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Inhibitors against the activation of AP-1 and NFAT

A technology of AP-1, compound, applied in the direction of anti-inflammatory agent, digestive system, antifungal agent, etc., can solve unknown problems, etc.

Inactive Publication Date: 2005-08-24
INST OF MEDICINAL MOLECULAR DESIGN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it was not known that N-phenylsalicylamide derivatives could inhibit the activation of AP-1 or NFAT in the past

Method used

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  • Inhibitors against the activation of AP-1 and NFAT
  • Inhibitors against the activation of AP-1 and NFAT
  • Inhibitors against the activation of AP-1 and NFAT

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0511] Example 1: Production of compound of compound number 1

[0512] In argon, in 5-bromosalicylic acid (217mg, 1mmol), 3,5-bis(trifluoromethyl)benzylamine (243mg, 1mmol), 4-dimethylaminopyridine (12mg, 0.1mmol), To the mixture of tetrahydrofuran (10ml), add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (hereinafter referred to as WSC·HCl; 192mg, 1mmol), and stir at room temperature 1 hour. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, saturated brine, dried over anhydrous magnesium sulfate, and the residue obtained by distillation under reduced pressure was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4:1) to obtain the title compound as a white solid (244.8 mg, 55.4%).

[0513] 1 H-NMR(DMSO-d 6 ): δ 4.69 (2H, d, J = 5.7 Hz), 6.93 (1H, d, J = 8.7 Hz), 7.56 (1H, dd, J = 8.7, 2.4 Hz), 8.02 (1H, d, J = 2.4 Hz), 8.06 (3H, s), 9.41 (1H, t, J=5.7 Hz), 12...

Embodiment 2

[0514] Example 2: Production of compound of compound number 2

[0515] (1) 2-Acetoxy-N-(2-phenethyl)benzamide

[0516] To a benzene (8ml) solution in which O-acetylsalicylic chloride (0.20g, 1.00mmol) was dissolved, phenethylamine (0.12g, 1.00mmol) and pyridine (0.3ml) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1) to obtain White crystals of the title compound (155.5 mg, 54.9%).

[0517]1 H-NMR(CDCl 3 ): δ2.09 (3H, s), 2.92 (2H, t, J=6.8 Hz), 3.71 (2H, q, J=6.8 Hz), 6.32 (1H, brs), 7.07 (1H, dd, J= 8.4, 1.2 Hz), 7.23-7.35 (6H, m), 7.44 (1H, ddd, J=8.0, 7.6, 1.6 Hz), 7.73 (1H, dd, J=7.6, 1.6 Hz).

[0518] In the following exam...

Embodiment 3

[0526] Example 3: Production of compound of compound number 3

[0527] Containing 5-bromosalicylic acid (109mg, 0.5mmol), 2-amino-5-(morpholino)carbonylindan (141mg, 0.5mmol), triethylamine (70μl, 0.5mmol) in dichloromethane ( 5ml) solution was added WSC·HCl (96mg, 0.5mmol), heated and stirred at 40°C for 1.5 hours. After cooling, it was diluted with ethyl acetate, washed sequentially with 2N hydrochloric acid, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated, and the residue was subjected to silica gel column chromatography (dichloromethane: methanol = 19:1 ) Purification to obtain the title compound as a white solid (26 mg, 11.9%).

[0528] 1 H-NMR(CDCl 3 ): δ 2.66 (1H, dd, J = 16.2, 7.2 Hz), 2.82 (1H, dd, J = 16.2, 7.2 Hz), 3.16-3.25 (2H, m), 3.43-3.86 (8H, m), 4.79-4.92 (1H, m), 6.88 (1H, d, J=8.7Hz), 7.14-7.15 (3H, m), 7.46 (1H, dd, J=8.7, 2.4Hz), 7.74 (1H, d, J=7.8 Hz), 7.84 (1H, d, J=2.4 Hz).

[0529] [2-Amino-5-(morpholino)carbonylindan:...

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Abstract

A medicament inhibiting the activation of AP-1 which comprises as an active ingredient a substance selected from the group consisting of a compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof: wherein X represents a connecting group whose number of atoms in the main chain is 2 to 5 (said connecting group may be substituted), A represents hydrogen atom or acetyl group, E represents an aryl group which may be substituted or a hetero aryl group which may be substituted, ring Z represents an arene which may have one or more substituents in addition to the group represented by formula -O-A wherein A has the same meaning as that defined above and the group represented by formula -X-E wherein each of X and E has the same meaning as that defined above, or a heteroarene which may have one or more substituents in addition to the group represented by formula -O-A wherein A has the same meaning as that defined above and the group represented by formula -X-E wherein each of X and E has the same meaning as that defined above.

Description

Technical field [0001] The present invention relates to a medicine for inhibiting activator protein-1 (AP-1) or nuclear factor of activated T-cells (NFAT). Background technique [0002] N-phenyl salicylamide derivatives are described as plant growth inhibitors in the specification of U.S. Patent No. 4358443, and as medicines in the specification of European Patent No. 0221211, JP 62-99329 and U.S. Patent No. 6117859 The specification discloses that it can be used as an anti-inflammatory agent. In addition, International Publication No. 99 / 65499, International Publication No. 02 / 49632 and International Publication No. 02 / 076918 are used as NF-κB (nuclear factor-κB) inhibitors in International Publication No. 02 / 051397 No. Document is revealed as an inhibitor of cytokine production. However, it is not known that N-phenylsalicylamide derivatives can inhibit the activation of AP-1 or NFAT in the past. Summary of the invention [0003] The mechanism that people already know is that i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/00A61K31/055A61K31/121A61K31/15A61K31/166A61K31/167A61K31/17A61K31/18A61K31/185A61K31/192A61K31/216A61K31/222A61K31/275A61K31/357A61K31/381A61K31/402A61K31/403A61K31/4035A61K31/404A61K31/4164A61K31/421A61K31/426A61K31/433A61K31/437A61K31/44A61K31/4402A61K31/4406A61K31/4418A61K31/445A61K31/4453A61K31/47A61K31/496
CPCA61K31/4402A61K31/437A61K31/47A61K31/381A61K31/496A61K31/275A61K31/185A61K31/222A61K31/403A61K31/426A61K31/433A61K31/192A61K31/167A61K31/404A61K31/402A61K31/166A61K31/216A61K31/17A61K31/18A61K31/4035A61K31/4453A61K31/055A61K31/357A61K31/445A61K31/4418A61K31/44A61K31/421A61K31/00A61K31/4406A61K31/4164A61K31/15A61K31/121A61P1/02A61P1/04A61P1/14A61P1/16A61P1/18A61P3/02A61P3/04A61P3/06A61P3/10A61P9/00A61P9/10A61P9/12A61P11/00A61P11/06A61P13/12A61P17/00A61P17/04A61P17/06A61P17/14A61P19/02A61P19/06A61P19/10A61P21/00A61P25/00A61P25/08A61P27/02A61P29/00A61P31/04A61P31/10A61P31/12A61P31/18A61P35/00A61P35/02A61P37/00A61P37/08
Inventor 武藤进板井昭子
Owner INST OF MEDICINAL MOLECULAR DESIGN
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