CN103751167A - Application of benzyl-4-hydroxy-3,5-dimethoxy benzoate in preparation of drugs for treating or preventing rheumatoid arthritis - Google Patents

Abstract

The invention relates to the field of drugs, and particularly relates to a compound capable of inhibiting proteasomes and preventing and treating rheumatoid arthritis. The compound has the molecular structure of benzyl-4-hydroxy-3,5-dimethoxy benzoate. The compound has the beneficial effects that the compound can be used for treating rheumatoid arthritis, and has potential new drug development value.

Description

Benzyl-4-hydroxyl-3, the application of 5-dimethoxybenzoic acid ester in preparation treatment or prevention rheumatoid arthritis

technical field:

The present invention relates to drug world, be specifically related to the proteasome enzyme inhibition compound for preventing and treat or prevent rheumatoid arthritis.

background technology:

Rheumatoid arthritis (rheumatoid arthritis, RA) is one of clinical modal inflammatory arthropathy and main disability-causing factor.In the whole world, be about 0.5%-1.0%, the morbidity of RA is about 0.4% in China.RA can betide any age, and with advancing age, sickness rate also increases thereupon.Women is 45-55 year at the age occurred frequently, and sex and RA onset relation are close, men and women's the about 1:3 of ratio.RA is the chronic systemic inflammatory disease that a kind of cause of disease not yet understands, take pathological changes outside chronic, symmetry, many synovial jointss inflammation and joint as main clinical manifestation, belongs to autoimmune inflammatory diseases.Often take hand or wrist pain and swelling (the particularly swelling at wrist back), as onset symptoms, symptom continues not alleviate patient, though common symptomatic treatment can relief of symptoms, usually because medication is irregular or in shortagely cause symptom repeatedly.During disease progression, can there is deadlock in obvious morning, conventionally can reach more than 1 hour, and constantly increase the weight of; There is certain joint function disturbance simultaneously.

The medicine for the treatment of RA is divided into two large classes at present: control symptom medicine and control disease medicine.Due to RA etiology unknown, therefore there is no now, can be rated as the medicine of controlling disease.The antirheumatic of controlling symptom is divided into four classes: one, nonsteroidal antiinflammatory drug, be commonly referred to a line medicine, and this class drug kinds is various, and domestic market has reached tens of kinds.Two, steroid hormone, hormone is an extraordinary pain stop and anti-inflammation medicine, but long-term use separately can not improve the state of an illness, bring on the contrary many side effect, hormone is made transitionality before medication onset with being fine slowly as two wires, but consumption is little, and the time is unsuitable long.Heavier in the state of an illness, with the patient of extra-articular manifestation, short term therapy impacts, and necessary while combining the treatment of two wires medicine.Three, act on slowly antirheumatic, be commonly referred to two wires medicine, so-called slow effect medicated bag is drawn together antimalarial, golden salt, penicillamine and willow nitrogen sulfapyridine, and their treatment RA onsets are slow, and long term has certain mitigation to the RA state of an illness, therefore the feelings of also pretending illness are improved medicine.Four, immunosuppressant: commonly use and have methotrexate, cyclophosphamide, azathioprine, Radix Tripterygii Wilfordii, Caulis Sinomenii etc.

Proteasome (proteasomes) is ubiquitous in eukaryote and ancient bacterium, and in eukaryote, proteasome is arranged in nucleus and Cytoplasm.Main Function is the protein that degradation of cell is unwanted or sustain damage, and especially can participate in the running of adaptive immune system directly, and is playing the part of therein pivotal player.No matter to T cellular immunization, or B cellular immunization all plays positive facilitation.In addition, due to NF-κ B(anti-apoptosis and the proinflammatory disease regulatory factor of the active situation of proteasome participation generation, the expression of the regulating cell factor), therefore, it is relevant to inflammatory reaction and autoimmune disease that proteasome is considered to.The raising of proteasome activity level is relevant to the autoimmune disease of rheumatoid arthritis.

Therefore, proteasome enzyme inhibition thinks to treat the target spot of rheumatoid arthritis.However, the proteasome compound inhibitor of ripe exploitation does not come out, and is used for the treatment of rheumatoid arthritis.

