₃、 NR₃R4或 CONR₃R4， m为 0至 2的整数，、各自独立地选自氢、 C_M烷基或 C₃_₆环焼基；在一些实施方案中，选自氢、卤素、 C_M焼基、 C_M ^氧基、 CF₃、 OCF₃、羟基、 C_M烯基、 C_M炔基、 C^环烷基、氰基、 -S(0)_MR₃、 -COR₃、 COOR₃、 NR₃R4或 CONR₃R4， m为 0或 2， R₃、 R4各自独立地选自氢、甲基、乙基、丙基、环丙基、环戊基或环己基；在一些实施方案中，选自氢、卤素、 C_M焼基、 C_M焼氧基、 CF₃、 OCF₃或羟基；在一些实施方案中，选自氢、卤素、甲基、乙基、丙基、甲氧基、乙氧基、丙氧基、 CF₃、 OCF₃或羟基；在一些实施方案中， R₂选自氢、氟、氯、甲基、乙基、丙基、甲氧基、乙氧基、丙氧基、 CF₃、 OCF3或羟基；在一些实施方案中，选自氢、氟、氯、甲基、甲氧基、乙氧基、 CF₃、 OCF₃或羟基。 In some embodiments, selected from the group consisting of hydrogen, halogen, CM thiol, CM methoxy, CF ₃ , OCF ₃ , hydroxy, CM alkenyl, C _M alkynyl, C _3-6 cycloalkyl, cyano, S(0) _m R ₃ , -COR ₃ , COOR ₃ , NR ₃ R4 or CONR ₃ R4, m is an integer from 0 to 2, each independently selected from hydrogen, C _M alkyl or C ₃ _-6 ring enthalpy group; in some embodiments, is selected from hydrogen, halogen, C _M firing group, C _M ^ alkoxy, CF _{_3,} OCF _3, hydroxy, C _M alkenyl, C _M alkynyl, C ^ cycloalkyl, cyano a group, -S(0) _M R ₃ , -COR ₃ , COOR ₃ , NR ₃ R4 or CONR ₃ R4, m is 0 or 2, and R ₃ and R 4 are each independently selected from the group consisting of hydrogen, methyl, ethyl, and C. Base, cyclopropyl, cyclopentyl or cyclohexyl; in some embodiments, selected from hydrogen, halogen, C _M decyl, C _M methoxy, CF ₃ , OCF ₃ or hydroxy; in some embodiments, Selected from hydrogen, halogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, CF ₃ , OCF ₃ or hydroxy; in some embodiments, R _{2 is} selected from the group consisting of hydrogen, fluorine, chlorine , methyl, ethyl, propyl, methoxy Ethoxy, propoxy, CF _{3, OCF3} or hydroxy; in some embodiments, is selected from hydrogen, fluoro, chloro, methyl, methoxy, ethoxy, CF _{_3,} OCF _3, or hydroxy.

在一些实施方案中，式 I化合物选自下列化合物，其中，选自卤素、 C_M焼基或 C_M 焼氧基，选自氢、卤素、 CM烷基、 CM烷氧基、 CF₃、 OCF₃、羟基、 CM烯基、 CM炔基、 C_3-6环烷基、氰基、 -S(0)_mR₃、 -COR₃、 COOR₃、 N 3R4或 CONR₃R4， m为 0至 2的整数， R₃、 R4独立任选自氢、 C_M烷基、 C^环焼基。 In some embodiments, the compound of Formula I is selected from the group consisting of halogen, C _M decyl or C _M methoxy, selected from the group consisting of hydrogen, halogen, CM alkyl, CM alkoxy, CF ₃ , OCF ₃ , hydroxy, CM alkenyl, CM alkynyl, C ₃ 6 cycloalkyl, cyano, -S(0) _m R ₃ , -COR ₃ , COOR ₃ , N 3R4 or CONR ₃ R4, m is 0 to An integer of 2, R ₃ and R 4 are independently selected from the group consisting of hydrogen, C _M alkyl, and C^cyclodecyl.

在一些实施方案中，式 I化合物选自下列化合物，其中，选自卤素、 C_M焼基或 C_M 焼氧基，选自氢、卤素、 C_M烷基、 C_M烷氧基、 CF₃、 OCF₃、羟基、 C_M烯基、 C_M炔基、 ¾_-6环焼基、氰基、 -S(0)_MR₃、 -COR₃、 COOR₃、 Ν 或 CONR₃R4， m为 0或 2，、独立任选自氢、甲基、乙基、丙基、环丙基、环戊基、环己基。 In some embodiments, the compound of Formula I is selected from the group consisting of halogen, C _M decyl or C _M methoxy, selected from the group consisting of hydrogen, halogen, C _M alkyl, C _M alkoxy, CF ₃ , OCF ₃ , hydroxy, C _M alkenyl, C _M alkynyl, 3⁄4 _-6 cyclodecyl, cyano, -S(0) _M R ₃ , -COR ₃ , COOR ₃ , Ν or CONR ₃ R4, m is 0 or 2, , Independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclopentyl, cyclohexyl.

在一些实施方案中，式 I化合物选自下列化合物，其中，选自卤素、 C_M焼基或 C_M 焼氧基，选自氢、卤素、 C_M焼基、 C_M ^氧基、 CF₃、 OCF₃或羟基。 In some embodiments, the compound of Formula I is selected from the group consisting of halogen, C _M decyl or C _M methoxy, selected from the group consisting of hydrogen, halogen, C _M decyl, C _M oxy, CF ₃ , OCF ₃ or hydroxyl.

在一些实施方案中，式 I化合物选自下列化合物，其中，选自卤素、 C_M烷基或 C_M烷氧基，选自氢、卤素、甲基、乙基、丙基、甲氧基、乙氧基、丙氧基、 CF₃、 OCF₃或羟基。 In some embodiments, the compound of Formula I is selected from the group consisting of halogen, C _M alkyl or C _M alkoxy selected from the group consisting of hydrogen, halogen, methyl, ethyl, propyl, methoxy, Ethoxy, propoxy, CF ₃ , OCF ₃ or hydroxy.

在一些实施方案中，式 I化合物选自下列化合物，其中，选自卤素、 C_M焼基或 C_M 焼氧基，选自氢、氟、氯、甲基、乙基、丙基、甲氧基、乙氧基、丙氧基、 CF₃、 OCF₃或羟基。 In some embodiments, the compound of Formula I is selected from the group consisting of halogen, C _M decyl or C _M methoxy, selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl, propyl, methoxy. Base, ethoxy, propoxy, CF ₃ , OCF ₃ or hydroxy.

在一些实施方案中，式 I化合物选自下列化合物，其中，选自卤素、 C_M焼基或 C_M 焼氧基，选自氢、氟、氯、甲基、甲氧基、乙氧基、 CF₃、 OCF₃或羟基。 In some embodiments, the compound of Formula I is selected from the group consisting of halogen, C _M decyl or C _M methoxy, selected from the group consisting of hydrogen, fluorine, chlorine, methyl, methoxy, ethoxy, CF ₃ , OCF ₃ or hydroxyl.

在一些实施方案中，式 I化合物选自下列化合物，其中，选自卤素、甲基、乙基、丙基、甲氧基、乙氧基或丙氧基，其中选自氢、氟、氯、甲基、乙基、丙基、甲氧基、乙氧基、丙氧基、 CF₃、 OCF₃或羟基。 In some embodiments, the compound of Formula I is selected from the group consisting of halogen, methyl, ethyl, propyl, methoxy, ethoxy or propoxy, selected from the group consisting of hydrogen, fluorine, chlorine, Methyl, ethyl, propyl, methoxy, ethoxy, propoxy, CF ₃ , OCF ₃ or hydroxy.

在一些实施方案中，式 I化合物优选下列化合物，其中选自氟、氯、甲基、乙基、丙基、甲氧基、乙氧基或丙氧基，其中选自氢、氟、氯、甲基、乙基、丙基、甲氧基、乙氧基、丙氧基、 CF₃、 OCF₃或羟基。 In some embodiments, the compound of Formula I is preferably a compound selected from the group consisting of fluorine, chlorine, methyl, ethyl, propyl, methoxy, ethoxy or propoxy, selected from the group consisting of hydrogen, fluorine, chlorine, Methyl, ethyl, propyl, methoxy, ethoxy, propoxy, CF ₃ , OCF ₃ or hydroxy.

在一些实施方案中，式 I化合物优选下列化合物，其中选自氟、氯、甲基或甲氧基，其中选自氢、氟、氯、甲基、甲氧基、乙氧基、 CF₃、 OCF₃或羟基。 In some embodiments, the following compounds are preferred compounds of formula I, wherein is selected from fluoro, chloro, methyl or methoxy, which is selected from hydrogen, fluoro, chloro, methyl, methoxy, ethoxy, CF _3, OCF ₃ or hydroxyl.

I化合物或其盐，优选药学上可接受的盐举例如下，但不限于下列化合物或其盐: The compound I or a salt thereof, preferably a pharmaceutically acceptable salt, is exemplified by, but not limited to, the following compounds or salts thereof:

术语"药学上可接受的盐"是指在向接受者给药时，能够 (直接或间接)提供本文所述化合物的盐。其保持游离态碱 (酸)的生物有效性与性质，且不会在生物学或其它方面是不期望的。然而，应当理解，通式 I化合物的非药学上可接受的盐由于其可用于制备药学上可接受的盐因而也落入本发明范围内。 The term "pharmaceutically acceptable salt" refers to a salt capable of providing (directly or indirectly) a compound described herein when administered to a recipient. It maintains the bioavailability and properties of the free base (acid) and is not biologically or otherwise undesirable. However, it is to be understood that the non-pharmaceutically acceptable salts of the compounds of formula I are also within the scope of the invention as they are useful in the preparation of pharmaceutically acceptable salts.

式 I化合物的药学上可接受的盐包括，例如，具有碱金属如锂、钠、钾等的盐；具有碱土金属如钙、镁等的盐；具有锌或铝的盐；具有有机碱如铵、胆碱、二乙醇胺、赖氨酸、乙二胺、叔丁胺、叔辛胺、三 (羟甲基)氨基甲垸、 N-甲基葡萄糖胺、三乙醇胺和脱氢松香胺的盐；具有无机酸如盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸等的盐；或具有有机酸如甲酸、乙酸、丙酸、乙二酸、丙二酸、丁二酸、反丁烯二酸、顺丁烯二酸、乳酸、苹果酸、酒石酸、柠檬酸、甲磺酸、乙磺酸、苯磺酸等的盐；或具有酸性氨基酸如天冬氨酸、谷氨酸等的盐。 The pharmaceutically acceptable salt of the compound of the formula I includes, for example, a salt having an alkali metal such as lithium, sodium, potassium or the like; a salt having an alkaline earth metal such as calcium, magnesium or the like; a salt having zinc or aluminum; having an organic base such as ammonium a salt of choline, diethanolamine, lysine, ethylenediamine, tert-butylamine, tert-octylamine, tris(hydroxymethyl)carbamidine, N-methylglucamine, triethanolamine and dehydroabietylamine; a salt such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid or the like; or an organic acid such as formic acid, B Acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid Or a salt; or a salt having an acidic amino acid such as aspartic acid, glutamic acid or the like.

术语"前药"是指化合物的酯或碳酸盐，其通过以下方式形成，即将式 I化合物的一个或多个羟基与被焼基、焼氧基或芳基取代的酰化剂按常规方法反应形成醋酸酯、特戊酸酯、碳酸甲酯、苯甲酸酯。此外，前药还可包括酰胺，其同样是通过使用缩合剂按常规方法将式 I化合物的一个或多个羟基与 α-氨基酸或 β-氨基酸等反应而形成。 The term "prodrug" refers to an ester or carbonate of a compound formed by the conventional method of hydrating one or more hydroxyl groups of a compound of formula I with a thiol, decyloxy or aryl group. The reaction forms acetate, pivalate, methyl carbonate, benzoate. Further, the prodrug may further comprise an amide which is also formed by reacting one or more hydroxyl groups of the compound of the formula I with an α-amino acid or a β-amino acid or the like by a conventional method using a condensing agent.

本发明的化合物还可具有一个或多个立体异构体。除非另有说明，所有异构体都包括在内，例如对映异构体和非对映异构体。本发明的含有不对称碳原子的化合物可以以光学活性纯的形式、内消旋体或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。 The compounds of the invention may also have one or more stereoisomers. All isomers are included, such as enantiomers and diastereomers, unless otherwise indicated. The asymmetric carbon atom-containing compound of the present invention can be isolated in optically active pure form, in the meso form or in the racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by the use of chiral starting materials or chiral reagents.

