CN104945269A - Rhein carboxylic acid esters derivative and appliance - Google Patents
Rhein carboxylic acid esters derivative and appliance Download PDFInfo
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- CN104945269A CN104945269A CN201510348492.8A CN201510348492A CN104945269A CN 104945269 A CN104945269 A CN 104945269A CN 201510348492 A CN201510348492 A CN 201510348492A CN 104945269 A CN104945269 A CN 104945269A
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Abstract
The invention discloses a rhein carboxylic acid esters derivative, wherein the structure of the rhein carboxylic acid esters derivative is (img file='dest_path_image 001.TIF' wi='252' he='116'/),( img file='dest_path_image 002.TIF' wi='296' he='158'/), and also discloses an appliance of the pharmaceutic preparation which adopts the rhein carboxylic acid esters derivative as active ingredients in drugs which are used to treat and prepare diabetic nephropathy, arthrophlogosis, gouty arthritis, rheumatic arthritis and systemic lupus erythematosus.
Description
Technical field
The present invention relates to a kind of rhubarb yellow ramification of carboxylic esters, and the application in treatment diabetic nephropathy, sacroiliitis, urarthritis, rheumatic arthritis, systemic lupus erythematous medicine.
Background technology
Rhubarb yellow (Rhein) is the main pharmacodynamics composition of Chinese herb rhubarb, belongs to dihydroxyanthraquinone carboxylic acid compound, has significant anti-inflammatory, the pharmacologically active such as antitumor.Can be used for arthritic treatment clinically.The medicine diacerein gone on the market, is the diacetyl derivatize product of rhubarb yellow, as the prodrug of rhubarb yellow, is used for the treatment of degenerative osteoarthritis.Research shows, rhubarb yellow is evident in efficacy in the control of diabetic nephropathy (diabetic nephropathy, DN), plays Mutiple Targets, multi-level therapeutic action in DN each phase.Research shows, rhubarb yellow can suppress the generation of IL, TNF, TGF, improves the problem of mesangial cell and vascular endothelial cell proliferation, thus improve the pathological condition of renal glomerulus from the angle of cytokine adjustment; On the other hand; rhubarb yellow is by changing kidney gene expression profile, protecting endotheliocyte, improve cellular metabolism, improving the effect (Yu Jia etc. that insulin resistant reaches treatment diabetic nephropathy; the bioactivity research progress of rhubarb yellow and derivative thereof; [J] pharmacy and clinical study; 2008,16(2): 125-128).CN1178669 discloses the purposes of the salts for treating DN of rhubarb yellow or rhubarb yellow, but rhubarb yellow is water insoluble, alcohol and majority of organic solvent, this high degree limit its make medicine for Clinical practice may.Oral Rhubarb acid can not completely by gastrointestinal absorption, and bioavailability is poor.Not exclusively remaining in GI rhubarb yellow is easily metabolized to anthrone by enteric microorganism in absorption, and this is the possible cause that the untoward reaction of diarrhoea occurs rhubarb yellow.In addition, rhubarb yellow also has the problems such as carinogenicity, bioavailability are low, therefore needs further to study it.CN200810203112.1, CN200910028008.8, US5330981, CN200580003634.1 disclose a large amount of rhubarb yellow ester derivative.
Summary of the invention
The invention provides a kind of rhubarb yellow ester derivative, structure is as follows:
；
。
Rhubarb yellow ester derivative of the present invention or its salt can per os or parenterai administrations, and dosage is had nothing in common with each other because of the difference of medicine, and for adult, every day, 1-500mg was proper.
The dosage form of oral administration administration comprises: the suspension, syrup, spirit, lozenge etc. of granule, tablet, capsule, moisture or oil-containing.Described peroral administration preparation makes rhubarb yellow ester derivative of the present invention or its salt adopt ordinary method mix and prepare with conventional pharmaceutical excipient such as vehicle, disintegrating agent, tackiness agent, lubricant, antioxidant, Drug coating, tinting material, perfume compound, tensio-active agent etc.; The dosage form of parenterai administration comprises: injection liquid, injection, suppository etc.When preparing above-mentioned preparation, conventional preparation technique preparation can be used.
