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Inflammatory cytokine release inhibitor

a cytokine release inhibitor and inflammatory technology, applied in the field of pharmaceutical compositions, can solve the problems of inconvenient long-term use, drug is also aspirin is not suitable for long-term use, so as to inhibit the activation of nf-b and avoid side effects.

Inactive Publication Date: 2008-12-25
INST OF MEDICINAL MOLECULAR DESIGN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention provides medications for the preventive and therapeutic treatment of inflammatory disorders and autoimmune diseases such as chronic arthritis and osteoporosis, which are caused by the production and release of inflammatory cytokines. The medications specifically target the inhibition of IKK-β, which is a protein that induces the production of inflammatory cytokines and contributes to the chronicity of inflammation. The invention provides compounds that inhibit IKK-β and prevent the formation of inflammatory cytokine-induced feedback loops. The compounds have inhibitory activity against NF-κB activation and are devoid of side effects. The invention also provides methods for identifying and synthesizing the compounds."

Problems solved by technology

However, since huge amount of aspirin needs to be administered to sufficiently suppress NF-κB activation, and as a result, since possibility of side effects such as gastrointestinal disorders by prostaglandin synthesis inhibition and increase of bleeding tendency by anticoagulation is expected with high probability, aspirin is not suitable for long term application.
However, long term use is not suitable, because they have serious side effects such as aggravation of an infectious disease, generation of peptic ulcer, degradation of bone density, and central action.
Leflunomide as an immunosuppressive agent, as an isoxazole-tripe agent, also has NF-κB inhibitory action (Manna S., et al., J. Immunol., 164, 2095-2102 (1999)), however, the drug is also not suitable for long term use due to serious side effects.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-5-bromo-2-hydroxybenzamide (Compound No. 1).

[0487]Under argon atmosphere, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (it is abbreviated as WSC.HCl hereafter; 192 mg, 1 mmol) was added to a mixture of 5-bromosalicylic acid (217 mg, 1 mmol), 3,5-bis(trifluoromethyl)benzylamine (243 mg, 1 mmol), 4-dimethylaminopyridine (12 mg, 0.1 mmol) and tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (244.5 mmg, 55.4%) as a white solid.

[0488]1H-NMR (DMSO-d6): δ 4.69 (211, d, J=5.7 Hz), 6.93 (1H, d, J=8.71 Hz), 7.56 (1H, dd, J=8.7, 2.4 Hz), 8...

example 2

5-Bromo-2-hydroxy-N-(2-phenethyl)benzamide (Compound No. 2)

[0489](1) 2-Acetoxy-N-(2-phenethyl)benzamide.

[0490]o-Acetylsalicyloyl chloride (0.20 g, 1.00 mmol) was dissolved in benzene (8 mL). Phenethylamine (0.12 g, 1.00 mmol) and pyridine (0.3 mL) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=2:1-1:1) to give the title compound (155.5 mg, 54.9%) as a white crystal.

[0491]1H-NMR (CDCl3): δ 2.09 (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).

(2) 2-Hydroxy-N-(2-phenethyl)benzamide.

[0492]Methanol (5 mL) and 2 N...

example 3

5-Bromo-2-hydroxy-N-[5-(morpholinocarbonyl)indan-2-yl]benzamide (Compound No. 3).

[0496]WSC.HCl (96 mg, 0.5 mmol) was added to a solution of 5-bromosalicylic acid (109 mg, 0.5 mmol), 2-amino-5-(morpholino)carboanyindan (refer to Chem. Pharm. Bull., 2000, 48, 131; 141 mg, 0.5 mmol) and triethylamine (70 μl, 0.5 mmol) in dichloromethane (5 mL), and the mixture was stirred at 40° C. for 1.5 hours. After cooling, the reaction mixture was diluted with ethyl acetate, washed with 2 N hydrochloric acid, water and brine one after another, dried over anhydrous magnesium sulfate, concentrated, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol=19:1) to give the title compound (26 mg, 11.9%) as a white crystal.

[0497]1H-NMR (CDCl3): 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 (5H, m), 4.79-4.92 (1H, m), 6.88 (1H, d, J=8.7 Hz), 7.14-7.15 (3H, m), 7.46 (1H, dd, J=8.7, 2.4 Hz), 7.74 (1H, d, J=7.8 Hz), 7.84 (1...

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Abstract

A medicament having inhibitory activity against NF-κB activation, which comprises a compound represented by the following general formula (I) or a pharmacologically acceptable salt as an active ingredient:wherein X represents a connecting group, A represents hydrogen atom or acetyl group, E represents an aryl group or a heteroaryl group, and ring X represents an arene or a heteroarene.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application is a Divisional of U.S. application Ser. No. 10 / 433,619, which is a National Stage of PCT / JP2001 / 011084, filed Dec. 18, 2001, which was not published in English under PCT Article 21(2), and which claims priority of Japanese Application No. 2000-383202, filed Dec. 18, 2000. The entire disclosure of application Ser. No. 10 / 433,619 is considered as being part of this application, and the entire disclosure of application Ser. No. 10 / 433,619 is expressly incorporated by reference herein in its entirety.FIELD OF INVENTION[0002]The present invention relates to pharmaceutical compositions having inhibitory activity against the production and release of inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor (TNF-α), and having inhibitory activity against the activation of NF-κB.BACKGROUND ART[0003]Inflammation is a basic defense mechanism to various infestations, where inflammatory cytokine ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/5375A61K31/498A61K31/44A61K31/403A61K31/404C07D265/30C07D241/36C07D211/72C07D209/56C07D209/04A61K31/055A61K31/12A61K31/136A61K31/166A61K31/167A61K31/17A61K31/18A61K31/357A61K31/415A61K31/421A61K31/422A61K31/428A61K31/433A61K31/47A61K31/505A61K31/695C07D207/32C07D207/327C07D209/08C07D209/34C07D209/42C07D209/80C07D209/88C07D213/64C07D213/65C07D213/75C07D215/12C07D215/38C07D231/40C07D239/22C07D241/44C07D263/48C07D277/24C07D285/08C07D321/10C07D333/16C07D333/38C07D413/14C07D471/04
CPCA61K31/055A61K31/12A61K31/136A61K31/166A61K31/167A61K31/17A61K31/18A61K31/357A61K31/403A61K31/404A61K31/415A61K31/421A61K31/422A61K31/428A61K31/433A61K31/44A61K31/47A61K31/498A61K31/505A61K31/5375A61K31/695C07D207/327C07D209/08C07D209/34C07D209/42C07D209/80C07D209/88C07D213/64C07D213/65C07D213/75C07D215/12C07D215/38C07D231/40C07D239/22C07D241/44C07D263/48C07D277/24C07D285/08C07D321/10C07D333/16C07D333/38C07D413/14C07D471/04A61P1/00A61P1/04A61P1/16A61P1/18A61P11/00A61P11/06A61P13/12A61P15/00A61P17/00A61P17/06A61P17/14A61P19/02A61P19/06A61P19/10A61P21/00A61P21/02A61P21/04A61P25/28A61P27/02A61P29/00A61P3/00A61P3/10A61P31/04A61P31/10A61P31/12A61P31/14A61P35/00A61P35/02A61P3/04A61P3/06A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P7/02A61P9/00A61P9/10A61P9/12A61K31/16
Inventor MUTO, SUSUMUNAGANO, TATSUOSOTOME, TOMOMIITAI, AKIKO
Owner INST OF MEDICINAL MOLECULAR DESIGN
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