CN102675061B - The ether derivant of trans-resveratrol and medical use - Google Patents

The ether derivant of trans-resveratrol and medical use Download PDF

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CN102675061B
CN102675061B CN201110337963.7A CN201110337963A CN102675061B CN 102675061 B CN102675061 B CN 102675061B CN 201110337963 A CN201110337963 A CN 201110337963A CN 102675061 B CN102675061 B CN 102675061B
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resveratrol
trans
alkyl
compound
salt
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CN102675061A (en
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栗进才
张黎娟
卜令雷
李贝蓓
马逢时
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ACETAR BIO-TECH Inc
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Abstract

The ether derivant of trans-resveratrol and medical use, belong to field of medicaments.There is compound or its salt, solvate or hydrate that bioactive compound is general formula (I); Wherein X 1h or CH 2r 1, and X 2h or CH 2r 2, and X 3h or CH 2r 3, but X 1, X 2and X 3not all H, and X 1, X 2and X 3can be identical; R 1, R 2and R 3identical or different and each naturally by R 4the C replaced 1-6alkyl, or can by R 9optional replacement and O, S (O) can be selected from containing one or more nand NR 9additional heteroatomic 4-7 ring; R 4f, CF 3, OR 5, NR 6r 7or S (O) nr 8; R 5, R 6and R 7identical or different and each H naturally or by R 4the C of optional replacement 1-6alkyl, or NR 6r 7be selected from O, NR containing one or more 9with S (O) nheteroatomic C 4-6heterocycloalkyl ring; Each n is 0-2; R 8c 1-6alkyl; R 9as R 4that defined or by R 4or the C that halogen optionally replaces 1-4alkyl; And R 9h or C 1-6alkyl.Purposes: hepatic diseases, T-cell proliferation about or by the disease mediated treatment of pro-inflammatory cytokine.

