CN1948274A - Verakanol derivative, its preparation method and use - Google Patents
Verakanol derivative, its preparation method and use Download PDFInfo
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- CN1948274A CN1948274A CN 200610134004 CN200610134004A CN1948274A CN 1948274 A CN1948274 A CN 1948274A CN 200610134004 CN200610134004 CN 200610134004 CN 200610134004 A CN200610134004 A CN 200610134004A CN 1948274 A CN1948274 A CN 1948274A
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Abstract
The present invention belongs to the field of medicine technology, and discloses a resveratrol derivative, its preparation method and application. Said invention uses 3,5-dialkoxyl-4'-hydroxydiphenylethene and P-hydroxybenzaldehyde as raw material and adopts a certain preparation process to prepare the invented compound resveratrol derivative. Said invention also provides its chemical structure formula, and its medicinal alkali and medicinal salt have good effect for preventing and curing tumor, angiocardiopathy and inflammation diseases.
Description
Technical field:
The invention belongs to medical technical field, relate to derivative of several trans-resveratrols and its production and use.
Background technology:
Trans-resveratrol extensively is present in the foods such as Chinese medicines such as a mao leaf black false hellebore, giant knotweed, rheum officinale and grape.As far back as nineteen thirty-nine, Japan just from hair leaf black false hellebore extraction separation obtained trans-resveratrol (Japanization association will, 1939,60:1090～1100).Last century late nineteen eighties, the epidemiological survey that WHO carries out is found, although the Frenchman likes to eat this high-fat food of cheese, but Frenchman's Incidence of CHD is than other western countries low (promptly so-called " French antinomy "), and tracing it to its cause is to contain trans-resveratrol in Frenchman's grape wine of liking to drink.Further investigation finds that trans-resveratrol has good preventing and therapeutic action to multiple diseases such as tumour, cardiovascular disorder, inflammation.
Trans-resveratrol mainly shows as atherosclerosis and suppresses LDL oxidation (Biochem Pharmacol, 1997,53 (9): 1347～1355 cardiovascular effect; Life Sci, 1997,61 (21): 2103～2110; Biochem Mol Biol Int, 1999,47 (6): 1089～1096; Biochem Pharmacol, 811～816), anticoagulant (JP61-171427 1998,55 (6):; Planta Med, 274～276), reperfusion injury (CardioVasc Res, 2000,47:549～555 behind the ischemia resisting 1992,58 (3):; Free Radic Biol Med, 1999,27 (1-2): 160～169; J Stud Alcohol, 730～735) and promote blood vessel to relax, protect and keep endothelium integrity (Gen Pharmacol, 1996,27 (2): 363～366 2001,62 (6):; J Hypertens, 2000,18 (12): 1833～1840) etc. many-sided.
1997, report such as Jang M (Science, 1997,275:218～220) trans-resveratrol had good cancer prevention effect, and carcinogenic three phases is all had very strong restraining effect.Discover that trans-resveratrol suppresses starting the stage of cancer by anti-oxidant and antimutagenic effect, suppress the short stage of cancer, suppress the cancer extension phase by the inducing cancer cell Differentiation by anti-inflammatory action and inhibition cyclooxygenase, peroxidase activity.Using DMBA as inducer, TPA is during the skin carcinoma of the mouse of carcinogenic promoting agent is tested, give trans-resveratrol 1,5,10 and 25 μ mol weekly for twice respectively, after 18 weeks, compare with control group, the tumour incidence reduces by 50,63,63 and 88% respectively, and the skin carcinoma number reduces by 68,81,76 and 98% respectively, simultaneously, any toxicity performance is not arranged.Therefore, think that trans-resveratrol is a good cancer chemopreventive agent.Discover that trans-resveratrol is to the effect of tumour (Int J Biochem Cell Biol, 2001,33 (8): 775～783 anti-oxidant with it; ), anti-inflammatory (Science, 1997,275:218～220; J Pharm Pharmacol, 1185～1189), suppress tumor cell proliferation (Clin Cancer Res, 2001,7 (5): 1466～1,473 2004,56 (9):; CancerLett, 2001,163 (1): 43～49; Carcinogenesis, 1999,20 (2): 237～242; Exp Cell Res, 1999,249:109～115; Biochem Biophy Res Commun, 1998,250:53～58 etc.), inducing apoptosis of tumour cell and differentiation (Blood, 1998,92 (3): 996～1002; The Fourth Military Medical University's journal, 2004,25 (19): 1797～1799; 1031～1033) etc. the Shaanxi medical journal, 2004,33 (11): many-sided effect is relevant.
141～150), suppress H in addition, trans-resveratrol also has prevention senile dementia (J Neurochemistry, 2000,75 (1):
+-K
+1947～1951), various active such as antibiotic-ATP enzyme (Biochem Pharmacol, 1992,44 (10):.