Rhubarb yellow ester derivative of the present invention may be used for preparing the medicine for the treatment of and comprising the diseases such as diabetes, diabetic nephropathy, sacroiliitis, rheumatoid arthritis, urarthritis, systemic lupus erythematous.
Specific embodiment
The present invention will be further described in conjunction with the embodiments.
Help understand the present invention further by embodiment.Concrete material, species and condition used are all in order to demonstrate the invention, instead of limit zone of reasonableness of the present invention.There is steric isomer in what molecular structure of the present invention had, they are split by chiral reagent controlled syntheses or molecule or purified post obtains simple steric isomer, and these steric isomers all do not illustrate in the present embodiment but do not limit the present invention.
embodiment 1: the preparation of the rhubarb yellow amino ethyl ester described in this patent
(1) preparation of rhubarb yellow acyl chlorides
Take rhubarb yellow 2.5g, put in 500ml round-bottomed flask, add methylene dichloride 200ml, sulfur oxychloride 100ml, put 50 DEG C of oil bath pans and be heated to backflow, after stirring reaction 5h, solution becomes clear from muddiness, and recycling design obtains yellow solid powder.
(2) preparation of rhubarb yellow morpholine ethanol ester
Pressed powder 350ml toluene obtained for upper step is dissolved, put in 70 DEG C of oil baths and stir, by rhubarb yellow and monoethanolamine mol ratio (1:1), take 0.55g monoethanolamine to dissolve with a small amount of methylene dichloride, slowly be added drop-wise in reaction solution, regulate pH to alkalescence with triethylamine, solution becomes red-brown, reacts stopping in 2 hours.
(3) recrystallization
Wash above-mentioned reaction solution to water layer with water substantially colourless, reaction solution to 50 DEG C is revolved steaming evaporate to dryness, solid obtains faint yellow solid powder through re crystallization from toluene and is about 2.5g.
Molecular weight: 327, molecular formula is: C
17h
13nO
6.
Element Analyzing: C 62.38%, H 3.98%, N 4.28%, O 29.36%;
ESI-MS (m/s): 328[M+1]
+, 326[M-1]
+;
1H-NMR(CDCl3)δ: 12.22(1H, s), 11.39(1H, s), 7.46(1H, dd, J=7.5, 1.1Hz), 7.62(1H, d, J=1.5Hz), 7.53(1H, t, J=8.4Hz), 7.38(1H, dd, J=8.4, 1.1Hz), 7.39(1H, d, J=1.6Hz), 3.81(4H, s), 3.67(2H, s), 3.54(2H, s);
13C-NMR(CDCl3)δ: 191.4, 182.3, 167.4, 163.5, 161.3, 155.6, 147.6, 144.1, 138.4, 135.0, 132.6, 128.3, 117.9, 116.4, 115.7, 65.8, 48.0, 42.5。
embodiment 2: the preparation of the diacerein morpholine ethyl ester described in this patent
Diacerein: morpholine ethanol=1:1(mol ratio) feed intake, diacerein 3.68g pressed powder 350ml toluene dissolves, put in 80 DEG C of oil baths and stir, separately get a small amount of methylene dichloride of morpholine ethanol 1.31g to dissolve, slowly be added drop-wise in reaction solution, regulate pH to alkalescence with triethylamine, solution becomes red-brown, reacts stopping in 5 hours.
Wash above-mentioned reaction solution to water layer with water substantially colourless, reaction solution to 60 DEG C is revolved steaming evaporate to dryness, solid obtains faint yellow solid powder through re crystallization from toluene and is about 4.5g.
Molecular weight: 481, molecular formula is: C
25h
23nO
9.
