CN102161648A - Preparation method and applications of isoflavone type compounds with selective estrogen receptor modulating activity - Google Patents
Preparation method and applications of isoflavone type compounds with selective estrogen receptor modulating activity Download PDFInfo
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Abstract
The invention relates to the pharmaceutical chemistry field, in particular to isoflavone type compounds (I), a preparation method of the compounds, medicinal composites with the compounds and medicinal applications of the compounds and the medicinal composites, in particular to the applications used as a selective estrogen receptor modulator.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to a quasi-isoflavone compounds (I), their preparation method contains the medicinal compositions of these compounds and their medical use, particularly as the purposes of selective estrogen receptor modulators.
Background technology
Oestrogenic hormon has biological effect widely, it not only has irreplaceable effect in the keeping of the growth of female sex organ, secondal sexual character, and bone metabolism, lipid metabolism, cardiovascular systems, neural system etc. are also had important regulatory role.After the women entered climacteric, body inner estrogen level significantly descended, and this not only can cause a series of vegetative nervous system dysfunctions, also may cause coronary heart disease, atherosclerosis and osteoporosis diseases.The disease that oestrogen deficiencies brought though traditional estrogen replacement therapy can treat or alleviate has many potential side effects.Therefore, seek the medicine of safer controversies in hormone replacement in the elderly, be the problem that medical circle is paid close attention to always.Wherein, the research of selective estrogen receptor modulators (SERMS) receives publicity day by day.
Selective estrogen receptor modulators is to estrogen receptor (ER) tool high-affinity, can produce tissue selectivity excitement or antagonistic action, represent medicine raloxifene, arzoxifene as it, to ovary, mammary gland and endometrial estrogen receptor tool antagonistic activity, then has the estrogen agonist activity for bone and blood fat, therefore can be used for treating estrogen-dependent diseases, as osteoporosis, mammary cancer and some gynaecopathias.Because this tissue selectivity, when clinical use, side effect or untoward reaction that such medicine produced are starkly lower than oestrogenic hormon.The research and development of such medicine has become drug research and hot of research and development.
Structure activity study shows, raloxifene and analogue thereof be phenolic hydroxy group but also contain alkaline side chain not only, and in alkaline side chain, compare with the fragment that does not contain ring texture, its inherent estrogen activity of side chain that contains ring texture is littler and activity antagonism estradiol (estradiol) is more complete.
In recent years, be present in the non-steroid compound that has estrogen-like effects in the plant---phytoestrogen, be considered to be expected to become more safely the estrogen replacement product, seek the medicine of effectively safe estrogen-dependent diseases for the mankind and showed new prospect.
Phytoestrogen is representative with daidzein (daidzein) and Sophoricol (genistein), these natural products and the synthetic derivative that obtains thereof have biologic activity widely, comprise anti-oxidant, antibiotic, antiviral, parasiticide, anti-inflammatory and cardiac vascular activity.
The chemical structure of daidzein and Sophoricol is very similar to endogenous estrogen, determined structure and estradiol homology and with the avidity of estrogen receptor.In recent years, people have been primarily focused on daidzein and Sophoricol on the bone-loss that prevention causes owing to estrogen deficiency.(7-isopropyl flavones ipriflavone) is a kind of isoflavones that obtains from the daidzein transformation to ipriflavone, has been used as the treatment of osteoporosis in Japanese and some European countries.But it is few that generally speaking, relevant isoflavonoid is used for the bibliographical information of selective estrogen receptor modulators.
Summary of the invention
The present invention has studied the structure and the pharmacological action of ipriflavone, raloxifene and analogue thereof, according to pharmacophoric group principle of hybridization, bioisostere principle, with daidzein and Sophoricol is parent, introduce substituted-amino alkoxyl group side chain at its 7 and 4 ', design, synthesized the compound of a series of brand news, and detect them the MCF-7 cell activity.Preliminary pharmacological tests result shows: designed compound has higher selective estrogen receptor and regulates active.
The logical formula I of compound of the present invention is as follows:
Wherein Q represents hydrogen, hydroxyl, chlorine, bromine, iodine, amino, nitro;
R
1Expression H ,-(CH
2)
nNR
3R
4Or-CH
2CHOHCH
2NR
5R
6, n=1-6; R
2Expression H ,-CH
2CHOHCH
2NR
5R
6Or-CH
2CHOHCH
2NR
7R
8NR
3R
4, NR
5R
6And NR
7R
8Represent various amino respectively, represent morpholinyl, pyrrolidyl, piperidyl and various substituted piperazinyl especially.
