Acetylenic sulfonamide thiol TACE inhibitors

A technology of butynyloxy and alkyl groups, applied in the preparation of thiols, active ingredients of amides, anti-inflammatory agents, etc., can solve the problems of bioavailability and pharmacokinetics.

Inactive Publication Date: 2005-10-26
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 peptides or peptoids, making their use difficult in terms of bioavailability and pharmacokinetics
Additionally, many of these molecules are nonselective as potent inhibitors of matrix metalloproteinases, especially MMP-1

Method used

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  • Acetylenic sulfonamide thiol TACE inhibitors
  • Acetylenic sulfonamide thiol TACE inhibitors
  • Acetylenic sulfonamide thiol TACE inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0170] 4-(2-Butynyloxy)-benzenesulfonic acid sodium salt

[0171] In a solution formed by 52.35g (0.225mol) of 4-hydroxybenzenesulfonic acid sodium salt in 1L of isopropanol and 225mL of 1.0N sodium hydroxide solution, add 59.96g (0.45mol) of 1-bromo-2-butane alkyne. The resulting mixture was heated to 70° for 15 hours, then the isopropanol was removed by evaporation in vacuo. The resulting white precipitate was collected by filtration, washed with isopropanol and diethyl ether, and dried in vacuo to yield 56.0 g (100%) of butynyl ether as a white solid.

Embodiment 2

[0173] 4-(2-Butynyloxy)-benzenesulfonyl chloride

[0174] 6.77mL (0.087mol) of DMF (N,N-dimethylformamide ), then add 7.24g (0.029mol) embodiment 1 product. The reaction mixture was stirred at 0° for 10 minutes, then allowed to warm to room temperature and stirred for 2 days. The reaction mixture was then poured into ice and extracted with 150 mL of hexane. The organics were washed with water and brine, washed with Na 2 SO 4 Drying, filtration, and concentration in vacuo yielded 6.23 g (88%) of yellow solid of sulfonyl chloride; mp 63-65° C., EI (electron impact) mass spectrometry: 243.9 (M + ).

Embodiment 3

[0176] 2-butynyloxy-benzene

[0177] In a solution formed by dissolving 6.14 g of triphenylphosphine (0.023 mol) in 100 mL of benzene and 40 mL of THF (tetrahydrofuran), 1.75 mL (0.023 mol) of 2-butyn-1-ol was added. After 5 minutes a solution of 2.00 (0.023 mol) phenol in 10 mL THF was added to the reaction mixture, followed by 3.69 mL (0.023 mol) of diethyl azodicarboxylate. The resulting reaction mixture was stirred at room temperature for 18 hours, then concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate / hexanes to give 2.18 g (70%) of butynyl ether as a clear liquid. EI (electron impact) mass spectrometry: 146.0MH + .

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Abstract

Compounds of formula (B): (1a), or (1b), (1c) are provided wherein the variables are as defined herein which are useful in disease conditions mediated by TNF- alpha , such as rheumatoid arthritis, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, Crohn's disease and degenerative cartilage loss.

Description

(1) Technical field [0001] The present invention relates to alkyaryl sulfonamide thiols as inhibitors of TNF-alpha converting enzyme (TACE). The compounds of the present invention are very useful in diseases mediated by TNF-α, such as rheumatoid arthritis, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, Crohn's disease and degenerative cartilage loss. (2) Background technology [0002] TNF-alpha converting enzyme (TACE) catalyzes the formation of TNF-alpha from membrane-bound TNF-alpha precursor protein. TNF-α is a pro-inflammatory cytokine, which is considered to play a major role in the following diseases: rheumatoid arthritis [Shire, M.G.; Muller, G.W.Exp.Opin.Ther.Patents 1998, 8 (5), 531; Grossman, J.M. Branhn, E.J. Woman'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 et al. J. Clin. Invest. 1988, 81, 1925; Miethke et al. J. Exp. Med. 1992, 175, 9...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/12A61KA61K31/18A61K31/5375A61PA61P1/04A61P3/10A61P9/00A61P9/04A61P19/02A61P25/00A61P25/28A61P29/00A61P31/04A61P31/18A61P37/00A61P37/06A61P43/00C07B53/00C07CC07C309/42C07C309/87C07C319/02C07C323/49C07C327/06C07C327/46C07DC07FC07F9/53
CPCC07C327/46C07C323/49C07C309/42A61K31/18A61K31/5375C07C1/00C07D295/12C07C319/02C07F1/00C07C309/87C07F9/53C07B53/00C07C327/06C07D295/13A61P1/04A61P19/02A61P25/00A61P25/28A61P29/00A61P31/04A61P31/18A61P37/00A61P37/06A61P43/00A61P9/00A61P9/04A61P3/10
Inventor J·I·莱文J·M·陈
Owner WYETH HOLDINGS CORP
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