术语"卤素"是指氟、氯、溴或碘，优选氟或氯。 The term "halogen" means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.

术语"羟基"指 -ΟΗ基团。 The term "hydroxy" refers to a hydrazine group.

术语"氰基"指 -CN基团。 The term "cyano" refers to a -CN group.

术语"焼基"是指由碳原子和氢原子组成的直链或支链的饱和的脂肪烃基团，其通过单键与分子的其余部分连接。所述烷基优选具有 1-8个碳原子的 C^烷基，更优选具有 1-4个碳原子的 C_M焼基。所述焼基可以是未取代的或是被一个或多个选自卤素和羟基的取代基所取代。未取代的烷基的非限制性实例包括但不限于诸如甲基、乙基、丙基、 2-丙基、正丁基、异丁基、叔-丁基、正-戊基、 2-甲基丁基、新戊基、正己基、 2-甲基己基等等。所述取代的焼基包括但不限于诸如羟甲基、羟乙基、三氟甲基、三氟乙基等等。 The term "mercapto" refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, which is attached to the remainder of the molecule by a single bond. The alkyl group preferably has a C alkyl group of 1 to 8 carbon atoms, more preferably a C _M fluorenyl group having 1 to 4 carbon atoms. The thiol group may be unsubstituted or substituted by one or more substituents selected from the group consisting of halogen and hydroxy. Non-limiting examples of unsubstituted alkyl groups include, but are not limited to, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methyl Butyl, neopentyl, n-hexyl, 2-methylhexyl and the like. The substituted indenyl group includes, but is not limited to, hydroxymethyl, hydroxyethyl, trifluoromethyl, trifluoroethyl, and the like.

术语"烷氧基"是指式 -ORa基团，其中 Ra为上文所定义的烷基基团，优选含有 1-8个碳原子的 C^烷基，更优选含有 1-4个碳原子的 C_M烷基。所述烷基可以是未取代的或是被一个或多个选自卤素和羟基的取代基所取代。未取代的焼氧基的非限制性实例包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、叔-丁氧基、正-戊氧基、 2-甲基丁氧基、新戊氧基、正己氧基、 2-甲基己氧基等等。所述取代的焼氧基包括但不限于诸如三氟甲氧基、三氟乙氧基等等。 The term "alkoxy" refers to a radical of the formula -ORa, wherein Ra is an alkyl radical as defined above, preferably a C alkyl radical having from 1 to 8 carbon atoms, more preferably from 1 to 4 carbon atoms. C _M alkyl. The alkyl group may be unsubstituted or substituted by one or more substituents selected from the group consisting of a halogen and a hydroxyl group. Non-limiting examples of unsubstituted alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, plus - Pentyloxy, 2-methylbutoxy, neopentyloxy, n-hexyloxy, 2-methylhexyloxy and the like. The substituted decyloxy group includes, but is not limited to, such as trifluoromethoxy, trifluoroethoxy, and the like.

术语"环烷基"是指由氢原子和碳原子组成的饱和的非芳族单环烃基，优选具有 3-8个碳原子的 ^₈环烷基，更优选具有 3-6个碳原子 ^₆环烷基。环烷基的非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基等。 The term "cycloalkyl" refers to a saturated non-aromatic monocyclic hydrocarbon consisting of hydrogen atoms and carbon atoms, preferably having 3-8 carbon atoms ^ ₈ cycloalkyl group, more preferably having 3-6 carbon atoms ^ ₆ cycloalkyl. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

本发明另一方面提供式 I化合物的制备方法，该方法包括将如式 1-6所示化合物在有机溶剂中与还原剂反应，其中和的定义同前述式 I相同，

其中，有机溶剂选自乙腈、四氢呋喃、二氯甲烷、 ***、甲苯或其组合，优选乙腈；还原剂选自三乙基硅烷和三氟化硼***；反应温度为 0〜- 20°C，优选 -5〜- 10°C，更优选 -5°C。 Another aspect of the present invention provides a process for the preparation of a compound of formula I, which comprises reacting a compound of formula 1-6 with a reducing agent in an organic solvent, wherein the definition of the sum is the same as in the above formula I,

Wherein, the organic solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, dichloromethane, diethyl ether, toluene or a combination thereof, preferably acetonitrile; the reducing agent is selected from the group consisting of triethylsilane and boron trifluoride diethyl ether; the reaction temperature is 0 to 20 ° C, preferably -5 to - 10 ° C, more preferably -5 ° C.

再一方面提供一种如式 1-6所示的化合物，其中， i和的定义同前述式 I相同， In still another aspect, there is provided a compound of formula 1-6, wherein the definition of i and is the same as formula I above.

本发明再一方面提供一种如式 1-6所示的化合物用于制备式 I化合物的用途。

A further aspect of the invention provides the use of a compound of formula 1-6 for the preparation of a compound of formula I.

本发明再一方面提供如式 1-6所示化合物的制备方法，该方法包括在有机溶剂中，在碱性物质存在下，将如式 1-5所示化合物与如式 I-5a所示化合物反应，反应结束后脱掉糖基上的保护基制得如式 1-6所示化合物，其中和 R₂的定义同前述式 I中相同， A further aspect of the invention provides a process for the preparation of a compound of formula 1-6, which comprises reacting a compound of formula 1-5 with a compound of formula 1-5 in an organic solvent in the presence of a basic material The compound is reacted, and after the reaction, the protecting group on the glycosyl group is removed to obtain a compound of the formula 1-6, wherein the definition of R _{2 is} the same as in the above formula I,

其中，有机溶剂选自四氢呋喃、 ***、正己烷、甲苯或其组合，优选四氢呋喃；碱性物质选自叔丁基锂、正丁基锂、二异丙基氨基锂 (LDA)，优选叔丁基锂；反应温度为 -60〜- 90°C，优选 -78〜- 80°C _; 脱掉糖基上的保护基的反应条件为，将反应混合物在甲基磺酸的甲醇溶液中于室温下反应。 Wherein, the organic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, n-hexane, toluene or a combination thereof, preferably tetrahydrofuran; the basic substance is selected from the group consisting of t-butyllithium, n-butyllithium, lithium diisopropylamide (LDA), preferably t-butyl. Lithium; reaction temperature is -60 to -90 ° C, preferably -78 to - 80 ° C _; the reaction conditions for removing the protecting group on the glycosyl group are, the reaction mixture is in a methanolic solution of methanesulfonic acid at room temperature reaction.

一方面提供如式 1-5所示的化合物，其中和 R₂的定义同前述式 I相同，

本发明再一方面提供如式 1-5所示化合物的制备方法，该方法包括，在有机溶剂中将如式 1-4所示化合物与还原剂反应，其中和 R₂的定义同前述式 I相同，

Provided on the one hand a compound of the formula 1-5, wherein R _{2 is} as defined above for the formula I,

A further aspect of the invention provides a process for the preparation of a compound of formula 1-5, which comprises reacting a compound of formula 1-4 with a reducing agent in an organic solvent, wherein R _{2 is} as defined above for formula I the same,

1-4 1-5 。 1-4 1-5.

其中，有机溶剂选自二氯甲烷、乙腈、甲苯、四氢呋喃、 ***或其组合，优选二氯甲烷和乙腈的混合物；还原剂选自三乙基硅烷和三氟化硼***；反应温度为 0~20°C，优选 0°C。 Wherein, the organic solvent is selected from the group consisting of dichloromethane, acetonitrile, toluene, tetrahydrofuran, diethyl ether or a combination thereof, preferably a mixture of dichloromethane and acetonitrile; the reducing agent is selected from the group consisting of triethylsilane and boron trifluoride diethyl ether; the reaction temperature is 0~ 20 ° C, preferably 0 ° C.

一方面提供如式 1-4所示化合物，其中和 R₂的定义同前述式 I相同。 As aspect provides a compound of formula 1-4, and wherein R ₂ is the same as defined in the formula I.

本发明再一方面提供如式 1-4所示化合物的制备方法，该方法包括在有机溶剂中，在碱性物质存在下，将如式 1-3所示化合物与如式 I-3a所示化合物反应，反应结束后用淬灭剂终止反应，和的定义同前述式 I相同，

A further aspect of the invention provides a process for the preparation of a compound of formula 1-4, which comprises reacting a compound of formula 1-3 with a compound of formula 1-3 in an organic solvent in the presence of a basic material. The compound is reacted, and after the reaction is completed, the reaction is terminated with a quencher, and the definition of the same is the same as the above formula I,

其中，有机溶剂选自四氢呋喃、 ***、正己烷、甲苯或其组合，优选四氢呋喃；碱性物质选自叔丁基锂、正丁基锂、二异丙基氨基锂 (LDA)，优选正丁基锂；反应温度为 -60〜- 90°C，优选 -₇₈〜- ₈(T_{C ;} 淬灭剂选自氯化铵、甲酸、醋酸、稀盐酸、稀硫酸等。

Wherein, the organic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, n-hexane, toluene or a combination thereof, preferably tetrahydrofuran; the basic substance is selected from the group consisting of t-butyl lithium, n-butyl lithium, lithium diisopropylamide (LDA), preferably n-butyl. Lithium; reaction temperature is -60 to -90 ° C, preferably _{-78 to} - ₈ (T _{C ;} quenching agent is selected from the group consisting of ammonium chloride, formic acid, acetic acid, dilute hydrochloric acid, dilute sulfuric acid, and the like.

其中，如式 1-3所示化合物可市售获得，也可以通过本领域技术人员已知的标准方法容易地制备，例如：在 0°C，用还原剂例如硼烷二甲硫醚在有机溶剂如四氢呋喃中处理如式 1-1所示化合物，得到如式 1-2所示化合物；在 0°C下， DCM (二氯甲烷）溶剂中，用 PCC C氯铬酸吡啶嗡盐)处理如式 1-2所示化合物，得到如式 1-3所示化合物。其中如 1-1所示化合物可市售获得。

Among them, the compounds of the formulae 1-3 are commercially available, and can also be easily prepared by standard methods known to those skilled in the art, for example: at 0 ° C, with a reducing agent such as borane dimethyl sulfide in organic Treatment of a compound of formula 1-1 in a solvent such as tetrahydrofuran affords a compound of formula 1-2; treatment with DCC (dichloromethane) solvent in PCC C chlorochromic acid pyridinium salt at 0 ° C The compound of the formula 1-2 gives the compound of the formula 1-3. Among them, a compound such as 1-1 is commercially available.

1-1 I-2 I-3 1-1 I-2 I-3

其中，如式 I-3a所示化合物可市售获得，也可以通过本领域技术人员已知的标准方法容易地制备。例如：将对溴碘苯、 R₂基苯硼酸、四（三苯基膦）钯、碳酸钾在甲苯或者 N， N- 二甲基甲酰胺溶剂中于 10CTC下反应，反应完毕用乙酸乙酯和水萃取，有机相蒸干溶剂，残余物经硅 I-3a所示化合物。

Among them, the compound represented by the formula I-3a is commercially available, and can also be easily produced by standard methods known to those skilled in the art. For example: reacting p-bromoiodobenzene, R ₂ -phenylbenzeneboronic acid, tetrakis(triphenylphosphine)palladium, potassium carbonate in toluene or N, N-dimethylformamide solvent at 10CTC, and reacting with ethyl acetate And water extraction, organic phase evaporation of dry solvent, residue The compound is subjected to a compound represented by silicon I-3a.

一方面提供一种如式 I所示化合物的制备方法，该方法包括如下反应步骤: In one aspect, there is provided a process for the preparation of a compound of formula I, which process comprises the following reaction steps:

(a) 有机溶剂中，在碱性物质存在下，将如式 1-3所示化合物与如式 I-3a所示化合物反应，反应结束后用淬灭剂终止反应； (a) reacting a compound of the formula 1-3 with a compound of the formula I-3a in the presence of a basic substance in an organic solvent, and quenching the reaction with a quencher after completion of the reaction;

(b) 在有机溶剂中将如式 1-4所示化合物与还原剂反应； (b) reacting a compound of formula 1-4 with a reducing agent in an organic solvent;

(c) 在有机溶剂中，在碱性物质存在下，将如式 1-5所示化合物与如式 I-5a所示化合物反应，反应结束后脱掉糖基上的保护基制得如式 1-6所示化合物； (c) reacting a compound of the formula 1-5 with a compound of the formula I-5a in the presence of a basic substance in an organic solvent, and removing the protecting group on the glycosyl group after completion of the reaction. a compound of 1-6;

(d) 将化合物 1-6在有机溶剂中与还原剂反应制得如式 I所示化合物； (d) reacting compound 1-6 with a reducing agent in an organic solvent to obtain a compound of formula I;

其中和的定义同前述式 I相同。 The definition of and is the same as the above formula I.

