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tlr4/md2 inhibitors and their application in anti-inflammatory drugs

A technology of anti-inflammatory drugs and inhibitors, which is applied in the field of new TLR4/MD2 inhibitors, can solve the problems of unreported structure and pharmacological activity, etc., and achieve clear anti-inflammatory effects, inhibit release, and strong effects

Active Publication Date: 2020-02-18
SHANXI MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] 4-(5-Dimethylamino-1-naphthalene)sulfonyloxybenzoxazol 2-one (DSB) and its derivatives N-substituted-4-(5-dimethylamino-1-naphthalene)sulfonyl Oxybenzoxazole 2-ketone compounds are a class of new structural compounds independently designed and synthesized by the inventors, and their structures and pharmacological activities have not been reported at home and abroad

Method used

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  • tlr4/md2 inhibitors and their application in anti-inflammatory drugs
  • tlr4/md2 inhibitors and their application in anti-inflammatory drugs
  • tlr4/md2 inhibitors and their application in anti-inflammatory drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1: Preparation and structural confirmation of compound 4-(5-dimethylamino-1-naphthalene)sulfonyloxybenzoxazol-2-one (DSB)

[0045] Weigh 500 mg of the compound 4-hydroxybenzoxazolone and dissolve it in 30 mL of anhydrous acetone, gradually add 500 μL of acid-binding agent triethylamine dropwise, react in an ice bath for 30 minutes, and slowly add 5-dimethylamino-1-naphthalene dropwise 20 mL of anhydrous acetone solution of 900 mg of sulfonyl chloride, reacted at room temperature for 30 min, then refluxed at 55°C for 6 h, evaporated the solvent, and separated by column chromatography to obtain the target compound 4-(5-dimethylamino-1-naphthalene)sulfonyl Oxybenzoxazol-2-one (DSB) 700mg.

[0046] Structural characterization: molecular formula C 19 h 16 N 2 o 5 S (384.08g / mol); Yellow powder; Yield (%): 65.3%; mp (°C): 164.3-166.4°C; ESI-MS (m / z): 385.17 ([M+H]+); 1 H NMR (600MHz, CDCl 3 ):δ3.05(s,6H,CH 3 ), 6.44(d, J=8.4Hz, 1H, Ar-5-H), 6.83(t, 1H, J=8.4Hz,...

Embodiment 2

[0047] Example 2: Preparation and structural confirmation of compound N-benzyl-4-(5-dimethylamino-1-naphthalene)sulfonyloxybenzoxazol-2-one (DSB-2)

[0048] Weigh 50 mg of 4-(5-dimethylamino-1-naphthalenesulfonyloxy)benzoxazol-2-one (DSB) in a 50 mL eggplant-shaped bottle, dissolve in 20 mL of anhydrous acetone, add 96.9 mg of Water K 2 CO 3 In the reaction system, after reacting at room temperature for 30 minutes, add twice the equivalent of benzyl bromide, reflux at 60° C. for 6 hours, and monitor the end point of the reaction by TLC. Filter to remove solid K 2 CO 3 , spin to dry the solvent, take ethyl acetate / petroleum ether (1:9) as the eluent system, separate and purify by column chromatography to obtain the target compound N-benzyl-4-(5-dimethylamino-1-naphthalene)sulfonyl Oxybenzoxazol-2-one (DSB-2).

[0049] Structural characterization: molecular formula C 26 h 22 N 2 SO 5 , the yield is 51.40%; mp.162.0~164.8℃; the property is bright yellow solid powder; 1 ...

Embodiment 3

[0050] Example 3: Preparation and structural confirmation of the compound N-phenethyl-4-(5-dimethylamino-1-naphthalene)sulfonyloxybenzoxazol-2-one (DSB-3)

[0051] Weigh 100mg of 4-(5-dimethylamino-1-naphthalenesulfonyloxy)benzoxazol-2-one (DSB) into a 50mL eggplant-shaped bottle, dissolve it in 30mL of anhydrous acetone, add 120mg of anhydrous K 2 CO 3 In the reaction system, after reacting at room temperature for 45 minutes, add twice the equivalent of phenethyl bromide, reflux at 65° C. for 8 hours, and monitor the end point of the reaction by TLC. Filter to remove solid K 2 CO 3 , spin to dry the solvent, take ethyl acetate / petroleum ether (2:8) as the eluent system, separate and purify by column chromatography to obtain the target compound N-phenethyl-4-(5-dimethylamino-1-naphthalene)sulfonate Acyloxybenzoxazol-2-one (DSB-3).

[0052] Structural characterization: molecular formula C 27 h 24 N 2 SO 5 , yield 39.03%; mp.141.8~145.3°C; property is yellow-green solid...

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Abstract

The invention relates to a novel anti-inflammatory drug, in particular to TLR4 / MD2 inhibitors, i.e., compounds N-substituted-4-(5-dimethylamino-1-naphthalene)sulfonyl oxy benzoxazole-2-one and application thereof in anti-inflammatory drugs. The compounds provided by the invention can significantly inhibit the release of NO and inflammatory cytokines IL-1 beta and IL-6 of lipopolysaccharide (LPS) induced mouse macrophages, can remarkably inhibit the expression of TLR4, MYD88 and IRAK4 in a TLR4 inflammatory signaling pathway, and prevents NF-k kappa B from entering nucleus, thereby inhibiting the expression of inflammatory effector molecules COX2 and IL-6 and further exerting anti-inflammatory activity; the compounds can significantly inhibit xylene-induced ear swelling in mice, and has higher efficacy compared with the clinically commonly used anti-inflammatory drug-celecoxib at the same dose; the compounds can obviously inhibit the release of mouse lung tissue inflammatory cytokines induced by LPS; the compounds can significantly inhibit the joint swelling and expression of inflammatory factors thereof in rats with collagen-induced arthritis, and is better in curative effect compared with the clinically commonly used anti-arthritic drug-phenylbutazone; the maximum oral tolerance is 5000 mg / kg, and the compounds are basically non-toxic compounds.

Description

technical field [0001] The present invention relates to a novel TLR4 / MD2 inhibitor, specifically a class of compound N-substituted-4-(5-dimethylamino-1-naphthalene)sulfonyloxybenzoxazol-2-one and its anti-inflammatory effect Application in inflammatory drugs. Background technique [0002] Inflammation is a defense response of the body against external infection or injury. However, when the inflammatory factors, such as NO, IL-1β, IL-6 and TNF-α, are not cleared in time, the damaged tissues and organs fail to After being repaired, inflammation seriously affects people's life and study, and becomes a common clinical disease. Inflammation occurs in multiple tissues and organs, such as pneumonia, nephritis, tonsillitis, and is closely related to the occurrence and development of various diseases, such as asthma, rheumatoid arthritis, gynecological diseases, atherosclerosis, diabetes, neurodegenerative diseases , kidney disease, cancer, etc. It has many pathological sites, var...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D263/58A61K31/423A61P29/00A61P25/28A61P19/02A61P11/00A61P1/00A61P15/14
CPCC07D263/58
Inventor 李青山唐莉罗捷然王晓燕赵蓓韩玲革班树荣梁泰刚赵晶晶
Owner SHANXI MEDICAL UNIV
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