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

A technology of SO2 and SO2R1A, which can be used in medical preparations containing active ingredients, sugar derivatives, organic chemistry, etc., and can solve problems such as chemical space difficulties

Active Publication Date: 2009-01-14
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

[0152] Example 1: (2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran- Synthesis of 3,4,5-triol

[0153]

[0154] The title compound was prepared by the following steps.

[0155] 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 was synthesized using methods known in the art. See for example, Nucleosides Nucleotides , 20:649-652 (2001) and references therein.

[0156] b. (3aS, 5R, 6R, 6aS)-6-(tert-butyl-dimethyl-silyloxy)-2,2-dimethyl- Tetrahydro-furo[2,3-d][1,3]dioxole-5-carbaldehyde Preparation: In N2 CH of oxalyl chloride (0.76ml, 8.7mmol) at -78°C 2 Cl 2 (55ml) dropwise added DMSO (0.84ml, 11.8mmol) in CH 2 Cl 2 (5ml) solution. After 15 minutes, CH containing the alcohol from step A (2.40 g, 7.9 mmol) was added dropwise. 2 Cl 2 (20ml). After 15 minutes, slowly add NEt 3 . The reaction was slowly warmed to room temperature o...

Embodiment 2

[0162] Example 2: (3S, 4R, 5R, 6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-2,3,4, Synthesis of 5-tetrol

[0163]

[0164] The alcohol (51 mg, 0.093 mmol) from step D of Example 1 was dissolved in a sealed vial at 80 °C with 1:1 AcOH:H 2 O (1 ml) was treated for 18 hours. The reaction was cooled to room temperature, diluted with EtOAc to transfer to a flask, and concentrated in vacuo. The residue was dissolved in CH 2 Cl 2 , with NaHCO 3 and MgSO 4 Worked for 30 minutes, filtered and concentrated in vacuo. The product was purified by flash chromatography (4 g SiO 2 , 0-12%MeOH:CH 2 Cl 2 , 30 minutes, 10ml / min), suspended in H 2 O and lyophilized to give (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%), as a white solid. NMR showed a 1:1 ratio of α and β anomers.

[0165] 1 H NMR (400MHz, methanol-d 4 )δppm 7.34 (dd, J=8.08, 4.04Hz, 1H), 7.22-7.30 (m, 2H), 7.09 (d, J=8.34Hz, 2H), 6...

Embodiment 3

[0166] Example 3: (2S, 3R, 4R, 5S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-ethoxy-tetrahydro-pyran- Synthesis of 3,4,5-triol

[0167]

[0168] A 0.35 M HCl solution in EtOH was prepared by adding AcCl (0.025 ml, 0.35 mmol) to EtOH (1 ml) and stirring for 15 minutes. The alcohol from Example 1, Step D (61 mg, 0.11 mmol) was treated with this solution in a sealed vial for 2 hours at 80°C. The reaction was cooled to room temperature and washed with concentrated NH 4 OH quenched until basic, with NaHCO 3 Treat for 30 min with CH 2 Cl 2 Diluted, filtered and concentrated in vacuo. The product was purified by flash chromatography (4 g SiO 2 , 0-10%MeOH:CH 2 Cl 2 , 40 minutes, 10ml / min), suspended in H 2 O and lyophilized to give (2S,3R,4R,5S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-ethoxy-tetrahydro -pyran-3,4,5-triol (40 mg, 0.095 mmol, 85%) as a white solid. NMR showed a 1.75:1 ratio of α and β anomers.

[0169] 1H NMR (400MHz, chloroform-d) δppm: 7.28-7.32 (m,...

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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 priority to US Provisional Application 60 / 948,780, filed July 10, 2007, which is hereby incorporated by reference in its entirety. technical field [0002] The present invention relates to methods of treating metabolic diseases and disorders, such as diabetes, and to compounds and pharmaceutical compositions useful in such methods. Background technique [0003] Sodium-glucose cotransporter 2 (SGLT2) is a transporter that reabsorbs glucose from renal filtrate and prevents glucose loss in urine. Because competitive inhibitors of SGLT2 cause renal excretion of glucose, they can normalize high blood glucose levels associated with diseases such as diabetes. Handlon, A.L., Expert Opin. Ther. Patents 15(11):1531-1540 (2005). [0004] A number of SGLT2 inhibitors have been disclosed. See, eg, Handlon, supra; US Patent 6,515,117; US Patent Applications US 2006 / 0035841, US 2004 / 0138439. At least one inhibitor is in clinical development for the treatm...

Claims

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Application Information

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Patent Type & Authority Applications(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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