  

summary of the invention:

The present invention seeks to the feature for existing proteasome compound inhibitor, design a kind of compound, can effectively treat or prevent rheumatoid arthritis.

technical scheme

Proteasome enzyme inhibition compound, is characterized in that its chemical constitution is benzyl-4-hydroxyl-3,5-dimethoxybenzoic acid ester, the application in treatment or prevention medicine for treating rheumatoid arthritis.

useful result:

Proteasome enzyme inhibition compound chemical structure in the present invention is benzyl-4-hydroxyl-3, and 5-dimethoxybenzoic acid ester can targeting proteasome enzyme inhibition, reaches the effect of prevention or treatment rheumatoid arthritis.

Inventor knows that through great many of experiments proteasome enzyme inhibition compound can suppress the development of adjuvant type rat kind rheumatic arthritis and DBA/1 mice collagen type rheumatoid arthritis, experimental results show that and have the arthritic effect of significant treatment rheumatoid type in body.Illustrate that proteasome enzyme inhibition compound of the present invention can be as treatment or prevention medicine for treating rheumatoid arthritis.

the chemical structural formula of compound

compoundbenzyl-4-hydroxyl-3,5-dimethoxybenzoic acid ester

The specific embodiment

Benzyl-4-hydroxyl-3,5-dimethoxybenzoic acid ester is purchased from sigma company.

Embodiment 1

Proteasome enzyme inhibition compound is immanoprotection action in collagen-induced mouse arthritis animal model

Build collagen type mouse arthritis animal model, the therapeutical effect of research proteasome enzyme inhibition compound to mice Collagen-induced Arthritis (collagen induced arthritis, CIA).Adopt mice as animal subject, 90 of SPF level DBA/1 mices (are provided by Shanghai western pul-Bi Kai laboratory animal company limited (Sino-British SIPPR Lab. Animal Ltd), animal production licence number: SCXK (Shanghai) 2008-0016), male, age in 7-8 week, body weight is 18-22 g, be divided at random 6 groups, it is respectively Normal group, model control group, low middle high 3 the dosage groups of compound (0.4,0.8,1.6 mg/kg) and positive drug control group (methotrexate 2 mg/kg).Except normal group, within the 0th day, each experimental group is set up mice CIA model, and method is chicken cartilage II Collagen Type VI (c II) becomes 4 mg/ml solution with 0.1 mol/l acetate dissolution, in 4 ℃ of refrigerator overnight.Experiment was fully emulsified with complete Freund's adjuvant (CFA) equal-volume containing 4 mg/ml Myeobaeterium tuberculosis strain H37Rv with II Collagen Type VI the same day, after DBA/1 mouse anesthesia, in every injection emulsifying agent of its afterbody Intradermal, 50 μ l carry out sensitization, carry out immunity again after fully emulsified with the II Collagen Type VI (c II) of 4 mg/ml and incomplete Freund's adjuvant (IFA) equal-volume after 21 d with the emulsifying agent of same dose in afterbody.Modeling the 30th d plays subcutaneous injection administration: 3 dosage groups (0.4,0.8,1.6 mg/kg) of compound: every day twice, continuous 10 days; Positive drug control group (methotrexate 2 mg/kg): every five days once, continuous 3 times; Normal group and model control group (normal saline): continuous 10 days.Respectively within after modeling the 21st day to the 70th day every 3 days, weighing in, joint scoring, detect left and right metapedes ankle diameter respectively and observe medicine to the arthritic impact of mice collagen type.

Result: after modeling, mice is compared with normal mouse, latter the 27th day of immunity, CIA mice foot pawl redness, arthritis index scoring is increased, and model group 45-60 days is swelling peak, and model group started body weight from the 35th day to be increased hardly, and the later stage also has decline slightly.Proteasome enzyme inhibition compound immanoprotection action concrete outcome in collagen-induced mouse arthritis animal model is as follows:

The impact of proteasome enzyme inhibition compound on the left whole pawl swelling of mice collagen type arthritis, positive controls, the left back ankle diameter of the high, medium and low dosage group of proteasome enzyme inhibition compound and model group comparison, all have utmost point significant difference (P<0.01) experimental result to have statistical significance.The impact of proteasome enzyme inhibition compound on the right whole pawl swelling of mice collagen type arthritis, positive controls, the right back ankle diameter of the high, medium and low dosage group of proteasome enzyme inhibition compound and model group comparison, all have utmost point significant difference (P<0.01), experimental result has statistical significance.The impact of proteasome enzyme inhibition compound on collagen type arthritis mice clinical score, the basic, normal, high dosage group of compound extremity are marked significantly lower than model control group (P < 0.01), with relatively utmost point significant difference of model control group, experimental result has statistical significance.Proteasome enzyme inhibition compound affects collagen type arthritis Mouse Weight, the high, medium and low dosage group of compound body weight is significantly higher than model control group (P < 0.01), with relatively utmost point significant difference of model control group, experimental result has statistical significance.

