CN101104616A - Dehydrosilibinin diester derivatives, preparation method and use thereof - Google Patents
Dehydrosilibinin diester derivatives, preparation method and use thereof Download PDFInfo
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Abstract
The present invention relates to an anti-free radical oxidation, liver-protective, senile dementia preventing and anti-aging active dehydrogenation silybin double-ester derivative and the related medicinal salt or solvent compound. The invention also relates to the preparation method for the compound on the formula 1, as well as the related medication compounds and the curatorial uses. The compound of the invention can protect the liver cells of a rat liver cell injury in vitro model, which can be expected to prevent liver damage in drug use; the compound of the invention is provided with the biological activities of in vitro removing superoxide anion free radicals and diphenyl-benzyl-hydrazine free radicals, and restraining generation of grease peroxide induced by free radicals. The compound can strongly confront the PC12 cells damage caused by free radicals, which can be expected to prevent various diseases caused by free radicals in drug use.
Description
Technical field
The invention belongs to organic chemistry and pharmaceutical chemistry field, particularly, the present invention relates to the preparation method and the purposes of Dehydrosilibinin diester derivatives.This compounds obtains by complete synthesis and semisynthetic method.The present invention causes rat suckling mouse primary hepatocyte damage external model with this series compound to hydrogen peroxide and has carried out hepatocellular injury protection screening active ingredients.This compounds is found to have the protection liver cell and promotes the effect that liver cell is repaired.The present invention tests this compounds antioxidant radical activity again, finds the activity that its lipoperoxide with external removing ultra-oxygen anion free radical, removing free radical scavenging activity, inhibition free yl induction generates.Above activity shows that this compounds can be expected and is used to prepare prevention or treats acute chronic hepatic injury class disease and caused or other physiological changes relevant with oxyradical or the medicine of disease by oxyradical.This compounds also shows the very strong PC12 cell injury effect that Green Tea Extract is caused, promptly the PC12 cell to the simulation cranial nerve cell has the anti-oxidative damage provide protection.And under same concentration, its energy force rate positive control Quercetin of removing free radical protection cell is also strong.Illustrate that it is anti-oxidant to the protection cranial nerve, prevent and treat senile dementia active effect is arranged.Above-mentioned activity shows that again this compounds can expect the medicine that is used to prepare the impaired relevant brain lesions of prevention presenile dementia and other and cranial nerve oxidation.
Technical background
A lot of diseases are caused by oxidation.The oxygen pressure is caused by the imbalance between body cell generation and the removing free radical, can bring out multiple disease.Oxygen is pressed can cause nervous system disorders, as apoplexy, and Parkinson's disease, alzheimer's disease.It is also relevant with the pathology approach of other disease in addition, as heart trouble, autoimmune disorder, tumour, virus disease (as AIDS, hepatitis).Therefore seeking new antioxidant becomes treatment and presses the effective way of the various diseases that causes by oxygen, so Study on antioxidants will be that down centurial treatment disease prolongs one of important directions of life.Filter out the antioxidant of high-efficiency low-toxicity rapidly, especially natural product or be the derivative of skeleton with the natural product is a shortcut of exploitation antioxygenation mechanism new drug.
In numerous Green Tea Extract natural products, Silymarin is one of medicine of a few widespread use clinically.This medical instrument of the clinical trial certificate of three more than ten years has definite curative effect and hypotoxicity (to consult people such as Flora K., Am.J.Gastroenterol.1998,93,139-143 page or leaf; Saller, people such as R., Drugs, 2001,61 (14), 2035-2063 page or leaf).Silibinin content is maximum in the Silymarin, and activity is also the highest.This medicine effect mainly contain following some.(1) Green Tea Extract activity: silymarin is for by CCl
4, the hepatic injury that GalN, alcohols and other hepatotoxin cause has provide protection.People such as nineteen ninety Lotteron have reported that in the Mouse Liver microsome silymarin can reduce by CCl
4These show that all silymarin is the chain interruption antioxidant or is free-radical scavengers external lipid peroxidation that metabolism causes and the peroxidation that caused separately by reduced coenzyme.(2) protection liver plasma membrane: keep flowability of cell membranes by the anti peroxidation of lipid reaction, the protection liver plasma membrane.Can also block combining of special acceptor on mycotoxins phalloidin and α-amanitine etc. and the liver cell, suppress it, interrupt its liver sausage circulation, thereby the enhance hepatocyte film be for the resistibility of multiple damage factor hepatocellular attack and transmembrane transport.(3) promote hepatocellular reparation and regeneration: silibinin can combine with estradiol receptor after entering cell, and make it to activate, activated receptors can enhance hepatocyte nuclear RNA polysaccharase 1 activity, rna transcription is strengthened, promote enzyme and proteinic synthetic, and promote the synthetic of DNA indirectly, help hepatocellular reparation and regeneration.(4) antitumor action: various active oxygens can form 8-hydroxyl guanine by the oxidation guanine, cause dna damage, and then cause tumour, and silibinin has also shown the effect of prevention and treatment tumour as an effective Green Tea Extract material.
