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Nonsteroidal antiinflammatories

An inflammation and drug technology, applied in the field of non-steroidal compounds, which can solve the problems of impossible anti-inflammatory effect and metabolic effect

Inactive Publication Date: 2004-10-20
SCHERING AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In animal experiments, however, these compounds did not exhibit any of the advantages associated with steroidal glucocorticoids, i.e., it was not possible to separate the anti-inflammatory effects from metabolic effects, such as suppression of adrenal function

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0329] Embodiment 1 (method 1)

[0330] 5-{2-Hydroxy-3-[1-(2-methoxyphenyl)-cyclopropyl]-2-trifluoromethyl-propionamido}-o-hydroxymethylbenzoic acid lactone

[0331] 500 mg of 5-{3-[1-(2-methoxyphenyl)-cyclopropyl]-2-oxo-propionamido}-o-hydroxymethylbenzoic acid lactone was dissolved in 15 mL of di methylformamide, and mixed with 0.77 ml of trifluoromethyl-trimethylsilane and 500 mg of cesium carbonate under ice cooling. After stirring at room temperature for 18 hours, 5 ml of a 1 mol / L tetrabutylammonium fluoride solution in tetrahydrofuran was added, a few drops of water were added, and the mixture was stirred at room temperature for one hour. After addition of 100 ml of water, extraction is carried out with ethyl acetate, the organic phase is dried over sodium sulfate and concentrated by evaporation. The crude product is chromatographed on silica gel. Elution with hexane / ethyl acetate (80:20) afforded the pure title compound.

[0332] The mixture o...

Embodiment 2

[0336] 5-{3-[1-(5-Fluoro-2-methoxyphenyl)-cyclopropyl]-2-hydroxy-2-trifluoromethyl-propionamido}-o-hydroxymethylbenzoic acid lactone

[0337] By 5-{3-[1-(5-fluoro-2-methoxyphenyl)-cyclopropyl]-2-oxo-propionamido}-o-hydroxymethylbenzoic acid lactone by similar to Example 1 The method is obtained, its flash point is 170-179 ° C (racemate).

Embodiment 3

[0338] Embodiment 3 (method 2)

[0339] 5-[2-Hydroxy-4-(2-methoxyphenyl)-4-methyl-2-trifluoromethyl-pentanamido]-o-hydroxymethylbenzoic acid lactone

[0340] 400 mg of 2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-trifluoromethyl-pentanoic acid in 5 mL of dimethylacetamide at 0 °C with 0.23 mL of thionyl chloride mix. After stirring at 0°C for 30 minutes, 390 mg of 5-aminophthalide in 2 ml of dimethylacetamide were added and the mixture was stirred at this temperature for a further 4 hours. Then ice water was added, extraction was carried out with ethyl acetate, and after drying over sodium sulfate, the crude product was chromatographed on silica gel. Elution with hexane / ethyl acetate (50:50) gave the title compound as crystals with a flash point of 134-135°C.

[0341] After separation of the racemate, the obtained

[0342] (+)-enantiomer with a flash point of 135-136°C, [α] D +192.2° (c=1, CHCl 3 )

[0343] (-)-enantiomer with a flash point of 136-...

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Abstract

The invention relates to the use of compounds of general formula (I), wherein A, B, A, Ar, R<1>, R<2> and R<3> have the meanings detailed more closely in the description, for producing medicaments with an antiinflammatory action. The compounds of general formula (I) show a clear dissociation between antiinflammatory and metabolic effects.

Description

technical field [0001] The present invention relates to the use of non-steroidal compounds for the manufacture of medicaments with anti-inflammatory activity and to the non-steroidal compounds themselves. Background technique [0002] In addition to many steroidal compounds (glucocorticoids) that bind well to the glucocorticoid receptor and have anti-inflammatory effects, non-steroidal compounds are also known to bind to the glucocorticoid receptor, however they have not yet shown inflammation suppression [See Nature Medicine 4 (1998) 92, Mol. Pharmacol. 52 (1997) 571]. In addition, non-steroidal compounds derived from steroidal compounds have been described to have affinity for the glucocorticoid receptor and may have anti-inflammatory effects mediated through this receptor [J.Med.Chem.36, 3278- 3285]. In animal tests, however, these compounds did not exhibit any of the advantages associated with steroidal glucocorticoids, ie it was not possible to separate the anti-infla...

Claims

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Application Information

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IPC IPC(8): C07D237/32A61K31/16A61K31/165A61K31/343A61K31/365A61K31/38A61K31/381A61K31/50A61K31/502A61K31/535A61K31/536A61K31/5365A61P1/00A61P1/08A61P1/16A61P7/00A61P9/00A61P11/00A61P17/00A61P19/02A61P23/00A61P25/00A61P27/02A61P27/16A61P29/00A61P35/00A61P37/00C07D265/02C07D307/88C07D333/72
CPCC07D265/02A61K31/5365C07D307/88A61K31/502A61P1/00A61P1/08A61P1/16A61P11/00A61P17/00A61P19/02A61P23/00A61P25/00A61P27/02A61P27/16A61P29/00A61P35/00A61P37/00A61P7/00A61P9/00A61K31/343A61K31/536
Inventor 曼弗雷德·莱曼康拉德·克鲁利凯维奇维尔纳·斯库巴拉彼得·施特雷尔克弗兰克·卡尔克布伦纳罗兰·埃克尔特克劳迪娅·吉森
Owner SCHERING AG
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