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Glucokinase activators

A compound, low-level technology, applied in the direction of organic chemistry, organic active ingredients, chemical instruments and methods, etc., can solve problems such as increasing the sensitivity of GK sensor systems

Inactive Publication Date: 2004-05-26
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But GK gene mutations are not found in most patients with type 2 diabetes, and compounds that activate GK, therefore, increasing the sensitivity of the GK sensor system may still be effective in treating hyperglycemia in all types of diabetes

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0445] (A) 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-yl-propionamide:

[0446]

[0447] 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared in Example 38, 2.0 g, 6.96 mmol), benzotriazol-1-yloxy-tris(dimethyl A solution of amino)phosphonium hexafluorophosphate (4.62g, 10.44mmol) and 2-aminothiazole (1.05g, 10.44mmol) in dichloromethane (50mL) was treated with triethylamine (2.9mL, 20.88mmol) deal with. The reaction mixture was stirred for 14h. The reaction mixture was then diluted with water (10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed sequentially with water (1×10 mL), 1N aqueous sodium hydroxide solution (1×10 mL), 1N aqueous hydrochloric acid solution (1×10 mL) and saturated aqueous sodium chloride solution (1×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. 3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-yl was obtained by flash chromatography (Merck Sil...

Embodiment 2

[0459] 2-(4-Bromo-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide

[0460]

[0461] Diisopropylamine (7.7mL, 54.88mmol) in dry tetrahydrofuran (23mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10mL) The solution in was cooled to -78°C under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexane (22.0 mL, 54.88 mmol). The resulting reaction mixture was stirred at -78 °C for 30 min, then added dropwise to dry THF (23 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone ( The reaction mixture was treated with a solution of 4-bromophenylacetic acid (5.62 g, 26.13 mmol) in 10 mL). The color of the reaction mixture turned dark and was stirred at -78°C for 1 h while a solution of iodomethylcyclopentane (5.76 g, 27.44 mmol) in a small amount of dry THF was added dropwise. The reaction mixture was heated to 25 °C and stirred for 24 h. The reaction mixture was rapidly cooled with water, then concentrated in vacuo to remove tetrahydrofuran. ...

Embodiment 3

[0464] (A) 3-cyclopentyl-2-(4-methylsulfonyl-phenyl)-N-thiazol-2-yl-propionamide

[0465]

[0466]Diisopropylamine (3.3mL, 23.5mmol) in dry tetrahydrofuran (50mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10mL) The solution was cooled to -78°C under nitrogen and then treated with a 10 M solution of n-butyllithium in hexane (2.35 mL, 23.5 mmol). The yellow reaction mixture was stirred at -78°C for 30 min, then a solution of 4-methylsulfonylphenylacetic acid (2.40 g, 11.2 mmol) in a small amount of dry THF was added dropwise. A solution of 4-methylsulfonylphenylacetic acid in dry tetrahydrofuran was added about halfway, and a precipitate formed. Addition of the remaining solution of 4-methylsulfonylphenylacetic acid in dry THF was continued and the reaction mixture thickened substantially. After complete addition of the solution of 4-methylsulfonylphenylacetic acid in dry THF, the reaction mixture became very viscous and difficult to stir. Additional dry THF ...

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PUM

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Abstract

The present invention relates to compounds of formula (I) wherein R<1>, R<2>, R<3> and R<4> are as defined in claim 1 and pharmaceutically acceptable salts thereof. The compounds are glucokinase activators which increase insulin secretion in the treatment of type II diabetes.

Description

Background technique [0001] Glucokinase (GK) is one of four hexokinases found in mammals [Colowick, S.P., The Enzymes, Vol.9 (P. Boyer, ed.) Academic Press, New York, NY, 1-48 page, 1973]. Hexokinase catalyzes the first step in glucose metabolism, the conversion of glucose to glucose-6-phosphate. Glucokinase has a limited cellular distribution, mainly in pancreatic β-cells and liver parenchyma cells. In addition, GK is a rate-controlling enzyme for glucose metabolism in these two cell types, which is well known to play a key role in whole-body glucose homeostasis [Chipkin, S.R., Kelly, K.L. and Rudermam, N.B. In Joslin's Diabetes ( C.R. Khan and G.C. Wier, eds), Lea and Febiger, Philadelphia, PA, pp. 97-115, 1994]. The concentration of glucose at which GK exhibits half-maximal activity is approximately 8 mM. The other three hexokinases were saturated with much lower concentrations (<1 mM) of glucose. Thus, as blood glucose concentration increases from fasting (5 mM) to...

Claims

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Application Information

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IPC IPC(8): A61K31/17A61K31/4168A61K31/42A61K31/421A61K31/426A61K31/433A61K31/4402A61K31/455A61K31/50A61K31/505A61P3/10A61P43/00C07C275/50C07C317/44C07C323/60C07C323/62C07DC07D213/75C07D213/80C07D213/803C07D213/82C07D233/88C07D237/20C07D237/22C07D239/42C07D241/28C07D253/07C07D261/14C07D263/34C07D263/48C07D277/20C07D277/38C07D277/46C07D277/56C07D277/58C07D285/12C07D285/135
CPCC07C317/44C07C323/62C07D239/42C07D237/22C07C2101/08C07D285/135C07D277/46C07D213/75C07C2101/02C07D253/07C07C2101/04C07D233/88C07D277/56C07D261/14C07D263/48C07D277/58C07C2101/14C07D213/80C07C275/50C07C2101/10C07D213/82C07C2601/02C07C2601/04C07C2601/08C07C2601/10C07C2601/14A61P3/00A61P3/10A61P43/00
Inventor 弗雷德·托马斯·比扎罗温迪·莱亚·科比特安东尼奥·福塞拉约瑟夫·弗朗西斯·格里波南希-埃伦·海恩斯乔治·威廉姆·霍兰罗伯特·弗朗西斯·凯斯特佩奇·E·马哈尼拉马凯斯·萨拉布
Owner F HOFFMANN LA ROCHE & CO AG
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