The silibinin compounds has definite curative effect, but because the market that the some shortcomings on its water-soluble and bioavailability have limited this medicine.So seek the new derivative of silibinin class, make it can have pharmacologically active higher or that upgrade, in the hope of obtaining the new drug of independent intellectual property right, real genus is necessary.
Summary of the invention
The purpose of this invention is to provide a kind of have anti-oxidant, remove free radical activity, protection liver cell and the organic damage of liver, treatment presenile dementia stagnate disease, antidotal dehydro-silibinin dibasic acid esters active compound.Particularly, the invention provides dehydro-silibinin di-esters derivative shown in a kind of formula I and pharmacologically acceptable salt thereof or its solvate.
Formula I
Wherein, n=1-5; X is nitrogen or oxygen, R
1, R
2Be hydrogen, alkyl, cycloalkyl, replacement or unsubstituted aryl, 7 among the formula I ', 8 ' steric configuration be respectively or be R configuration or S configuration simultaneously.
The preferred formula I compound of the present invention comprises:
Compound I-1:2-[2,3-dihydro-3-(4-N, N-diethyl amido formyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-] 7-(4-N, N-diethyl amido formyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone;
Compound I-2:2-[2,3-dihydro-3-(4-pyrrolidyl formyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-7-(4-pyrrolidyl formyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone;
Compound I-3:2-[2,3-dihydro-3-(4-N-anilino formyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-7-(4-N-anilino formyl methoxyl group 3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone;
Compound I-4:2-[2,3-dihydro-3-(4-N-p-Chlorobenzoic acid amide base formyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-7-(4-N-p-Chlorobenzoic acid amide base formyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone;
Compound I-5:2-[2,3-dihydro-3-(4-N-P-nethoxyaniline base formyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-7-(4-N-P-nethoxyaniline base formyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone;
Compound I-6:2-[2,3-dihydro-3-(4-N-is to toluidine formyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-7-(4-N-is to toluidine formyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone;
Compound I-7:2-[2,3-dihydro-3-(4-N-2,4-dichlorobenzene amido formyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-dihydro-7-(4-N-2,4-dichlorobenzene amido formyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone;
Compound I-8:2-[2,3-dihydro-3-(4-ethoxycarbonyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-7-(4-ethoxycarbonyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone;
Another object of the present invention provides the preparation method of the dehydro-silibinin di-esters derivative shown in a kind of formula I.The preparation method of formula I compound is:
Wherein, n=1-5; X is nitrogen or oxygen, R
1, R
2Be hydrogen, alkyl, cycloalkyl, replacement or unsubstituted aryl, X
1Be halogen, alkali is salt of wormwood, sodium bicarbonate, yellow soda ash, potassium hydroxide, sodium hydroxide.Reaction solvent is a tetrahydrofuran (THF), N, and dinethylformamide, methyl-sulphoxide, temperature of reaction is that room temperature extremely refluxes, the reaction times is 0.5-20 hour.Wherein I-a comprise natural or synthetic silibinin (silybin) with and optical isomer.
Another object of the present invention has provided the purposes that formula I compound is used to prevent and treat liver cell and liver organic damage and relevant hepatitis disease thereof.
A further object of the present invention has provided a kind of pharmaceutical composition that is used to prevent and treat liver cell and the organic damage of liver and relevant hepatitis disease thereof that contains formula I compound.
Another object of the present invention provided a kind of contain formula I compound be used to prepare anti-ageing, the purposes of preventing and treating the presenile dementia disease drug based on resisting oxidation free radical mechanism.
A further object of the present invention provided a kind of contain formula I compound be used to prepare anti-ageing, medicine and the pharmaceutical composition of preventing and treating degenerative brain disorder based on resisting oxidation free radical mechanism.
Another purpose of the present invention has provided being used to prepare by oxyradical and causing or the physiological change relevant with oxyradical or disease is particularly cardiovascular and the purposes of cerebrovascular disease medicine of formula I compound;
A further object of the present invention has provided a kind of being used to prepare by oxyradical and causing or the physiological change relevant with oxyradical or disease is particularly cardiovascular and the pharmaceutical composition of cerebrovascular disease medicine of formula I compound of containing.
