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Acetylenic alpha-amino acid-based sulfonamide hydroxamic acid tace inhibitors

a technology of acetyl aryl sulfonamide and tace inhibitor, which is applied in the direction of phosphorous compound active ingredients, biocide, group 5/15 element organic compounds, etc., can solve the problems of bioavailability and pharmacokinetic problems

Inactive Publication Date: 2005-05-26
WYETH HOLDINGS CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although a variety of TACE inhibitors are known, many of these molecules are peptidic and peptide-like which suffer from bioavailability and pharmacokinetic problems.
In addition, many of these molecules are non-selective, being potent inhibitors of matrix metalloproteinases and, in particular, MMP-1.

Method used

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  • Acetylenic alpha-amino acid-based sulfonamide hydroxamic acid tace inhibitors
  • Acetylenic alpha-amino acid-based sulfonamide hydroxamic acid tace inhibitors
  • Acetylenic alpha-amino acid-based sulfonamide hydroxamic acid tace inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

4-But-2-ynyloxy-benzenesulfonic Acid Sodium Salt

[0452] To a solution of 52.35 g (0.225 mol) of 4-hydroxybenzenesulfonate sodium salt in 1 L of isopropanol and 225 mL of a 1.0N solution of sodium hydroxide was added 59.96 g (0.45 mol) of 1-bromo-2-butyne. The resulting mixture was heated to 70° for 15 h and then the isopropanol was removed by evaporation in vacuo. The resulting white precipitate was collected by filtration, washed with isopropanol and ether and dried in vacuo to give 56.0 g (100%) of the butynyl ether as a white solid.

example 2

4-But-2-ynyloxy-benzenesulfonyl Chloride

[0453] To a 0° solution of 43.8 mL (0.087 mol) of 2M oxalyl chloride / dichloroethane solution in 29 mL of dichloromethane was dropwise added 6.77 mL (0.087 mol) of DMF followed by 7.24 g (0.029 mol) of the product of Example 1. The reaction mixture was stirred for 10 minutes at 0° then let warm to room temperature and stirred for 2 days. The reaction was then poured into ice and extracted with 150 mL of hexanes. The organics were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 6.23 g (88%) of the sulfonyl chloride as a yellow solid; m.p. 63-65° C. EI Mass Spec: 243.9 (M+).

example 3

But-2-ynyloxy-benzene

[0454] To a solution of 6.14 g (0.023 mol) of triphenylphosphine dissolved in 100 mL of benzene and 40 mL of THF was added 1.75 mL (0.023 mol) of 2-butyn-1-ol. After five minutes 2.00 (0.023 mol) phenol, dissolved in 10 mL of THF, was added to the reaction followed by 3.69 mL (0.023 mol) of diethyl azodicarboxylate. The resulting reaction mixture was stirred for 18 h at room temperature and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate / hexanes (1:10) to provide 2.18 g (70%) of the butynyl ether as a clear liquid. EI Mass Spec: 146.0 MH+

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Abstract

Compounds of the formula: are useful in treating disease conditions mediated by TNF-α, such as rheumatoid arthritis, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, Crohn's disease and degenerative cartilage loss.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 60 / 155,249, filed Jan. 27, 1999.FIELD OF INVENTION [0002] This invention relates to acetylenic aryl sulfonamide hydroxamic acids which act as inhibitors of TNF-α converting enzyme (TACE). The compounds of the present invention are useful in disease conditions mediated by TNF-α, such as rheumatoid arthritis, osteoartis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, Crohn's disease and degenerative cartilage loss. BACKGROUND OF THE INVENTION [0003] TNF-α converting enzyme (TACE) catalyzes the formation of TNF-α from membrane bound TNF-α precursor protein. TNF-α is a pro-inflammatory cytokine that is believed to have a role in rheumatoid arthritis [Shire, M. G.; Muller, G. W. Exp. Opin. Ther. Patents 1998, 8(5), 531; Grossman, J. M.; Brahn, E. J. Women's Health 1997, 6(6), 627; Isomaki, P.; Punnonen, J. Ann. Med 1997, 29, 499; Camussi, G.; Lupia, E. Drugs, 1998, 55(5), 613.] septic shock [Mathison, e...

Claims

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Application Information

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IPC IPC(8): A61K31/5375A61K31/54C07C311/29C07D213/68C07D279/10C07D279/12C07D309/12C07F9/36
CPCA61K31/5375A61K31/54C07C311/29C07C2101/04C07F9/36C07D279/10C07D279/12C07D309/12C07D213/68C07C2601/04
Inventor LEVIN, JEREMY I.CHEN, JAMES M.COLE, DEREK C.DU, MILA T.LAAKSO, LEIF M.
Owner WYETH HOLDINGS CORP
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