Just because of trans-resveratrol has above-mentioned multiple biological activity, cause that people are to trans-resveratrol and derivative thereof, the research of analogue, mostly be the methyl-derivatives of trans-resveratrol greatly, ester, hydroxy analogs etc., wherein trans-resveratrol 3, the two methylates of 5---3, the 5-dimethoxy-4 ' '-hydroxy stibene (Pterostilbene, the red sandalwood Stilbene) is the Verakanol derivative that is subjected to extensive concern, it extensively is present in Guangxi Sanguis Draxonis (CHINA JOURNAL OF CHINESE MATERIA MEDICA, 1998,23 (10): 616～618), grape (J AgricFood Chem, 2000,48 (12): 6103～6105), propolis (Experientia, 1978,157～159) etc. 34 (2): in, have anti-oxidant, antiproliferative, reducing blood-fat, medium tenacity suppresses the activity (IC of COX-1 and COX-2
50Be respectively 19.8 μ M and 83.9 μ M), induce HL-60 apoptosis (IC
5070 μ M), the canceration (ED that prevents DMBA to bring out
504.8 μ M), hypoglycemic activity is (to the diabetogenic rat model of streptozotocen, its blood sugar reducing function and N1,N1-Dimethylbiguanide are close) and anti-mycotic activity (its anti-mycotic activity is five times of trans-resveratrol) (J Agric FoodChem, 2002,50 (12): 3453～3457; J Nat Prod, 1997,60 (6): 609～610; JAgric Food Chem, 2005,53 (9): 3403～3407; J OrgChem, 2004,69 (21): 7101～7107).
The red sandalwood Stilbene also has powerful antiproliferative effect, strong and selectivity is strong than the trans-resveratrol effect, can suppress α-and λ-archaeal dna polymerase, also can suppress duplicating of SV40 DNA, its suppress active and α-, δ-close with the triple AG14361 aphidocolins of ξ-DNA (Aphidicolin).To malignant melanoma cell B16M-F10, every day, the red sandalwood Stilbene processing with 40 μ M had significant inhibitory effect in 60 minutes, and inhibiting rate reaches 56% (Neoplasia, 2005,7 (1): 37～47).(Int J Biochem Cell Biol such as Tolomeo M, 2005,37 (8): 1709～1726) the report red sandalwood can be induced the leukemia cell's of anti-multiple medicines and BCR-ABL expression remarkable apoptosis, and to almost not influence of normal cell, the investigator thinks that 3 in its molecular structure, 5-dimethoxy are its active essential structures.
Summary of the invention:
The present invention is a lead compound with trans-resveratrol and red sandalwood Stilbene, and multiple derivative of trans-resveratrol and its production and use is provided.
Compound of the present invention, the same with trans-resveratrol with the red sandalwood Stilbene, multiple diseases such as tumour, cardiovascular disorder, inflammation are had good preventing and therapeutic action, the activity of some compounds obviously is better than trans-resveratrol and red sandalwood Stilbene.And these compounds can improve the stability of trans-resveratrol and red sandalwood Stilbene and can improve its pharmacokinetic parameter by salify because of there being substituted amido in the structure.
The starting raw material 3 for preparing compound of the present invention, the preparation of 5-dialkoxy-4 '-hydroxy stibene, can be with 3, the 5-resorcylic acid is a raw material, under the effect of alkali, become ether to become ester simultaneously with halohydrocarbon or sulfuric ester, then through reduction, halo, after the triethyl-phosphite reaction, with 4-benzyloxy phenyl aldehyde the Wittig-Horner reaction taking place forms 3 immediately, 5-dialkoxy-4 '-benzyloxy toluylene, again at aluminum chloride/N, N, slough benzyl under the effect of-xylidine and make 3,5-dialkoxy-4 '-hydroxy stibene.With 3, the 5-dimethoxy-4 ' '-hydroxy stibene is an example, its synthetic route is as follows:
Compounds process for production thereof of the present invention comprises: with 3,5-dialkoxy-4 '-hydroxy stibene is a raw material, under the effect of alkali, with 1,2-dihalo-ethane (or 1,3-two Halopropanes or 1,4-dihalo-butane) the halogen-containing alkoxy substituted toluylene of reaction generation, with various replacement secondary amines reactions halogen is converted into various substituted amidos again; Or with 3,5-dialkoxy-4 '-hydroxy stibene is a raw material, under the effect of alkali, makes with 2-substituted amido halogen ethane (or 3-substituted amido Halopropane or 4-substituted amido halogen butane) reaction; Or with 3,5-dialkoxy-4 '-hydroxy stibene is a raw material, under the effect of alkali, make the alkoxy substituted toluylene of hydroxyl with 2-halogen ethanol (or 3-halogen propyl alcohol or 4-halogen butanols) reaction, again with reactions such as halogenating agent such as thionyl chloride, phosphorus trihalide, phosphorus pentachloride, phosphorus oxychloride with hydroxy halogeno, with various replacement secondary amines reactions halogen is converted into various substituted amidos again.
