(1S)-1,5-anhydro-1-[5-[4-[2-[[(2-hydroxy-1,1-dimethylethyl)aminocarbonyl]amino]ethyl]benzyl]-2-hydroxy-4-methylphenyl]-D-glucitol

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (1S)-1,5-anhydro-1-[5-[4-[2-[[(2-hydroxy-1,1-dimethylethyl)aminocarbonyl]amino]ethyl]benzyl]-2-hydroxy-4-methylphenyl]-D-glucitol
• 英文别名: 1-(1-hydroxy-2-methylpropan-2-yl)-3-[2-[4-[[4-hydroxy-2-methyl-5-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]phenyl]methyl]phenyl]ethyl]urea
• 化学式: C₂₇H₃₈N₂O₈
• 分子量: 518.607
• InChiKey: AUGARWHQIUJYHM-RXFVIIJJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  37
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  172
• 氢给体数：
  8
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  4-(苄氧基)-5-溴-2-甲基苯甲酸 在 吡啶 、 盐酸 、 三乙基硅烷 、 正丁基锂 、 草酰氯 、 三氟化硼乙醚 、 对甲苯磺酸 、 对硝基苯基氯甲酸酯 、 N,N-二甲基甲酰胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 氯仿 、 水 、 甲苯 、 乙腈 为溶剂， 生成 (1S)-1,5-anhydro-1-[5-[4-[2-[[(2-hydroxy-1,1-dimethylethyl)aminocarbonyl]amino]ethyl]benzyl]-2-hydroxy-4-methylphenyl]-D-glucitol
  参考文献：
  名称：

  Discovery of a potent, low-absorbable sodium-dependent glucose cotransporter 1 (SGLT1) inhibitor (TP0438836) for the treatment of type 2 diabetes

  摘要：

  The design and synthesis of a novel class of low-absorbable SGLT1 inhibitors are described. To achieve low absorption in the new series, we performed an optimization study based on a strategy to increase TPSA. Fortunately, the optimization of an aglycon moiety and a side chain of the distal aglycon moiety led to the identification of compound 30b as a potent and low-absorbable SGLT1 inhibitor. Compound 30b showed a desirable PK profile in Sprague-Dawley (SD) rats and a favorable glucose-lowering effect in diabetic rats.

  DOI：

  10.1016/j.bmcl.2018.09.035

文献信息

• 4-ISOPROPYL-6-METHOXYPHENYL GLUCITOL COMPOUND
  申请人：Kakinuma Hiroyuki

  公开号：US20130165645A1

  公开（公告）日：2013-06-27

  A compound, which inhibits SGLT1 (sodium-dependent glucose transporter 1) activity to suppress absorption of glucose or the like, thereby suppressing abnormal glucose tolerance or postprandial hyperglycemia in diabetes, is provided. Specifically, a 4-isopropyl-6-methoxyphenyl glucitol compound represented by the following formula (I), or a pharmaceutically acceptable salt thereof, is provided:

  提供了一种化合物，它抑制SGLT1（钠依赖型葡萄糖转运蛋白1）的活性，从而抑制葡萄糖等物质的吸收，进而抑制糖尿病患者的异常葡萄糖耐量或餐后高血糖。具体来说，提供了下列式（I）所代表的4-异丙基-6-甲氧基苯基葡糖醇化合物，或其药用可接受的盐：
• CRYSTAL FORM OF 4-ISOPROPYLPHENYL GLUCITOL COMPOUND AND PROCESS FOR PRODUCTION THEREOF
  申请人：Kimura Yoshihiro

  公开号：US20130144050A1

  公开（公告）日：2013-06-06

  A highly stable crystal of (1S)-1,5-anhydro-1-[5-(4-(1E)-4-[(1-[2-(dimethylamino)ethyl]amino}-2-methyl-1-oxopropan-2-yl)amino]-3,3-dimethyl-4-oxobut-1-en-1-yl}benzyl)-2-methoxy-4-(propan-2-yl)phenyl]-D-glucitol, and a process for producing the crystal are provided. Specifically, an ethanolate having the following physical properties, and a plurality of other crystal forms transformed from the ethanolate are provided: (a) Having peaks at 2θ=5.9 degrees, 17.1 degrees, 17.6 degrees and 21.5 degrees in X-ray powder diffraction (Cu—Kα); (b) Showing characteristic absorption bands at 3538 cm −1 , 3357 cm −1 , 2964 cm −1 , 1673 cm −1 , 1634 cm −1 and 1505 cm −1 in an infrared absorption spectrum; and (c) Having a melting point in a vicinity of 111° C.

  提供了(1S)-1,5-脱水-1-[5-(4-(1E)-4-[(1-[2-(二甲氨基)乙基]氨基}-2-甲基-1-氧代丙酰基)氨基]-3,3-二甲基-4-氧代丁-1-烯-1-基}苯甲基)-2-甲氧基-4-(异丙基)苯基]-D-葡萄糖醇的高度稳定的晶体以及制备该晶体的方法。具体而言，提供了以下物理性质的乙醇酸盐和从乙醇酸盐转化而来的多种晶体形式：(a) 在X射线粉末衍射(Cu-Kα)中，在2θ=5.9度、17.1度、17.6度和21.5度处具有峰；(b) 在红外吸收光谱中显示出3538 cm−1、3357 cm−1、2964 cm−1、1673 cm−1、1634 cm−1和1505 cm−1的特征吸收带；以及(c) 具有接近111℃的熔点。
• C-PHENYL GLYCITOL COMPOUND
  申请人：Kakinuma Hiroyuki

