Heterocyclo-substituted imidazoles for the treatment of inflammation

Inactive Publication Date: 2005-05-05
GD SEARLE & CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential.
An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.

Method used

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  • Heterocyclo-substituted imidazoles for the treatment of inflammation
  • Heterocyclo-substituted imidazoles for the treatment of inflammation
  • Heterocyclo-substituted imidazoles for the treatment of inflammation

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0839]

2-(4-Chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole

Step 1: Preparation of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide

[0840] To a suspension of 4-(methylsulfonyl)aniline (7 g, 41 mmol) in toluene (400 mL), trimethylaluminum (2M solution in toluene, 30.5 mL, 61 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 4-chlorobenzonitrile (11.3 g, 82 mmol) in toluene (200 mL) was added over 10 minutes and the reaction mixture was heated to 80-85° C. After 16 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride / methanol. The combined filtrates were concentrated in vacuo and the resulting yellowish solid was stirred with a mixture of hexane / ether (2 / 1, 1000 mL). The intermediate was filtered and washed with mo...

example 2

[0842]

2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole

[0843] A mixture of 2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole from Example 1 (6.2 g, 15.4 mmol) and p-toluenesulfonic acid monohydrate (0.9 g, 4.7 mmol) in toluene (300 mL) was heated to reflux for 84 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude residue was redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentrating in vacuo, the crude mixture was purified by chromatography on silica gel using hexane / ethyl acetate (1 / 1) to give pure 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole (4.21 g, 71%) as a white solid: mp (DSC) 183° C. Anal. Calc'd. for C17H12N2SO2F3Cl: C, 50.94, H, 3.02, N, 6.99. Found: C, 50.64, H, 3.03, N, 6.85.

example 3

[0844]

1-(4-Fluorophenyl)-4-hydroxy-2-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole

Step 1: Preparation of 4-methylsulfonyl-N-[4-chlorophenyl]benzenecarboximidamide

[0845] To a suspension of 4-fluoroaniline (4 mL, 40 mmol) in toluene (120 mL), trimethylaluminum (2M solution in toluene, 21 mL, 42 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 3 hours. A solution of 4-(methylsulfonyl)benzonitrile (7.65 g, 40 mmol) in methylene chloride (100 mL) was added over 10 minutes and the reaction mixture was heated to 70-75° C. After 48 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride / methanol. The combined filtrates were concentrated in vacuo and the resulting crude intermediate (7.7 g) was purified by chromatography [silica gel, hexane / ethyl acetate, 25 / 75] to give 4-methyls...

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Abstract

A class of imidazolyl compounds is described for use in treating inflammation. Compounds of particular interest are defined by formula (V), wherein R3 is a radical selected from hydrido, alkyl, haloalkyl, aralkyl, heterocycloalkyl, heteroaralkyl, acyl, cyano, alkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylthio, cycloalkylthioalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, haloalkylsulfonyl, arylsulfonyl, halo, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heterocyclocarbonyl, cyanoalkyl, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-alkyl-N-arylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, haloalkylcarbonyl, carboxyl, aminocarbonyl, alkylaminocarbonyl, alkylaminocarbonylalkyl, heteroarylalkoxyalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, aralkoxy, aralkylthio, heteroaralkoxy, heteroaralkylthio, heteroarylalkylthioalkyl, heteroaryloxy, heteroarylthio, arylthioalkyl, aryloxyalkyl, arylthio, aryloxy. aralkylthioalkyl, aralkoxyalkyl, aryl and heteroaryl; wherein R4 is a radical selected from hydrido, alkyl and halo; and wherein R13 and R14 are independently selected from aryl and heterocyclo, wherein R13 and R14 are optionally substituted at a substitutable position with one or more radicals independently selected from alkylsulfonyl, aminosulfonyl, halo, alkylthio, alkyl, cyano, carboxyl, alkoxycarbonyl, haloalkyl, hydroxyl, alkoxy, hydroxyalkyl, alkoxyalkyl, haloalkoxy, amino, alkylamino, arylamino and nitro; provided at least one of R13 and R14 is aryl substituted with alkylsulfonyl or aminosulfonyl; or a pharmaceutically-acceptable salt thereof.

Description

RELATED CASE [0001] This is a continuation-in-part of International Application PCT / US95 / 09506, with an international filing date of Jul. 27, 1995, which is a continuation-in-part of patent application Ser. No. 08 / 464,154, with a filing date of Jun. 5, 1995, which is a continuation-in-part of patent application Ser. No. 08 / 282,395, with a filing date of Jul. 28, 1994.FIELD OF THE INVENTION [0002] This invention is in the field of antiinflammatory pharmaceutical agents and specifically relates to compounds, compositions and methods for treating inflammation and inflammation-associated disorders, such as arthritis. BACKGROUND OF THE INVENTION [0003] Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG2, PGH2 and PGE2, has been a common target of antiinflammatory drug discovery. However, common non-steroidal antiinflammatory drugs (NSAIDs) that are active in reducing the prostaglandin-induced pain and ...

Claims

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Application Information

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IPC IPC(8): A61K31/4178A61K31/4439A61K31/4709A61K31/5377C07D233/32C07D233/54C07D233/90C07D401/04C07D403/04C07D405/04C07D409/04C07D413/02C07D419/04
CPCC07D233/32C07D233/64C07D233/90C07D419/04C07D403/04C07D405/04C07D409/04C07D401/04
Inventor KHANNA, ISH K.WEIER, RICHARD M.COLLINS, PAUL W.YU, YIXU, XIANGDONGPARTIS, RICHARD A.KOSZYK, FRANCIS J.HUFF, RENEE M.
Owner GD SEARLE & CO
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