其中，步骤（a) 中有机溶剂选自四氢呋喃、 ***、正己烷、甲苯或其组合，优选四氢呋喃；碱性物质选自叔丁基锂、正丁基锂、二异丙基氨基锂 (LDA)，优选正丁基锂；反应温度为 -60〜- 90°C，优选 -78〜- 80°C ; 淬灭剂选自氯化铵、甲酸、醋酸、稀盐酸、稀硫酸等。 Wherein, the organic solvent in the step (a) is selected from the group consisting of tetrahydrofuran, diethyl ether, n-hexane, toluene or a combination thereof, preferably tetrahydrofuran; the basic substance is selected from the group consisting of t-butyl lithium, n-butyl lithium, lithium diisopropylamide (LDA). Preferably, n-butyllithium; reaction temperature is -60 to -90 ° C, preferably -78 to -80 ° C; the quenching agent is selected from the group consisting of ammonium chloride, formic acid, acetic acid, dilute hydrochloric acid, dilute sulfuric acid and the like.

步骤（b) 中有机溶剂选自二氯甲烷、乙腈、甲苯、四氢呋喃、 ***或其组合，优选二氯甲烷和乙腈的混合物；还原剂选自三乙基硅烷和三氟化硼***；反应温度为 0~20°C，优选 0°C。 The organic solvent in the step (b) is selected from the group consisting of dichloromethane, acetonitrile, toluene, tetrahydrofuran, diethyl ether or a combination thereof, preferably a mixture of dichloromethane and acetonitrile; the reducing agent is selected from the group consisting of triethylsilane and boron trifluoride diethyl ether; It is 0 to 20 ° C, preferably 0 ° C.

步骤（c) 中有机溶剂选自四氢呋喃、 ***、正己烷、甲苯或其组合，优选四氢呋喃；碱性物质选自叔丁基锂、正丁基锂、二异丙基氨基锂 (LDA)，优选叔丁基锂；反应温度为 -60〜- 90°C，优选 -78〜- 80°C ; 脱掉糖基上的保护基的反应条件为，将反应混合物在甲基磺酸的甲醇溶液中于室温下反应。 The organic solvent in the step (c) is selected from the group consisting of tetrahydrofuran, diethyl ether, n-hexane, toluene or a combination thereof, preferably tetrahydrofuran; the basic substance is selected from the group consisting of t-butyl lithium, n-butyl lithium, lithium diisopropylamide (LDA), preferably Tert-butyllithium; reaction temperature is -60 to -90 ° C, preferably -78 to - 80 ° C; the reaction condition for removing the protecting group on the glycosyl group is, the reaction mixture is in a methanol solution of methanesulfonic acid The reaction was carried out at room temperature.

步骤（d)中有机溶剂选自乙腈、四氢呋喃、二氯甲烷、 ***、甲苯或其组合，优选乙腈; 还原剂选自三乙基硅烷和三氟化硼***；反应温度为 0〜- 20°C，优选 -5〜- 10°C。 The organic solvent in the step (d) is selected from the group consisting of acetonitrile, tetrahydrofuran, dichloromethane, diethyl ether, toluene or a combination thereof, preferably acetonitrile; the reducing agent is selected from the group consisting of triethylsilane and boron trifluoride diethyl ether; and the reaction temperature is 0 to 20°. C, preferably -5 to -10 °C.

本发明再一方面提供一种药物组合物，其含有如式 I所示化合物或其盐、前药或立体异构体，以及一种或多种药学上可接受的载体、赋形剂和 /或介质。 According to still another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the formula I or a salt thereof, a prodrug or a stereoisomer A construct, and one or more pharmaceutically acceptable carriers, excipients and/or vehicles.

"药物组合物 "是指一种或多种本发明的化合物或其盐与在本领域中通常接受的用于将生物活性化合物输送至有机体，例如人，的载体、赋形剂和 /或介质的制剂。药物组合物的目的是有利于对有机体给予本发明的化合物。 "Pharmaceutical composition" means one or more compounds of the present invention or salts thereof and carriers, excipients and/or mediators which are generally accepted in the art for delivery of biologically active compounds to organisms, such as humans. Preparation. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the invention to an organism.

术语"药学上可接受的载体 "是指对有机体无明显剌激作用，而且不会损害该活性化合物的生物活性及性能的那些载体和稀释剂。 "药学上可接受的赋形剂和 /或介质 "是指与活性成分一同给药的、有利于活性成分的给药的惰性物质。 "药学上可接受的载体、赋形剂和 /或介质" 包括但不限于可用于人或家畜动物的任何载体、赋形剂、介质、助流剂、增甜剂、稀释剂、防腐剂、染料 /着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。所述赋形剂的非限制性实例包括碳酸钙、磷酸鈣、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇等等。 The term "pharmaceutically acceptable carrier" refers to those carriers and diluents which do not significantly irritate the organism and which do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable excipient and/or vehicle" means an inert substance which, together with the active ingredient, facilitates administration of the active ingredient. "Pharmaceutically acceptable carrier, excipient, and/or vehicle" includes, but is not limited to, any carrier, excipient, vehicle, glidant, sweetener, diluent, preservative, which can be used in human or livestock animals, Dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, disintegrating agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers. Non-limiting examples of such excipients include calcium carbonate, calcium phosphate, various sugars and various starches, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, and the like.

以纯的形式或以适宜的药物组合物形式的本发明化合物或其药学上可接受的盐的给药可通过提供类似用途的药剂的任何可接受给药模式来进行。本发明的药物组合物可通过将本发明的化合物与适宜的药学上可接受的载剂、稀释剂或赋形剂组合而制备，且可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等等。 Administration of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in pure form or in a suitable pharmaceutical composition can be carried out by any acceptable mode of administration which provides a medicament for similar use. The pharmaceutical compositions of the present invention can be prepared by combining a compound of the present invention with a suitable pharmaceutically acceptable carrier, diluent or excipient, and can be formulated into solid, semi-solid, liquid or gaseous preparations such as tablets. Agents, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols, and the like.

给予本发明化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、 ***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。优选的给药途径是口服给药。 Typical routes of administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, Intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration. A preferred route of administration is oral administration.

本发明的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等等。 The pharmaceutical composition of the present invention can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a dragee method, a pulverization method, an emulsification method, a lyophilization method, and the like.

在优选的实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药物可接受的载体、赋形剂和 /或介质混合，来配制该药物组合物。这些载体、赋形剂和介质能使本发明的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、桨剂、悬浮剂等，用于对患者的口服给药。 In a preferred embodiment, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions may be formulated by admixing the active compound withpharmaceutically acceptable carriers, excipients and/or vehicles which are well known in the art. These carriers, excipients and vehicles enable the compounds of the present invention to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients. Dosing.

可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体赋形剂混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅剂，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的赋形剂包括但不限于：填充剂，如糖，包括乳糖、蔗糖、甘露醇或山梨糖醇；纤维素制剂例如玉米淀粉、小麦淀粉、大米淀粉和马铃薯淀粉；以及其它物质，如明胶、黄芪胶、甲基纤维素、羟丙基甲基纤维素、羟甲基纤维素钠和 /或聚乙烯吡咯焼酮；崩解剂，如交联聚乙烯吡咯焼酮、琼脂或藻酸，也可以使用盐，如藻酸钠。可以根据通常药物实践中公知的方法任选地对糖衣剂的核心进行包衣，尤其使用肠溶包衣。 Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules. The core of a tablet or dragee. Suitable excipients include, but are not limited to, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch and potato starch; and other substances such as gelatin , tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; disintegrants, such as cross-linked polyvinylpyrrolidone, For agar or alginic acid, a salt such as sodium alginate may also be used. The core of the dragee may optionally be coated according to methods well known in the ordinary pharmaceutical practice, especially using enteric coatings.

药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。能够使用适当的赋形剂，例如填充剂、缓冲剂或表面活性剂。 The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form. Suitable excipients such as fillers, buffers or surfactants can be used.

本发明式 I化合物的剂量可根据患者的身体状况 (例如年龄、体重、待治疗疾病的类型和严重性)和给药途径而变化，并通常在约 0.01-300 mg/kg/天，临床医生可根据实际情况合宜地选择。 The dosage of the compound of formula I of the present invention may vary depending on the physical condition of the patient (e.g., age, weight, type and severity of the condition to be treated) and the route of administration, and is usually at about 0.01-300 mg/kg/day, clinician It can be chosen according to the actual situation.

本发明式 I化合物显示出极佳的 SGLT-2抑制活性和极佳的血糖降低作用。因此，本发明的化合物可用于治疗以下疾病或者延迟其进展或发病：糖尿病、糖尿病性视网膜病、糖尿病性神经病变、糖尿病性肾病变、伤口愈合延迟、胰岛素抵抗、高血糖症、高胰岛素血症、脂肪酸血浓度升高、甘油血浓度升高、高脂血症、肥胖症、高甘油三酯血症、 X综合征、动脉粥样硬化或高血压。特别的，本发明化合物可用于治疗或预防糖尿病 (例如 I型和 Π型糖尿病等)、糖尿病并发症 (例如糖尿病性视网膜病、糖尿病性神经病变、糖尿病性肾病变)或肥胖症，或用于治疗饭后高血糖症。 The compound of the formula I of the present invention exhibits excellent SGLT-2 inhibitory activity and excellent blood sugar lowering action. Therefore, the compounds of the present invention are useful for treating or delaying the progression or onset of the following diseases: diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia , elevated fatty acid blood levels, elevated glycerol blood levels, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, atherosclerosis or hypertension. In particular, the compounds of the invention are useful for the treatment or prevention of diabetes (eg, type I and sputum type diabetes, etc.), diabetic complications (eg, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy), or obesity, or Treating hyperglycemia after meals.

本发明再一方面提供式 I 化合物或其盐、前药或立体异构体在制备用于治疗受益于 SGLT-2抑制的疾病的药物中的用途，所述受益于 SGLT-2抑制的疾病选自糖尿病、糖尿病性视网膜病、糖尿病性神经病变、糖尿病性肾病变、伤口愈合延迟、胰岛素抵抗、高血糖症、高胰岛素血症、脂肪酸血浓度升高、甘油血浓度升高、高脂血症、肥胖症、高甘油三酯血症、 X综合征、动脉粥样硬化或高血压等疾病。 A further aspect of the invention provides the use of a compound of formula I, or a salt, prodrug or stereoisomer thereof, for the manufacture of a medicament for the treatment of a disease which is beneficial for the inhibition of SGLT-2, said disease benefiting from SGLT-2 inhibition From diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated fatty acid blood levels, elevated glycerolemia, hyperlipidemia , obesity, hypertriglyceridemia, X syndrome, atherosclerosis or hypertension.

本发明再一方面提供式 I化合物或其盐、前药或立体异构体在制备用于治疗糖尿病、糖尿病并发症、肥胖症、饭后高血糖症等疾病的药物中的用途。所述糖尿病并发症包括但不限于例如糖尿病性视网膜病、糖尿病性神经病变、糖尿病性肾病变等。 A further aspect of the invention provides the use of a compound of formula I or a salt, prodrug or stereoisomer thereof for the manufacture of a medicament for the treatment of a condition such as diabetes, diabetes complications, obesity, postprandial hyperglycemia and the like. The diabetic complications include, but are not limited to, for example, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, and the like.

本发明再一方面提供一种治疗受益于 SGLT-2抑制的疾病的方法，该方法包括给予有机体有效量的本发明所述的化合物或其药学上可接受的盐、或所述的药物组合物。所述受益于 SGLT-2抑制的疾病如前所描述。给药途径、给药剂量也参见前述。 A further aspect of the invention provides a method of treating a disease which is beneficial for inhibition of SGLT-2, the method comprising administering to the organism an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof . The disease benefiting from SGLT-2 inhibition is as previously described. The administration route and the dose to be administered are also referred to as described above.