Conclusion: proteasome enzyme inhibition compound has therapeutical effect to mice collagen type arthritis.

Embodiment 2

Proteasome enzyme inhibition compound is to immanoprotection action in adjuvant type rat arthritis animal model

Build adjuvant type rat arthritis animal model, the therapeutical effect of research proteasome enzyme inhibition compound to adjuvant-induced arthritis (Adjuvant arthritis, AA) rat.Adopt rat as animal subject, 90 of SPF level SD rats (are provided by Shanghai western pul-Bi Kai laboratory animal company limited (Sino-British SIPPR Lab. Animal Ltd), animal production licence number: SCXK (Shanghai) 2008-0016), male, body weight is 140 g-160 g, be divided at random 6 groups, it is respectively Normal group, model control group, low middle high 3 the dosage groups (0.2 of proteasome enzyme inhibition compound, 0.4,0.8 mg/kg) and positive drug control group (methotrexate 1 mg/kg).Except normal group, within the 0th day, each experimental group is set up rat AA model, and method is that the injection of wasting time fully afterwards in the left side of rat causes experimental animal model of CFA induced adjuvant arthritis in rats containing mycobacterium tuberculosis (H37RA, 10 mg/ml) complete Freund's adjuvant 0.08 ml of deactivation.Modeling plays subcutaneous injection administration on the 10th day: 3 dosage groups (0.2,0.4,0.8 mg/kg) of compound: every day twice, continuous 10 days; Positive drug control group (methotrexate 1 mg/kg): every five days once, continuous 3 times; Normal group and model control group (normal saline): continuous 10 days.Respectively at after modeling the 8th, 11,14,17,20,23 and 26 days, weigh in, joint scoring, detect left and right metapedes ankle diameter respectively and observe medicine to the arthritic impact of rat adjuvant type.

Result: after modeling, rat is compared with normal rat, the left back foot of AA rat can produce rapidly constitutional arthritis, occurs obvious swelling, and with festering; After about 10 d of right back foot, start to occur post-traumatic arthritis, the score value of scoring increases gradually; Ear's blood vessel hyperplasia is obvious simultaneously, obviously red and swollen; There is swelling in caudal articular process.Proteasome enzyme inhibition compound is immanoprotection action in adjuvanticity rat arthritis animal model, and concrete outcome is as follows:

The impact of proteasome enzyme inhibition compound on rat primary arthritis foot pawl swelling, the left back ankle diameter of basic, normal, high dosage group and the model group comparison of rat positive controls, proteasome enzyme inhibition compound, have utmost point significant difference (P<0.01); The left back ankle diameter of the basic, normal, high dosage group of proteasome enzyme inhibition compound and model group comparison, all have significant difference (P<0.05), and experimental result has statistical significance.The impact of proteasome enzyme inhibition compound on rat post-traumatic arthritis foot pawl swelling, rat positive controls, the right back ankle diameter of the basic, normal, high dosage group of proteasome enzyme inhibition compound and model group comparison, have significant difference (P<0.05).The impact of proteasome enzyme inhibition compound on adjuvant type rats with arthritis clinical score, the basic, normal, high dosage group of compound extremity are marked significantly lower than model control group (P < 0.05), all have statistical significance with model control group comparing difference.Proteasome enzyme inhibition compound is on the impact of adjuvant type rats with arthritis body weight, and the high, medium and low dosage group of compound body weight is significantly higher than model control group (P < 0.05), all has statistical significance with model control group comparing difference.

Conclusion: proteasome enzyme inhibition compound has therapeutical effect to AA rat arthritis.

  

Claims (1)

1. benzyl-4-hydroxyl-3, the application of 5-dimethoxybenzoic acid ester in treatment or prevention medicine for treating rheumatoid arthritis.