Embodiment
In order to understand essence of the present invention better, use the process of the formal specification compound of embodiment below respectively, embodiment has provided part physics and the chemistry and the Wave Spectrum data of representative compounds.Mandatory declaration, embodiments of the invention are to be used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Embodiment 1:Compound I-1 (2-[2,3-dihydro-3-(4-N, N-diethylamino formyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-7-(4-N, N-diethylamino formyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone) preparation:
Be dissolved in 15 milliliters of N 2.2 digest compound I-a (silibinin), in the dinethylformamide, add 1 gram salt of wormwood, 0.15 the gram potassiumiodide stirs the 0.67 gram N of adding down, the N-diethylchloro-acetamide, in stirred overnight at room temperature, reactant is poured in 30 milliliters of frozen water, separates out yellow mercury oxide, use ethyl acetate extraction, use the saturated common salt water washing behind the united extraction liquid, anhydrous sodium sulfate drying, filter, concentrate, get yellow solid, obtain yellow powder 1.2 grams, yield 60% through column chromatography.
Rf (chloroform: methyl alcohol=50: 1)=0.1;
1H NMR (400MHz, deuterated dimethyl sulfoxide): 1.02 (t, J=7.0Hz, 3H, CH3), 1.06 (t, J=7.0Hz, 3H, CH3), 1.17 (t, J=7.0Hz, 3H, CH3), 1.224 (t, J=7.0Hz, 3H, CH3), 3.32 (q, J=7.0Hz, 2H, NCH2), 3.37 (q, J=7.0Hz, 2H, NCH2), 3.42 (q, J=7.0Hz, 2H, NCH2), 3.44 (q, J=7.0Hz, 2H, NCH2), 3.53 (H-9 ' is a) for m, 1H, 3.79 (m, 1H, H-9 ' b), 3.88 (s, 3H, OCH3), (4.25 m, 1H, H-8 '), 4.95 (s, 2H, OCH2CO), 4.96 (s, 2H, OCH2CO), 5.02 (d, J=8.0Hz, 1H, H-7 '), 6.34 (s, 1H, H-6), 6.73 (s, 1H, H-8), 6.89-7.94 (m, 6H, Ar-H), 12.61 (s, 1H, 5-OH); ESI-MS 707[M+1]
+
Prepare compound shown in the embodiment 2-7 in the table one according to embodiment 1 identical method:
Table one:
Each compound physicochemical data:
Compound I-2 (2-[2,3-dihydro-3-(4-pyrrolidyl formyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-7-(4-pyrrolidyl formyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone): Rf (chloroform: methyl alcohol=50: 1)=0.10;
1H NMR (400MHz, deuterated dimethyl sulfoxide): 1.53 (m, 12H, CH2), 3.46 (m, 9H, NCH2,9 ' a), 3.75 (m, 1H, H-9 ' b), 3.86 (s, 3H, OCH3), (4.20 m, 1H, H-8 '), 4.93 (s, 2H, OCH2CO), 4.95 (s, 2H, OCH2CO), 5.00 (d, J=8.0Hz, 1H, H-7 '), 6.30 (s, J=2.0Hz, 1H, H-6), 6.32 (d, J=2.0Hz, 1H, H-8), 6.86-7.13 (m, 6H, Ar-H), 12.05 (s, 1H, 5-OH); ESI-MS 703[M+1]
+
Compound I-3 (2-[2,3-dihydro-3-(4-N-anilino formyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-7-(4-N-anilino formyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone): Rf (chloroform: methyl alcohol=50: 1)=0.10;
1H NMR (400MHz, deuterated dimethyl sulfoxide): 1.53 (m, 12H, CH2), 3.40 (m, 1H, 9 ' a), 3.46 (t, 8H, NCH2), 3.56 (m, 1H, H-9 ' b), 3.86 (s, 3H, OCH3), 4.20 (m, 1H, 8 '), 4.93 (s, 2H, OCH2CO), 4.95 (s, 2H, OCH2CO), 5.00 (d, J=8.0Hz, 1H, H-7 '), 6.30 (s, J=2.0Hz, 1H, H-6), 6.32 (d, J=2.0Hz, 1H, H-8), 6.86-7.13 (m, 16H, Ar-H), 12.05 (s, 1H, 5-OH); ESI-MS 747[M+1]
+
Compound I-4 (2-[2,3-dihydro-3-(4-N-p-Chlorobenzoic acid amide base formyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-7-(4-N-p-Chlorobenzoic acid amide base formyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone): Rf (chloroform: methyl alcohol=50: 1)=0.13;
1H NMR (400MHz, deuterated dimethyl sulfoxide): 3.40 (9 ' a), 3.58 (H-9 ' b) for m, 1H for m, 1H, 3.78 (s, 3H, OCH3), 4.26 (m, 1H, 8 '), 4.67 (s, 2H, OCH2CO), 4.85 (s, 2H, OCH2CO), (5.01 d, J=8.0Hz, 1H, H-7 '), 6.50 (s, J=2.0Hz, 1H, H-6), 7.02 (d, J=2.0Hz, 1H, H-8), 6.80-7.77 (m, 14H, Ar-H), 12.05 (s, 1H, 5-OH); ESI-MS815[M+1]
+
Compound I-5 (2-[2,3-dihydro-3-(4-N-P-nethoxyaniline base formyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-7-(4-N-P-nethoxyaniline base formyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone): Rf (chloroform: methyl alcohol=50: 1)=0.16;