Compounds process for production thereof of the present invention also comprises: be raw material with the p-Hydroxybenzaldehyde, under the effect of alkali, with 1,2-dihalo-ethane (or 1,3-two Halopropanes or 1,4-dihalo-butane) reaction generates 4-(2-halogen oxyethyl group) phenyl aldehyde or 4-(3-halogen propoxy-) phenyl aldehyde or 4-(4-halogen butoxy) phenyl aldehyde, with various replacement secondary amine reactions halogen is converted into various substituted amidos again, and then generation Wittig-Horner reaction makes target compound; Or 2-halogen ethanol (or 3-halogen propyl alcohol or 4-halogen butanols) is converted into various substituted amidos with various replacement secondary amine reactions with halogen, again with reactions such as halogenating agent such as thionyl chloride, phosphorus trihalide, phosphorus pentachloride, phosphorus oxychloride with hydroxy halogeno, under the effect of alkali, generate 4-(2-halogen oxyethyl group) phenyl aldehyde or 4-(3-halogen propoxy-) phenyl aldehyde or 4-(4-halogen butoxy) phenyl aldehyde, make target compound through the Wittig-Horner reaction with the p-Hydroxybenzaldehyde reaction.
Adopt the as above Verakanol derivative of method preparation respectively, its preparation method is simple, and process stabilizing is workable.Described compound, the same with trans-resveratrol with the red sandalwood Stilbene, multiple diseases such as tumour, cardiovascular disorder, inflammation are had good preventing and therapeutic action, the activity of some compounds obviously is better than trans-resveratrol and red sandalwood Stilbene.
Embodiment:
Embodiment 1:3,5-dimethoxy p-methyl synthetic
In the 250ml three-necked bottle, add 7.7g (0.05mol) 3, the 5-resorcylic acid, 20g (0.15mol) Anhydrous potassium carbonate, 15ml (0.15mol) methyl-sulfate and 160ml acetone, fully the stirring and refluxing reaction is 5 hours.Filtering salt of wormwood, acetone is removed in distillation.Add 160ml water and 160ml ether, divide and get organic layer, use ammoniacal liquor (16ml * 2) more successively, water (32ml), 5% hydrochloric acid (32ml * 2), water (16ml) is washed, and adds anhydrous sodium sulfate drying, steams and removes ether, natural crystallization, drying gets the 9.53g product, and yield is 93.6%, 42～43 ℃ of mp.
Embodiment 2:3,5-3,5-dimethoxybenzoic alcohol synthetic
In the 250ml three-necked bottle, add 4.0g (0.04mol) tetrahydrochysene lithium aluminium, the 30ml anhydrous diethyl ether.Stir down and drip 4.0g (0.02mol) 3, the 30ml anhydrous ether solution of 5-dimethoxy p-methyl drips off heating reflux reaction 4h.Stopped reaction drips wet ether of 10ml and 60ml water, drips dilute sulphuric acid (the 10ml vitriol oil is dissolved in 30ml water) again, reaction is violent, drips 80ml water again, divides and gets the ether layer, with twice of a small amount of extracted with diethyl ether water layer, the combined ether layer adds anhydrous sodium sulfate drying, steams and removes ether, the nature crystallization, get the 8.3g product, yield is 96.8%, 47～49 ℃ of mp.
Embodiment 3: dimethoxy-benzyl chloride synthetic
16.8g (0.1mol) 3, the 5-3,5-dimethoxybenzoic alcohol places three-necked bottle, adds the 150ml anhydrous diethyl ether, stirring makes its dissolving, drips 15ml (0.2mol) thionyl chloride, after dripping off, room temperature reaction 3h drips 100ml water in three-necked bottle under ice-water bath, divide and get ether layer, ether layer washing back adds anhydrous sodium sulfate drying, filter, steam ether, get white solid 18.9g, yield is 94.4%, 46～47 ℃ of mp.
Embodiment 4:(E) 3,5-dimethoxy-4 ' '-benzyloxy toluylene synthetic
3.7g (0.02mol) 3,5-dimethoxy benzyl chlorine and 7ml (0.04mol) triethyl-phosphite place the 50ml round-bottomed flask, heating reflux reaction 3h, excessive triethyl-phosphite is removed in underpressure distillation, get orange oily matter, in oily matter, add 15ml DMF, join then in the sodium ethylate (making), stir 5min, drip the 10ml DMF solution of corresponding 2.7g 4-benzyloxy phenyl aldehyde by 0.54g sodium and 10ml dehydrated alcohol, dropwise stirring at room 3h, pour into and separate out solid in the frozen water, suction filtration, the dry product white solid 10.0g that gets, 120～122 ℃ of mp, yield 80%.
1H-NMR(300MHz，CDCl
3)：δ(ppm)3.83(6H，s，CH
3)，5.09(2H，s，OCH
2Ph)，6.38(1H，t，J＝2.2Hz)，6.65(2H，d，J＝2.2Hz)，6.90(1H，d，J＝16.3Hz，-CH＝CH-)，6.97(2H，d，J＝8.7Hz)，7.04(1H，d，J＝16.3Hz，-CH＝CH-)，7.39(7H，m).