Preferred hydrogen of Q and hydroxyl.
NR
5R
6And NR
7R
8Preferred NHCH (CH
3)
2, NR
3R
4Preferred 1-pyrrolidyl, 1-morpholinyl, piperidino and 4-substituted-piperazinyl-1-base, the further preferable methyl of substituting group, ethyl and benzyl in 4-substituted-piperazinyl-1-base.
Most preferred 2 compounds are: Q is a hydrogen, R
1And R
2Be CH
2CHOHCH
2NHCH (CH
3)
2
Q is a hydrogen, R
2Be H, NR
3R
4Be the 1-morpholinyl, n is 4.
The compound of above-mentioned general formula can be:
7-[3-(4-methylpiperazine-1-yl) propoxy-]-4 '-hydroxy-isoflavone (4a);
7-[3-(4-benzyl diethylenediamine-1-yl) propoxy-]-4 '-hydroxy-isoflavone (4b);
7-[3-(tetramethyleneimine-1-yl) propoxy-]-4 '-hydroxy-isoflavone (4c);
7-[4-(morpholine-4-yl) butoxy]-4 '-hydroxy-isoflavone (4d);
7-[4-(4-hydroxyethyl piperazine-1-yl) butoxy]-4 '-hydroxy-isoflavone (4e);
7-[5-(morpholine-4-yl) pentyloxy]-4 '-hydroxy-isoflavone (4f);
7-[5-(4-ethyl piperazidine-1-yl) pentyloxy]-4 '-hydroxy-isoflavone (4g);
7-[6-(4-methylpiperazine-1-yl) hexyloxy]-4 '-hydroxy-isoflavone (4h);
7-[6-(morpholine-4-yl) hexyloxy]-4 '-hydroxy-isoflavone (4i);
7-[3-(tetramethyleneimine-1-yl) propoxy-]-5,4 '-dihydroxy isoflavone (4j);
7-[3-(4-benzyl diethylenediamine-1-yl) propoxy-]-5,4 '-dihydroxy isoflavone (4k);
7-[4-(4-methylpiperazine-1-yl) butoxy]-5,4 '-dihydroxy isoflavone (4l);
7-[4-(4-ethyl piperazidine-1-yl) butoxy]-5,4 '-dihydroxy isoflavone (4m);
7-[4-(tetramethyleneimine-1-yl) butoxy]-5,4 '-dihydroxy isoflavone (4n);
7-[5-(4-methylpiperazine-1-yl) pentyloxy]-5,4 '-dihydroxy isoflavone (4o);
7-[5-(4-benzyl diethylenediamine-1-yl) pentyloxy]-5,4 '-dihydroxy isoflavone (4p);
7-[6-(morpholine-4-yl) hexyloxy]-5,4 '-dihydroxy isoflavone (4q);
7-[6-(4-methylpiperazine-1-yl) hexyloxy]-5,4 '-dihydroxy isoflavone (4r);
7-[6-(4-ethyl piperazidine-1-yl) hexyloxy]-5,4 '-dihydroxy isoflavone (4s);
7,4 '-two (2-hydroxyl-3-isopropylamino propoxy-) isoflavones (6a);
7,4 '-two (the amino propoxy-of 2-hydroxyl-uncle's 3-fourth) isoflavones (6b);
7,4 '-two [2-hydroxyl-3-(4-methylpiperazine-1-yl) propoxy-] isoflavones (6c);
7,4 '-two [2-hydroxyl-3-(4-hydroxyethyl piperazine-1-yl) propoxy-] isoflavones (6d);
7,4 '-two (2-hydroxyl-3-diethylin propoxy-) isoflavones (6e);
7,4 '-two [2-hydroxyl-3-(morpholine-4-yl) propoxy-]-5-hydroxy-isoflavones (6f);
7,4 '-two [2-hydroxyl-3-(piperidines-1-yl) propoxy-]-5-hydroxy-isoflavones (6g);
Part of compounds preparation method of the present invention is as follows:
Part of compounds preparation method of the present invention can be:
Compound of the present invention can obtain with above-mentioned or similar above-mentioned preparation method, selects for use corresponding raw material to get final product according to the different of substituent difference and substituent position.
The pharmacology test result shows, the compound of logical formula I and pharmacy acceptable salt thereof have inhibition in various degree to vitro human breast cancer cell MCF-7 or promote the effect of propagation, therefore, the compound and the pharmacy acceptable salt thereof of logical formula I can be used for the treatment of the clinical disease relevant with estrogen receptor.Described and estrogen receptor diseases associated can be mammary cancer, ovarian cancer, endometriosis, artery smooth cell hyperplasia, carcinoma of endometrium, prostate cancer, osteoporosis, female climacteric syndrome and atherosclerosis.