1H NMR (400MHz, deuterated dimethyl sulfoxide): 3.40 (9 ' a), 3.59 (H-9 ' b) for m, 1H for m, 1H, 3.75 (s, 6H, OCH3), 3.77 (s, 6H, OCH3), 4.27 (m, 1H, H-8 '), 4.62 (s, 2H, OCH2CO), 4.80 (s, 2H, OCH2CO), 4.95 (d, J=8.0Hz, 1H, H-7 '), 6.51 (s, J=2.0Hz, 1H, H-6), 7.02 (d, J=2.0Hz, 1H, H-8), 6.86-7.13 (m, 14H, Ar-H), 12.38 (s, 1H, 5-OH); ESI-MS 809 [M+1]
+
Compound I-6 (2-[2,3-dihydro-3-(4-N-is to toluidine formyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-7-(4-N-is to toluidine formyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone): Rf (chloroform: methyl alcohol=50: 1)=0.13;
1H NMR (400MHz, deuterated dimethyl sulfoxide): 2.27 (CH3), 3.40 (H-9 ' a) for m, 1H for s, 6H, 3.59 (m, 1H, H-9 ' b), 3.78 (s, 3H, OCH3), 4.28 (m, 1H, H-8 '), 4.65 (s, 2H, 0CH2CO), 4.83 (s, 2H, OCH2CO), 4.96 (d, J=8.0Hz, 1H, H-7 '), 6.52 (s, J=2.0Hz, 1H, H-6), 7.03 (d, J=2.0Hz, 1H, H-8), 6.86-7.13 (m, 14H, Ar-H), 12.40 (s, 1H, 5-OH); ESI-MS 775[M+1]
+
Compound I-7:(2-[2,3-dihydro-3-(4-N-2,4-dichlorobenzene amido formyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-dihydro-7-(4-N-2,4-dichlorobenzene amido formyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone): Rf (chloroform: methyl alcohol=50: 1)=0.21; 1H NMR (400MHz, deuterated dimethyl sulfoxide): 3.40 (m, 1H, H-9 ' a), 3.60 (H-9 ' b) for m, 1H, 3.79 (s, 3H, OCH3), 4.29 (m, 1H, H-8 '), 4.75 (s, 2H, OCH2CO), 4.95 (s, 2H, OCH2CO), (4.97 d, J=8.0Hz, 1H, H-7 '), 6.53 (d, J=2.0Hz, 1H, H-6), 7.03 (d, J=2.0Hz, 1H, H-8), 6.86-7.13 (m, 12H, Ar-H), 12.36 (s, 1H, 5-OH); ESI-MS 885[M+1]
+
Embodiment 8:Compound I-8 ([2-[2,3-dihydro-3-(4-ethoxycarbonyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-2,3-dihydro-7-(4-ethoxycarbonyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone) preparation:
The method identical according to embodiment 1 replaces N with the raw material ethyl chloroacetate, and the N-diethylchloro-acetamide obtains Compound I-8:Rf (chloroform: ethyl acetate: formic acid=25: 1: 0.25)=0.10;
1H NMR (400MHz, deuterated dimethyl sulfoxide): 1.23 (t, J=7.2Hz, 3H, CH3), 1.31 (t, J=7.2Hz, 3H, CH3), 3.58 (m, 1H, 9 ' a), 3.86 (m, 1H, H-9 ' b), 4.13 (m, 1H, H-8 '), 4.20 (q, J=7.2Hz, 2H, CH2CH3), 4.28 (q, J=7.2Hz, 2H, CH2CH3), (4.28 m, 1H, H-8 '), 4.67 (s, 2H, H-9), 4.82 (s, 2H, OCH2CO), 5.99 (d, J=8.0Hz, 1H, OCH2CO), 6.35 (s, 1H, H-6), 6.41 (s, 1H, H-8), 6.96-8.01 (m, 6H, Ar-H), 12.50 (s, 1H, 5-OH); ESI-MS 653[M+1]
+
Formula I compound has multiple important biological, the present invention causes rat suckling mouse primary hepatocyte damage external model with this series compound to hydrogen peroxide and has carried out hepatocellular injury protection screening active ingredients, and this compounds is found to have the protection liver cell and promote the effect that liver cell is repaired; The present invention tests this compounds antioxidant radical activity again, find that it has external removing ultra-oxygen anion free radical, removes free radical scavenging activity, suppresses the activity that lipoperoxide of free yl induction generates, more than actively show that this compounds can be expected and be used to prepare prevention or treat acute chronic hepatic injury class disease and cause or other physiological changes relevant or the medicine of disease with oxyradical by oxyradical; This compounds also shows the very strong PC12 cell injury effect that Green Tea Extract is caused; promptly the PC12 cell to the simulation cranial nerve cell has the anti-oxidative damage provide protection; and under same concentration; its energy force rate positive control Quercetin of removing free radical protection cell is more effective, illustrate such dehydro-silibinin di-esters derivative to protect cranial nerve anti-oxidant, prevent and treat senile dementia active effect arranged.
