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Isobenzofuran derivatives, pharmaceutical compositions and preparations thereof, and uses thereof

A technology of derivatives and compositions, applied in the field of medicine, can solve the problems of poor selectivity of SGLT1 and SGLT2, large adverse reactions, and failure to apply on a large scale, and achieve low toxicity, excellent pharmacodynamic properties, and good SGLT-2 inhibition active effect

Active Publication Date: 2021-03-30
ZHENJIANG SAN AN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The first natural product applied to SGLT-2 inhibitors is phlorizin, but because it is easily hydrolyzed into glycosides and phlorizin by lactase in the body, and has poor selectivity to SGLT1 and SGLT2, adverse reactions are relatively rare. Large, therefore, failed to be applied on a large scale

Method used

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  • Isobenzofuran derivatives, pharmaceutical compositions and preparations thereof, and uses thereof
  • Isobenzofuran derivatives, pharmaceutical compositions and preparations thereof, and uses thereof
  • Isobenzofuran derivatives, pharmaceutical compositions and preparations thereof, and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1a

[0076] (1S, 3'R, 4'S, 5'S, 6'R)-6-[(4-pentadeuterioethylphenyl)methyl]-3', 4', 5',6'-tetrahydro-6'-(hydroxymethyl)spiro[isobenzofuran-1(3H),2'-[2H]pyran]-3',4',5'-triol

[0077]

[0078]

[0079] Step 1: Preparation of intermediate (1S, 3'R, 4'S, 5'S, 6'R)-6-[(methoxycarbonyloxy)methyl]-3',4',5',6'-tetrahydro -3',4',5'-bis(methoxycarbonyloxy)-6'-[(methoxycarbonyloxy)methyl]-spiro[isobenzofuran-I(3H),2'-[ 2H]pyran](compound 2)

[0080] Under argon, the commercial product (1S,3'R,4'S,5'S,6'R)-tetrahydro-6,6'-bis(hydroxymethyl)-spiro[isobenzofuran-I(3H), 2'-[2H]pyran]-3',4',5'-triol (compound 1) (1 equivalent) and 4-dimethylaminopyridine (10 equivalents) were dissolved in anhydrous acetonitrile, ice bath Under cooling, methyl chloroformate (7 eq.) was added slowly. After the addition was complete, the mixture was warmed to 25°C and stirred for 1 hour. LC-MS and TLC showed that the reaction of the intermediate was basically complete. Water was added to terminate the re...

Embodiment 1a-2

[0088] (1S, 3'R, 4'S, 5'S, 6'R)-6-[(4-pentadeuterioethylphenyl)methyl]-3', 4', 5',6'-tetrahydro-6'-(hydroxymethyl)spiro[isobenzofuran-1(3H),2'-[2H]pyran]-3',4',5'-triol .

[0089]

[0090] Step 1: Preparation of Compound 7

[0091] With stirring at room temperature, to Ac 2 Sodium periodate (2.8g, 12.9mmol, 0.56eq) and iodine (2.2g, 8.7mmol, 0.37eq) were sequentially added to a mixed solution of O (9mL) and acetic acid (18mL). After addition, cool to 0°C in an ice-salt bath. Concentrated sulfuric acid (17.7g, 180.4mmol, 7.8eq) was added dropwise to the above mixture. Control the internal temperature not higher than 5°C. After dropping, stir for 10 minutes. Then compound 6 (4.5g, 23.2mmol, 1.0eq) was added in batches, and the addition was completed within 30 minutes, and the internal temperature was controlled not to be higher than 0°C. After the addition, the temperature was raised to room temperature and stirred for 1 hour, then the temperature was raised to 30-45° ...

Embodiment 1b

[0107] The compound shown in preparation formula V

[0108] Under the protection of argon, the compound represented by formula II was dissolved in acetone and water (volume ratio 1:1.5, 300% by weight), cooled to 5°C, and water (100% by weight) was added to the mixture to crystallize 24 hours. The resulting crystals were centrifuged to obtain the compound (Formula V) as monohydrate crystals (moisture content: 4.40% by weight). LC-MS: 392 (M+1).

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Abstract

The invention provides isobenzofuran derivatives with a structure represented by a formula I shown in the description for an SGLT-2 inhibitor, a pharmaceutical composition and preparation of the derivatives, and an application of the derivatives, wherein in the description, R1 and R2 are independently selected from hydrogen or deuterium and at least contain one deuterium. The isobenzofuran derivatives having the structure represented by the formula I provided by the invention have good SGLT-2 inhibitory activity, excellent pharmacodynamic properties, and lower toxicity.

Description

technical field [0001] The invention belongs to the field of medicine, and provides an isobenzofuran derivative having the structure of formula I for use as an SGLT-2 inhibitor, a pharmaceutical composition or preparation containing this compound, and a medicine for treating diseases such as diabetes use in . Background technique [0002] Currently, about 100 million people in the world suffer from type 2 diabetes mellitus (NIDDM), which is mainly hyperglycemia caused by excessive glycogen production and peripheral insulin resistance. Hyperglycemia is a major risk factor for diabetic complications and may directly lead to impaired insulin secretion in patients with advanced type II diabetes. Normalization of plasma glucose in type 2 diabetic patients improves insulin action and counteracts diabetic complications. [0003] SGLT-2 (sodium-glucose cotransporter-2, also known as SGLT2) is a transmembrane protein that is mainly distributed in the S1 site of the proximal convolu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/01A61K31/7048A61P5/50A61P3/10A61P3/04A61P3/06A61P3/08A61P9/10A61P9/00A61P3/00
CPCA61P3/00A61P3/04A61P3/06A61P3/08A61P3/10A61P5/50A61P9/00A61P9/10C07B2200/05C07H19/01
Inventor 陈兴海奥玛·派克黄求理彭伟帕旺·佩特鲁谢锦荣
Owner ZHENJIANG SAN AN PHARMA
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