Be part pharmacology test and result below.
Instrument:
Bechtop (Chinese mugwort Kelin, Suzhou treating plant company limited)
Constant temperature CO
2Incubator (German Heraeus)
Enzyme-linked immunosorbent assay instrument (U.S. BIO-RAD)
Inverted biologic microscope (Japanese OLYMPUS)
Dull and stereotyped shaking table (the bright laboratory apparatus in Jiangsu Province factory)
Reagent:
DMEM(GIBCO)
Trypsin SIGMA)
Foetal calf serum (GIBCO), carbon serum (HYCLONE)
MTT(SIGMA)
DMSO(SIGMA)
Cell strain:
Human breast cancer cell MCF-7
[method]
1. get and be in one bottle in cell in good condition exponential phase of growth, add 0.05% tryptic digestive juice, digestion comes off attached cell, counting 4～6 * 10
4Individual/ml, make cell suspension.
2. obtained cell suspension is inoculated on 96 orifice plates, and constant temperature CO is put in 180 μ l/ holes
2Cultivated 24 hours in the incubator.
3. change no phenol red (containing 5%CDT-FBS) substratum effect 24 hours.
4. change test solution, adding is subjected to the reagent thing, and cultivated respectively 48,72 hours in 20 μ l/ holes.
5. MTT is added in 96 orifice plates, 20 μ l/ holes, reaction is 4 hours in the incubator.
6. inhale and remove supernatant liquor, add DMSO, 150 μ l/ holes, jolting is 5 minutes on the dull and stereotyped shaking table.
7. be the light absorption value that the 570nm place measures every hole with enzyme-linked immunosorbent assay instrument at wavelength, and calculate cell inhibitory rate.
Part of compounds The selection result (compound number is corresponding to the numbering of compound among the embodiment)
*P＜0.05,
*P＜0.01,
* *P＜0.001vs solvent control group
The medicine primary-screened sample is counted n=3.
Under this experiment condition, the conclusion that obtains is:
4d, 4h, 4l, 6a have significant inhibitory effect to the propagation of MCF-7 cell, and 48,72 hours inhibiting rate is all greater than 50% (p＜0.01).
The pharmacology test result shows that The compounds of this invention has inhibition in various degree to vitro human breast cancer cell MCF-7 or promotes the effect of propagation, can be used to prevent the clinical disease relevant with estrogen receptor with treatment.These diseases can be mammary cancer, ovarian cancer, endometriosis, artery smooth cell hyperplasia, carcinoma of endometrium, prostate cancer, osteoporosis, female climacteric syndrome and atherosclerosis.
Embodiment
Fusing point shows micro melting point apparatus (manufacturing of Tyke, Beijing Instr Ltd.) mensuration with capillary tube technique or X-4 numeral, and thermometer is not proofreaied and correct; The IR spectrum changes infrared spectrophotometer with FTIR-8400S type fourier and measures;
1The H-NMR spectrum is marked in the TMS with BRUKER DRX-300 or BRUKER DRX-500 type nmr determination; Mass spectrum is measured with the LCMS-2010EV mass spectrograph.
Embodiment 1
Daidzein (1a)
With Resorcinol 1.1g (10mmol), p-hydroxyphenylaceticacid 1.52g (10mmol) joins the BF of new steaming
3Among the ether 6ml, temperature is 70 ℃ in being heated to, reaction 3h, cooling, ice bath add exsiccant DMF 8ml down, are warming up to 55 ℃, drip the mixed solution of methylsulfonyl chloride 4ml and DMF6ml, 0.5h dropwises, and is warming up to 70 ℃ of reaction 3h gradually, suction filtration is poured in the 50ml frozen water in cooling into, washing, oven dry, ethyl alcohol recrystallization, get shallow white solid 2.2g, yield 86.6%, mp316-319 ℃.
Embodiment 2
Sophoricol (1b)
Phloroglucinol 3.8 grams (0.03mol), p-hydroxybenzylcyanide 4.0 grams (0.03mol), anhydrous ZnCl
22.5 gram (0.018mol), ether 50ml puts in the reaction flask, stirs following about 0 ℃ and feeds HCl gas, has orange solids to produce airtight spending the night gradually.The ether that inclines next day adds 50ml water backflow 3h, the suction filtration oven dry, Powdered yellow solid (2,4,6,4 '-tetrahydroxy deoxybenzoin) 7.3 grams, yield 93.6%, mp250 ℃ (decomposition).