Formula I compound or pharmaceutically acceptable salt thereof of the present invention and solvate thereof can combine with spoke material or carrier pharmaceutically commonly used, have the acute and chronic injury of protection liver cell and can be used to the pharmaceutical composition or the healthcare products that prevent and treat hepatic diseases thereby prepare.Above-mentioned various kinds of drug composition or healthcare products can adopt drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment.
Formula I compound or pharmaceutically acceptable salt thereof of the present invention and solvate thereof can also with the liver protecting that has now gone on the market and liver disease medicine medicine such as Biphenylylmethylcarbinol; silymarin; silybin meglumine; Oleanolic Acid; Tensicor; Protoporphrin Disodium (protoporphyrin disodium); Malotilate (malotilate); ursodesoxycholic acids etc. are united use; prepare and have protection liver active composition, can expect to be used for the treatment of acute and chronic hepatitis; chronic hepatitis; early stage liver more changes; fatty liver and toxic liver injury disease medicine or healthcare products.Above-mentioned various kinds of drug composition or healthcare products can adopt drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, comprise the conventional preparation of pharmaceutics general knowledge that employing has now been generally acknowledged and various slowly-releasings, controlled release form or the nanometer formulation that gets.
Formula I compound or pharmaceutically acceptable salt thereof of the present invention and solvate thereof can be united use with the Green Tea Extract oxidant drug that has now gone on the market such as superoxide-dismutase (SOD) etc., prepare and have defence the free radical active antioxidant compositions of infringement or the healthcare products that cause, be used for the treatment of that ultra-oxygen anion free radical or other types free radical cause or other physiological changes or the disease relevant with abnormal free radical comprises diseases such as inflammation, autoimmune disorder, tumour, myocardial ischemia, myocardial hypertrophy, aging, transformation reactions, atherosclerosis.Above-mentioned various kinds of drug composition or healthcare products can adopt drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, comprise the conventional preparation of pharmaceutics general knowledge that employing has now been generally acknowledged and various slowly-releasings, controlled release form or the nanometer formulation that gets.
Formula I compound or pharmaceutically acceptable salt thereof of the present invention and solvate thereof can also be bright with the anti-presenile dementia medicine that has now gone on the market and nootropics such as his Kelin, E2020, this ground brother, lycoremine, Clausenamide, huperzine are first-class unites use; prepare and have the infringement that causes of defence free radical, the protection active antioxidant compositions of cranial nerve or healthcare products, be used to prevent and treat senile dementia with and relevant dysnoesia disease.Above-mentioned each pharmaceutical composition or healthcare products can adopt injection, tablet, percutaneous absorption patch or plant drug forms such as burying agent, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment, comprise the conventional preparation of pharmaceutics general knowledge that employing has now been generally acknowledged and various slowly-releasings, controlled release form or the nanometer formulation that gets.
The oxygen pressure is caused by the imbalance between body cell generation and the removing free radical, can bring out multiple disease.Oxygen is pressed can cause nervous system disorders, as apoplexy, and Parkinson's disease, alzheimer's disease.It is also relevant with the pathology approach of other disease in addition, as heart trouble, autoimmune disorder, tumour, virus disease (as AIDS, hepatitis).Therefore seek new antioxidant and become the various diseases that causes is pressed in treatment by oxygen effective way.The present invention is with the activity test of the super oxyradical of external removing negatively charged ion; External removing free radical scavenging activity (1,1-diphenyl-2-picrylhydrazyl, activity test DPPH); Measure compound to oxydol H
2O
2Due to the provide protection of PC12 (pheochromocytoma on the kidney of rats) cell injury; The anti-oxidant activity of compound in the test explanation claims of the present invention such as lipoperoxide generation of compound inhibition free yl induction.
In order to understand essence of the present invention and the application prospect of compound of the present invention on drug development better, below with pharmacology embodiment form respectively with the compound of preparing among the present invention to hydrogen peroxide cause rat suckling mouse primary hepatocyte damage external model hepatocellular injury protection activity, external removing ultra-oxygen anion free radical, remove the DPPH free radical activity, the lipoperoxide that suppresses free yl induction generates activity and to by oxydol H
2O
2Due to the The pharmacological results of provide protection of PC12 (pheochromocytoma on the kidney of rats) cell injury, its new purposes in pharmacy field is described.Pharmacology embodiment has provided the part activity data of representative compounds.Mandatory declaration, pharmacology embodiment of the present invention and the pharmacodynamics model that is adopted are to be used to illustrate the present invention rather than limitation of the present invention.The simple modifications that essence according to the present invention is carried out the present invention, and other indications of the simple and easy expansion on the cause of disease basis that the embodiment of the invention contained all belong to the scope of protection of present invention.