Element Analyzing: C 62.37%, H 4.78%, N 2.91%, O 29.94%;
ESI-MS (m/s):482[M+1]
+, 481[M-1]
+;
1H-NMR(CDCl3)δ: 12.12(1H, s), 12.09(1H, s), 11.29(1H, s), 11.19(1H, s), 10.59(1H, s),7.68(1H, dd, J=7.5Hz), 7.62(1H, dd, J=6.5Hz), 7.59(1H, d, J=1.5Hz), 7.56(1H, t, J=8.4Hz), 7.48(1H, dd, J=8.4, 1.1Hz), 7.39(1H, d, J=1.6Hz), 7.27(1H, d, J=1.5Hz), 7.19(1H, d, J=1.6Hz),3.81(4H, s), 3.77(2H, s), 3.54(2H, s)，3.52 (2H, s);
13C-NMR(CDCl3)δ: 193.1, 191.2, 184.3,178.2，16,6.4, 163.5, 161.3,157.5 ,155.6, 153.1， 148.3, 146.5,144.7, 137.2, 136.1, 133.7, 129.7, 121.7, 117.8, 116.6, 66.7, 49.1, 45.8。
the anti-DN pharmacodynamic study of Rhein derivatives described in embodiment 3 this patent
(1) pharmacodynamic observation index: transforming growth factor (TGF-β) and fibronectin (FN).TGF-β and FN is the important cytokine in diabetic nephropathy (DN) pathogenic process.TGF-β known causes the strongest cytokine of sclerization in diabetic nephropathy, in vitro or in experiment in vivo, short-term blocks the increase of TGF-'beta ' activity energy T suppression cell epimatrix and alleviates renal fibrosis; FN is mainly distributed in extracellular matrix, form ECM(basilar membrane) one of two kinds of main non-collagen sugar albumen, just because of the excessive buildup of renal glomerulus Col IV, the normal ECM composition such as FN, LN during DN, just cause GBM to thicken and mesentery expansion, become the basis occurring degradation clinical symptom under proteinuria, renal function Progressive symmetric erythrokeratodermia.
(2) experimental technique: this vitro Drug shaker test, select TGF-β and FN as target index, mesangial cell under low sugar (simulation Normal group) and height sugar (simulation diabetic nephropathy model group) are cultivated, after the process of trial drug, the method for real-time fluorescence quantitative PCR is utilized to observe the expression of TGF-β and FN culture condition in vitro.In cultivating with high sugar in experiment TGF-β and FN be expressed as 1, the expression of Normal group (low sugar cultivations) and trial drug group with it than <1 for this drugs on cytokine has restraining effect, indicate that in vitro tests has good anti-DN activity; >1 person represents that In Vitro Anti DN activity is more weak to this cytokine unrestraint effect.In the expression experiment of cytokine, often kind of medicine carries out six groups of repeated samplings, and carries out statistical procedures.
(3) experimental result: the results are shown in Table 1.
Table 1 this patent medicine is to the TGF-β of mesangial cell and FN expression of results (n=6; X ±
s)
| Index | Low sugar control group | Model group | Rhubarb yellow amino ethyl ester | Diacerein morpholine ethyl ester |
| TGF | 0.623 | 1 | 0.735* | 0.633* |
| FN | 0.155 | 1 | 0.505 | 0.423 |
Compare with model group, * P<0.05.
(4) experiment conclusion: drugs on cytokine has remarkable restraining effect, indication in vitro tests has good anti-DN active.
rhein derivatives antigout sacroiliitis pharmacodynamic study described in embodiment 4 this patent
(1) observation index: sole of the foot volume × 100% before swelling rate (%)=(cause scorching metapedes sole of the foot volume-cause scorching front foot sole of the foot volume)/cause is scorching; Inhibitory rate of intumesce (%)=(model group toes swelling rate-administration group toes swelling rate)/model group swelling rate × 100%.
(2) experimental technique: experiment is divided into model control group, administration group.Often organize 10 rats, gavage every day 2 times, patent drug group gavage gives this patent Rhein derivatives, rhubarb yellow amino ethyl ester (YW-1) per daily dose 7.5mg/kg, diacerein morpholine ethyl ester (YW-2) 11 mg/kg, continuous 1 week, model group gave the physiological saline of same volume, regular supply food and water.After last administration, to model control group rat paw injection Monosodium urate, to cause after the administration of local organization swelling pain last 1 hour, first to make marks line with marking pen on the ankle joint of right side, right ankle joint is put into the test cup of toes capacity measurer to mark line place, record causes scorching front foot sole of the foot water displacement; Then toe position after 75% alcohol disinfecting Rat Right is used, the prior Monosodium urate solution 0.1ml (100mg/ml) prepared through sterilizing is injected rat paw is subcutaneous causes inflammation, measurement cause scorching after 1,2,3,4,5h measures Rat Right metapedes sole of the foot water displacement, by formulae discovery swelling rate; Tested each group is caused scorching rear 5 results averaged measured, calculate inhibitory rate of intumesce.