2,4,6,4 '-tetrahydroxy deoxybenzoin 1.3 gram (5mmol) is dissolved among the 20ml DMF, adds BF below 10 ℃
3Et
2O 6ml, stirring at room 30min, heating is kept and is dripped CH about 60oC
3SO
2Cl solution (10mlCH
3SO
2Cl is dissolved in 20ml DMF), 30min drips off, and is warming up to 90-100 ℃, reaction 4h, shallow brownish black reaction solution, stir down reaction solution poured in the 200ml frozen water, suction filtration, washing, drying, sundown solid 1.05 grams, yield 77.8%, mp264～266 ℃.
Embodiment 3
7-(3-bromine propoxy-)-4 '-hydroxy-isoflavone (3a)
Daidzein 1.3g (5.1mmol), N, dinethylformamide 30ml, salt of wormwood 0.7g (5.1mmol), a small amount of potassiumiodide, 1,3-dibromopropane 1.1g (5.4mmol), stirring at room 24h, filter is gone among the cold water 100ml, and 10%HCl is neutralized to pH3-4, ethyl acetate (50mL, 30mL * 3) extraction, water (15mL * 2) washing, anhydrous MgSO
4Drying is steamed and is removed ethyl acetate, gets crude product, post layer (ethyl acetate: sherwood oil=2.5: 1) separate, get little yellow solid 350mg, yield 18.7%, mp:175-177 ℃.
1H-NMR(300MHz，acetone)：δ2.28-2.36(m，2H，CH
2)，3.82-3.86(t，2H，J＝6.5Hz，CH
2Br)，4.31-4.35(t，2H，J＝6.0Hz，CH
2O)，6.88-6.91(dd，2H，J＝6.6，2.0Hz，3’，5’-H)，7.06-7.10(dd，1H，J＝8.8，2.4Hz，6-H)，7.09-7.10(d，2H，J＝2.4Hz，8-H)，7.47-7.50(dd，2H，J＝6.6，2.0Hz，2’，6’-H)，8.09-8.12(d，1H，J＝8.8Hz，5-H)，8.18(s，1H，2-H)，8.40(s，1H，4’-OH).IR(KBr，υ，cm
-1)：3379，3229，1628，1562，1514，1443，1379，1258，1043，831.
Embodiment 4
7-(4-bromine butoxy)-4 '-hydroxy-isoflavone (3b)
The preparation method is similar to 3a, gets yellowish pink solid 260mg, yield 16.7%, mp:166-168 ℃.
1H-NMR(300MHz，DMSO-d
6)δ：1.87-2.02(m，4H，CH
2CH
2)，3.60-3.65(t，2H，J＝6.4Hz，CH
2Br)，4.15～4.19(t，2H，J＝6.2Hz，CH
2O)，6.80-6.83(d，2H，J＝8.6Hz，3’，5’-H)，7.05-7.09(dd，1H，J＝8.8，2.2Hz，6-H)，7.14-7.15(d，1H，J＝2.2Hz，8-H)，7.39-7.42(d，2H，J＝8.6Hz，2’，6’-H)，8.01-8.04(d，1H，J＝8.8Hz，5-H)，8.35(s，1H，2-H)，9.49(s，1H，4’-OH)。IR(KBr，υ，cm
-1)：3368，1620，1572，1514，1443，1258，1047，832。
Embodiment 5
7-(5-bromine pentyloxy)-4 '-hydroxy-isoflavone (3c)
The preparation method is similar to 3a, gets khaki color solid 370mg, yield 23.0%, mp:129-133 ℃.
1H-NMR (500MHz, DMSO-d
6) δ: 1.53-1.59 (m, 2H, CH
2), 1.77-1.91 (m, 4H, 2 * CH
2), 3.66-3.68 (t, 2H, J=6.6Hz, CH
2Br), 4.12-4.14 (t, 2H, J=6.4Hz, CH
2O), 6.81-6.83 (dd, 2H, J=6.8,1.8Hz, 3 ', 5 '-H), 7.05-7.07 (dd, 1H, J=8.8,2.3Hz, 6-H), 7.12-7.13 (d, 1H, J=2.3Hz, 8-H), 7.40-7.42 (dd, 2H, J=6.8,1.8Hz, 2 ', 6 '-H), and 8.01-8.03 (d, 1H, J=8.8Hz, 5-H), 8.35 (s, 1H, 2-H), 9.50 (s, 1H, 4 '-OH) .IR (KBr) υ: 3400,2868,1626,1595,1514,1441,1387,1256,1200,825cm
-1.
