1- (-d-glycopyranosyl) - 3 - (4-cyclopropylphenylmethyl) - 4 - halogeno indole derivatives and use thereof as sglt inhibitors

A technology of cyclopropylphenylmethyl and glucopyranosyl, applied in the field of new indole derivatives, can solve problems such as lactic acidosis, hypoglycemia, edema and heart failure, achieve excellent results, and excellently lower blood sugar Effect

Inactive Publication Date: 2009-08-05
MITSUBISHI TANABE PHARMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these antidiabetic agents have various side effects
Examples: Biguanides cause lactic acidosis, sulfonylureas cause severe hypoglycemia, insulin sensitizers cause edema and heart failure, and alpha-glucosidase inhibitors cause abdominal gas and diarrhea

Method used

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  • 1- (-d-glycopyranosyl) - 3 - (4-cyclopropylphenylmethyl) - 4 - halogeno indole derivatives and use thereof as sglt inhibitors
  • 1- (-d-glycopyranosyl) - 3 - (4-cyclopropylphenylmethyl) - 4 - halogeno indole derivatives and use thereof as sglt inhibitors
  • 1- (-d-glycopyranosyl) - 3 - (4-cyclopropylphenylmethyl) - 4 - halogeno indole derivatives and use thereof as sglt inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0134] 3-(4-Cyclopropylphenylmethyl)-4-fluoro-1-(β-D-glucopyranosyl)indole

[0135]

[0136] (1) A mixture of 4-fluoroindoline (185mg) and D-glucose (267mg) in water (0.74ml)-ethanol (9ml) was refluxed under argon for 24 hours. The solvent was evaporated under reduced pressure to give crude 4-fluoro-1-(β-D-glucopyranosyl)indoline, which was used in the next step without further purification.

[0137](2) The above compound was suspended in chloroform (8ml), and pyridine (0.873ml), acetic anhydride (1.02ml) and 4-(dimethylamino)pyridine (catalytic amount) were sequentially added thereto. After stirring at room temperature for 21 hours, the reaction solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed twice with 10% aqueous copper(II) sulfate, then with saturated aqueous sodium bicarbonate, and dried over magnesium sulfate. The insoluble matter was filtered off, and the filtrate was evaporated under reduced pr...

Embodiment 2

[0143] Example 2: 4-Chloro-3-(4-cyclopropylphenyl-methyl)-1-(B-D-glucopyranosyl)indole

[0144]

[0145] (1) Take 4-chloroindoline (2.88g) and D-glucose (3.38g) in ethanol (150ml)-H 2 O (10 mL) the mixture was refluxed overnight under argon. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0-88:12) to obtain 4-chloro-1-(β-D-glucopyranosyl)indoline ( 3.35 g) of a colorless foam. APCI-mass spectrum m / Z 316 / 318 (M+H). 1 H-NMR (DMSO-d 6)δ 2.87-3.02(m, 2H), 3.07-3.12(m, 1H), 3.20-3.32(m, 2H), 3.38-3.47(m, 2H), 3.51-3.60(m, 2H), 3.68-3.73 (m, 1H), 4.34-4.37(m, 1H), 4.63(d, J=8.3Hz, 1H), 4.93(d, J=5.1Hz, 1H), 5.03(d, J=4.0Hz, 1H) , 5.06 (d, J=4.5Hz, 1H), 6.53 (d, J=8.0Hz, 1H), 6.60 (d, J=8.0Hz, 1H), 6.99 (t, J=7.9Hz, 1H).

[0146] (2) Dissolve the above-mentioned compound (3.3g) in 1,4-dioxane (150ml), and add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone ( 2.85g). The mixture was sti...

Embodiment 3

[0153] 3-(4-Cyclopropylphenylmethyl)-4,6-difluoro-1-(β-D-glucopyranosyl)indole

[0154]

[0155] In a similar manner to Example 1, the title compound was obtained as a colorless foam from 4,6-difluoroindoline. APCI-mass spectrum m / Z 463 (M+NH 4 ). 1 H-NMR (DMSO-d 6 )δ 0.58-0.62(m, 2H), 0.88-0.91(m, 2H), 1.82-1.88(m, 1H), 3.20-3.50(m, 4H), 3.59-3.70(m, 2H), 3.99(s , 2H), 4.54(t, J=5.7Hz, 1H), 5.10(d, J=5.3Hz, 1H), 5.19(d, J=5.0Hz, 1H), 5.22(d, J=5.8Hz, 1H ), 5.35(d, J=9.0Hz, 1H), 6.78(t, J=9.6Hz, 1H), 6.96(d, J=8.0Hz, 2H), 7.11(d, J=8.0Hz, 2H), 7.22 (s, 1H), 7.30 (dd, J=10.0, 1.7Hz, 1H).

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Abstract

Novel indole derivatives of formula (I) or a pharmaceutically acceptable salt thereof: wherein R is fluorine, or chlorine, and R is hydrogen, or fluorine, which are SGLT inhibitors and are useful for treatment or prevention of diabetes and related conditions.

Description

technical field [0001] The present invention relates to novel indole derivatives having activity as inhibitors of sodium-dependent glucose transporters (SGLT) found in the intestine or kidney. Background technique [0002] Diet therapy and exercise therapy are necessary in the treatment of diabetes. Insulin or antidiabetic agents are used when these therapies are insufficient to control the patient's condition. Currently, examples of the antidiabetic agent include biguanides, sulfonylureas, insulin sensitizers, and α-glucosidase inhibitors. However, these antidiabetic agents have various side effects. For example, biguanides can cause lactic acidosis, sulfonylureas can cause severe hypoglycemia, insulin sensitizers can cause edema and heart failure, and alpha-glucosidase inhibitors can cause abdominal distension and diarrhea. Under these circumstances, there is a need for novel antidiabetic agents that have excluded these side effects. [0003] Recently, it has been repo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/04A61K31/706
CPCC07H19/04A61P13/12A61P17/02A61P25/00A61P25/18A61P3/00A61P3/04A61P3/06A61P3/08A61P7/00A61P9/10A61P9/12A61P3/10C07D405/06C07D405/04A61K31/706
Inventor 野村纯弘坂槙茂辉
Owner MITSUBISHI TANABE PHARMA CORP
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