Description

The ether derivant of trans-resveratrol and medical use
Technical field
The invention belongs to field of medicaments, particularly the ether derivant of trans-resveratrol and their therepic use.
Technical background
1989, the epidemiology survey of world's cardiovascular disorder Controlling System of the World Health Organization (WHO) confirms, " French antinomy " phenomenon and France are that global maximum Production of Wine and country of consumption are closely related, reason there is one in grape wine to be called resveratrol (Resverartol, be called for short Res) material, it has the prevention coronary heart disease effect of highly significant, and this finds to cause scientist to the research boom of trans-resveratrol.Resveratrol, chemical name mattress triphenol, it has cis and trans two kinds of configurations, and the latter is the rock steady structure of Res, and biological activity is more extensive.Its structural formula is:
This compound is degeneration-resistant material-plant antitoxin (Phytoalxeni) as vitis spp at first and is found, and in succession finds in various plants again later.As medicinal plant Cassia tora, Li Lu, giant knotweed etc., what have is exactly even food, as grape and peanut.Content can be variant because of the difference of kind in grape for resveratrol, and Pericarpium Vitis viniferae is the main synthesising part of synthesis resveratrol, and the content of resveratrol is very high.Since self-discovery Res, people conduct in-depth research its pharmacologically active successively, and in its pharmacological action, the most attractive two aspects are: (1) affects arachidonic metabolism.All direct or indirect relevant therewith of many pathological processes known today, as inflammatory reaction, coagulation process, atherosclerotic generation, anaphylaxis, gastric acid secretion, adjustment neuroendocrine, short cell fission etc., Res is to the double inhibition effect of lipoxygenase and epoxidase, and prompting Res has the value of further investigation in these areas.(2) there is anti-oxidant, anti-oxidizing activities.The anti-oxidant activity of current phenolic compound receives the concern of people, and cause and the change procedure of the numerous diseases such as free radical and aging, cancer, radiation injury, viral hepatitis, Ischemia Reperfusion damage, senium praecox, diabetes, sacroiliitis are closely related.In recent years trans-resveratrol and derivative research thereof are found, to employing CCl 4cause in the impact experiment of mouse liver injury, compared with model group, trans-resveratrol and derivative thereof can make ALT, AST of rising obviously reduce, and illustrate that its tool in liver protecting has certain effect.
But analyze from the structure of trans-resveratrol and find, trans-resveratrol is mattress triphenol structure, and this type of compound structure exists oxidizable, t 1/2time is short, and patent medicine index such as to be not suitable at the shortcoming, significantly limit its development and use.Content of the present invention is exactly in this context, has carried out structural modification and transformation and its biological activity preferred to the trans-resveratrol with physiologically active
Summary of the invention
The object of this invention is to provide a kind of ether derivant and therepic use thereof of trans-resveratrol, can solve trans-resveratrol itself because of facile hydrolysis in vivo, biological metabolism is fast, and in body, t1/2 is shorter affects the problems such as result for the treatment of.
The ether derivant of trans-resveratrol, is characterized in that:
1. the compound or its salt of general formula (I), solvate or water and thing,
Wherein X 1h or CH 2r 1, and X 2h or CH 2r 2, and X 3h or CH 2r 3, but X 1, X 2and X 3not all H, and X 1, X 2and X 3can be identical;
2. R 1, R 2and R 3identical or different and each naturally by R 4the C replaced 1-6alkyl, or can by R 9optional replacement and O, S (O) can be selected from containing one or more nand NR 9additional heteroatomic 4-7 ring;
3. R 4f, CF 3, OR 5, NR 6r 7, S (O) nr 8or 3,5,6-trimethylpyrazine base;
4. R 5, R 6and R 7identical or different and each H naturally or by R 4the C of optional replacement 1-6alkyl, or NR 6r 7be selected from O, NR containing one or more 9with S (O) nheteroatomic C 4-6heterocycloalkyl ring; Each n is 0-2;
5. R 8c 1-6alkyl;
6. R 9as R 4that defined or by R 4or the C that halogen optionally replaces 1-4alkyl; And R 9h or C 1-6alkyl.
X 1cH 2r 1and X 2cH 2r 2and X 3cH 2r 3.
X 1be H and X 2cH 2r 2and X 3cH 2r 3.
X 1cH 2r 1and X 2h and X 3h.
X 1be H and X 2h is and X 3cH 2r 3.
R 4cF 3, OR 5, NR 6r 7or S (O) nr 8.Each n is 0-2;
General formula (I) structure comprises its cis-trans-isomer or mixture.
Be mainly used in the medicine of hepatic diseases, treating acute and chronic hepatitis, hepatitis B.
For the preparation for the treatment of or prevention and T-cell proliferation about or the purposes of the medicine of disease that mediated by pro-inflammatory cytokine.
Compound of the present invention can be monoether (X 1cH 2r 1or X 2cH 2r 2or X 3cH 2r 3, hereafter formula 1) or bis ether, wherein X 1cH 2r 1or X 2cH 2r 2, and X 3cH 2r 3(formula 2) or three ether X 1cH 2r 1, and X 2cH 2r 2, and X 3cH 2r 3(formula 3).
Other side of the present invention comprises the pharmaceutical composition containing formula 1 compound, and they are in the purposes for the treatment of liver, inflammatory diseases.
Will be appreciated that compound of the present invention can contain the carbon atom of one or more Asymmetrical substitute.In formula (1), (2) and (3) compound, the existence of these asymmetric centers one or more can produce steric isomer, and in every case, the present invention should be understood to expand to all this steric isomers, comprise enantiomer and Fei Nai reflects isomer, and composition thereof, comprise racemic mixture.
Term " C 1-6alkyl " refer to the straight or branched moieties with 1-6 carbon atom, comprise such as, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl etc.
Term " C 4-6heterocyclylalkyl refers to have 3-6 carbon atom and one or more are selected from the heteroatomic saturated heterocyclic part of N, O, S, and comprise such as, azetidinyl, oxetanyl, pyrrolidyl, tetrahydrofuran base, piperidyl, THP trtrahydropyranyl, pyrazinyl, 3,5,6-trimethylpyrazine base etc.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.
