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Imidazo [1,2-b] pyridazine compounds as modulators of liver x receptors

A technology of compounds and oxides, used in anti-inflammatory agents, drug combinations, organic chemistry, etc.

Inactive Publication Date: 2011-02-09
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In addition to the lipid and triglyceride effects described above, it is also believed that activation of LXRs results in inhibition of inflammatory and pro-inflammatory gene expression

Method used

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  • Imidazo [1,2-b] pyridazine compounds as modulators of liver x receptors
  • Imidazo [1,2-b] pyridazine compounds as modulators of liver x receptors
  • Imidazo [1,2-b] pyridazine compounds as modulators of liver x receptors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0635] Ethyl 2-hydroxy-4-oxo-2-(trifluoromethyl)butyrate

[0636] A stirred solution of ethyl 3,3,3-trifluoro-2-oxopropanoate (15.0 g, 88 mmol) and ethyl 3,3,3-trifluoro-2-oxopropionate (15.0 g, 88 mmol) in dichloromethane (176 mL) was added in one portion with L-proline (5.08 g, 44.1 mmol) The aldehyde (4.95 mL, 88 mmol) was treated and the reaction was stirred for 2 hours. Quench with water and extract with dichloromethane. in MgSO 4 The combined organics were dried over and concentrated to yield 16.81 g (89%) of the title compound as an orange viscous liquid.

Embodiment 2

[0638] 4-(Trifluoromethyl)pyridazin-3(2H)-one

[0639] Ethyl 2-hydroxy-4-oxo-2-(trifluoromethyl)butyrate (16.62 g, 78 mmol) in EtOH (40 mL) was treated with hydrazine hydrate (5.66 mL, 116 mmol) and stirred at room temperature 1.5 hours, then heated at reflux for 1.5 hours. The ethanol was removed in vacuo, the resulting material was partitioned between water and ethyl acetate, and the layers were separated. The aqueous layer was extracted with additional ethyl acetate. in MgSO 4 The combined organic layers were dried over and concentrated in vacuo to yield the title compound as a yellow / orange solid (9.75 g, 77%).

Embodiment 3

[0641] 3-Chloro-4-(trifluoromethyl)pyridazine

[0642] p-4-(trifluoromethyl)pyridazin-3(2H)-one (9.3 g, 56.7 mmol) in POCl at reflux 3 The mixture in (75 mL) was heated for 1.5 hours. The solvent was removed with saturated NaHCO 3 The resulting material was carefully neutralized with an aqueous solution, followed by solid K 2 CO 3 (use ethyl acetate to reduce foaming) to neutralize. The mixture was extracted with ethyl acetate. The combined organics were washed with brine, over MgSO 4 dry on. The product was purified by silica gel chromatography eluting with a gradient from 5:95 to 30:70 E:H to give the title compound (3.51 g, 34%) as an orange liquid.

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PUM

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Abstract

This invention relates generally to imidazo[1,2-b] pyridazine-based modulators of Liver X receptors (LXRs) having formula (I) and related methods: Formula (I) wherein R2 is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is: (i) substituted with 1 R6, and (ii) optionally substituted with from 1-5 Re; and R1, R3, R4, R5, R6 and Re are defined herein.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims the benefit of US Provisional Application No. 61 / 015,856, filed December 21, 2007, which is incorporated herein by reference in its entirety. technical field [0003] The present invention generally relates to imidazo[1,2-b]pyridazine-based modulators of liver X receptors (LXRs) and related methods. Background technique [0004] Arteriosclerosis is one of the leading causes of death in developed countries. Some independent risk factors associated with arteriosclerosis include the presence of relatively high serum LDL cholesterol levels and relatively low serum HDL cholesterol levels in affected patients. Thus, some anti-arteriosclerotic treatment regimens include the administration of agents (eg, statins) to reduce higher serum LDL cholesterol levels. [0005] Agents that increase a patient's HDL cholesterol levels may also be used in anti-arteriosclerotic treatment regimens. HDL cholesterol i...

Claims

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Application Information

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IPC IPC(8): A61K31/5025A61P9/00A61P3/00C07D487/04
CPCC07D487/04A61P17/00A61P17/16A61P19/02A61P19/04A61P19/08A61P25/28A61P29/00A61P3/00A61P3/04A61P3/06A61P43/00A61P7/12A61P9/00A61P9/10A61P3/10
Inventor 罗伯特·雷·小辛浩斯
Owner WYETH LLC
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