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Prolyl hydroxylase inhibitors

A compound and solvate technology, applied in the field of quinoxaline-5-carboxamide derivatives, can solve problems such as increasing Epo production and increasing HIF-α levels

Inactive Publication Date: 2011-03-02
GLAXO SMITHKLINE LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, inhibition of prolyl hydroxylase leads to increased levels of HIF-α, which increases Epo production

Method used

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Examples

Experimental program
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Effect test

preparation example Construction

[0248] Exemplary preparation method

[0249] Program

[0250] Included within the present invention are methods of synthesizing compounds according to Schemes 1-5:

[0251] plan 1

[0252]

[0253] a) fuming nitric acid, concentrated sulfuric acid, heated; b) ammonia (ammonium hydroxide), ethanol; c) sodium hydride or sodium methoxide, methanol; d) H 2 , Pd / C, ethyl acetate, or i. bromine, acetic acid or dichloromethane, ii. tin(II) chloride dihydrate, ethanol, acetonitrile, or H 2 , Pd / C, ethyl acetate, then R 2 C(O)C(O)R3 , acetonitrile / water or methanol, heating or microwave radiation; e) boron tribromide, dichloromethane; f) ethyl glycine hydrochloride, triethylamine or diisopropylethylamine, HATU or PyBOP, N, N-Dimethylformamide or dichloromethane; g) NaOH, ethanol or THF / methanol.

[0254] Scenario 2

[0255]

[0256] a) Phosphorus oxychloride, heating b) Boron tribromide, dichloromethane; c) Glycine ethyl ester hydrochloride, triethylamine or diisopropylethy...

Embodiment 1

[0268]

[0269] N-[(6-Hydroxy-3-phenyl-5-quinoxalinyl)carbonyl]glycine

[0270] 1a) Methyl 2-amino-6-fluoro-3-nitrobenzoate

[0271] To fuming nitric acid (3.87 mL, 86.6 mmol) was slowly added concentrated sulfuric acid (7.27 mL, 136.4 mmol) at 0°C. After stirring for 5 minutes, methyl 2,6-difluorobenzoate (3.90 mL, 29.0 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 30 minutes, the reaction mixture was poured into ice-water and extracted three times with dichloromethane. The combined organic fractions were washed with saturated aqueous sodium bicarbonate solution over MgSO 4 Dry, filter, and concentrate in vacuo to give a colorless oil. MS(ES+)m / e 218[M+H] + . On standing, the oil solidified to a white solid, which was dissolved in ethanol (50.0 mL) and treated with ammonia (1.0 mL, 29% in water) at ambient temperature. After 4 hours, additional ammonia (0.8 mL, 29% in water) was added and the reaction mixture was stirr...

Embodiment 2

[0285]

[0286] N-[(6-Hydroxy-3-methyl-5-quinoxalinyl)carbonyl]glycine

[0287] 2a) Methyl 3-methyl-6-(methoxy)-5-quinoxalinecarboxylate

[0288] To a solution of the compound from Example 1 b) (0.307 g, 1.36 mmol) in ethyl acetate (25.0 mL) was added 10% palladium on carbon (0.072 g, 0.068 mmol), and the reactor was then evacuated and purged with nitrogen. The reduction was carried out under 50 psi hydrogen overnight using a Parr shaker. Pass the reaction mixture through Filter, wash with ethyl acetate, and concentrate in vacuo. A suspension of the resulting yellow oil in water (15.0 mL) and acetonitrile (5.0 mL) was treated with methylglyoxal (40 wt % in water) (0.245 g, 1.36 mmol) and heated at 60 °C for 1 h . After cooling, the reaction mixture was diluted with brine and extracted three times with ethyl acetate. The combined organic layers were subjected to MgSO 4 Dry, filter, and concentrate in vacuo to afford the title compound (0.273 g, 87%) as an orange s...

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Abstract

The invention described herein relates to certain quinoxaline-5-carboxamide derivatives of formula (I) which are antagonists of HIF prolyl hydroxylases and are useful for treating diseases benefiting from the inhibition of this enzyme, anemia being one example.

Description

technical field [0001] The present invention relates to certain quinoxaline-5-carboxamide derivatives which are inhibitors of HIF prolyl hydroxylase and thus have utility in the treatment of diseases which would benefit from inhibition of this enzyme (anemia being an example) use. Background of the invention [0002] Anemia occurs when red blood cells are low or abnormal, which leads to low oxygen levels in the blood. Anemia is commonly seen in cancer patients, especially those receiving chemotherapy. Anemia is commonly observed in people older than middle age, in patients with renal disease, and in a wide range of diseases associated with chronic disease. [0003] Generally, anemia is caused by decreased production of erythropoietin (Epo), which prevents erythropoiesis (maturation of red blood cells). Epo production can be increased by inhibition of prolyl hydroxylase, which regulates hypoxia-inducible factor (HIF). [0004] One strategy to increase erythropoietin (Epo)...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G06F19/00
CPCC07D403/04C07D417/04C07D405/04C07D241/44C07D409/04C07D413/04C07D417/14C07D409/14C07D241/42C07D401/04A61P7/06A61P9/10A61P43/00Y02A90/10
Inventor 马里拉·科伦杜克·M·菲奇
Owner GLAXO SMITHKLINE LLC
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