Substituted -1,3,8-triazaspiro[4.5]decane-2,4-diones

A technology of heterocycloalkyl and alkyl, applied in the field of substituted -1,3,8-triazaspiro[4.5]decane-2,4-dione, can solve problems such as poor effectiveness

Inactive Publication Date: 2012-05-16
SCHERING AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Under low oxygenation, HIF-α hydroxylation is less efficient and HIF-α is available for dimerization with HIF-β

Method used

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  • Substituted -1,3,8-triazaspiro[4.5]decane-2,4-diones
  • Substituted -1,3,8-triazaspiro[4.5]decane-2,4-diones
  • Substituted -1,3,8-triazaspiro[4.5]decane-2,4-diones

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0484] Preparation of intermediate A (compound A-1)

[0485]

[0486] Tert-butyl 4-oxopiperidine-1-carboxylate (105 g, 527 mmol), potassium cyanide (51.5 g, 790 mmol) and ammonium carbonate (152 g, 1581 mmol) were dissolved in water (350 mL) The mixture in ethanol (350 mL) was heated to 95 °C for 2 hours and cooled by an ice bath with slow stirring. The solid was collected by filtration, washed with 100 mL of water / ethanol = 1:1 (vol:vol), and dried in a desiccator. LCMS (Method B): 2.21 minutes, m / z (MH-Boc) + = 170.1.

Embodiment 1

[0488] 3-biphenyl-4-yl-1-(4-hydroxypyrimidin-2-yl)-8-[(3-methylpyridin-2-yl)methyl]-1,3,8-triazepine Spiro[4.5]decane-2,4-dione, (1-1)

[0489]

[0490] Step A (compound 1-A)

[0491] A solution of Intermediate A (A-1 ) (23.77 mmol), 4-iodobiphenyl (22.58 mmol) in acetonitrile (80 ml) and DMF (80 mL) was degassed for 15 min with nitrogen flow. Join sequentially N,N' - Dimethylethylenediamine (5.94 mmol), copper(I) iodide (5.94 mmol) and potassium carbonate (71.3 mmol). The resulting mixture was heated to 85°C for 15 hours, combined with ethyl acetate (300 mL) and water (300 mL). The organic layer from this combined step was separated. The organic extracts were washed with water (2 x 300 mL), dried over sodium sulfate and concentrated. Purification was accomplished by column chromatography on silica gel: eluting with a gradient of 0-100% hexanes in ethyl acetate. Yield a white solid, 1-A. LCMS (Method B): 3.21 minutes, m / z (MH-Boc) + = 321.0.

[0492] Step ...

Embodiment 3

[0532] 3-1

[0533] 3-Biphenyl-4-yl-8-[(3-methylpyridin-2-yl)methyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione (3-1)

[0534] Compound 3-1 was prepared according to the general procedure described for Example 1, omitting Step B, and subsequently isolated as a salt of trifluoroacetic acid using preparative HPLC (Method C). 1 HNMR (CDCl 3 ): δ = 2.25(m, 2H), 2.37(m, 2H), 2.46(s, 3H), 2.96(m, 2H), 3.74(s, 2H), 6.87(s, 1H), 7.16-7.70( m, 10H), 8.40 (d, 1H, J = 4.2 Hz); LCMS (method A), 1.50 min, m / z (MH) + = 427.

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Abstract

The present invention relates to substituted 1,3,8-triazaspiro[4.5]decame-2,4-diones useful as HIF prolyl hydroxylase inhibitors to treat anemia and like conditions.

Description

Background of the invention [0001] Insufficient delivery of oxygen to cells and tissues is associated with anemia, defined as a defect in the oxygen-carrying capacity of the blood, and ischemia, in which limitations in blood supply are caused by vasoconstriction or blockage. Anemia can be caused by loss of red blood cells (hemorrhage), excessive red blood cell destruction (hemolysis), or defects in erythropoiesis (production of red blood cells from precursors found in the bone marrow). Symptoms of anemia can include weakness, dizziness, fatigue, pallor, impaired cognitive function and an overall decrease in quality of life. Chronic and / or severe anemia can lead to exacerbation of myocardial, cerebral or peripheral ischemia and lead to heart failure. Ischemia is defined as the absolute or relative shortage of oxygen to a tissue or organ, and can result from conditions such as atherosclerosis, diabetes, thromboembolism, hypotension, and the like. The heart, brain and kidneys a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/10A61K31/44
CPCA61K31/44C07D471/10A61P3/00A61P5/00A61P7/06A61P43/00
Inventor J.M.皮尔斯J.J.黑尔S.苗P.瓦查尔
Owner SCHERING AG
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