The salt of formula (1), (2) and (3) compound comprises pharmacologically acceptable salts, such as from inorganic or that organic acid is derivative acid salt, example hydrochloric acid salt, hydrobromide, p-tosylate, phosphoric acid salt, vitriol, perchlorate, acetate, trifluoroacetate, propionic salt, Citrate trianion, malonate, succinate, lactic acid salt, oxalate, tartrate and benzoate etc.
Salt can also be formed with alkali.This salt comprises from inorganic or that organic bases is derivative salt, and such as an alkali metal salt is as magnesium or calcium salt, and organic amine salt is as morpholine, piperidines, dimethylamine or diethylamine salt etc.
The compound of formula (1), (2) and (3) is by any proper method known in the art and/or prepared by following method.Will be appreciated that when need formula (1), (2) or (3) particular stereoisomer time, synthetic method described herein and suitable homochiral initial substance can be used, and/or conventional isolation techniques (such as, HPLC) can be used from mixture to split isomer.
Compound of the present invention is prepared by following method.In description below and general formula, except as otherwise noted, radicals R 1, R 2, R 3, R 4, R 5, R 6, R 7and R 8, be as defined above.Will be appreciated that before any reaction starts, to be present in following various compound and to wish the functional group that retains, as amino, hydroxyl or carboxyl may need to be protected form.In this case, the removing of blocking group can be the final step in specific reaction.The suitable protecting group of this functionality will be apparent to those skilled in the art.
Can according to the physical-chemical differences of component, in the known manner, by the end product of any mixture separation Cheng Chun of gained end product or intermediate or intermediate, such as, by chromatography, distillation method, fractional crystallization, or form salt when suitable or possible.
Beneficial effect of the present invention is, introduces the physicochemical constant that trans-resveratrol hydroxyl protection can change resveratrol compound, makes its not easy in inactivation in vivo; Increased Plasma Half-life, accretion rate slows down, thus prolong drug action time; reducing to wanting number of times, facilitating patient's medication.The trans-resveratrol ether compound of synthesis, is expected to be developed to a class newtype drug.
Below in conjunction with embodiment, the invention will be further described
Embodiment
Embodiment 1
The synthesis of trans-resveratrol trioxy-ethane
Get monobromethane 0.68g (6.24mmol), salt of wormwood (8.5g, 0.062mol) adds in the there-necked flask with whipping appts, add 20mlDMF.0.39g trans-resveratrol (1.71mmol) and 10mlDMF mixed solution is dripped after stirring, 95 DEG C are warming up to after dropwising, continue reaction 5h, filter, filtrate decompression revolves steaming, reclaims organic solvent and obtains yellow solid, be separated through silica gel column chromatography, obtain trans-resveratrol trioxy-ethane 0.32g, yield is 71.2%. 1H-NMR(CDCl 3，300MHz)δ：7.3(m，2H)，6.8(4H，m)，6.6(2H，d)，6.2(1H，t)，4.2-4.3(6H，m)，1.4-1.5(9H，m)；m/e：312。
Embodiment 2
The synthesis of trans-resveratrol trioxy--3-picoline
Take trans-resveratrol (3.9g, 0.017mol), salt of wormwood (8.5g, 0.062mol) adds in 250mL three-necked bottle.Add DMF (100mL), be heated to 100 DEG C, then by 3-chloromethyl pyridine hydrochloride (10.4g, 0.062mol) in 10min, gradation adds, reaction maintenance 95 DEG C, reacting by heating 4h, TLC detection reaction degree, after reaction terminates substantially, be cooled to room temperature, suction filtration obtains filtrate, add 100mL water, extract with ethyl acetate 100mL × 3, after combined ethyl acetate layer use water (50mL × 3) washing, with anhydrous sodium sulfate drying, yellow solid is obtained after reclaim under reduced pressure ethyl acetate, be separated through silicagel column, collect product, after decompression and solvent recovery, obtain faint yellow solid trans-resveratrol trioxy--3-picoline 6.54g, yield 65.1%, 1hNMR (CDCl 3, 300MHz) and δ: 8.6 (s, 3H), 8.58 (d, 3H), 7.79 (d, 3H), 7.3 (m, 5H), 6.8 (4H, m), 6.6 (2H, d), 6.2 (1H, t), m/e:501.
The compound of embodiment 1 and 2 shows effect in dimethylbenzene inducing mouse ear swelling and 10% egg white induced rat foot swelling model.
Dimethylbenzene inducing mouse ear swelling is tested
Kunming mouse 60, is divided into model group, embodiment one and two compound group medication group, trans-resveratrol group and positive controls (acetylsalicylic acid) at random, often organizes 10.Ig administration, once a day, continuous 7 days, model group then ig gave equal-volume solvent (1.0% Xylo-Mucine).After last administration, 1h smears dimethylbenzene 0.05ml in two sides before and after the left ear of mouse, and auris dextra compares, and mouse dislocation is put to death after 2h, two ears are cut along auricle baseline, lay round auricle at same position respectively with the punch tool of diameter 8mm, weigh, with the difference of left and right auricle weight for swelling.Result display embodiment one and two compound p-Xylol causes mice auricle swelling obvious restraining effect.
Dimethylbenzene inducing mouse ear swelling experimental result
Compare with model group: * P < 0.05
10% egg white induced rat foot swelling experiment
Wistar kind rat 40, ♂, be divided into model group, embodiment one and two compound group medication group, trans-resveratrol group and positive controls (acetylsalicylic acid) at random, often organize 8, ig administration, every day 1 time, continuous 7d, model group then ig gives equal-volume solvent (1.0% Xylo-Mucine).Cause inflammation in every mouse right toes subcutaneous injection 10% egg white 0.1mL after administration 1h, respectively before causing inflammation and cause scorching after 0.25,0.5,1,2,4h, cause scorching parapodum volume with Volumemeter measurement, cause the difference of scorching forward and backward volume for swelling with each mouse.Result display embodiment one and two compound has obvious restraining effect to pedal swelling caused by 10% egg white.
10% egg white induced rat foot swelling experimental result
Compare with model group: * P < 0.05