本发明式 I化合物亦可与其他抗糖尿病剂联用治疗上述疾病或者延缓所述疾病的进展或发病，其他抗糖尿病剂的实例包括但不限于：双胍类 (例如，二甲双胍或苯乙双胍)、葡萄糖苷酶抑制剂 (例如，阿卡波糖、米格列醇)、胰岛素 (例如，赖脯胰岛素、甘精胰岛素、地特胰岛素、门冬胰岛素、德谷胰岛素)、氯茴苯酸类 (例如，瑞格列奈)、磺酰脲类 (例如，格列美脲、格列本脲、格列齐特、氯磺丙脲、格列吡嗉)、噻唑烷二酮类 (例如，曲格列酮、罗格列酮、吡格列酮)、 PPAR-α/γ双重激动剂 (例如，莫格列他)、 GLP-1受体激动剂 (例如，艾塞那肽、利拉鲁肽)和 DPP4抑制剂 (例如西格列汀、沙格列汀、阿格列汀)。具体实施方式 The compounds of formula I of the present invention may also be used in combination with other anti-diabetic agents to treat or delay the progression or onset of the disease. Examples of other anti-diabetic agents include, but are not limited to, biguanides (e.g., metformin or phenformin), Glucosidase inhibitors (eg, acarbose, miglitol), insulin (eg, insulin lispro, insulin glargine, insulin detemir, insulin aspart, insulin), meglitinide ( For example, repaglinide, sulfonylureas (eg, glimepiride, glibenclamide, gliclazide, chlorpropamide, glibenclamide), thiazolidinediones (eg, koji) a glitazone, rosiglitazone, pioglitazone), a PPAR-α/γ dual agonist (eg, moglitastat), a GLP-1 receptor agonist (eg, exenatide, liraglutide), and DPP4 inhibitors (eg, sitagliptin, saxagliptin, alogliptin). detailed description

下面结合具体实施例对本发明做进一步的描述，但本发明不限于本文描述的任何具体优选的实施方案。本领域技术人员应该理解，对本发明技术特征所作的等同替换，或相应的改进，仍属于本发明的保护范围之内。 The invention is further described in conjunction with the specific embodiments, but the invention is not limited to any specific preferred embodiments described herein. It should be understood by those skilled in the art that equivalent substitutions, or corresponding modifications, of the technical features of the present invention are still within the scope of the present invention.

本发明具体实施例中使用的初始原料、反应试剂等如无特别注明均为市售产品。 The starting materials, reaction reagents and the like used in the specific examples of the present invention are all commercially available products unless otherwise specified.

1 化合物 1的制备 1 Preparation of compound 1

化合物 1-3的制备： Preparation of Compound 1-3:

在圆底烧瓶中加入 70.6 g 2-氯 -5-溴苯甲酸 (1-1)、 500mL四氢呋喃， 0°C下缓慢滴加 200mL 2M硼烷二甲硫醚络合物；加毕，室温（约 25°C )搅拌过夜； 0°C下缓慢滴加甲醇至无气泡冒出；减压浓缩蒸干反应液；向残余物中加入 300mL水和 300mL乙酸乙酯，萃取分层，有机相用饱和食盐水洗一次，用无水硫酸钠干燥，过滤，将滤液浓缩至干得到化合物 1-2，无需纯化直接进行下步反应。 Add 70.6 g of 2-chloro-5-bromobenzoic acid (1-1), 500 mL of tetrahydrofuran to a round bottom flask, and slowly add 200 mL of 2M borane dimethyl sulfide complex at 0 ° C; Stirring at about 25 ° C overnight; slowly adding methanol to the bubble-free evolution at 0 ° C; evaporation and drying the reaction mixture under reduced pressure; adding 300 mL of water and 300 mL of ethyl acetate to the residue, extracting and separating, organic phase The mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated to dryness to afford compound 1-2, and the next step was carried out without purification.

在圆底烧瓶中加入 60g PCC、 60g硅胶粉，混匀后加入 500mL二氯甲烷，冷却到 0°C，搅拌下滴加 45g化合物 1-2的二氯甲烷溶液 (150mL)，维持 (TC， TLC监测反应。待反应完全后，减压浓缩蒸干反应液，硅胶柱层析分离纯化（洗脱剂： V S/V ««=10/1 )得到 38g化合物 1-3，两步产率为 90%， MS m/z (ESI) 242.9 [M+Na]⁺ _D 60 g of PCC and 60 g of silica gel powder were added to the round bottom flask, and after mixing, 500 mL of dichloromethane was added, and the mixture was cooled to 0 ° C, and 45 g of a solution of Compound 1-2 in dichloromethane (150 mL) was added dropwise with stirring to maintain (TC, The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was evaporated to dryness and evaporated to silica gel column chromatography (eluent: VS/V ««=10/1) to give 38 g of compound 1-3. 90%, MS m/z (ESI) 242.9 [M+Na] ⁺ _D

化合物 1-4的制备： Preparation of Compound 1-4:

在圆底烧瓶中加入 23.3g 4-溴联苯、重蒸干燥的四氢呋喃 (150mL)，冷却到 -80°C，缓慢滴加 55mL 2M正丁基锂，滴完后于该温度下搅拌反应两小时。然后缓慢滴加 21.9g 5-溴 -2-氯苯甲醛 (1-3)与四氢呋喃组成的溶液 (80mL)，于 -78°C搅拌反应 2小时，饱和氯化铵溶液萃灭反应。静置分层，水相用乙酸乙酯萃取一次，合并有机相并用无水硫酸钠干燥，过滤，滤液浓缩至干，硅胶柱层析分离纯化（洗脱剂： V ^s/V ^^ /l )得到 31.7g化合物 1-4，产率为 85%， MS m/z (ESI) 396.9 [M+Na]⁺。 23.3 g of 4-bromobiphenyl, re-distilled tetrahydrofuran (150 mL) was added to a round bottom flask, cooled to -80 ° C, and 55 mL of 2 M n-butyllithium was slowly added dropwise. After the dropwise addition, the reaction was stirred at the same temperature. hour. Then, a solution (80 mL) of 21.9 g of 5-bromo-2-chlorobenzaldehyde (1-3) and tetrahydrofuran was slowly added dropwise, and the mixture was stirred at -78 °C for 2 hours, and then the mixture was evaporated. The mixture was allowed to stand for crystallization. The aqueous phase was extracted with ethyl acetate. EtOAc was evaporated. EtOAcjjjjjjjjjjjjjjjjjj l) 31.7 g of compound 1-4 are obtained in a yield of 85%, MS m/z (ESI) 396.9 [M+Na] ⁺ .

化合物 1-5的制备： Preparation of Compound 1-5:

将 lO.Og化合物 1-4溶于二氯甲烷和乙腈组成的混合溶剂 (二氯甲烷：乙腈 =l : l,100mL)中，冷却至 0°C，加入 3当量的三乙基硅焼，搅拌十分钟，向其中缓慢滴加 1.5当量的三氟化硼乙醚溶液，保持反应体系温度不高于 20°C，滴完后搅拌过夜。次日 TLC检测，反应结束后用饱和碳酸氢钠溶液萃灭反应，分出有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩至干得到 9.0g化合物 1-5，产率为 95%， MS m/z (ESI) 380.9 [M+Na]⁺。 1O.Og of compound 1-4 was dissolved in a mixed solvent of dichloromethane and acetonitrile (dichloromethane: acetonitrile = 1 : 1 , 100 mL), cooled to 0 ° C, and 3 equivalents of triethylsilyl hydride was added. After stirring for ten minutes, 1.5 equivalent of a solution of boron trifluoride diethyl ether was slowly added dropwise thereto, keeping the temperature of the reaction system not higher than 20 ° C, and stirring was continued overnight after the dropwise addition. After the reaction, the reaction was carried out with a saturated aqueous solution of sodium bicarbonate, and the organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness The rate was 95%, MS m/z (ESI) 380.9 [M+Na] ⁺ .

2,3,4,6-四 -O-三甲基硅基 -D-葡萄糖酸内酯的制备： Preparation of 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone:

在 500mL圆底烧瓶中加入 14.0 g葡萄糖酸内酯，加入 120mL四氢呋喃和 64 g N-甲基吗啡啉，冷却到 0°C，搅拌下缓慢滴加 52 g三甲基氯硅烷。加毕室温搅拌 5 h，冷却到 0°C加水 250mL淬灭反应，加入 200mL甲苯，分液，有机相用水洗，无水硫酸钠干燥，减压旋干溶剂得到 2,3,4,6-四 -0-三甲基硅基 -D-葡萄糖酸内酯 36.5 g，产率 90%。 Into a 500 mL round bottom flask, 14.0 g of gluconolactone was added, 120 mL of tetrahydrofuran and 64 g of N-methylmorpholine were added, and the mixture was cooled to 0 ° C, and 52 g of trimethylchlorosilane was slowly added dropwise with stirring. Stir at room temperature for 5 h, cool to 0 ° C and add 250 mL of water to quench the reaction, add 200 mL of toluene, separate the liquid, wash the organic phase with water, dry over anhydrous sodium sulfate, and then dry the solvent under reduced pressure to give 2,3,4,6- Tetra-O-trimethylsilyl-D-gluconolactone 36.5 g, yield 90%.

化合物 1-6的制备： Preparation of Compounds 1-6:

将 7.1g化合物 1-5的无水四氢呋喃溶液 (50mL)在氩气保护下冷却至 -80°C，向其中滴加含 1.5当量叔丁基锂的环己焼溶液，并在 -78 °C下搅拌 1.5小时，再向其中滴加含 1.5当量 2,3,4,6- 四 _₀-三甲基娃基 -D-葡萄糖酸内酯的四氢呋喃溶液，滴毕，于 -78°C下搅拌 3小时，再向其中加入 5当量甲基磺酸的甲醇溶液，缓慢升至室温并搅拌过夜。再用碳酸氢钠水溶液中和反应液，减压蒸发除去四氢呋喃和甲醇，残余物用乙酸乙酯萃取水相 4次；合并有机相，无水硫酸钠干燥，过滤，滤液浓缩至干得到化合物 1-6粗品。粗品不经处理直接用于下一步反应。 7.1 g of a solution of compound 1-5 in anhydrous tetrahydrofuran (50 mL) was cooled to -80 ° C under argon atmosphere, and a solution of 1.5 eq of t-butyl lithium in cyclohexane was added dropwise thereto at -78 ° C. After stirring for 1.5 hours, a solution of 1.5 equivalents of 2,3,4,6-tetra- ₀ -trimethylsilyl-D-gluconolactone in tetrahydrofuran was added dropwise thereto, and the mixture was dropped at -78 ° C. After stirring for 3 hours, 5 equivalents of a solution of methanesulfonic acid in methanol was added thereto, and the mixture was slowly warmed to room temperature and stirred overnight. The mixture was neutralized with aqueous sodium hydrogencarbonate, and the mixture was evaporated to dryness. -6 crude. The crude product was used directly in the next reaction without treatment.

化合物 1的制备： Preparation of Compound 1:

在圆底烧瓶中加入化合物 1-6粗品 (7.8g)和乙腈 (50mL)，冷却到 -10°C，向其中加入 3当量的三乙基硅烷，然后缓慢加入 1.5当量的三氟化硼***， -5 °C下搅拌反应 5小时，饱和碳酸氢钠溶液萃灭反应后，用乙酸乙酯萃取四次，有机相用无水硫酸钠干燥，过滤，滤液浓缩至干，残余物经硅胶色谱分离纯化（洗脱剂：乙酸乙酯），得到 4.0g目标化合物 1，两步产率为 45%。 In a round bottom flask, a crude compound 1-6 (7.8 g) and acetonitrile (50 mL) were added, cooled to -10 ° C, 3 equivalents of triethylsilane was added thereto, and then 1.5 equivalents of boron trifluoride etherate was slowly added. The reaction was stirred at -5 °C for 5 hours. After EtOAc (EtOAc m.) Separation and purification (eluent: ethyl acetate) gave 4.0 g of title compound 1 in a step yield of 45%.

JH NM (400MHz, CDCl₃)57.45(d, J=7.2Hz, 2H), 7.40-7.38(d, J=8.0Hz, 2H), 7.34-7.30(t, 2H). 7.37-7.26(m, 1H), 7.25-7.23(m, 1H), 7.17-7.11(m, 4H), 5.00(br, 1H), 4.77(br, 1H), 4.05-3.94(m, 3H), 3.77(br,lH), 3.67(br, 2H), 3.58-3.54(m, 1H), 3.49-3.44(m, 1H), 3.37-3.33(m, 1H), 3.21-3.19(m, 1H), 3.11(br, 1H)。 JH NM (400MHz, CDCl ₃ ) 57.45 (d, J=7.2Hz, 2H), 7.40-7.38 (d, J=8.0Hz, 2H), 7.34-7.30(t, 2H). 7.37-7.26(m, 1H ), 7.25-7.23(m, 1H), 7.17-7.11(m, 4H), 5.00(br, 1H), 4.77(br, 1H), 4.05-3.94(m, 3H), 3.77(br,lH), 3.67 (br, 2H), 3.58-3.54 (m, 1H), 3.49-3.44 (m, 1H), 3.37-3.33 (m, 1H), 3.21-3.19 (m, 1H), 3.11 (br, 1H).