Pharmacology embodiment 1:The activity test of the external removing ultra-oxygen anion free radical of Compound I-1
The detection that Compound I-1 is removed the ultra-oxygen anion free radical ability is to use azophenlyene-N metilsulfate-NADH (phenazine methosulfate-NADH) system, with the calibrating of nitroblue tetrazolium (nitroblue tetrazolium) method of reducing.In the pH value is 8.0 16mM Tris-HCl damping fluid, produce ultra-oxygen anion free radical with 3 milliliters of NADH, 50 μ M nitroblue tetrazolium and 10 μ M azophenlyene-N metilsulfates that contain 78 μ M, detect its activity in the Compound I-1 of different concns.The color of ultra-oxygen anion free radical and nitroblue tetrazolium resultant of reaction is monitored under the 560nm wavelength with spectrophotometer, and Quercetin is used as the positive control medicine.Test-results sees Table two.
Table two
| Sample | Test concentrations (μ g/mL) | To the ultra-oxygen anion free radical clearance rate |
| Compound I-1 Quercetin | 40 40 | 29.48％ 63.24％ |
Test-results shows that Compound I-1 has certain ultra-oxygen anion free radical scavenging(action), but under same concentration, its removing ability is less than the Quercetin height.Conclusion: such dehydro-silibinin di-esters compound belongs to the antioxidant with certain removing ultra-oxygen anion free radical ability.
Pharmacology embodiment 2:The external removing free radical scavenging activity of Compound I-2 (1,1-diphenyl-2-picrylhydrazyl, activity test DPPH)
The methanol solution of DPPH has strong absorption value at 517nm, and when it was reduced by polyphenoils, absorption value descended, and absorbancy is low more, and its antioxygenation is strong more.The concentration that contains 25 μ L in 250 μ L reaction systems is the Compound I-2 of 40 μ g/mL, and the methanol solution 40 μ L of DPPH (0.4mg/mL) and methanol solution 185 μ L, 37 ℃ of water-baths measured absorbancy after 30 minutes at the 517nm place.The methanol solution of DPPH and the Quercetin of same concentrations are respectively as negative, positive control.Test-results sees Table three.
Table three
| Sample | Test concentrations (μ g/mL) | To the ultra-oxygen anion free radical clearance rate |
| Compound I-2 | 40 | 44.18％ |
| Quercetin | 40 | 87.42％ |
Test-results shows that Compound I-2 has certain DPPH free radical scavenging effect, but under same concentration, its removing ability is less than the Quercetin height.Conclusion: such dehydro-silibinin di-esters compound belongs to the antioxidant with certain removing DPPH free radical ability.
Pharmacology embodiment 3:Compound I-1 pair oxydol H
2O
2Due to the provide protection activity test of PC12 cell injury
H
2O
2It is a kind of precursor of main living radical, it can cause the apoptosis of central nervous system cell, PC12 cell (pheochromocytoma on the kidney of rats) can be simulated cranial nerve cell, therefore use it always and be used as studying the model that concerns between medicine and the neurocyte, with the survival rate of MTT survey cell, if testing compound has removing by H
2O
2The effect of free radical that causes and neuroprotective cell, the OD value is high, and cell survival rate is just high, otherwise just low.(Xiaoqiu Xiao etc., Neurosci Lett.1999 275:73-76) are improved the provide protection of measuring compound to Tang Xican institute reported method.PC12 cell DMEM culture medium culturing contains 10% foetal calf serum in the substratum, 100U/mL penicillin and 100U/mL Streptomycin sulphate.Cell is added in 96 orifice plates with the density in 6000 in every hole, at 37 ℃, and 50%CO
2Cultivated 36 hours in the incubator of damp atmosphere.The mtt assay that cell survival rate is observed and improved with inverted microscope.Cell is after 36 hours hatch, and the dimethyl sulfoxide solution that adds the Compound I-1 of newly joining respectively joins in each hole with concentration gradient.Act on the H that adding is newly joined after 2 hours
2O
2(final concentration is 500 μ mol/L) effect 3 hours, the microscopic examination record discards original fluid, adds new nutrient solution 100 μ L, adds MTT 10 μ L then, and after 3 hours, the careful suction removed nutrient solution, adds 150 μ L DMSO Rong Xie Jia Za, in 570nm place reading; Make positive control with Quercetin, test-results sees Table four.