(3) experimental result: in table 2, table 3.
Table 2. this patent medicine causes the impact (n=10 of scorching rear pedal swelling degree to SD rat MSU toes; X ±
s)
Compare with model group, * P<0.05, * * P<0.01.
Table 3. this patent medicine causes the impact (n=10 of the scorching rear average swelling rate of 5h and inhibitory rate of intumesce to the sufficient sole of the foot; X ± s)
| Group | Average swelling rate (%) after administration | Inhibitory rate of intumesce (%) |
| Model control group | 14.36±2.33 | |
| YW-1 | 10.18±1.99** | 29.11 |
| YW-2 | 9.54±2.22** | 33.57 |
* P<0.01, compares with model group.
(4) conclusion: this patent Rhein derivatives gastric infusion significantly can alleviate the rat paw edema degree caused by injection urate.Good restraining effect is had to the acute gout inflammation that Monosodium urate causes
the anti-system lupus erythematosus of Rhein derivatives described in embodiment 5 this patent, rheumatic arthritis pharmacodynamic study
What injection adjuvant caused is immune inflammation, can cause sufficient sole of the foot inflammatory swelling to rat paw injection complete Freund's adjuvant.
(1) observation index: swelling (ml)=(cause scorching metapedes sole of the foot water displacement-cause scorching front foot sole of the foot water displacement)/cause scorching front foot sole of the foot water displacement × 100; Inhibitory rate of intumesce (%)=(model group swelling degree of the paw-administration group swelling degree of the paw)/model group swelling degree of the paw × 100.
(2) experimental technique: experiment is divided into 2 groups, medicine group and blank group, gavage every day 2 times, medicine group gives this patent Rhein derivatives, rhubarb yellow amino ethyl ester (YW-1) per daily dose 10mg/kg, diacerein morpholine ethyl ester (YW-2) per daily dose 15mg/kg, continuous 1 week, model group gives the physiological saline of same volume, regular supply food and water.After last administration, before injection adjuvant, first draw mark line in lower limb ankle with marking pen, the degree of depth that during for demarcating toes volumetric measurement, lower limb are placed in measuring cup, measuring double, averaging as causing the basic value before inflammation; Within after last administration 1 hour, injection adjuvant 0.1ml, measures Rat Right metapedes sole of the foot Volume of Displacement again after 18h, double with 75% alcohol disinfecting Rat Right metapedes sole of the foot position.According to swelling and inhibitory rate of intumesce between water displacement calculating group.
(3) experimental result: in table 4.
Table 4 patent drug on Carrageenan brings out the restraining effect (n=10 of rat toes swelling; X ±
s)
Compare with control group, * P<0.05.
(4) experiment conclusion: this patent Rhein derivatives gastric infusion has significant effect to the experimental immune sacroiliitis preventing adjuvant from bringing out.
the anti-acute arthritis pharmacodynamic study of Rhein derivatives described in embodiment 6 this patent
Local injection carrageenin can cause prostaglandin(PG) (PG) to synthesize and increase, and PG participates in acute inflammatory reaction with kassinin kinin together with vaso-active substance, and the object of this experiment is also understand this patent Rhein derivatives to acutely inflamed therapeutic action.
(1) observation index: swelling (ml)=(cause scorching metapedes sole of the foot water displacement-cause scorching front foot sole of the foot water displacement)/cause scorching front foot sole of the foot water displacement × 100; Inhibitory rate of intumesce (%)=(model group swelling degree of the paw-administration group swelling degree of the paw)/model group swelling degree of the paw × 100.
(2) experimental technique: experiment is divided into 2 groups, medicine group and blank group, gavage every day 2 times, medicine group gives this patent Rhein derivatives, rhubarb yellow amino ethyl ester (YW-1) per daily dose 6mg/kg, diacerein morpholine ethyl ester (YW-2) per daily dose 10mg/kg, continuous 1 week, model group gives the physiological saline of same volume, regular supply food and water.After last administration, before injection carrageenin, first draw mark line in lower limb ankle with marking pen, the degree of depth that during for demarcating toes volumetric measurement, lower limb are placed in measuring cup, the data that (cause scorching latter 0 hour) before measuring injection proinflammatory agent; Within 1 hour after last administration, injection carrageenin 0.1ml causes inflammation with 75% alcohol disinfecting Rat Right metapedes sole of the foot position, measure cause scorching after 1,2,4,6h Rat Right metapedes sole of the foot Volume of Displacement, calculate swelling and inhibitory rate of intumesce.