Embodiment 5:(E)-3,5-dimethoxy-4 ' '-preparation of hydroxy stibene
6.2g (0.018mol) (E)-3, the 5-dimethoxy-4 ' '-the benzyloxy toluylene is dissolved in the 50ml exsiccant methylene dichloride, add 6.9ml (0.054mol) N, accelerine, gradation adds 9.6g (0.072mol) aluminum trichloride (anhydrous) under the ice bath, room temperature reaction 10 hours is poured into reaction solution in the frozen water that contains appropriate hydrochloric acid, divides and gets organic layer, twice of dichloromethane extraction of water layer, merge organic layer, use 5% sodium bicarbonate respectively, after the water washing, anhydrous magnesium sulfate drying, filter, steaming vibrating dichloromethane, column chromatography for separation (eluent sherwood oil-methylene dichloride 1: 1) obtains (E)-3, the 5-dimethoxy-4 ' '-hydroxy stibene, white solid 3.0g, 87～89 ℃ of mp, yield 64%.
1H-NMR(300MHz，CDCl
3)：δ(ppm)3.83(6H，s，OCH
3)，4.80(1H，brs，-OH)，6.38(1H，br)，6.64(2H，d)，6.82(2H，d，J＝8.6Hz)，6.89(1H，d，J＝16.3Hz，-CH＝CH-)，7.03(1H，d，J＝16.3Hz，-CH＝CH-)，7.40(2H，d，J＝8.6Hz).
Embodiment 6:(E)-3,5-dimethoxy-4 ' '-preparation of (2-bromine oxethyl) toluylene:
(E)-3,5-dimethoxy-4 ' '-hydroxy stibene is dissolved in the ethanol, hydro-oxidation sodium, potassiumiodide and excessive 1, the 2-ethylene dibromide, 70 ℃ were reacted 2 days, filtered the filtrate evaporate to dryness, column chromatography, use the methylene dichloride wash-out, obtain compound (E)-3, the 5-dimethoxy-4 ' '-(2-bromine oxethyl) toluylene, yield is about 37～44%, mp99～101 ℃.
Use the same method, with 1,3-two Halopropanes/1,4-dihalo-butane substitutes glycol dibromide can make compound (E)-3,5-dimethoxy-4 ' '-(3-halogen propoxy-) toluylene/(E)-3, the 5-dimethoxy-4 ' '-(4-halogen butoxy) toluylene.
Embodiment 7: the preparation of amido alkyl ether derivative
Above-mentioned halogen-containing alkoxy substituted toluylene is dissolved in tetrahydrofuran (THF) or ethanol, add corresponding amine, back flow reaction 2～3 days, the reaction solution evaporated under reduced pressure, residue 10% diluted hydrochloric acid dissolution, behind the ethyl acetate extraction, the acid layer is transferred pH10～11, separate out precipitation, ethyl acetate extraction three times merges three times extraction liquid, wash twice after, anhydrous magnesium sulfate drying, filter, the pressure reducing and steaming solvent gets solid or semi-solid thing, column chromatography for separation (eluent is a methylene dichloride) gets amido alkyl ether target compound.
Amido alkyl ether compound is dissolved in ethyl acetate, and under the ice bath, logical hydrogen chloride gas is separated out white precipitate, filters, and drying obtains respective compound and gets hydrochloride.
(E)-3, the 5-dimethoxy-4 ' '-(2-diethylin oxyethyl group) toluylene (RE9943), light yellow semi-solid 0.4g, yield 43%.
1H-NMR(300MHz，CDCl
3)：δ(ppm)1.09(6H，t，J＝7.1Hz，N(CH
2CH
3)
2)，2.66(4H，q，J＝7.1Hz，N(CH
2CH
3)
2)，2.90(2H，t，J＝6.2Hz，CH
2N(CH
2CH
3)
2)，3.83(6H，s，OCH
3)，4.06(2H，t，J＝6.3Hz，OCH
2CH
2N)，6.37(1H，t，J＝2.1Hz)，6.64(2H，d，J＝2.2Hz)，6.90(1H，d，J＝16.0Hz，-CH＝CH-)，6.89(2H，d，J＝8.7Hz)，7.03(1H，d，J＝16.2Hz，-CH＝CH-)，7.42(2H，d，J＝8.7Hz).ESI-MS：356.2[M+H]
+，3530.9[M-H]
-.
(E)-3,5-dimethoxy-4 ' '-(2-piperidyl oxyethyl group) toluylene hydrochloride (RE9944), white solid 0.3g, mp189～191 ℃, yield 37%.
