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Glucokinase activators and pharmaceutical compositions containing the same as an active ingredient

a technology of active ingredients and activators, which is applied in the direction of drug compositions, biocides, metabolic disorders, etc., can solve the problems of weight gain, side effects of agents,

Inactive Publication Date: 2010-10-21
LG LIFE SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0463]The present invention further provides a pharmaceutical composition for the activation of glucokinase, which comprises the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof as an active ingredient together with pharmaceutically acceptable carriers.

Problems solved by technology

Diabetes affects harmful influences on human health, causing various complications.
However, these agents show some side effects, such as weight gain, according to the respective mechanisms of action (Moller D. E., Nature, 2001, 414, 821).

Method used

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  • Glucokinase activators and pharmaceutical compositions containing the same as an active ingredient
  • Glucokinase activators and pharmaceutical compositions containing the same as an active ingredient
  • Glucokinase activators and pharmaceutical compositions containing the same as an active ingredient

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of [(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-4-yl]-methanol

[0588]

[0589]The compound (1.3 g, 3.3 mmol) prepared in Preparation 20 was dissolved in tetrahydrofuran (10 ml), methanol (10 ml) and water (10 ml). Lithium hydroxide hydrate (0.4 g, 9.8 mmol) was added thereto, and the mixture was stirred for 4 h at room temperature. The reaction solution was concentrated by distillation under reduced pressure. 1N hydrochloric acid was added to the residue, which was then extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (820 mg, Yield 80%).

[0590]1H-NMR (500 HMz, CDCl3); δ 11.17˜11.08 (m, 1H), 7.09 (m, 1H), 6.99 (t, 1H), 6.96 (s, 1H), 6.52 (m, 1H), 4.72 (m, 1H), 4.04 (m, 1H), 3.75 (m, 1H), 3.65 (m, 1H), 3.51 (m, 1H), 3.40 (m, 1H), 1.90 (m, 2H), 1.60-1.49 (m, 4H), 1.41-1.24 (m, 2H)

[0591]Mass Spectrum (ESI, m / z):...

example 2

Synthesis of {(R)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol

[0592]

[0593](Step 1)

[0594]The compound (900 mg, 2.7 mmol) prepared in Preparation 19 was dissolved in 1,2-dichloroethane (100 ml). Tetrahydro-4H-pyran-4-one (0.8 ml, 8.13 mmol), sodium triacetoxyborohydride (1.72 g, 8.13 mmol) and acetic acid (0.47 ml, 8.13 mmol) were added thereto, and the mixture was stirred for 48 h at room temperature. After completion of the reaction, the reaction solution was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give 2,2-dimethylpropionic acid (R)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-ylmethyl ester.

[0595]1H-NMR (400 HMz, CDCl3); δ 10.91 (br s, 1H), 7.01˜6.91 (m, 3H), 6.48 (d, J=7.2 Hz, 1H), 4.86 (m, 1H), 4.34 (m 2H), 4.00 (m, 2H), 3.61 (m, 1...

example 3

Synthesis of {(R)-2-[7-(tetrahydro-furan-3-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol

[0600]

[0601]The compound (940 mg, 2.9 mmol) prepared in Preparation 19 and tetrahydrofuran-3-one instead of tetrahydro-4H-pyran-4-one were reacted according to the same procedure as Example 2 to give the title compound (650 mg, Yield 69%).

[0602]1H-NMR (500 HMz, CDCl3); δ 10.58 (br s, 1H), 7.14 (d, J=7.95 Hz, 1H), 7.00 (m, 1H), 6.94 (m, 1H), 6.48 (d, J=7.35 Hz, 1H), 4.79 (m, 1H), 4.15˜3.95 ((m, 3H), 3.90˜3.65 (m, 4H), 3.50˜3.39 (m, 2H), 2.20 (m, 1H), 1.83 (m, 1H)

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PUM

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Abstract

The present invention relates to new compounds of formula (1) exhibiting excellent activity for glucokinase, and pharmaceutical compositions comprising the same as an active ingredient.

Description

TECHNICAL FIELD[0001]The present invention relates to new compounds exhibiting excellent activity for glucokinase (glucokinase activators, GKAs), and pharmaceutical compositions comprising the same as an active ingredient.BACKGROUND ART[0002]Diabetes affects harmful influences on human health, causing various complications. Diabetes may be classified into type 1 diabetes where insulin is not excreted due to the destruction of pancreatic cells, and type 2 diabetes where insulin is not produced due to the other conditions or the body does not response to insulin. The type 2 diabetes occupies 90% or more of the total patients suffered from diabetes. Typical complications accompanied with diabetes include hyperlipidemia, hypertension, retinosis, renal failure, etc. (Zimmer P., et al., Nature, 2001, 414, 782). As the therapeutic agents for diabetes, sulfonyl ureas (facilitating insulin secretion in the pancreatic cells), biguanides (suppressing glucose production in the liver), α-glucosi...

Claims

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Application Information

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IPC IPC(8): A61K31/541C07D417/04C07D417/14C07D487/04A61K31/5377A61K31/519A61K31/496A61K31/44A61K31/427A61P3/10A61P3/04C07D403/04
CPCC07D417/04C07D487/04C07D417/14A61P13/12A61P25/00A61P27/02A61P3/04A61P3/06A61P43/00A61P9/12A61P3/10A61K31/404A61K31/427
Inventor KIM, SOON HALEE, SUNG BAEYOON, SEUNG HYUNCHO, MI KYOUNGKIM, KYOUNG HEEPARK, HEUI SULKIM, HYOUNG JIN
Owner LG LIFE SCI
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