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Biaryl substituted heterocycle inhibitors of lTA4H for treating inflammation

A substituent, phenyl technology, applied in the field of diaryl-substituted heterocyclic inhibitors, can solve the problems of increasing the risk of MI and stroke

Inactive Publication Date: 2015-01-14
DECODE GENETICS EHF
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Specific DNA variations in the gene encoding LTA4H also increase the risk of MI and stroke, as described in the literature [Hakonarsson et al., J.Am.Med.Assoc.293, 2245-2256 (2005)]

Method used

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  • Biaryl substituted heterocycle inhibitors of lTA4H for treating inflammation
  • Biaryl substituted heterocycle inhibitors of lTA4H for treating inflammation
  • Biaryl substituted heterocycle inhibitors of lTA4H for treating inflammation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0212]

[0213] step 1

[0214] (R)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylate tert-butyl ester: Add (R)-Boc-prolinol (500mg, 2.48mmol ) in pyridine (1.5 mL) was added tosyl chloride (565 mg, 2.96 mmol) in pyridine (1 mL), and the resulting mixture was stirred at 0° C. for 20 minutes, then warmed to room temperature. The mixture was stirred at room temperature for 8 hours. The solvent was removed from the resulting suspension, and 1N aqueous HCl was added to the crude product, extracted with EtOAc. The organic layer was saturated NaHCO 3 Wash with aqueous solution, then water and brine. Anhydrous Na for organic layer 2 SO 4 Drying and removal of solvent in vacuo afforded the title product (800 mg, 91%) as a viscous oil: MS; m / z 378 (M+Na); 1 H NMR (400MHz, CDCl 3 ); 4.07-4.14 (m, 2H), 7.34 (br s, 2H), 7.77 (d, 2H, J = 8.0 Hz); HPLC (ELSD); 99%.

[0215] step 2

[0216] (R)-2-(4-Benzyl-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester: A...

Embodiment 2

[0220]

[0221] step 1

[0222] (S)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester: at 0°C, to S-(-)-1-Boc-2-pyrrolidine To a solution of methanol (22 g, 110 mmol) in pyridine (56 mL) was added a solution of p-toluenesulfonyl chloride (22.9 g, 120 mmol) in pyridine (56 mL) portionwise over 5 minutes. The resulting pale yellow reaction mixture was stirred at 0 °C for 2 hours, then at room temperature overnight. Pyridine was removed in vacuo. The crude oil was extracted into ethyl acetate (400 mL), washed sequentially with 0.5M HCl (100 mL), saturated NaHCO 3 Aqueous solution (100 mL) and brine (100 mL) washed. The combined organic layers were washed with anhydrous Na 2 SO 4 Drying, filtration and concentration in vacuo afforded the title compound (39 g, >100%) as a yellow oil;

[0223] step 2

[0224] (S)-2-(4-Benzyl-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester: Add 4-hydroxydiphenylmethane (0.77g, 4.18mmol) at 0°C To...

Embodiment 3

[0228]

[0229] step 1

[0230] 4-[(S)-2-(4-Benzyl-phenoxymethyl)-pyrrolidin-1-yl]-butyric acid methyl ester: To Example 2 (1.5 g, 4.94 mmol) in DMF (23 mL) Potassium carbonate (1.4 g, 10.1 mmol) and methyl 4-bromobutyrate (0.72 mL, 6.26 mmol) were added to the solution in . The resulting slurry was stirred overnight at room temperature. The solvent was concentrated under reduced pressure and the crude product was taken up in ethyl acetate. The organic layer was washed with water, brine, and Na 2 SO 4 Dry, filter and concentrate in vacuo. The crude product was purified by flash chromatography on silica gel using hexane / EtOAc (gradient system) to afford the title compound (0.73 g, 40%) as a yellow oil.

[0231] step 2

[0232] 4-[(S)-2-(4-Benzyl-phenoxymethyl)-pyrrolidin-1-yl]-butyric acid: To a solution of the product from Step 1 (0.13 g, 0.35 mmol) was added 2N NaOH (0.29mL, 0.58mmol) and 80% MeOH / H 2 O (4 mL). The resulting slurry was stirred at 50°C for 67 hour...

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Abstract

The present invention relates to a chemical genus of biaryl substituted heterocycle inhibitors of LTA4H (leukotriene A4 hydrolase) useful for the treatment and prevention and prophylaxis of inflammatory diseases and disorders. The compounds have general formula Psi: An example is

Description

technical field [0001] The present invention relates to a chemical class of diaryl substituted heterocyclic inhibitors of LTA4H (leukotriene A4 hydrolase) useful in the treatment and prevention of inflammatory diseases and disorders. Background technique [0002] The end product of the leukotriene pathway is a potent inflammatory lipid mediator derived from arachidonic acid. They may contribute to atherogenesis and destabilization of atherosclerotic plaques through lipid oxidation and / or pro-inflammatory effects. As described in the literature, genes on chromosome 13q12 have been identified to play a major role in myocardial infarction (MI) [Helgadottir et al., Nature Genetics doi: 10.1038 / ng1311, 8 Feb 2004]. This gene (ALOX5AP), hereinafter referred to as the MI disease gene, comprises a nucleic acid encoding 5-lipoxygenase activating protein (FLAP), which is hereinafter referred to as FLAP. DNA variants in the FLAP gene were associated with a 1.8-fold increased risk of ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/08C07D207/09C07D401/06C07D413/06C07D211/22C07D409/12C07D207/46C07D241/04C07D207/26C07D207/12C07D401/12C07D413/12C07D405/12C07D417/12C07D403/12A61K31/40
CPCC07D207/08C07D207/263C07D401/06C07D211/22C07D405/12C07D409/12C07D413/12C07D241/04C07D207/12C07D413/06C07D401/14C07D401/12C07D207/26C07D207/46C07D207/09C07D417/12C07D403/12A61P1/04A61P11/00A61P11/06A61P19/02A61P25/00A61P29/00A61P37/08A61P43/00A61P7/02A61P9/04A61P9/10A61K31/40
Inventor J·辛格V·桑达纳亚卡M·格尼P·于L·比德尔B·马马特赵镭R·K·米什拉
Owner DECODE GENETICS EHF
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