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2-pyridine derivatives as inhibitors of neutrophile elastase

A compound, C1-C6 technology, used in non-central analgesics, drug combinations, organic active ingredients, etc., can solve problems such as tissue destruction

Inactive Publication Date: 2008-03-12
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

An imbalance between human NE and antiproteases is believed to cause excess human NE, resulting in uncontrolled tissue destruction

Method used

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  • 2-pyridine derivatives as inhibitors of neutrophile elastase
  • 2-pyridine derivatives as inhibitors of neutrophile elastase
  • 2-pyridine derivatives as inhibitors of neutrophile elastase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0268] N-{[3-(2-Hydroxyethyl)isoxazol-5-yl]methyl}-6-methyl-5-(1-methyl-1H-pyrazole-5- Base)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

[0269] a) 5-iodo-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid prop-2-ynylamide

[0270] In a flask, 6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid (as described in Intermediate Example 1 Prepared as described above, 0.5g, 1.68mmol) was dissolved in CH 2 Cl 2 (7ml) and TFA (3ml). N-iodosuccinimide (0.378 g, 1.68 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Volatiles were removed by evaporation to give the 5-iodinated product, which was dissolved in CH 2 Cl 2 (5ml), add SOCl 2 (5ml). The mixture was stirred for 1 hour, then concentrated well. The crude solid acid chloride was dissolved in 1,4-dioxane (10ml, anhydrous) and a mixture of Hunigs base (DIPEA, 1ml) and propargylamine (0.165g, 3mmol) was add...

Embodiment 2

[0280] 5-(3,5-Dimethylisoxazol-4-yl)-N-{[3-(2-hydroxyethyl)isoxazol-5-yl]methyl}-6-methanol Base-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dioxypyridine-3-carboxamide

[0281] According to the method described in Example 1c, from 5-iodo-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid {3-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-ylmethyl}-amide (Example 1b, 0.032g, 0.051mmol), 3, 5-Dimethylisoxazol-4-yl-boronic acid (0.020g, 0.142mmol) and Na 2 CO 3 (2M, 1.5ml) The compound was prepared except that the intermediate was partitioned between EtOAc / water and the organic phase was purified on silica followed by hydrolysis. Purification by preparative HPLC and lyophilization afforded 0.010 g (38%) of the title compound as a white solid.

[0282] 1 H NMR (DMSO-d 6 ): δ9.88(1H, t, J=6.3Hz); 8.18(1H, s); 8.01(1H, d, J5.5Hz); 7.92(1H, d, J 7.2Hz); 7.87-7.79(2H , m); 6.23(1H, s); 4.60(2H, d, J6.3Hz); 3.62(2H, t, J 6.6Hz); 2.69(2H, t, J 6.6H...

Embodiment 3

[0285] N-{[3-(2-Hydroxyethyl)isoxazol-5-yl]methyl}-5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl Base) phenyl] -1,2-dihydropyridine-3-carboxamide

[0286]Hydrolysis of 5-iodo-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid according to the hydrolysis procedure described in Example 1c {3-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-ylmethyl}-amide (Example 1b, 0.14g, 0.22mmol). Purification by preparative HPLC and lyophilization afforded 0.060 g (50%) of the title compound as a white solid.

[0287] Intermediate Example 2

[0288] 6-methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro- Pyridine-3-carboxylic acid

[0289] a) 6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylic acid ethyl ester

[0290] Under nitrogen atmosphere, 6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylic acid (Intermediate Example 1b, 13.1 g, 43.9 mmol), sodium carbonate (5....

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Abstract

The invention provides compounds of formula wherein R1, R3, R4, R5, R6, R14, X, W and Z are as defined in the specification and optical isomers, racemates and tautomers thereof, and pharmaceutically acceptable salts thereof; together with processes for their preparation, pharmaceutical compositions containing them and their use in therapy. The compounds are inhibitors of human neutrophil elastase.

Description

technical field [0001] The present invention relates to 2-pyridone derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. Background technique [0002] Elastase is probably the most destructive enzyme in the body, with the ability to degrade virtually all connective tissue components. The uncontrolled proteolytic degradation of elastase has been implicated in several pathological conditions. Human neutrophils (hNE), a member of the chymotrypsin superfamily of serine proteases, are a 33 KDa enzyme stored in the azurophilic granules of neutrophils. In neutrophils, the concentration of NE exceeds 5mM, and its total cell content is estimated to reach 3pg. Once activated, NE is rapidly released from the granules into the extracellular space, and a certain proportion remains bound to the neutrophil plasma membrane (see Kawabat et al. 2002, Eur. J. Pharmacol. 451, 1-10). The main intracellular physiological function of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/82A61K31/4412A61K31/4427A61K31/444A61P11/00A61P11/06A61P29/00C07D401/12C07D413/12C07D413/14
CPCC07D413/14C07D213/82C07D413/12A61P1/04A61P11/00A61P11/02A61P11/06A61P11/16A61P19/02A61P27/16A61P29/00A61P35/00A61P43/00A61P9/10A61P9/12A61K31/4412A61K31/4427C07D213/83
Inventor 彼得·汉森卡罗利那·拉维茨汉斯·朗安东尼奥斯·尼基蒂迪斯
Owner ASTRAZENECA AB