MS m/z (ESI) 464.1 [M+Na]+。实施例 2 化合物 2的 MS m/z (ESI) 464.1 [M+Na]+. Example 2 Compound 2

中间体 4-溴 -4'-氟联苯的制备： Preparation of intermediate 4-bromo-4'-fluorobiphenyl:

在 250mL的圆底烧瓶中加入 4 g对溴碘苯、 2.9 g 4-氟苯硼酸、 0.84 g四（三苯基膦）钯、 5.8 g碳酸钾和 lOOmL甲苯或者 Ν,Ν-二甲基甲酰胺。氮气保护下加热到 100°C，薄层色谱板检测反应进度。反应完毕加水 100mL、乙酸乙酯 150mL分液，有机相分别用 1N盐酸和饱和食盐水洗涤，无水硫酸钠干燥，蒸干溶剂，硅胶柱色谱分离纯化（洗脱剂为石油醚）得到 4-溴 -4，-氟联苯 1.6 g，产率为 46%， MS m/z (ESI) 272.9 [M+Na]+。 In a 250 mL round bottom flask, 4 g of p-bromoiodobenzene, 2.9 g of 4-fluorophenylboronic acid, 0.84 g of tetrakis(triphenylphosphine)palladium, 5.8 g of potassium carbonate, and 100 mL of toluene or hydrazine, dimethyl-dimethyl ketone were added. Amide. Heat to 100 ° C under nitrogen and the TLC plate was used to check the progress of the reaction. After the completion of the reaction, 100 mL of water and 150 mL of ethyl acetate were added, and the organic phase was washed with 1N hydrochloric acid and brine, dried over anhydrous sodium sulfate, and evaporated and evaporated. Bromo-4,-fluorobiphenyl 1.6 g, 46% yield, MS m/z (ESI) 272.9 [M+Na]+.

化合物 2的制备方法参考实施例 1，用中间体 4-溴 -4'-氟联苯代替实施例 1中的 4-溴联苯，总产率为 35%。 Preparation of Compound 2 Referring to Example 1, the 4-bromobiphenyl in Example 1 was replaced with the intermediate 4-bromo-4'-fluorobiphenyl to give a total yield of 35%.

^JH NM (400MHz, CDC1₃) 57.52-7.5 l(m, 1H), 7.31-7.24(m, 4H), 7.08-7.05(m, 5H), 6.88-6.86(m, 1H), 5.35(br, 1H), 5.05(br, 1H), 4.45-4.43(m, 1H), 4.15(s, 1H), 3.98(s, 2H), 3.64-3.58(m, 5H), 3.58(s,3H), 3.25-3.16(m, 2H)。 ^J H NM (400MHz, CDC1 ₃ ) 57.52-7.5 l(m, 1H), 7.31-7.24(m, 4H), 7.08-7.05(m, 5H), 6.88-6.86(m, 1H), 5.35(br, 1H), 5.05(br, 1H), 4.45-4.43(m, 1H), 4.15(s, 1H), 3.98(s, 2H), 3.64-3.58(m, 5H), 3.58(s,3H), 3.25 -3.16 (m, 2H).

MS m/z (ESI) 481.1 [M+Na]+。实施例 3 化合物 3的 MS m/z (ESI) 481.1 [M+Na]+. Example 3 Compound 3

中间体 4-溴 -4'-氯联苯的制备方法参考实施例 2中 4-溴 -4'-氟联苯的制备，只是用 4-氯苯硼酸代替 4-氟苯硼酸。 Intermediate 4-Bromo-4'-chlorobiphenyl was prepared by referring to the preparation of 4-bromo-4'-fluorobiphenyl in Example 2 except that 4-chlorophenylboronic acid was used instead of 4-fluorophenylboronic acid.

化合物 3的制备方法参考实施例 1，用中间体 4-溴 -4'-氯联苯代替实施例 1中的 4-溴联苯，总产率为 30%。 The preparation method of Compound 3 was carried out in the same manner as in Example 1. The 4-bromobiphenyl in Example 1 was replaced with the intermediate 4-bromo-4'-chlorobiphenyl, and the total yield was 30%.

^JH NM (400 MHz, DMSO-de) 57.58-7.56(m, 2H), 7.49-7.48(m, 2H), 7.47-7.46(m, 2H), 7.40-7.37(m, 2H), 7.28-7.23(m, 3H), 4.94(m, 2H), 4.84(d, J=6.0 Hz, 2H), 4.43(m, 2H), 4.14-3.99(m, 3H), 3.70-3.66(m, 1H), 3.46-3.40(m,lH), 3.27-3.08(m, 4H)。 ^J H NM (400 MHz, DMSO-de) 57.58-7.56 (m, 2H), 7.49-7.48 (m, 2H), 7.47-7.46 (m, 2H), 7.40-7.37 (m, 2H), 7.28-7.23 (m, 3H), 4.94 (m, 2H), 4.84 (d, J = 6.0 Hz, 2H), 4.43 (m, 2H), 4.14-3.99 (m, 3H), 3.70-3.66 (m, 1H), 3.46-3.40 (m, lH), 3.27-3.08 (m, 4H).

MS m/z (ESI) 498.1 [M+Na]+。

MS m/z (ESI) 498.1 [M+Na]+.

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化合物 6的制备方法参考实施例 1，用中间体 4-溴 -4，-三氟甲基联苯代替实施例 1中的 4- 溴联苯，总产率为 31%。 Preparation of Compound 6 Referring to Example 1, the 4-bromobiphenyl of Example 1 was replaced with the intermediate 4-bromo-4,-trifluoromethylbiphenyl to give a total yield of 31%.

^JH NM (400 MHz, DMSO-de) 57.60-7.58(m, 2H), 7.53-7.55(m, 2H), 7.50-7.48(m, 2H), 7.43_7.40(m, 2H), 7.32-7.29(m, 3H), 4.97(m, 2H), 4.83(d, J=6.0 Hz, 2H), 4.45(m, 2H), 4.13-3.99(m, 3H), 3.75-3.73(m, IH), 3.50-3.46(m,lH), 3.30-3.12(m, 4H)。 ^J H NM (400 MHz, DMSO-de) 57.60-7.58 (m, 2H), 7.53-7.55 (m, 2H), 7.50-7.48 (m, 2H), 7.43_7.40 (m, 2H), 7.32- 7.29(m, 3H), 4.97(m, 2H), 4.83(d, J=6.0 Hz, 2H), 4.45(m, 2H), 4.13-3.99(m, 3H), 3.75-3.73(m, IH) , 3.50-3.46 (m, lH), 3.30-3.12 (m, 4H).

MS m/z (ESI) 531.1 [M+Na]+。 MS m/z (ESI) 531.1 [M+Na]+.

实施例 7 化合物 7 Example 7 Compound 7

中间体 4-溴 -4'-甲氧基联苯的制备方法参考实施例 2中 4-溴 -4'-氟联苯的制备，只是用 4- 甲氧基苯硼酸代替 4-氟苯硼酸。 Preparation of intermediate 4-bromo-4'-methoxybiphenyl. Refer to the preparation of 4-bromo-4'-fluorobiphenyl in Example 2 except that 4-methoxybenzeneboronic acid is used instead of 4-fluorophenylboronic acid. .

化合物 7的制备方法参考实施例 1，用中间体 4-溴 -4'-甲氧基联苯代替实施例 1中的 4-溴联苯，总产率为 31%。 Preparation of Compound 7 Referring to Example 1, the 4-bromobiphenyl in Example 1 was replaced with the intermediate 4-bromo-4'-methoxybiphenyl to give a total yield of 31%.

^JH NM (400MHz,DMSO-d6) 57.56-7.50(m, 4H), 7.39-7.37(m, 2H), 7.24-7.22(m, 3H), 6.98(d, J=8.0Hz, 2H), 4.93(s, 2H), 4.83(d, J=4.2Hz, IH), 4.44-4.42(t, J=5.2Hz, IH), 4.12-3.98(m, 3H), 3.76(s, 3H), 3.70-3.66(m, IH), 3.43-3.41(m, 2H), 3.24-3.10(m,4H)。 ^J H NM (400MHz, DMSO-d6) 57.56-7.50(m, 4H), 7.39-7.37(m, 2H), 7.24-7.22(m, 3H), 6.98(d, J=8.0Hz, 2H), 4.93 (s, 2H), 4.83 (d, J = 4.2 Hz, IH), 4.44-4.42 (t, J = 5.2 Hz, IH), 4.12-3.98 (m, 3H), 3.76 (s, 3H), 3.70- 3.66 (m, IH), 3.43-3.41 (m, 2H), 3.24-3.10 (m, 4H).

MS m/z (ESI) 493.1 [M+Na]+。 MS m/z (ESI) 493.1 [M+Na]+.

实施例 8 化合物 8的 Example 8 Compound 8

化合物 8的制备方法参考实施例 1，只是用 2-氟 -5-溴苯甲酸代替 2-氯 -5-溴苯甲酸，总产率为 33%。 The preparation of Compound 8 was carried out in the same manner as in Example 1, except that 2-fluoro-5-bromobenzoic acid was used instead of 2-chloro-5-bromobenzoic acid, and the total yield was 33%.

^JH NM (400MHz, CDC1₃) 57.43(d, J=7.6Hz, 2H), 7.39-7.37(d, J=7.6Hz, 2H), 7.33-7.29(m, 2H), 7.24-7.22(m, IH), 7.16-7.14(m, 4H), 6.93-6.89(m, IH), 3.98-3.93(m, IH), 3.89-3.83(m, 2H), 3.75-3.73(m, IH), 3.66(s, 2H), 3.59-3.55(m, IH), 3.52-3.48(m, IH), 3.34-3.35(m, IH), 3.23-3.21(m, 1H)。 ^J H NM (400MHz, CDC1 ₃ ) 57.43 (d, J=7.6Hz, 2H), 7.39-7.37 (d, J=7.6Hz, 2H), 7.33-7.29(m, 2H), 7.24-7.22(m, IH), 7.16-7.14(m, 4H), 6.93-6.89(m, IH), 3.98-3.93(m, IH), 3.89-3.83(m, 2H), 3.75-3.73(m, IH), 3.66( s, 2H), 3.59-3.55 (m, IH), 3.52-3.48 (m, IH), 3.34-3.35 (m, IH), 3.23-3.21 (m, 1H).

MS m/z (ESI) 447.2 [M+Na]+。实施例 9 化合物 9的制 MS m/z (ESI) 447.2 [M+Na]+. Example 9 Preparation of Compound 9

化合物 9的制备方法参考实施例 1，只是用 2-甲氧基 -5-溴苯甲酸代替 2-氯 -5-溴苯甲酸，总产率为 34%。 The preparation method of the compound 9 was carried out with reference to Example 1, except that 2-methoxy-5-bromobenzoic acid was used instead of 2-chloro-5-bromobenzoic acid, and the total yield was 34%.

^JH NM (400MHz,CDCl₃) 57.35-7.32(m, 4H), 7.13-7.10(m, 7H), 6.70(d, J=8.4Hz, IH), 5.04(s_: IH), 5.03(br, IH), 4.80(br, IH), 3.97-3.93(m, IH), 3.96(s, IH), 3.93-3.84(m, 3H), 3.77-3.69(m, 3H)_: 3.61(s, 3H), 3.55-3.53(m, IH), 3.47-3.43(m, IH), 3.22-3.20(m, IH), 3.02(br, 1H)。 ^J H NM (400MHz, CDCl ₃ ) 57.35-7.32(m, 4H), 7.13-7.10(m, 7H), 6.70(d, J=8.4Hz, IH), 5.04(s _: IH), 5.03(br, IH), 4.80(br, IH), 3.97-3.93(m, IH), 3.96(s, IH), 3.93-3.84(m, 3H), 3.77-3.69(m, 3H) _: 3.61(s, 3H) , 3.55-3.53 (m, IH), 3.47-3.43 (m, IH), 3.22-3.20 (m, IH), 3.02 (br, 1H).

MS m/z (ESI) 459.1[M+Na]⁺ ₀ 实施例 10 化合物 10 MS m/z (ESI) 459.1 [M+Na] ⁺ ₀ Example 10 Compound 10

中间体 4-溴 -4'-甲基联苯的制备方法参考实施例 2中 4-溴 -4'-氟联苯的制备，只是用 4-甲基苯硼酸代替 4-氟苯硼酸。 Intermediate 4-bromo-4'-methylbiphenyl was prepared by referring to the preparation of 4-bromo-4'-fluorobiphenyl in Example 2 except that 4-methylbenzeneboronic acid was used in place of 4-fluorophenylboronic acid.