Table four
| Sample | Test concentrations (μ g/mL) | Cell survival rate before the dosing | Cell survival rate after the dosing |
| Compound I-1 | 32 16 8 | 32.36％ 35.77％ 35.22％ | 98.26％ 98.13％ 84.50％ |
| Quercetin | 32 16 8 | 38.01％ 38.36％ 39.55％ | 89.89％ 88.80％ 78.81％ |
Test-results shows that Compound I-1 has the PC12 cell injury effect that very strong antagonism hydroxy radical qiao causes, promptly the PC12 cell to the simulation cranial nerve cell has anti-oxidant damage to prevent provide protection.And under same concentration, its energy force rate positive control Quercetin of removing free radical protection cell is also high.Conclusion: such dehydro-silibinin di-esters compound belongs to the antioxidant of the PC12 cytosis with potent protection simulation cranial nerve cell.
Measure compound to H
2O
2Due to the PC12 cell decrease the mechanism of action that anti-provide protection can be used as its protection maincenter cranial nerve cell of preliminary discussion.So this compounds shows the provide protection to PC12 cell due to the hydrogen peroxide damage, illustrates that its treatment to the senile dementia card has active effect.
Pharmacology embodiment 4:Compound I-2 suppresses the activity test of the lipoperoxide generation of free yl induction
1. experimental principle: lipid peroxidation is the product that free radical acts on polyunsaturated fatty acid, and the generation positive correlation of content and free radical because body has the provide protection of oxidation resistant enzyme system and non-enzyme system, constantly produces free radical and constantly is eliminated again.With advancing age, intravital antioxidant constantly descends, and the ability of removing free radical weakens gradually, and lipid peroxidation then strengthens, and lipid peroxidation product increases.Therefore, the working sample lipoid peroxidization resistant is that screening is anti-oxidant, one of important indicator of antiaging agent.
2. the lipoperoxide generation of Compound I-2 inhibition free yl induction is to detect by the mouse hepatomicrosome:
(1) preparation of hepatomicrosome: the experimental rat sacrificed by decapitation, take out liver rapidly, prepare hepatomicrosome with ultracentrifugation.(2) sample is to the restraining effect of mouse liver lipid peroxidation; Containing FeSO
4Add in the 200 μ g/mL microsomes in 1 milliliter of damping fluid of (4 μ mol/L) and vitamins C Vc (50 μ mol/L),, add the I-2 sample of different concns simultaneously, add 1 milliliter of Tricholroacetic Acid stopped reaction to induce the generation lipid peroxidation.Add 1.5 milliliters of thiobarbituricacids, 100 ℃ of boiling water baths 20 minutes, centrifugal, under the 532nm wavelength, measure the supernatant absorbancy.Lipid peroxidation is represented with the mda that generates in the reaction, tests with Quercetin as positive control.Test-results sees Table five.
Table five
| Sample number into spectrum | IC 50(mol/L) |
| The I-2 Quercetin | 2.15×10 -6 2.35×10 -6 |
Test-results shows that Compound I-2 has the lipoperoxide generative capacity of very strong inhibition free yl induction, and promptly pair cell has the anti-oxidative damage provide protection.And under same concentration, its pair cell anti-oxidative damage energy force rate positive control Quercetin is also strong.Conclusion: such dehydro-silibinin di-esters compound belongs to and has potent protection cell antioxidant.Point out it to have effect anti-oxidant, anti-ageing and that expection is used to prepare antioxidant and anti-aging class disease.
Pharmacology embodiment 5:The provide protection test of the two hydrogen damage by water wound models of Compound I-8 pair SD neonate rat primary hepatocyte
Get SD rat freshman suckling mouse liver, make hepatocyte suspension, centrifugal 3 times, resuspended with nutrient solution, can obtain most of suspension of hepatic parenchymal cells that is.Above-mentioned hepatocyte suspension is added in the culture plate of 96 holes (0.1 milliliter in every hole), put 5%CO
2In the incubator, cultivation is after 12 hours down at 37 ℃, and supernatant is abandoned in suction, adds the H of 0.6mmol/L
2O
2Act on after 1 hour, go into the I-8 specimen test soup of high, medium and low 3 kinds of different concns respectively, establish solvent and positive controls simultaneously.After cultivating end, inhale and abandon supernatant, collect the liver cell sample, the 570nm wavelength with enzyme border instrument calculating protection ratio, the results are shown in Table six down.
Table six
| Sample number into spectrum | Concentration (μ g/mL) | Protection ratio (%) |
| Quercetin | 100 50 10 1 | 35.8 19.5 5.8 3.6 |
| I-8 | 100 50 10 1 | 16.3 14.0 3.5 1.2 |
Test-results shows: Compound I-8 has the ability that certain protection SD neonate rat primary hepatocyte is avoided the hydrogen peroxide damage, promptly SD neonate rat primary hepatocyte is had the anti-oxidative damage provide protection.But under same concentration, its pair cell anti-oxidative damage protective capability is lower than positive control Quercetin; Conclusion: such dehydro-silibinin di-esters compound belongs to and has effective protection neonate rat primary hepatocyte anti-oxidative damage material.Point out it to have liver protecting and expection and be used to the effect for preparing the prevention or treat acute chronic hepatic injury class disease.