1H-NMR(300MHz，D
2O)：δ(ppm)2.01(6H，m)，2.70(2H，brs)，3.38(4H，brs)，3.67(6H，s，OCH
3)，4.19(2H，brs)，6.31(1H，s)，6.57(2H，s)，6.74(1H，d，J＝16.0Hz，-CH＝CH-)，6.83(2H，d，J＝8.2Hz)，6.92(1H，d，J＝16.1Hz，-CH＝CH-)，7.30(1H，d，J＝8.2Hz).ESI-MS：368.1[M+H]
+.
(E)-3, the 5-dimethoxy-4 ' '-[2-(N-morpholine) oxyethyl group] toluylene hydrochloride (RE9945), white solid 0.34g, 199～202 ℃ of mp, yield 34%.
1H-NMR(300MHz，D
2O)：δ(ppm)3.37(4H，brs)，3.55(2H，brs)，3.72(6H，s)，3.96(4H，brs)，4.29(2H，brs)，6.36(1H，s)，6.61(2H，s)，6.90(4H，m)，7.33(2H，brs).
(E)-3, the 5-dimethoxy-4 ' '-[2-(N-Pyrrolidine) oxyethyl group] toluylene (RE9946), light yellow semi-solid 0.45g, yield 45%.
1H-NMR(300MHz，CDCl
3)：δ(ppm)1.84(4H，brs)，2.71(4H，brs)，2.96(2H，brs，OCH
2CH
2N)，3.82(6H，s，OCH
3)，4.17(2H，t，J＝5.5Hz，OCH
2CH
2N)，6.38(1H，t，J＝2.2Hz)，6.65(2H，d，J＝2.1Hz)，6.90(1H，d，J＝16.2Hz，-CH＝CH-)，6.91(2H，d，J＝8.7Hz)，7.03(1H，d，J＝16.1Hz，-CH＝CH-)，7.43(1H，d，J＝8.7Hz).
(E)-3, the 5-dimethoxy-4 ' '-[2-N-(4-methylpiperazine base) oxyethyl group] toluylene hydrochloride (RE9947), white solid 0.50g, 194～197 ℃ of mp, yield 37%.
1H-NMR(300MHz，DMSO-d
6)：δ(ppm)2.81(3H，s，N-CH
3)，3.62(10H，m)，3.76(6H，s，OCH
3)，4.39(2H，brs，OCH
2CH
2N)，6.38(1H，s)，6.73(2H，d，J＝2.1Hz)，7.01(2H，d，J＝8.6Hz)，7.04(1H，d，J＝16.3Hz，-CH＝CH-)，7.22(1H，d，J＝16.4Hz，-CH＝CH-)，7.55(2H，d，J＝8.7Hz)，11.50(1H，brs，HCl).
(E)-3, the 5-dimethoxy-4 ' '-(3-dimethylin propoxy-) toluylene hydrochloride (RE9948), white solid 0.25g, 126～130 ℃ of mp, yield 28%.
1H-NMR(300MHz，DMSO-d
6)：δ(ppm)2.13(2H，m，OCH
2CH
2CH
2N)，2.77(6H，s，N(CH
3)
2)，3.19(2H，t，J＝7.5Hz，OCH
2CH
2CH
2N)，3.76(6H，s，OCH
3)，4.07(2H，t，J＝5.9Hz，OCH
2CH
2CH
2N)，6.38(1H，s)，6.73(2H，d，J＝2.1Hz)，6.94(2H，d，J＝8.7Hz)，7.02(1H，d，J＝16.4Hz，-CH＝CH-)，7.21(1H，d，J＝16.4Hz，-CH＝CH-)，7.53(2H，d，J＝8.7Hz)，10.33(1H，brs，HCl).
13C-NMR(300MHz，DMSO-d
6)：δ(ppm)23.97，42.20，54.16，55.28，64.95，99.57，104.29，114.83，126.42，127.94，128.56，129.94，139.46，158.09，160.73.ESI-MS：342.2[M+H]
+.
(E)-3, the 5-dimethoxy-4 ' '-[3-(N-piperidyl) propoxy-] toluylene hydrochloride (RE9949), white solid 0.30g, 190～193 ℃ of mp, yield 34%.
1H-NMR(300MHz，DMSO-d
6)：δ(ppm)1.77(5H，m)，2.17(2H，m)，2.86(2H，m)，3.14(2H，m)，3.44(3H，m)，3.76(6H，s，OCH
3)，4.07(2H，t，J＝5.9Hz，OCH
2CH
2CH
2N)，6.38(1H，t，J＝2.0Hz)，6.73(2H，d，J＝2.1Hz)，6.95(2H，d，J＝8.7Hz)，7.02(1H，d，J＝16.4Hz，-CH＝CH-)，7.21(1H，d，J＝16.4Hz，-CH＝CH-)，7.53(2H，d，J＝8.7Hz)，10.18(1H，brs，HCl).
13C-NMR(300MHz，DMSO-d
6)：δ(ppm)21.48，22.51，23.42，52.13，53.47，55.29，65.12，99.57，104.29，114.83，126.42，127.96，128.57，129.93，139.47，158.10，160.73.ESI-MS：382.2[M+H]
+.