化合物 10的制备方法参考实施例 1，用 2-甲氧基 -5-溴苯甲酸代替 2-氯 -5-溴苯甲酸，用中间体 4-溴 -4'-甲基联苯代替实施例 1中的 4-溴联苯，总产率为 33%。 Preparation method of compound 10 Referring to Example 1, 2-chloro-5-bromobenzoic acid was replaced by 2-methoxy-5-bromobenzoic acid, and the intermediate 4-bromo-4'-methylbiphenyl was used instead of the example. 4-bromobiphenyl in 1 with a total yield of 33%.

^JH NM (400MHz,CDCl₃) 57.37-7.35(m, 4H), 7.17-7.12(m, 6H), 6.72(d, J=8.4Hz, IH), 5.07(s, IH), 5.07(br, IH), 4.83(br, IH), 3.97-3.94(m, IH), 3.83(s, IH), 3.97-3.84(m, 3H), 3.75-3.68(m, 3H), 3.62(s, 3H), 3.58-3.56(m, IH), 3.50-3.45(m, IH), 3.24-3.22(m, IH), 3.12(br, IH), 3.3 l(s, 3H)。 ^J H NM (400MHz, CDCl ₃ ) 57.37-7.35(m, 4H), 7.17-7.12(m, 6H), 6.72(d, J=8.4Hz, IH), 5.07(s, IH), 5.07(br, IH), 4.83(br, IH), 3.97-3.94(m, IH), 3.83(s, IH), 3.97-3.84(m, 3H), 3.75-3.68(m, 3H), 3.62(s, 3H) , 3.58-3.56(m, IH), 3.50-3.45(m, IH), 3.24-3.22(m, IH), 3.12(br, IH), 3.3 l(s, 3H).

MS m/z (ESI) 473.0 [M+Na]+。 MS m/z (ESI) 473.0 [M+Na]+.

实施例 11 化合物 11的 Example 11 Compound 11

化合物 11的制备方法参考实施例 1，用 2-甲基 -5-溴苯甲酸代替 2-氯 -5-溴苯甲酸，总产率为 33%。 The preparation method of Compound 11 was carried out in the same manner as in Example 1, except that 2-methyl-5-bromobenzoic acid was used in place of 2-chloro-5-bromobenzoic acid, and the total yield was 33%.

^JH NM (400MHz, CDC1₃) 57.47(d, 2H), 7.45-7.3 l(m, 2H), 7.27-7.23(m, IH), 7.15(d, 2H), 7.05(t, 2H), 5.03(t, IH), 4.84(s, IH), 4.15(d, IH), 4.12(s, IH), 4.11(s, 2H), 4.01-3.99(d, IH), 3.88(s, 2H), 3.70(s,lH), 3.63(s, IH), 3.55-3.50(t, 2H), 3.24(d, IH), 3.18(s, IH), 3.08(s, IH), 2.10(s, 3H)。 MS m/z (ESI) 443.0 [M+Na]+。 ^J H NM (400MHz, CDC1 ₃ ) 57.47(d, 2H), 7.45-7.3 l(m, 2H), 7.27-7.23(m, IH), 7.15(d, 2H), 7.05(t, 2H), 5.03 (t, IH), 4.84(s, IH), 4.15(d, IH), 4.12(s, IH), 4.11(s, 2H), 4.01-3.99(d, IH), 3.88(s, 2H), 3.70(s,lH), 3.63(s, IH), 3.55-3.50(t, 2H), 3.24(d, IH), 3.18(s, IH), 3.08(s, IH), 2.10(s , 3H). MS m/z (ESI) 443.0 [M+Na]+.

实施例 12 化合物 1 Example 12 Compound 1

中间体 4-溴 -4'-氟联苯的制备参考实施例 2，化合物 12的制备方法参考实施例 1，用 2- 甲基 -5-溴苯甲酸代替 2-氯 -5-溴苯甲酸，用中间体 4-溴 -4'-氟联苯代替 4-溴联苯，总产率为 37%。 Preparation of intermediate 4-bromo-4'-fluorobiphenyl Reference Example 2, Preparation method of compound 12 Referring to Example 1, 2-chloro-5-bromobenzoic acid was used in place of 2-chloro-5-bromobenzoic acid. The intermediate 4-bromo-4'-fluorobiphenyl was used in place of 4-bromobiphenyl with a total yield of 37%.

^JH NM (400MHz, CDC1₃) 57.41-7.38(m, 2H), 7.33-7.3 l(d, 2H), 7.14-7.13(d, 2H), 7.07-6.98(m, 5H), 4.92(s, IH), 4.68(s, IH), 4.03-4.01(s, 2H), 3.90-3.86(m, 2H), 3.71(s, 2H), 3.62-3.46(m, 4H), 3.29-3.27(d, IH), 3.00(s, IH), 2.12(s, 3H)。 ^J H NM (400MHz, CDC1 ₃ ) 57.41-7.38(m, 2H), 7.33-7.3 l(d, 2H), 7.14-7.13(d, 2H), 7.07-6.98(m, 5H), 4.92(s, IH), 4.68(s, IH), 4.03-4.01(s, 2H), 3.90-3.86(m, 2H), 3.71(s, 2H), 3.62-3.46(m, 4H), 3.29-3.27(d, IH), 3.00(s, IH), 2.12(s, 3H).

MS m/z (ESI) 461.0 [M+Na]+。 MS m/z (ESI) 461.0 [M+Na]+.

实施例 13 化合物 1 Example 13 Compound 1

化合物 13的制备方法参考实施例 1，用 2-甲基 -5-溴苯甲酸代替 2-氯 -5-溴苯甲酸，用中间体 4-溴 -4'-氯联苯代替实施例 1中的 4-溴联苯，总产率为 37%。 Preparation method of compound 13 Referring to Example 1, 2-chloro-5-bromobenzoic acid was used instead of 2-chloro-5-bromobenzoic acid, and intermediate 4-bromo-4'-chlorobiphenyl was used instead of Example 1. 4-bromobiphenyl, the total yield was 37%.

^JH NM (400MHz, CDC1₃) 57.49(d, J=8.0Hz, 2H), 7.4 l(d, J=80Hz, 2H), 7.37-7.33(m, 2H), 7.16-7.14(m, 2H), 7.10-7.0 l(m, 2H), 7.37-7.33(m, 5H), 4.75(br, IH), 4.51(br, IH), 4.05-4.01(m, IH), 3.93(s, 2H), 3.78-3.74(m, 3H), 3.66-3.55(m, 3H), 3.51-3.45(m, 2H), 3.33-3.30(m, IH), 2.88(br, IH), 2.15(s, 3H)。 ^J H NM (400MHz, CDC1 ₃ ) 57.49(d, J=8.0Hz, 2H), 7.4 l(d, J=80Hz, 2H), 7.37-7.33(m, 2H), 7.16-7.14(m, 2H) , 7.10-7.0 l(m, 2H), 7.37-7.33(m, 5H), 4.75(br, IH), 4.51(br, IH), 4.05-4.01(m, IH), 3.93(s, 2H), 3.78-3.74 (m, 3H), 3.66-3.55 (m, 3H), 3.51-3.45 (m, 2H), 3.33-3.30 (m, IH), 2.88 (br, IH), 2.15 (s, 3H).

MS m/z (ESI) 455.0 [M+H]+。 MS m/z (ESI) 455.0 [M+H]+.

实施例 14 化合物 14的制备 Example 14 Preparation of Compound 14

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MS m/z (ESI) 527.0 [M+Na]+。 MS m/z (ESI) 527.0 [M+Na]+.

实施例 17 化合物 Example 17 Compound

中间体 4-溴 -4，-三氟甲基联苯的制备方法参考实施例 2中 4-溴 -4，-氟联苯的制备，只是用 4-三氟甲基苯硼酸代替 4-氟苯硼酸。 The preparation method of the intermediate 4-bromo-4,-trifluoromethylbiphenyl refers to the preparation of 4-bromo-4,-fluorobiphenyl in the second embodiment, except that 4-trifluoromethylbenzeneboronic acid is used instead of 4-fluoro Phenylboronic acid.

化合物 17的制备方法参考实施例 1，用 2-甲基 -5-溴苯甲酸代替 2-氯 -5-溴苯甲酸，用中间体 4-溴 -4，-三氟甲基联苯代替实施例 1中的 4-溴联苯，总产率为 32%。 Preparation method of compound 17 Referring to Example 1, 2-chloro-5-bromobenzoic acid was replaced by 2-methyl-5-bromobenzoic acid, and the intermediate 4-bromo-4,-trifluoromethylbiphenyl was used instead. The 4-bromobiphenyl in Example 1 had a total yield of 32%.

^JH NM (500MHz, CDC1₃) 57.62-7.58(m, 4H), 7.44-7.42(m, 2H), 7.16-7.13(m, 5H),4.14-4.08(m, 2H), 3.97-3.94(m, 2H), 3.83-3.77(m, 2H),3.68-3.60(m, 2H), 3.52-3.49(m, IH), 3.40-3.38(m, IH), 2.94(br, IH), 2.58(br, IH), 2.19(s, 3H)。 ^J H NM (500MHz, CDC1 ₃ ) 57.62-7.58(m, 4H), 7.44-7.42(m, 2H), 7.16-7.13(m, 5H), 4.14-4.08(m, 2H), 3.97-3.94(m , 2,,,,,,,, , IH), 2.19(s, 3H).

MS m/z (ESI) 511.0 [M+Na]+。 MS m/z (ESI) 511.0 [M+Na]+.

实施例 18 化合物 18的制备 Example 18 Preparation of Compound 18

中间体 4-溴 -4'-乙氧基联苯的制备方法参考实施例 2中 4-溴 -4'-氟联苯的制备，只是用 4- 乙氧基苯硼酸代替 4-氟苯硼酸。 The preparation method of the intermediate 4-bromo-4'-ethoxybiphenyl refers to the preparation of 4-bromo-4'-fluorobiphenyl in Example 2 except that 4-ethoxybenzeneboronic acid is used instead of 4-fluorophenylboronic acid. .

化合物 18的制备方法参考实施例 1，用 2-甲基 -5-溴苯甲酸代替 2-氯 -5-溴苯甲酸，用中间体 4-溴 -4'-乙氧基联苯代替实施例 1中的 4-溴联苯，总产率为 34%。 Preparation method of compound 18 Referring to Example 1, 2-chloro-5-bromobenzoic acid was used instead of 2-chloro-5-bromobenzoic acid, and the intermediate 4-bromo-4'-ethoxybiphenyl was used instead of the example. 4-bromobiphenyl in 1 with a total yield of 34%.

^JH NM (500MHz, CDC1₃) 57.44-7.39(m, 4H), 7.15-7.08(m, 5H), 6.91-6.89(d, J=7.2Hz, 2H), 4.14-4.02(m, 2H), 3.92(s, 2H), 3.82-3.74(m, 2H), 3.67-3.59(m, 2H), 3.51-3.47(m, IH), 3.39-3.37(m, IH), 2.19(s, 3H), 1.31-1.24(m, 3H)。 ^J H NM (500MHz, CDC1 ₃ ) 57.44-7.39(m, 4H), 7.15-7.08(m, 5H), 6.91-6.89(d, J=7.2Hz, 2H), 4.14-4.02(m, 2H), 3.92(s, 2H), 3.82-3.74(m, 2H), 3.67-3.59(m, 2H), 3.51-3.47(m, IH), 3.39-3.37(m, IH), 2.19(s, 3H), 1.31-1.24 (m, 3H).

MS m/z (ESI) 487.0 [M+Na]+。 MS m/z (ESI) 487.0 [M+Na]+.

实施例 19 体外活性实验 Example 19 In vitro activity assay

本实施例的目的是测试实施例化合物 1-18对 SGLT-2和 SGLT-1的体外选择性抑制作用。众所周知， SGLT-1不仅仅分布在肾脏，还在肠、心脏和气管中都有分布，分布于肠中的 SGLT-1 被抑制后将会发生碳水化合物类养料吸收障碍，从而引起胃肠道不良反应，而分布于心脏的 SGLT-1被抑制后将会带来心肌细胞缺乏营养的高风险。因此，对 SGLT-2有抑制作用的同时，不影响 SGLT-1的活性，成为化合物能否开发成药的关键因素之一。 The purpose of this example was to test the in vitro selective inhibition of SGLT-2 and SGLT-1 by the use of Example Compounds 1-18. It is well known that SGLT-1 is not only distributed in the kidney, but also distributed in the intestine, heart and trachea, and distributed in the intestine SGLT-1. After being inhibited, carbohydrate nutrient absorption disorder will occur, which may cause gastrointestinal side effects, and the inhibition of SGLT-1 distributed in the heart will bring about a high risk of lack of nutrition of cardiomyocytes. Therefore, while inhibiting SGLT-2, it does not affect the activity of SGLT-1, and is one of the key factors for the development of a compound into a drug.