  公开号：US20100022460A1

  公开（公告）日：2010-01-28

  Provided is a novel C-phenyl glycitol compound that may serve as a prophylactic or therapeutic agent for diabetes by inhibiting both SGLT1 activity and SGLT2 activity, thereby exhibiting a glucose absorption suppression action and a urine glucose excretion action. A C-phenyl glycitol compound represented by Formula (I) below or a pharmaceutically acceptable salt thereof or a hydrate thereof wherein R 1 and R 2 are the same or different and represent a hydrogen atom, a hydroxyl group, a C 1-6 alkyl group, a C 1-6 alkoxy group or a halogen atom, R 3 is a hydrogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or a halogen atom, Y is a C 1-6 alkylene group, —O—(CH 2 )n— (n is an integer of 1 to 4) or a C 2-6 alkenylene group, provided that when Z is —NHC(═NH)NH 2 or —NHCON(R B )R C , n is not 1, Z is —CONHR A , —NHC(═NH)NH 2 or —NHCON(R B )R C ,

  提供的是一种新型C-苯基甘露醇化合物，可以作为预防或治疗糖尿病的药物，通过抑制SGLT1活性和SGLT2活性，从而表现出抑制葡萄糖吸收和尿液葡萄糖排泄的作用。该化合物表示为以下式子（I）的C-苯基甘露醇化合物，或其药学上可接受的盐或水合物，其中R1和R2相同或不同，表示氢原子、羟基、C1-6烷基、C1-6烷氧基或卤素原子，R3表示氢原子、C1-6烷基、C1-6烷氧基或卤素原子，Y表示C1-6烷基、-O-(CH2)n-（n为1至4的整数）或C2-6烯基烷基，但当Z为-NHC（=NH）NH2或-NHCON（RB）RC时，n不为1，Z为CONHRA，-NHC（=NH）NH2或-NHCON（RB）RC。
• C-phenyl glycitol compound
  申请人：Taisho Pharmaceutical Co., Ltd

  公开号：US07973012B2

  公开（公告）日：2011-07-05

  Provided is a novel C-phenyl glycitol compound that may serve as a prophylactic or therapeutic agent for diabetes by inhibiting both SGLT1 activity and SGLT2 activity, thereby exhibiting a glucose absorption suppression action and a urine glucose excretion action. A C-phenyl glycitol compound represented by Formula (I) below or a pharmaceutically acceptable salt thereof or a hydrate thereof wherein R1 and R2 are the same or different and represent a hydrogen atom, a hydroxyl group, a C1-6 alkyl group, a C1-6 alkoxy group or a halogen atom, R3 is a hydrogen atom, a C1-6 alkyl group, a C1-6 alkoxy group or a halogen atom, Y is a C1-6 alkylene group, —O—(CH2)n- (n is an integer of 1 to 4) or a C2-6 alkenylene group, provided that when Z is —NHC(═NH)NH2 or —NHCON(RB)RC, n is not 1, Z is —CONHRA, —NHC(═NH)NH2 or —NHCON(RB)RC,

  提供一种新型的C-苯基甘露醇化合物，可以作为预防或治疗糖尿病的药物，通过抑制SGLT1活性和SGLT2活性，从而表现出葡萄糖吸收抑制作用和尿糖排泄作用。所述C-苯基甘露醇化合物如下式（I）所示，或其药学上可接受的盐或水合物，其中R1和R2相同或不同，表示氢原子、羟基、C1-6烷基、C1-6烷氧基或卤素原子，R3表示氢原子、C1-6烷基、C1-6烷氧基或卤素原子，Y表示C1-6烷基、—O—（CH2）n-（n是1到4的整数）或C2-6烯基烷基，但当Z为—NHC（═NH）NH2或—NHCON（RB）RC时，n不为1，Z为—CONHRA、—NHC（═NH）NH2或—NHCON（RB）RC。
• 4-ISOPROPYLPHENYL GLUCITOL COMPOUNDS AS SGLT1 INHIBITORS
  申请人：Kakinuma Hiroyuki

  公开号：US20110306759A1

  公开（公告）日：2011-12-15

  The present invention provides 4-isopropylphenyl glucitol compounds which have no tendency to accumulate in the body and which inhibit SGLT1 activity to suppress postprandial hyperglycemia (or impaired glucose tolerance) through suppression of glucose absorption in the small intestine, whereby the compounds, for example, can suppress the onset of diabetes and metabolic syndrome or can treat these diseases. A 4-isopropylphenyl glucitol compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: wherein R 1 represents a hydrogen atom, etc., R 2 represents a methyl group, etc., R 3 represents a C 1-4 alkyl group substituted with an amino group(s), etc., and R 4 represents a hydrogen atom, etc.

  本发明提供了4-异丙基苯基葡萄糖醇化合物，其没有在体内积累的趋势，并通过抑制小肠中的葡萄糖吸收来抑制SGLT1活性，从而抑制餐后高血糖（或糖耐量受损），例如，这些化合物可以抑制糖尿病和代谢综合征的发生或治疗这些疾病。化合物由以下式（I）表示：其中R1表示氢原子等，R2表示甲基基团等，R3表示C1-4烷基基团，该基团被氨基团等取代，R4表示氢原子等，或其药学上可接受的盐。