Inhibitors of sodium glucose co-transporter 2 and methods of their use

A pharmaceutical preparation, SO2R1A technology, applied in medical preparations containing active ingredients, sugar derivatives, organic chemistry, etc., can solve problems such as chemical space difficulties

Active Publication Date: 2013-04-10
LEXICON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In fact, "discovering unexplored chemical spaces has become increasingly difficult for would-be drug inventors due to the relative uniformity of glycosides in the SGLT2 patent literature"

Method used

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  • Inhibitors of sodium glucose co-transporter 2 and methods of their use
  • Inhibitors of sodium glucose co-transporter 2 and methods of their use
  • Inhibitors of sodium glucose co-transporter 2 and methods of their use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0151] Example 1: (2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran- Synthesis of 3,4,5-triol

[0152]

[0153] The title compound was prepared by the following steps.

[0154] A. [(3aS, 5S, 6R, 6aS)-6-(tert-butyl-dimethyl-silyloxy)-2,2-dimethyl- Tetrahydro-furo[2,3-d][1,3]dioxol-5-yl]-methanol Preparation: This compound is synthesized using methods known in the art. See for example, Nucleosides Nucleotides , 20:649-652 (2001) and references therein.

[0155] B. (3aS, 5R, 6R, 6aS)-6-(tert-butyl-dimethyl-silyloxy)-2,2-dimethyl- Tetrahydro-furo[2,3-d][1,3]dioxol-5-carbaldehyde Preparation: in N 2 Add oxalyl chloride (0.76ml, 8.7mmol) to CH 2 Cl 2 (55ml) DMSO (0.84ml, 11.8mmol) CH was added dropwise to the solution 2 Cl 2 (5ml) Solution. After 15 minutes, CH containing alcohol from step A (2.40 g, 7.9 mmol) was added dropwise 2 Cl 2 (20ml). After 15 minutes, slowly add NEt 3 . Allow the reaction to slowly warm to room temperature within 105 min...

Embodiment 2

[0161] Example 2: (3S, 4R, 5R, 6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-2,3,4, Synthesis of 5-tetraol

[0162]

[0163] The alcohol (51 mg, 0.093 mmol) from step D of Example 1 was used in a sealed vial at 80°C with 1:1 AcOH:H 2 O (1ml) treatment for 18 hours. The reaction was cooled to room temperature, diluted with EtOAc to transfer to a flask, and concentrated in vacuo. Dissolve the residue in CH 2 Cl 2 , Use NaHCO 3 And MgSO 4 Treated for 30 minutes, filtered and concentrated in vacuo. The product was purified by flash chromatography (4g SiO 2 , 0-12% MeOH: CH 2 Cl 2 , 30 minutes, 10ml / min), suspended in H 2 O, and lyophilize to obtain (3S, 4R, 5R, 6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-2, 3,4,5-tetraol (31 mg, 0.079 mmol, 85%), a white solid. NMR showed a 1:1 ratio of α and β anomers.

[0164] 1 H NMR (400 MHz, methanol-d 4 )δppm 7.34 (dd, J = 8.08, 4.04 Hz, 1H), 7.22-7.30 (m, 2H), 7.09 (d, J = 8.34 Hz, 2H), 6.80 (d, J = 8.08 Hz, 2...

Embodiment 3

[0165] Example 3: (2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-ethoxy-tetrahydro-pyran- Synthesis of 3,4,5-triol

[0166]

[0167] A 0.35M HCl in EtOH solution was prepared by adding AcCl (0.025ml, 0.35mmol) to EtOH (1ml) and stirring for 15 minutes. The alcohol (61 mg, 0.11 mmol) from Example 1, Step D was treated with this solution in a sealed vial at 80°C for 2 hours. Cool the reaction to room temperature and use concentrated NH 4 OH quenched until it became basic, with NaHCO 3 Treat for 30 minutes, use CH 2 Cl 2 Dilute, filter and concentrate in vacuo. The product was purified by flash chromatography (4g SiO 2 , 0-10% MeOH: CH 2 Cl 2 , 40 minutes, 10ml / min), suspended in H 2 O, and lyophilize to obtain (2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-ethoxy-tetrahydro -Pyran-3,4,5-triol (40mg, 0.095mmol, 85%), a white solid. NMR showed a 1.75:1 ratio of α and β anomers.

[0168] 1 H NMR (400MHz, chloroform-d) δ ppm: 7.28-7.32 (m, 1H), 7.14 (m, 2H), 7...

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Abstract

Compounds and pharmaceutical compositions comprising them are disclosed that may be useful for the treatment of diseases and disorders such as diabetes and obesity.

Description

[0001] This application claims the priority of U.S. Provisional Application 60 / 948,780 filed on July 10, 2007, the entire contents of which are incorporated herein by reference. Technical field [0002] The present invention relates to methods of treating metabolic diseases and disorders such as diabetes, and to compounds and pharmaceutical compositions used in the methods. Background technique [0003] Sodium-glucose cotransporter 2 (SGLT2) is a transporter that reabsorbs glucose from kidney filtrate and prevents glucose loss in the urine. Because competitive inhibitors of SGLT2 cause renal excretion of glucose, they can normalize high blood sugar levels associated with diseases such as diabetes. Handlon, A.L, Expert Opin.Ther.Patents 15(11): 1531-1540 (2005). [0004] Many SGLT2 inhibitors have been published. See, for example, Handlon, ibid.; U.S. Patent 6,515,117; U.S. Patent Application US 2006 / 0035841, US 2004 / 0138439. At least one inhibitor is in clinical development for ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H15/203A61K31/7034A61P3/10A61P3/04
Inventor 尼克勒·C·古德温布赖斯·A·哈里森斯彭尼尔·D·金博尔罗斯·玛博恩大卫·B·拉瓦琳斯
Owner LEXICON PHARM INC
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