Inhibitor of phospholipase enzymes

A technology selected from, alkyl, applied in the field of chemical inhibitors, can solve the problem of unpurified protein

Inactive Publication Date: 2001-06-13
GENETICS INST INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the protein was n

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 24

[0162] Each of the compounds in Examples 2-11 below was prepared by a first step as described in Example 1, Step 9, using the appropriate thiol, followed by a second step as described in Example 1, Step 10. Example 24-[(3-Chloro-5-[(cyclopentylcarbonyl)amino]-2-{[(2-furylmethyl)sulfanyl]methyl}-1H-indol-1-yl ) Methyl] benzoic acid Example 34-[(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-{[(4-hydroxyl-6-phenyl-2-pyrimidinyl)sulfanyl ]methyl}-1H-indol-1-yl)methyl]benzoic acid embodiment 4

[0163] 4-{[3-Chloro-5-[(cyclopentylcarbonyl)amino]-2-({[4-(2-thienyl)-2-pyrimidinyl]sulfanyl}methyl)-1H-ind Indol-1-yl]methyl}benzoic acid Example 54-({3-Chloro-5-[(cyclopentylcarbonyl)amino]-2-[(2,4-dibromophenoxy)methyl] -1H-indol-1-yl}methyl)benzoic acid Example 64-({3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(cyclopentylsulfanyl)methyl ]-1H-indol-1-yl}methyl)benzoic acid Example 74-({3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(propylsulfanyl)methyl ]-1H-indol-1-yl}methyl)benzoic acid Ex...

Embodiment 12

[0166]Step 2 - The title compound was prepared from the intermediate of Step 1 following the procedure described in Example 1, Steps 8-10, using the appropriate thiol. Example 124-({5-[(3-carboxypropionyl)amino]-3-chloro-2-[(phenethylsulfanyl)methyl]-1H-indol-1-yl}methyl) Benzoic acid example 134-[(5-[(3-carboxypropionyl)amino]-3-chloro-2-{[(3-methylbenzyl)sulfanyl]methyl}-1H-indole- 1-yl)methyl]benzoic acid Example 14 4-({2-({[4-(tert-butyl)benzyl]sulfanyl}methyl)-5-[(3-carboxypropionyl)amino] -3-Chloro-1H-indol-1-yl}methyl)benzoic acid Example 15 4-({3-Chloro-5-(3-furanoylamino)-2-[(2-naphthylsulfanyl )methyl]-1H-indol-1-yl}methyl)benzoic acid

[0167] The title compound was prepared as described in Example 43 using the appropriate acylating reagent.

[0168] The following Examples 17-21 were prepared as described in Example 43 using the appropriate acylating reagent. Example 17 4-({3-chloro-5-{[3-(diethylamino)propionyl]amino}-2-[(2-naphthylsulfanyl)methyl]-1H-indole-1 ...

Embodiment 2

[0168] The following Examples 17-21 were prepared as described in Example 43 using the appropriate acylating reagent. Example 17 4-({3-chloro-5-{[3-(diethylamino)propionyl]amino}-2-[(2-naphthylsulfanyl)methyl]-1H-indole-1 - Base} methyl) benzoic acid example 18 4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(3-thienylcarbonyl)amino]-1H-ind Indol-1-yl}methyl)benzoic acid Example 19 4-({5-{[(benzylamino)carbonyl]amino}-3-chloro-2-[(2-naphthylsulfanyl)methyl] -1H-indol-1-yl}methyl)benzoic acid Example 204-({5-{[(butylamino)carbonyl]amino}-3-chloro-2-[(2-naphthylsulfanyl )methyl]-1H-indol-1-yl}methyl)benzoic acid Example 213-[({1-(4-carboxybenzyl)-3-chloro-2-[(2-naphthylsulfane Base)methyl]-1H-indol-5-yl}amino)carbonyl]benzoic acid Example 224-{[5-(benzyloxy)-2-[(E)-2-carboxyvinyl]-3 -(2-Naphthoyl)-1H-indol-1-yl]methyl}benzoic acid Step 1

[0169] Cool the solution of 2(tert-butyldimethylsilyloxymethyl)-5-benzyloxyindole (2.0g, 5.4mmol) in anhydrous ether (10ml) to -78°C, add ...

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Abstract

Novel compounds are disclosed which inhibit the activity of phospholipase enzymes, particularly cytosolic phospholipase A2. Pharmaceutical compositions comprising such compounds and methods of treatment using such compositions are also disclosed.

Description

Background of the invention [0001] The present invention relates to chemical inhibitors of the activity of various phospholipases, especially phospholipase A2. [0002] Leukotrienes and prostaglandins are important mediators of inflammation, each of which leads to inflammatory responses in different ways. Leukotrienes recruit inflammatory cells such as neutrophils to the site of inflammation, facilitate extravasation of these cells and stimulate the release of superoxides and proteases that damage the tissue. Leukotrienes also play a pathophysiological role in allergic reactions experienced in asthma [see B. Samuelson et al., Science, 237:1171-76 (1987)]. Prostaglandins aggravate inflammation by increasing blood flow and thus enhancing leukocyte infiltration to the inflamed site. Prostaglandins also exacerbate pain responses induced by stimuli. [0003] Prostaglandins and leukotrienes are unstable, are not stored in cells, but are synthesized from arachidonic acid in respon...

Claims

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Application Information

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IPC IPC(8): A61K31/40A61K31/403A61K31/404A61K31/4709A61K31/506A61K31/5377A61P29/00A61P43/00C07D209/10C07D209/12C07D209/14C07D209/18C07D209/30C07D209/42C07D401/12C07D403/04C07D403/06C07D403/12C07D405/12C07D409/12C07D409/14C07D413/04C07D417/10
CPCC07D401/12C07D209/30C07D209/12C07D403/12C07D405/12C07D409/14C07D209/42A61P29/00A61P43/00
Inventor J·S·赛拉N·凯拉J·C·麦库F·洛夫林J·E·贝米斯Y·B·向
Owner GENETICS INST INC
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