(E)-3, the 5-dimethoxy-4 ' '-(3-N-morpholine propoxy-) toluylene hydrochloride (RE9950), white solid 0.32g, 177～181 ℃ of mp, yield 39%.
1H-NMR(300MHz，DMSO-d
6)：δ(ppm)2.19(2H，brs，OCH
2CH
2CH
2N)，3.07(2H，m)，3.24(2H，m)，3.42(4H，m)，3.76(6H，s，OCH
3)，3.96(2H，m)，4.08(2H，t，J＝5.6Hz，OCH
2CH
2CH
2N)，6.38(1H，brs)，6.72(2H，d，J＝2.1Hz)，6.95(2H，d，J＝8.7Hz)，7.02(1H，d，J＝16.4Hz，-CH＝CH-)，7.21(1H，d，J＝16.4Hz，-CH＝CH-)，7.53(2H，d，J＝8.7Hz)，10.96(1H，brs，HCl).
13C-NMR(300MHz，DMSO-d
6)：δ(ppm)23.11，51.15，53.57，55.29，63.31，65.08，99.59，104.31，114.86，126.44，127.96，128.58，129.96，139.48，158.10，160.74.ESI-MS：3384.2[M+H]
+.
(E)-3, the 5-dimethoxy-4 ' '-[3-(N-Pyrrolidine base) propoxy-] toluylene hydrochloride (RE9951), white solid 0.40g, 139～142 ℃ of mp, yield 41%.
1H-NMR(300MHz，DMSO-d
6)：δ(ppm)1.86(2H，m)，2.00(2H，m)，2.13(2H，m)，3.00(2H，m)，3.25(2H，m)，3.62(2H，m)，3.76(6H，s，OCH
3)，4.08(2H，t，J＝6.0Hz，OCH
2CH
2CH
2N)，6.38(1H，s)，6.73(2，d，J＝2.2Hz)，6.95(2H，d，J＝8.7Hz)，7.02(1H，d，J＝16.4Hz，-CH＝CH-)，7.21(1H，d，J＝16.5Hz，-CH＝CH-)，7.53(2H，d，J＝8.7Hz)，10.35(1H，brs，HCl).
13C-NMR(300MHz，DMSO-d
6)：δ(ppm)22.76，25.37，51.40，53.19，55.12，55.29，64.91，99.57，104.30，114.83，126.42，127.96，128.57，129.94，139.47，158.09，160.74.ESI-MS：368.2[M+H]
+.
(E)-3, the 5-dimethoxy-4 ' '-[3-N-(4-methylpiperazine base) propoxy-] toluylene dihydrochloride (RE9952), white solid 0.53g, 194～197 ℃ of mp, yield 44%.
1H-NMR (300MHz, DMSO-d
6): δ (ppm) 2.16 (2H, brs, OCH
2CH
2CH
2N), 2.81 (4H, brs, piperazine rings), 3.45 (3H, s, N-CH
3, overlap with the water peak), 3.62 (4H, brs, piperazine rings), 3.76 (6H, s), 4.08 (2H, brs, OCH
2CH
2CH
2N), 6.38 (1H, brs), 6.73 (2H, d, J=2.0Hz), 6.96 (2H, d, J=8.6Hz), 7.02 (1H, d, J=16.4Hz ,-CH=CH-), 7.21 (1H, d, J=16.4Hz,-CH=CH-), 7.53 (2H, d, J=8.7Hz), 11.5 (2H, brs, 2HCl).
13C-NMR (300MHz, DMSO-d
6): δ (ppm) 23.60,42.19,48.44,49.91,53.32,55.28,64.97,99.56,104.29,114.84,126.41,127.94,128.57,129.92,139.46,158.08,160.73.ESI-MS:397.3[M+H]
+.
(E)-3, the 5-dimethoxy-4 ' '-(3-diethylin propoxy-) toluylene hydrochloride (RE9953), white solid 0.15g, 170～173 ℃ of mp, yield 27%.
1H-NMR(300MHz，DMSO-d
6)：δ(ppm)1.22(6H，t，J＝7.2Hz，N(CH
2CH
3)
2)，2.13(2H，m，OCH
2CH
2CH
2N)，3.12(6H，m，N(CH
2CH
3)
2 and OCH
2CH
2CH
2N)，3.76(6H，s，O(CH
3)
2)，4.09(2H，t，J＝6.0Hz，OCH
2CH
2CH
2N)，6.38(1H，t，J＝2.0Hz)，6.73(2H，d，J＝2.1Hz)，6.95(2H，d，J＝8.7Hz)，7.03(1H，d，J＝16.4Hz，-CH＝CH-)，7.21(1H，d，J＝16.4Hz，-CH＝CH-)，7.53(2H，d，J＝8.7Hz)，10.44(1H，brs，HCl).