复苏 hSGLTl和 hSGLT2-T-Rex293细胞系 (Invitrogen公司)于 24孔板中，用标准 DMEM 培养基 (Hyclone公司)培养，并加四环素共培养 12小时，以诱导目的基因 hSGLTl或 hSGLT2 的超表达。在测定葡萄糖转运时，吸去培养基，每孔加 500μ1含有 NaCl或无 NaCl的 HEPES 缓冲液和 20μηιο1/ί的 14C-a-methyl-D- glucopyranoside(PerkinElmer公司），并加入实施例 1-18 制备的化合物进行相应实验，同时阴性对照组加入 DMSO，阳性对照组加入 Dapagliflozin, 放在 37°C培养箱中培养 2个小时，吸去培养基，洗涤细胞 5次，加闪烁液裂解，用 Tri-Carb2800 闪烁仪 (PerkinElmer公司)进行相应测定。 The hSGLT1 and hSGLT2-T-Rex293 cell lines (Invitrogen) were cultured in a 24-well plate using standard DMEM medium (Hyclone) and tetracycline was added for 12 hours to induce overexpression of the target gene hSGLT1 or hSGLT2. In the determination of glucose transport, the medium was aspirated, and 500 μl of HEPES buffer containing NaCl or no NaCl and 14C-a-methyl-D-glucopyranoside (PerkinElmer) of 20 μηιο1/ί were added to each well, and Examples 1-18 were added. The prepared compound was subjected to the corresponding experiment, and the negative control group was added with DMSO, and the positive control group was added with Dapagliflozin, and cultured in a 37 ° C incubator for 2 hours, the medium was aspirated, the cells were washed 5 times, and scintillation solution was used for lysis. - Carb2800 scintillation apparatus (PerkinElmer) to make the corresponding measurements.

根据实验中 360/460 nm测定荧光值的动态变化，采用 GraphPad-Prism软件分析数据。氯化钠依赖的葡萄糖吸收的计算：用有氯化钠条件下的每分钟阳性细胞计数减去无氯化钠条件下的每分钟阳性细胞计数来计算。 Data were analyzed using GraphPad-Prism software based on the dynamic changes in fluorescence values measured at 360/460 nm in the experiment. Calculation of sodium chloride-dependent glucose uptake: Calculated by counting positive cells per minute in the presence of sodium chloride minus the positive cell count per minute in the absence of sodium chloride.

测试样品抑制百分数的计算：测试样品的抑制百分数是通过在有测试样品存在条件下每分钟阳性细胞计数与 DMSO存在条件下每分钟阳性细胞计数的比较而得到的。测试样品的药效是在 8个不同梯度浓度下进行测定的，每种浓度有 3个重复，并计算每个浓度下的样品抑制百分数，以进行样品 IC50的计算。 Calculation of Percentage of Test Sample Inhibition: The percent inhibition of the test sample was obtained by comparing the positive cell count per minute in the presence of the test sample to the positive cell count per minute in the presence of DMSO. The efficacy of the test samples was determined at 8 different gradient concentrations, with 3 replicates for each concentration, and the percent inhibition of each sample was calculated to calculate the IC50 of the sample.

IC50的计算：通过利用 XL Fit (IDBS, Guilford, U.K.)程序制定符合 4参数经验模型的量- 效反应曲线来计算样品的 IC50数值。结果见表 1。 IC50 calculation: The IC50 value of the sample was calculated by using the XL Fit (IDBS, Guilford, U.K.) program to develop a dose-response curve that fits the 4-parameter empirical model. The results are shown in Table 1.

表 1、化合物 1-18对 SGLT-2和 SGLT-1的选择性抑制作用 Table 1. Selective inhibition of SGLT-2 and SGLT-1 by compounds 1-18

009S

οοιε Οοιε

OOLZ OOLZ

0091 0091

0^8 οο^ε 0^8 οο^ε

9099 / 0Z OAV

9099 / 0Z OAV

9099 / 0Z OAV

：与对照药相比，本发明化合物对 SGLT-2具有非常好的选择性抑制作用。对 SGLT-2的抑制作用与对照药物相当，对 SGLT-1的影响较小，优于对照药物，可以预见本发明化合物具有很好的成药性。实施例 20 药代动力学研究 : The compounds of the present invention have very good selective inhibition of SGLT-2 compared to the control drug. The inhibitory effect on SGLT-2 is comparable to that of the control drug, and has little effect on SGLT-1, which is superior to the control drug. It is expected that the compound of the present invention has good drug-forming properties. Example 20 Pharmacokinetic Study

本实施例是为了验证本发明化合物的药代动力学性质，具体以化合物 11为例。 This example is intended to verify the pharmacokinetic properties of the compounds of the invention, specifically taking compound 11 as an example.

1、实验方法 1, experimental methods

实验动物： SD大鼠； Experimental animals: SD rats;

体重： 180-200g; Weight: 180-200g;

给药剂量： IV 3 mg/kg PO 3mg/kg_; Dosage: IV 3 mg / kg PO 3mg / kg _;

药物配制：给药体积： IV 0.5 ml/100g PO 1.0ml/100g_; Drug preparation: Dosing volume: IV 0.5 ml / 100g PO 1.0ml / 100g _;

母液浓度： 2 mg/ml; Mother liquor concentration: 2 mg/ml;

溶解方法： 2%DMSO， 4%乙醇， 4%蓖麻油， 90%水； Dissolution method: 2% DMSO, 4% ethanol, 4% castor oil, 90% water;

采血时间点： IV： Omin, 2min, lOmin, 3 Omin, lh , 2h, 3h, 4h, 6h, 8h, 12h, 16h, 24h; PO: Omin, 5min, 15min, 3 Omin, lh, 2h, 3h, 4h, 6h, 8h, 12h, 16h, 24h; Blood collection time: IV: Omin, 2min, lOmin, 3 Omin, lh, 2h, 3h, 4h, 6h, 8h, 12h, 16h, 24h; PO: Omin, 5min, 15min, 3 Omin, lh, 2h, 3h, 4h, 6h, 8h, 12h, 16h, 24h;

肝素配制： 120 IU/mg_; Preparation of heparin: 120 IU/mg _;

终浓度： lO IU/ΙΟμΙ 即 l IU/μΙ, 5-10 IU/ml血； Final concentration: lO IU/ΙΟμΙ ie l IU/μΙ, 5-10 IU/ml blood;

肝素提前一天加入 EP管中，烘箱烤干，备用； Heparin is added to the EP tube one day in advance, oven dried, and ready for use;

口服： 4只老鼠，雄性；静脉： 4只老鼠，雄性； Oral: 4 mice, male; Vein: 4 mice, male;

血样预处理： 1.血样 8000G离心取血清； 2.放置 -20°C保存； Blood sample pretreatment: 1. Blood sample 8000G centrifuge to take serum; 2. Place -20 ° C to save;

血样分析预处理：（1 )、 20μ1甲醇:水（1:1 )加入 ΕΡ管中；（2)、 20μ1内标 ^g/ml加入 EP管中；（3)、加入 ΙΟΟμΙ血清，震荡 30秒；（4)、加入 800μ1乙酸乙酯，涡旋 15分钟；（5)、 14000G离心 5分钟，取有机层；（6)、 45°C浓缩吹干; (7)、流动相定容（1:1 ); (8)、 LC-MS-MS 分析； Blood sample analysis pretreatment: (1), 20μ1 methanol: water (1:1) was added to the fistula; (2), 20μ1 internal standard ^g/ml was added to the EP tube; (3), ΙΟΟμΙ serum was added, shocked for 30 seconds (4), add 800μ1 ethyl acetate, vortex for 15 minutes; (5), centrifuge at 14000G for 5 minutes, take the organic layer; (6), concentrate at 45 °C; (7), mobile phase constant volume (1) :1 ); (8), LC-MS-MS analysis;

标准曲线终浓度点： 50ng/ml, lOOng/ml, 200ng/ml, 400ng/ml, 600ng/ml,

Standard curve final concentration point: 50ng/ml, lOOng/ml, 200ng/ml, 400ng/ml, 600ng/ml,

6 g/ml, 12 g/ml,4(^g/ml ; 6 g/ml, 12 g/ml, 4 (^g/ml;

标准曲线处理：（1 )、 20μ1待测物加入 EP管中；（2)、 20 μΐ内标 propranolol ^g/ml加入 EP管中；（3)、加入 ΙΟΟμΙ空白血清；（4)、震荡 30秒；（5)、加入 800μ1乙酸乙酯，涡旋 15 分钟； (6)、 14000G离心 5分钟，取有机层； (7)、 45°C浓缩吹干; (8)、流动相定容 ( 1:1 ); Standard curve processing: (1), 20μ1 analytes were added to the EP tube; (2), 20 μΐ internal standard propranolol ^g/ml was added to the EP tube; (3), ΙΟΟμΙ blank serum was added; (4), shock 30 (5), add 800μ1 ethyl acetate, vortex for 15 minutes; (6), centrifuge at 14000G for 5 minutes, take the organic layer; (7), concentrate at 45 °C; (8), mobile phase constant volume ( 1:1);

候选药物出峰时间： 1.6min_; Candidate drug peak time: 1.6min _;

内标出峰时间： 1.8min。 Internal standard peak time: 1.8min.

2、实验数据见表 2。 2. The experimental data is shown in Table 2.

表 2、化合物 11的药代动力学数据 Table 2. Pharmacokinetic data for Compound 11

3、实验结果 3, the experimental results

结果表明：化合物 11有较长的半衰期和较适宜的平均保留时间，药物在体内的时间不会太短，也不会太长；清除率相对较低；表观分布容积直接反映了药物在体内的分布， 1.4 L * kg— ¹ 说明该候选药物倾向于分布在组织中，对分布在肾小管中的 SGLT2能够提供足够的药物以产生有效的抑制作用。口服生物利用度理想，在雄性大鼠中具有 91.4%。说明化合物 11在大鼠体内吸收性质良好、代谢稳定，整体表现出了优越的药物代谢性质。 The results showed that: Compound 11 has a longer half-life and a better average retention time. The time of the drug in the body is not too short or too long; the clearance rate is relatively low; the apparent volume of distribution directly reflects the drug in vivo. The distribution, 1.4 L * kg - ¹ indicates that the drug candidate tends to be distributed in the tissue, and SGLT2 distributed in the renal tubule can provide sufficient drugs to produce effective inhibition. Oral bioavailability is ideal, with 91.4% in male rats. It is indicated that compound 11 has good absorption properties and stable metabolism in rats, and exhibits superior drug metabolism properties as a whole.

Claims

权利要求书 Claim

1.一种如式 I所示的 C-三基葡萄糖苷类化合物或其盐、前药或立体异构体， A C-trisylglucoside compound of the formula I or a salt, prodrug or stereoisomer thereof,

其中选自卤素、 d_₈焼基或 d_₈烷氧基， R₂选自氢、卤素、 d_₈烷基、 d_₈烷氧基、 CF₃、 OCF₃、羟基、 C_1-4烯基、 C_1-4炔基、 C_3-8环烷基、氰基、 -S(0)_mR₃、 -COR₃、 COOR₃、 N 3R4 或 CONR₃R4， m为 0至 2的整数，、各自独立地选自氢、 C_1-8烷基或 C_3-8环焼基。 Wherein selected from halogen, d- ₈ fluorenyl or d- ₈ alkoxy, R _{2 is} selected from the group consisting of hydrogen, halogen, d- ₈ alkyl, d- ₈ alkoxy, CF ₃ , OCF ₃ , hydroxy, C _1-4 alkenyl, C _1-4 alkynyl, C _3-8 cycloalkyl, cyano, -S(0) _m R ₃ , -COR ₃ , COOR ₃ , N 3R4 or CONR ₃ R4, m is an integer from 0 to 2, Each is independently selected from hydrogen, C _1-8 alkyl or C _3-8 cyclodecyl.

2. 根据权利要求 1所述的如式 I所示的 C-三芳基葡萄糖苷类化合物或其盐、前药或立体异构体，其中，选自卤素、 C_M烷基或 C_M烷氧基。 The C-triaryl glucoside compound of the formula I, or a salt, prodrug or stereoisomer thereof, according to claim 1, wherein the compound is selected from the group consisting of halogen, C _M alkyl or C _M alkoxy base.

