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Heteroaryl 5-thio-beta-d-glucopyranoside derivatives and remedies for diabetes containing the same

A glucopyranoside and thiol technology, applied in the field of pharmaceuticals and heteroaryl 5-thio-β-D-glucopyranoside compounds, can solve the problem of not involving SGLT inhibition and no β-selective glucopyranoside. Glycosylation chemical synthesis method, does not involve problems such as heteroaryl 5-thio-β-D-glucopyranoside derivatives

Inactive Publication Date: 2006-04-19
TAISHO PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, for derivatives of 5-thioglucosinolate in which the ring oxygen atom of glucose is converted to a sulfur atom, there is no chemical synthesis method for β-selective glucosylation, so there is no reference to heteroaryl 5-thioglucosyl -Report example of β-D-glucopyranoside derivatives
Therefore, there are also no reports involving SGLT inhibition of heteroaryl 5-thio-β-D-glucopyranoside derivatives

Method used

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  • Heteroaryl 5-thio-beta-d-glucopyranoside derivatives and remedies for diabetes containing the same
  • Heteroaryl 5-thio-beta-d-glucopyranoside derivatives and remedies for diabetes containing the same
  • Heteroaryl 5-thio-beta-d-glucopyranoside derivatives and remedies for diabetes containing the same

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0149] The production method of the compound of the present invention is explained below.

[0150] You can use the following process to use PR X R Y R Z Phosphines represented by R 21 -N=N-R 22 Under the conditions of Mitsunobu reaction (Org.Reactions, volume 42, item 335) of the azo reagent represented, make the 5-thio-D-glucopyranoside compound of formula (IV) and the heteroaryl compound of formula (VI) Alcohol reaction to prepare heteroaryl 5-thio-β-D-glucopyranoside compounds.

[0151]

[0152] In addition, the compound of the present invention can be prepared by deprotecting a protecting group such as a sugar hydroxyl group or prodrugizing as necessary.

[0153] "Heteroaryl alcohol" means a compound in which an OH group is substituted on a heteroaryl group, and includes the keto form of a keto-enol tautomer.

[0154] "PR X R Y R Z Indicated phosphines", R X ~R Z Can be the same or different, means can be C 1-6 Alkyl-substituted phenyl (e.g. phenyl, tolyl), ...

reference example 1

[0317] Preparation of 4-(4-ethylbenzyl)-3-hydroxy-1-isopropyl-5-methyl-1H-pyrazole

[0318] In 1,2-dihydro-4-(4-ethylbenzyl)-5-methyl-3H-pyrazol-3-one (synthesized according to WO0116147; 1.0g, 4.6mmol), benzyl alcohol (600mg , 5.5 mmol) and triphenylphosphine (1.46 g, 5.5 mmol) in tetrahydrofuran (30 mL), diethyl azodicarboxylate (40% toluene solution, 5.1 mmol) was added dropwise under ice-cooling. After stirring overnight at room temperature, the residue obtained by concentrating the reaction solution was purified by silica gel column chromatography (hexane: ethyl acetate = 75:25 to 70:30) to obtain 3-benzyloxy-4- (4-Ethylbenzyl)-5-methyl-1H-pyrazole (550 mg, 39%).

[0319] 1 H-NMR (300MHz, CDCl 3 ): δ1.21(t, J=7.6Hz, 3H), 2.11(s, 3H), 2.60(q, J=7.6Hz, 2H), 3.66(s, 2H), 5.24(s, 2H), 7.03 -7.15(m, 4H).

[0320] ESI m / z=307(M+H).

[0321] mp 80.0-83.0℃.

[0322] At room temperature, in the above obtained 3-benzyloxy-4-(4-ethylbenzyl)-5-methyl-1H-pyrazole (200mg, 0.65mm...

reference example 2

[0330] Preparation of 1-acetyl-4-[(3-fluoro-4-methoxyphenyl)methyl]-3-hydroxy-5-methyl-1H-pyrazole

[0331] 1,2-dihydro-4-[(3-fluoro-4-methoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one (synthesized according to WO0236602; 4.11g, A mixture of 0.0174 mol), acetic anhydride (41 mL) and acetic acid (41 mL) was stirred at 135°C for 8 hours and at room temperature for 12 hours. After concentrating the reaction liquid, toluene was added and concentrated again. Methanol (400 mL) and 25 wt % sodium methoxide methanol solution (0.37 mL) were added to the obtained residue, followed by stirring for 20 hours. The residue obtained by concentrating the reaction solution was purified by silica gel column chromatography (hexane: ethyl acetate = 4:1 to 1:1) to obtain 1-acetyl-4-[(3-fluoro-4-methanol) as a colorless powder Oxyphenyl)methyl]-3-hydroxy-5-methyl-1H-pyrazole (960 mg, 20%).

[0332] 1 H-NMR (300MHz, CDCl 3 ): δ2.50(s, 3H), 2.51(s, 3H), 3.61(s, 2H), 3.85(s, 3H), 6.80-6.99(m, 3H). ...

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Abstract

There is provided a heteroaryl 5-thio- beta -D-glucopyranoside compound of the following formula, which has an inhibitory effect on SGLT2 activity, or a pharmaceutically acceptable salt thereof or a hydrate thereof. There is also provided a pharmaceutical preparation, particularly a prophylactic or therapeutic agent for diabetes, diabetes-related diseases or diabetic complications, which comprises such a compound as an active ingredient.

Description

technical field [0001] The present invention relates to a heteroaryl 5-thio-β-D-glucopyranoside compound that inhibits the activity of sodium-dependent glucose transporter 2 (SGLT2), which is specifically present in the kidney and participates in glucose reabsorption, and Medicines containing the compound as an active ingredient, especially medicines for treating diabetes. Background technique [0002] While chronic hyperglycemia reduces insulin secretion, it also reduces insulin sensitivity, which further triggers blood sugar elevation and worsens diabetes. So far, biguanide drugs, sulfonylurea drugs, glucosidase inhibitors, insulin resistance improving agents, and the like have been used as therapeutic drugs for diabetes. However, it is reported that biguanides have side effects of lactic acidosis, sulfonylureas have side effects of hypoglycemia, and glucosidase inhibitors have side effects such as diarrhea and severe liver damage. Therefore, it is desired to develop a n...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/02A61K31/7056A61P3/10A61P43/00
CPCC07D409/12C07H17/02C07D409/14A61P43/00A61P3/10
Inventor 柿沼浩行佐藤正和天田英明浅沼肇土屋优子
Owner TAISHO PHARMACEUTICAL CO LTD
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