13C-NMR(300MHz，DMSO-d
6)：δ(ppm)8.55，23.15，46.24，47.83，55.28，64.94，99.57，104.29，114.84，126.42，127.96，128.57，129.93，139.48，158.08，160.73.ESI-MS：370.2[M+H]
+
Embodiment 8: the part target compound is induced the experiment of people's acute promyelocytic leukemia cell apoptosis
1. experimental technique
1.1 cell cultures
The ATCC in the U.S. is purchased in people's acute promyelocytic leukemia cell strain (NB4), is incubated to contain 10% in heat-killed foetal calf serum, 100IU/ml penicillin, 100 μ g/ml Streptomycin sulphates and 1mmol/lL glutamine RPMI1640 nutrient solution, 37 ℃, 5%CO
2Hatch in the saturated humidity incubator.
1.2 the mensuration of cell viability
Cell viability is measured by the trypan blue method of exclusion.Take by weighing trypan blue, add a small amount of distilled water and grind, add distilled water and be diluted to 4%, use filter paper filtering, 4 ℃ of preservations.During use, this mother liquor is diluted to 0.4% working concentration with PBS.Get NB4 cell (1 * 10
5/ ml) be inoculated in 12 orifice plates, every hole 2ml.Prepare the individual cells suspension after adding the different concns drug incubation, get the 0.4% trypan blue solution that 50 μ l cell suspensions add 50 μ l, mixing in 3 minutes, is observed in microscopically, and dead cell is dyed blueness, and viable cell is refused to dye.With blood counting chamber difference living cell counting and dead cell (about 300 cells altogether).The percentage that viable count accounts for total cell count is cell survival rate.
1.3 apoptotic morphologic detection
Utilize the two morphological change of dying method investigation apoptotic cell of acridine orange (AO) and bromination second pyridine (EB).The NB4 cell of taking the logarithm vegetative period is with every hole 1 * 10
5The cell density of individual/ml is inoculated in 12 orifice plates, every hole 2ml.After the drug treating, get the 1ml cell suspension, centrifugal, abandon or adopt supernatant liquor, be resuspended among the 25 μ l PBS, add AO/EB equal-volume mixed solution 3 μ l (100 μ g/ml AO, 100 μ g/ml EB) then, mixing.Inhale a mixed solution and put on clean glass slide, use the cover glass mounting, under fluorescent microscope, observe and take pictures.
EB refuses to dye and cell that nuclear shrinkage, germination, foaming and apoptotic body occur is considered to apoptotic cell.Different zones is selected 300 cells at random under mirror, and it is apoptosis rate that apoptotic cell accounts for its per-cent.
| Compound | Concentration (μ M) | Inhibiting rate (%) | Survival rate (%) | Apoptosis rate (%) |
| Control group RE9943 RE9944 RE9945 RE9945HCl RE9946 RE9949 | 0 25 25 25 25 25 25 | 0 94 88 69 82 90 91 | 96 12 6 60 22 15 9 | 2.4 / / 40.8 67.8 100 / |
The experiment proved that described compound all has better therapeutic effect to tumour, inflammation, cardiovascular disorder.
Claims (4)
1, Verakanol derivative is characterized in that: by Verakanol derivative or its pharmacologically acceptable salt of following general formula (I) expression:
R wherein
1And R
2Be methyl or ethyl or propyl group; N is 1～4; NR
3R
4Be common amine, as the piperazine of dimethylamine, diethylamine, dipropyl amine, Diisopropylamine, Pyrrolidine, piperidines, morpholine or replacement.