3. 根据权利要求 2所述的如式 I所示的 C-三芳基葡萄糖苷类化合物或其盐、前药或立体异构体，其中，选自卤素、甲基、乙基、丙基、甲氧基、乙氧基或丙氧基。 The C-triaryl glucoside compound of the formula I, or a salt, prodrug or stereoisomer thereof, according to claim 2, which is selected from the group consisting of halogen, methyl, ethyl, propyl, Methoxy, ethoxy or propoxy.

4. 根据权利要求 1-3任意一项所述的如式 I所示的 C-三芳基葡萄糖苷类化合物或其盐、前药或立体异构体，其中，选自氢、卤素、 C_M烷基、 C_M焼氧基、 CF₃、 OCF₃、羟基、 C_M 烯基、 C_M炔基、 C_3-6环烷基、氰基、 -S(0)_mR₃、 -COR₃、 COOR₃、 NR₃R4或 CONR₃R4， m为 0至 2的整数， R₃、 R4各自独立地选自氢、 C_M焼基或 C^环烷基。 The C-triaryl glucoside compound of the formula I, or a salt, prodrug or stereoisomer thereof, according to any one of claims 1 to 3, wherein the compound is selected from the group consisting of hydrogen, halogen, C _M alkyl, C _m firing group, CF _{_3,} OCF _3, hydroxy, C _m alkenyl, C _m alkynyl, C _3-6 cycloalkyl, _{_{cyano, -S (0) m R 3}} , -COR 3 , COOR ₃ , NR ₃ R4 or CONR ₃ R4, m is an integer from 0 to 2, and R ₃ and R 4 are each independently selected from hydrogen, C _M decyl or C^ cycloalkyl.

5. 根据权利要求 4所述的如式 I所示的 C-三芳基葡萄糖苷类化合物或其盐、前药或立体异构体，其中， m为 0或 2，、各自独立地选自氢、甲基、乙基、丙基、环丙基、环戊基或环己基。 The C-triaryl glucoside compound of the formula I, or a salt, prodrug or stereoisomer thereof, according to claim 4, wherein m is 0 or 2, each independently selected from hydrogen , methyl, ethyl, propyl, cyclopropyl, cyclopentyl or cyclohexyl.

6. 根据权利要求 5所述的如式 I所示的 C-三芳基葡萄糖苷类化合物或其盐、前药或立体异构体，其中，选自氢、卤素、 CH焼基、 CH烷氧基、 CF₃、 0CF₃或羟基。 The C-triaryl glucoside compound of the formula I, or a salt, prodrug or stereoisomer thereof, according to claim 5, wherein the compound is selected from the group consisting of hydrogen, halogen, CH thiol, CH alkoxy Base, CF ₃ , 0CF ₃ or hydroxyl.

7. 根据权利要求 6所述的如式 I所示的 C-三芳基葡萄糖苷类化合物或其盐、前药或立体异构体，其中，选自氢、氟、氯、甲基、甲氧基、乙氧基、 CF₃、 OCF₃或羟基。 The C-triaryl glucoside compound of the formula I, or a salt, prodrug or stereoisomer thereof, according to claim 6, wherein the compound is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, methoxy Base, ethoxy, CF ₃ , OCF ₃ or hydroxyl.

8. 根据权利要求 1所述的如式 I所示的 C-三芳基葡萄糖苷类化合物或其盐、前药或立体异构体，其中，选自卤素、 C_M烷基或 C_M焼氧基，选自氢、卤素、 C_M焼基、 C_M焼氧基、 CF₃、 OCF₃、羟基、 C_1-4烯基、 C_1-4炔基、〔_3-6环焼基、氰基、 -S(0)_mR₃、 -COR₃、 COOR₃、 NR₃R4或 CONR₃R4， m为 0至 2的整数， R₃、独立任选自氢、 C_M焼基或 C_3-6环焼基。 The C-triaryl glucoside compound of the formula I, or a salt, prodrug or stereoisomer thereof, according to claim 1, wherein the compound is selected from the group consisting of halogen, C _M alkyl or C _M oxime Base selected from hydrogen, halogen, C _M decyl, C _M methoxy, CF ₃ , OCF ₃ , hydroxy, C _1-4 alkenyl, C _1-4 alkynyl, [ _3-6 cyclodecyl, cyanide a group, -S(0) _m R ₃ , -COR ₃ , COOR ₃ , NR ₃ R4 or CONR ₃ R4, m is an integer from 0 to 2, R ₃ , independently selected from hydrogen, C _M thiol or C _{3 -6} ring thiol.

9. 根据权利要求 8所述的如式 I所示的 C-三芳基葡萄糖苷类化合物或其盐、前药或立体异构体，其中，选自卤素、 d_₄烷基或 d_₄焼氧基， R₂选自氢、卤素、 C_M焼基、 d_₄焼氧基、 CF₃、 OCF₃、羟基、 C_M烯基、 C_M炔基、〔_3-6环烷基、氰基、 -S(0)_mR₃、 -COR₃、 COOR₃、 NR₃R4或 CONR₃R4， m为 0或 2， R₃、 R4独立任选自氢、甲基、乙基、丙基、环丙基、环戊基或环己基。 The C-triaryl glucoside compound of the formula I, or a salt, prodrug or stereoisomer thereof, according to claim 8, wherein the compound is selected from the group consisting of halogen, d- ₄ alkyl or d- ₄ Base, R _{2 is} selected from the group consisting of hydrogen, halogen, C _M fluorenyl, d_ ₄焼 oxygen Base, CF ₃ , OCF ₃ , hydroxyl, C _M alkenyl, C _M alkynyl, [ _3-6 cycloalkyl, cyano, -S(0) _m R ₃ , -COR ₃ , COOR ₃ , NR ₃ R4 Or CONR ₃ R4, m is 0 or 2, and R ₃ and R 4 are independently selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclopentyl or cyclohexyl.

10. 根据权利要求 9所述的如式 I所示的 C-三芳基葡萄糖苷类化合物或其盐、前药或立体异构体，其中，选自卤素、（ ₄焼基或 ( -₄焼氧基， R₂选自氢、卤素、（ ₄焼基、烷氧基、 CF₃、（¾^₃或羟基。 The C-triaryl glucoside compound of the formula I, or a salt, prodrug or stereoisomer thereof, according to claim 9, wherein the compound is selected from the group consisting of halogen, ( ₄ fluorenyl or ( _-4焼) Oxy, R _{2 is} selected from the group consisting of hydrogen, halogen, ( ₄ fluorenyl, alkoxy, CF ₃ , ( _3⁄4 ^ ₃ or hydroxy).

11. 根据权利要求 10所述的如式 I所示的 C-三芳基葡萄糖苷类化合物或其盐、前药或立体异构体，其中，！^选自氟、氯、甲基或甲氧基，其中 R₂选自氢、氟、氯、甲基、甲氧基、乙氧基、 CF₃、 0CF₃或羟基。 The C-triaryl glucoside compound of the formula I, or a salt, prodrug or stereoisomer thereof, according to claim 10, wherein ^ is selected from the group consisting of fluorine, chlorine, methyl or methoxy, wherein R _{2 is} selected from the group consisting of hydrogen, fluorine, chlorine, methyl, methoxy, ethoxy, CF ₃ , 0CF ₃ or hydroxy.

12. 根据权利要求 1所述的如式 I所示的 C-三芳基葡萄糖苷类化合物或其盐、前药或立体异构体，其选自下列化合物或其盐： The C-triaryl glucoside compound according to claim 1, or a salt, prodrug or stereoisomer thereof, which is selected from the group consisting of the following compounds or salts thereof:

13. —种如式 I所示化合物的制备方法，该方法包括将如式 1-6所示化合物在有机溶剂中与还原剂反应，其中和的定义与权利要求 1~12任意一项中的式 I相同， 13. A process for the preparation of a compound of formula I, which comprises reacting a compound of formula 1-6 with a reducing agent in an organic solvent, the definition of which is in accordance with any of claims 1 to 12. Formula I is the same,

1-6 1-6

14. 一种如式 1-6所示的化合物，其中，和的定义同与权利要求 1〜12任意一项中的式 I相同， A compound of the formula 1-6, wherein the definition of the sum is the same as the formula I according to any one of claims 1 to 12,

15. 一种如式 I所示化合物的制备方法，该方法包括如下反应步骤： 15. A process for the preparation of a compound of formula I, which process comprises the following reaction steps:

(a) 在有机溶剂中，在碱性物质存在下，将如式 1-3所示化合物与如式 I-3a所示化合物反应，反应结束后用淬灭剂终止反应； (a) reacting a compound of the formula 1-3 with a compound of the formula I-3a in the presence of a basic substance in an organic solvent, and quenching the reaction with a quencher after completion of the reaction;

(b)在有机溶剂中将如式 1-4所示化合物与还原剂反应； (b) reacting a compound of formula 1-4 with a reducing agent in an organic solvent;

(d)将如式 1-6所示化合物在有机溶剂中与还原剂反应制得如式 I所示化合物；其中和的定义与权利要求 1~12任意一项中的式 I相同。 (d) A compound of the formula 1-6 is reacted with a reducing agent in an organic solvent to obtain a compound of the formula I; wherein the definition of the compound is the same as the formula I in any one of claims 1 to 12.

16. 一种如式 1-5所示的化合物，其中， i和 R₂的定义与权利要求 1~12任意一项中的式 I相，

16. A compound of the formula 1-5, wherein the definition of i and R _{2 is} in accordance with Formula I in any one of claims 1 to 12,

-5 -5

17. 一种药物组合物，其含有权利要求 1〜12任意一项所述的如式 I所示的 C-三芳基葡萄糖苷类化合物或其盐、前药或立体异构体，以及一种或多种药学上可接受的载体、赋形剂和 / 或介质。 A pharmaceutical composition comprising the C-triaryl glucoside compound of the formula I according to any one of claims 1 to 12, a salt thereof, a prodrug or a stereoisomer thereof, and a Or a plurality of pharmaceutically acceptable carriers, excipients and/or vehicles.

18.权利要求 1〜12任意一项所述的如式 I所示的 C-三芳基葡萄糖苷类化合物或其盐、前药或立体异构体在制备用于治疗受益于 SGLT-2 抑制的疾病的药物中的用途，所述受益于 SGLT-2抑制的疾病选自糖尿病、糖尿病性视网膜病、糖尿病性神经病变、糖尿病性肾病变、伤口愈合延迟、胰岛素抵抗、高血糖症、高胰岛素血症、脂肪酸血浓度升高、甘油血浓度升高、高脂血症、肥胖症、高甘油三酯血症、 X综合征、动脉粥样硬化或高血压。 The C-triaryl glucoside compound of the formula I according to any one of claims 1 to 12, or a salt, prodrug or stereoisomer thereof, for use in the treatment for benefit from SGLT-2 inhibition. The use of the disease drug, the disease benefiting from SGLT-2 inhibition is selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia Symptoms, elevated fatty acid blood levels, elevated glycerol blood levels, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, atherosclerosis or hypertension.

19. 一种治疗受益于 SGLT-2抑制的疾病的方法，该方法包括给予有机体有效量的权利要求权利要求 1〜12任意一项所述的化合物或其药学上可接受的盐、或权利要求 17所述的药物组合物。 19. A method of treating a disease which is beneficial for the inhibition of SGLT-2, the method comprising administering to the organism an effective amount of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a claim The drug described in 17 combination.

20.根据权利要求 19所述的方法，其中，所述有机体为人。 The method according to claim 19, wherein the organism is a human.

21. 根据权利要求 19所述的方法，其中，所述受益于 SGLT-2抑制的疾病选自糖尿病、糖尿病性视网膜病、糖尿病性神经病变、糖尿病性肾病变、伤口愈合延迟、胰岛素抵抗、高血糖症、高胰岛素血症、脂肪酸血浓度升高、甘油血浓度升高、高脂血症、肥胖症、高甘油三酯血症、 X综合征、动脉粥样硬化或高血压。 21. The method according to claim 19, wherein the disease benefiting from SGLT-2 inhibition is selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, high Glucose, hyperinsulinemia, elevated fatty acid blood levels, elevated glycerol blood levels, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, atherosclerosis or hypertension.

22. 根据权利要求 19所述的方法，其中，给药途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、 ***内、鼻内、眼内、腹膜内、肌内、皮下或静脉内给药。 22. The method according to claim 19, wherein the administration route includes, but is not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, nasal Internal, intraocular, intraperitoneal, intramuscular, subcutaneous or intravenous administration.

23. 根据权利要求 19所述的方法，其中，是给予有机体有效量的如式 I所示的化合物，给药剂量为约 0.01-300 mg/kg/天。 23. The method according to claim 19, wherein an effective amount of a compound of formula I is administered to the organism at a dose of from about 0.01 to 300 mg/kg/day.