Claims (2)

1. the ether derivant of trans-resveratrol, is characterized in that: structural formula is trans-resveratrol trioxy--3-picoline or its salt of (I)
。
2. the purposes of the ether derivant of trans-resveratrol, is characterized in that: trans-resveratrol trioxy--3-picoline or its salt are for the preparation for the treatment of or prevention and the application of the medicine of disease that mediated by pro-inflammatory cytokine.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1688535A (en) * 2002-10-01 2005-10-26 维理生物技术公司 Novel bioactive diphenyl ethene compounds and their therapeutic applications
CN1977852A (en) * 2005-12-07 2007-06-13 周亚伟 Medicinal composition containing stilbene total glycoside and its use for pharmaceutical treating hepatitis B
CN101199504A (en) * 2007-11-21 2008-06-18 深圳海王药业有限公司 Function of stilbene oxygen acid or salt in preparing antiatheroscloresis medicament
US20100087442A1 (en) * 2002-04-25 2010-04-08 Ono Pharmaceutical Co., Ltd Diketohydrazine derivative compounds and drugs containing the compounds as the active ingredient

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100087442A1 (en) * 2002-04-25 2010-04-08 Ono Pharmaceutical Co., Ltd Diketohydrazine derivative compounds and drugs containing the compounds as the active ingredient
CN1688535A (en) * 2002-10-01 2005-10-26 维理生物技术公司 Novel bioactive diphenyl ethene compounds and their therapeutic applications
CN1977852A (en) * 2005-12-07 2007-06-13 周亚伟 Medicinal composition containing stilbene total glycoside and its use for pharmaceutical treating hepatitis B
CN101199504A (en) * 2007-11-21 2008-06-18 深圳海王药业有限公司 Function of stilbene oxygen acid or salt in preparing antiatheroscloresis medicament

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Resveratrol analogues as selective cyclooxygenase-2 inhibitors: synthesis and structure–activity relationship;Marek Murias等;《Bioorganic & Medicinal Chemistry》;20040911;第12卷;第5571-5578页 *
Synthesis and Cytotoxic Evaluation of a Series of Resveratrol Derivatives;Ban-Feng Ruan等;《CHEMISTRY & BIODIVERSITY》;20061231;第3卷;第975-981页 *

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