2, a kind of method of preparation I compound Verakanol derivative is characterized in that: this method comprises:
A. with 3, the 5-resorcylic acid is a raw material, under the effect of alkali, become ether to become ester simultaneously, then through reduction, halo, after the triethyl-phosphite reaction with halohydrocarbon or sulfuric ester, with 4-benzyloxy phenyl aldehyde the Wittig-Horner reaction taking place forms 3 immediately, 5-dialkoxy-4 '-benzyloxy toluylene again at aluminum chloride/N, is sloughed benzyl under the effect of accelerine and is made 3,5-dialkoxy-4 '-hydroxy stibene, accepted way of doing sth II compound
R wherein
1And R
2Has the implication in the claim 1; Alkali is mineral alkali, as yellow soda ash (potassium, lithium), sodium bicarbonate (potassium), sodium hydroxide (potassium, lithium), or is organic bases, as triethylamine, pyridine, sodium alkoxide (potassium), sodium hydride (potassium, lithium), sodium amide (potassium, lithium);
With the formula III compound condensation
X(CH
2)
nX (III)
Wherein X is a halogen, and n has the implication in the claim 1;
Obtain formula IV compound
Formula IV compound and HNR
3R
4Reaction obtains formula I compound; NR wherein
3R
4Has the implication in the claim 1;
B. under the effect of alkali, formula II compound
R wherein
1And R
2Has the implication in the claim 1; Alkali is mineral alkali, as yellow soda ash (potassium, lithium), sodium bicarbonate (potassium), sodium hydroxide (potassium, lithium), or is organic bases, as triethylamine, pyridine, sodium alkoxide (potassium), sodium hydride (potassium, lithium), sodium amide (potassium, lithium) and formula V compound condensation
X(CH
2)
nNR
3R
4 (V)
Wherein X is a halogen, and n has the implication in the claim 1; NR
3R
4Has the implication in the claim 1;
Obtain formula I compound;
C. under the effect of alkali, formula II compound
R wherein
1And R
2Has the implication in the claim 1; Alkali is mineral alkali, as yellow soda ash (potassium, lithium), sodium bicarbonate (potassium), sodium hydroxide (potassium, lithium), or is organic bases, as triethylamine, pyridine, sodium alkoxide (potassium), sodium hydride (potassium, lithium), sodium amide (potassium, lithium)
With formula VI compound condensation
X(CH
2)
nOH (VI)
Wherein X is a halogen, and n has the implication in the claim 1;
Obtain formula VII compound
Formula VII compound and halogenating agent such as thionyl chloride, phosphorus trihalide, phosphorus pentachloride, phosphorus oxychloride reaction obtain formula IV compound
Formula IV compound and HNR
3R
4Reaction obtains formula I compound; NR wherein
3R
4Has the implication in the claim 1;
D. formula VIII compound,
NR wherein
3R
4Has the implication in the claim 1; N has the implication in the claim 1; With formula IX or formula X compound
R wherein
1And R
2Has the implication in the claim 1; R
5Be lower paraffin hydrocarbons; Make formula I compound through Wittig reaction or Wittig-Horner reaction.
3, a kind of pharmaceutical composition is characterized in that: contain the Verakanol derivative of claim 1 Chinese style (I) expression of one or more pharmaceutically acceptable carrier and significant quantity or the compound that its pharmacologically acceptable salt is formed.
4, the application of claim 1 compound in preparation treatment tumour, inflammation, cardiovascular disease medicine.
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|---|---|---|---|
| CN200610134004A CN1948274B (en) | 2006-10-25 | 2006-10-25 | Verakanol derivative, preparation method and use thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610134004A CN1948274B (en) | 2006-10-25 | 2006-10-25 | Verakanol derivative, preparation method and use thereof |
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|---|---|
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| CN1948274B CN1948274B (en) | 2012-10-17 |
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ID=38017917
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|---|---|---|---|
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010010578A2 (en) * | 2008-07-23 | 2010-01-28 | Aptuit Laurus Private Limited | A key intermediate for the preparation of stilbenes |
| CN102816090A (en) * | 2012-09-10 | 2012-12-12 | 四川大学 | Carbamate compounds, preparation method and application thereof |
| CN103073440A (en) * | 2013-02-21 | 2013-05-01 | 四川大学 | Diphenylvinyloxy alkylamine compound and preparation method as well as application thereof |
| US8524782B2 (en) | 2008-07-23 | 2013-09-03 | Laurus Labs Private Limited | Key intermediate for the preparation of Stilbenes, solid forms of Pterostilbene, and methods for making the same |
| CN103450130A (en) * | 2013-09-13 | 2013-12-18 | 陕西嘉禾植物化工有限责任公司 | Toluylene compound and preparation method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1116264C (en) * | 2000-07-20 | 2003-07-30 | 北京孚曼生物技术有限公司 | Method for separating reseveratrol from resveratrol glucoside and application thereof |
| CN1323776A (en) * | 2001-05-31 | 2001-11-28 | 北京天纯维通生物技术有限公司 | Prepn. of resveratrol and resveratrol glycoside |
-
2006
- 2006-10-25 CN CN200610134004A patent/CN1948274B/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010010578A2 (en) * | 2008-07-23 | 2010-01-28 | Aptuit Laurus Private Limited | A key intermediate for the preparation of stilbenes |
| WO2010010578A3 (en) * | 2008-07-23 | 2010-11-11 | Aptuit Laurus Private Limited | A key intermediate for the preparation of stilbenes |
| US8524782B2 (en) | 2008-07-23 | 2013-09-03 | Laurus Labs Private Limited | Key intermediate for the preparation of Stilbenes, solid forms of Pterostilbene, and methods for making the same |
| CN102816090A (en) * | 2012-09-10 | 2012-12-12 | 四川大学 | Carbamate compounds, preparation method and application thereof |
| CN103073440A (en) * | 2013-02-21 | 2013-05-01 | 四川大学 | Diphenylvinyloxy alkylamine compound and preparation method as well as application thereof |
| CN103073440B (en) * | 2013-02-21 | 2015-06-03 | 四川大学 | Diphenylvinyloxy alkylamine compound and preparation method as well as application thereof |
| CN103450130A (en) * | 2013-09-13 | 2013-12-18 | 陕西嘉禾植物化工有限责任公司 | Toluylene compound and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1948274B (en) | 2012-10-17 |
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