(3) experimental result: in table 5.
Table 5 patent drug on Carrageenan causes the impact (n=10 of rat toes swelling degree; X ±
s)
Compare with model control group, * P<0.05, * * P<0.01.
Table 6 patent drug on Carrageenan causes the impact (n=10 of rat toes swelling degree; X ±
s)
Compare with model control group, * * P<0.01.
(4) experiment conclusion: this patent medicine Rhein derivatives gastric infusion has obvious restraining effect to the rat paw acute inflammation caused by carrageenin.
Claims (7)
1. a rhubarb yellow ramification of carboxylic esters, structure is as follows:
；
。
2. a pharmaceutical preparation, it comprises Rhein derivatives according to claim 1 as activeconstituents and pharmaceutical carrier.
3. the pharmaceutical preparation of claim 2, is characterized in that the formulation of wherein said pharmaceutical preparation comprises oral Preparation, injecting and administering preparations, local administration preparation.
4. the pharmaceutical preparation of claim 3, is characterized in that wherein said oral Preparation comprises ordinary tablet, slow releasing tablet, granule, hard or soft capsule, syrup, solution, emulsion.
5. the pharmaceutical preparation of claim 3, is characterized in that wherein said injecting and administering preparations comprises the aqueous solution, the oil-in-water microemulsion of aseptic injection, the injectable sterile powder of aseptic injection.
6. the pharmaceutical preparation of claim 3, is characterized in that wherein said local administration preparation comprises patch, suppository, creme, paste, gelifying agent, solution or suspension.
7. the pharmaceutical composition any one of claim 1-6 is for the preparation for the treatment of diabetic nephropathy, sacroiliitis, urarthritis, rheumatic arthritis, purposes in systemic lupus erythematous medicine.
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| CN201510348492.8A CN104945269A (en) | 2015-06-23 | 2015-06-23 | Rhein carboxylic acid esters derivative and appliance |
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|---|---|---|---|
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111281865A (en) * | 2018-12-06 | 2020-06-16 | 常州高新技术产业开发区三维工业技术研究所有限公司 | Application of levocarnitine and derivative thereof |
| CN112043691A (en) * | 2019-06-06 | 2020-12-08 | 常州高新技术产业开发区三维工业技术研究所有限公司 | Pharmaceutical composition and application thereof |
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|---|---|---|---|---|
| US5330981A (en) * | 1991-05-03 | 1994-07-19 | Istituto Gentili S.P.A. | Arylalkyl esters of 4,5-dihydroxy-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid having therapeutical activity |
| CN101296916A (en) * | 2005-08-10 | 2008-10-29 | 索塞R&D有限公司 | Dihydroxyanthraquinones and their use |
| CN103709052A (en) * | 2014-01-12 | 2014-04-09 | 何黎琴 | Rhein amino-alcohol ester type compound, and preparation method and pharmaceutical application thereof |
-
2015
- 2015-06-23 CN CN201510348492.8A patent/CN104945269A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5330981A (en) * | 1991-05-03 | 1994-07-19 | Istituto Gentili S.P.A. | Arylalkyl esters of 4,5-dihydroxy-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid having therapeutical activity |
| CN101296916A (en) * | 2005-08-10 | 2008-10-29 | 索塞R&D有限公司 | Dihydroxyanthraquinones and their use |
| CN103709052A (en) * | 2014-01-12 | 2014-04-09 | 何黎琴 | Rhein amino-alcohol ester type compound, and preparation method and pharmaceutical application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 余佳 等: "大黄酸及其衍生物的生物活性研究进展", 《药学与临床研究》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111281865A (en) * | 2018-12-06 | 2020-06-16 | 常州高新技术产业开发区三维工业技术研究所有限公司 | Application of levocarnitine and derivative thereof |
| CN112043691A (en) * | 2019-06-06 | 2020-12-08 | 常州高新技术产业开发区三维工业技术研究所有限公司 | Pharmaceutical composition and application thereof |
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Application publication date: 20150930 |