Claims (8)
1. dehydro-silibinin di-esters derivative and pharmacologically acceptable salt or its solvate shown in the formula I.
Formula I
Wherein, n=1-5; X is nitrogen or oxygen, R
1, R
2Be hydrogen, alkyl, cycloalkyl, replacement or unsubstituted aryl, 7 among the formula I ', 8 ' steric configuration be respectively or be R configuration or S configuration simultaneously.
2. according to the formula I compound of claim 1, they are:
Compound I-1:2-[2,3-dihydro-3-(4-N, N-diethyl amido formyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-7-(4-N, N-diethyl amido formyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone;
Compound I-2:2-[2,3-dihydro-3-(4-pyrrolidyl formyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-7-(4-pyrrolidyl formyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone;
Compound I-3:2-[2,3-dihydro-3-(4-N-anilino formyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-7-(4-N-anilino formyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone;
Compound I-4:2-[2,3-dihydro-3-(4-N-p-Chlorobenzoic acid amide base formyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-7-(4-N-p-Chlorobenzoic acid amide base formyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone;
Compound I-5:2-[2,3-dihydro-3-(4-N-P-nethoxyaniline base formyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-7-(4-N-P-nethoxyaniline base formyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone;
Compound I-6:2-[2,3-dihydro-3-(4-N-is to toluidine formyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-7-(4-N-is to toluidine formyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone;
Compound I-7:2-[2,3-dihydro-3-(4-N-2,4-dichlorobenzene amido formyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-dihydro 7-(4-N-2,4-dichlorobenzene amido formyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone;
Compound I-8:2-[2,3-dihydro-3-(4-ethoxycarbonyl methoxyl group-3-p-methoxy-phenyl)-2-methylol-1,4-benzodioxane-6-]-7-(4-ethoxycarbonyl methoxyl group-3-p-methoxy-phenyl)-3,5 ,-dihydroxyl-4H-1-chromene-4-ketone;
3. the preparation method of claim 1 Chinese style I compound comprises formula I-a and formula I-b are obtained formula I compound through over-churning:
N wherein, R
1, R
2, the definition of X is with the formula I in the claim 1; X
1Be halogen, alkali is salt of wormwood, sodium bicarbonate, yellow soda ash, potassium hydroxide, sodium hydroxide; Reaction solvent is a tetrahydrofuran (THF), N, and dinethylformamide, methyl-sulphoxide, temperature of reaction is that room temperature extremely refluxes, the reaction times is 0.5-20 hour; Prosposition and 7 among the I-a ', 8 ' steric configuration be respectively or be R configuration or S configuration simultaneously.
4. according to the pharmacological activity of the described dehydro-silibinin di-esters formula I compound of claim 1～2, its characteristics comprise the anti-oxidative damage provide protection that hydrogen peroxide is caused hepatocellular injury provide protection, external removing ultra-oxygen anion free radical that rat suckling mouse primary hepatocyte damage external model demonstrates, removes free radical scavenging activity, suppresses PC12 cell injury effect that effect that the lipoperoxide of free yl induction generates and formula I compound cause Green Tea Extract and the PC12 cell of simulation cranial nerve cell is demonstrated.
5. be used to prepare the purposes of preventing or treating acute chronic hepatic injury class disease, liver protecting class medicine according to the described dehydro-silibinin di-esters formula I compound of claim 1～2; Be used to prepare the purposes that control is caused by free radical or relevant other physiological changes or disease comprise disease medicaments such as inflammation, autoimmune disorder, tumour, myocardial ischemia, myocardial hypertrophy, aging, transformation reactions, atherosclerosis; And this compounds is used to prepare the pharmaceutical use of protection cranial nerve, the slow-witted disease of the senile disease of control.
6. be with the liver medicine, prevent and treat the senile dementia medicine, treat cardiovascular and cerebrovascular disease medicine, antiaging agent and/or antitumor drug or pharmaceutical composition according to the preparation-obtained guarantor of the purposes of claim 5.
7. one kind is used to prepare the pharmaceutical composition of removing free radical, anti-oxidant, protection hepatocellular injury and acute and chronic liver injury, the damage of protection cranial nerve cell, and it contains as the claim 1～2 of the treatment significant quantity of activeconstituents described Compound I or their compound or pharmaceutically acceptable salt thereof or solvate or their mixture and pharmaceutically acceptable auxiliaries.
8. according to the medicine or the pharmaceutical composition of claim 5～7, it can be that tablet, capsule, injection, aerosol, suppository, film, pill, paster agent, subcutaneous planting bury agent, externally-applied liniment, oral liquid or ointment, can also adopt the known control of modern pharmaceutical circle to fall or slow release formulation or nanometer formulation.
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