Embodiment 6
7-(6-bromine hexyloxy)-4 '-hydroxy-isoflavone (3d)
The preparation method is similar to 3a, gets khaki color solid 350mg, yield 21.0%, mp:141-143 ℃.
1H-NMR(500MHz，DMSO-d
6)δ：1.45-1.47(m，4H，CH
2CH
2)，1.75-1.77(m，2H，CH
2)，1.82-1.84(m，2H，CH
2)，3.53-3.56(t，2H，J＝6.5Hz，BrCH
2)，4.10-4.13(t，2H，J＝6.5Hz，CH
2O)，6.80-6.82(dd，2H，J＝6.6，2.0Hz，3’，5’-H)，7.05-7.07(dd，1H，J＝8.8，2.3Hz，6-H)，7.13(d，1H，J＝2.3Hz，8-H)，7.39-7.41(dd，2H，J＝6.6，2.0Hz，2’，6’-H)，8.00-8.02(d，1H，J＝8.8Hz，5-H)，8.36(s，1H，2-H)，9.55(s，1H，4’-OH).IR(KBr)υ：3418，3217，2854，1628，1583，1516，1443，1377，1259，829cm
-1.
Embodiment 7
7-(3-bromine propoxy-)-5,4 '-dihydroxy isoflavone (3e)
The preparation method is similar to 3a, shallow white solid 1.4g, yield 35.8%, mp:124～127 ℃.
1H-NMR(300MHz，acetone)δ：2.27-2.31(m，2H，CH
2)，3.80-3.84(t，2H，J＝6.5Hz，CH
2Br)，4.27-4.31(t，2H，J＝6.0Hz，CH
2O)，6.37-6.38(d，1H，J＝2.2Hz，6-H)，6.57-6.58(d，1H，J＝2.2Hz，8-H)，6.89-6.92(dd，2H，J＝6.6，2.0Hz，3’，5’-H)，7.45-7.48(dd，2H，J＝6.6，2.0Hz，2’，6’-H)，8.21(s，1H，2-H)，8.48(s，1H，4’-OH)，12.99(s，1H，5-OH).IR(KBr)υ：3468，3418，1657，1610，1568，1516，1501，1460，1319，1283，1252，1177，1157，1047，835cm
-1.
Embodiment 8
7-(4-bromine butoxy)-5,4 '-dihydroxy isoflavone (3f)
The preparation method is similar to 3a, yellowish pink solid 0.32g, yield 19.75%, mp:131～133 ℃.
1H-NMR(500MHz，DMSO-d
6)δ：1.85-1.91(m，4H，CH
2CH
2)，3.76-3.79(t，2H，J＝6.6Hz，CH
2Br)，4.16-4.18(t，2H，J＝6.5Hz，CH
2O)，6.38(d，1H，J＝2.2Hz，6-H)，6.59-6.60(d，1H，J＝2.2Hz，8-H)，6.88-6.90(dd，2H，J＝6.6，2.1Hz，3’，5’-H)，7.43-7.45(dd，2H，J＝6.6，2.1Hz，2’，6’-H)，8.37(s，1H，2-H)，12.96(s，1H，5-OH).IR(KBr)υ：3389，1663，1614，1572，1508，1445，1294，1254，1169，1047，825cm
-1.
Embodiment 9
7-(5-bromine pentyloxy)-5,4 '-dihydroxy isoflavone (3g)
The preparation method is similar to 3a, gets little yellow solid 0.68g, yield 40.6%, mp:108-110 ℃.
1H-NMR(500MHz，DMSO-d
6)δ：1.53-1.57(m，2H，CH
2)，1.74-1.78(m，2H，CH
2)，1.85-1.91(m，2H，CH
2)，3.55-3.58(t，2H，J＝6.7Hz，CH
2Br)，4.09-4.12(t，2H，J＝6.4Hz，CH
2O)，6.39(d，1H，J＝2.2Hz，6-H)，6.64(d，1H，J＝2.2Hz，8-H)，6.81-6.83(dd，2H，J＝6.6，2.0Hz，3’，5’-H)，7.38-7.40(dd，2H，J＝6.6，2.0Hz，2’，6’-H)，8.39(s，1H，2-H)，9.56(s，1H，4’-OH)，12.93(s，1H，5-OH).IR(KBr)υ：3325，1653，1607，1566，1506，1445，1292，1231，1175，1047，835cm
-1.
Embodiment 10
7-(6-bromine hexyloxy)-5,4 '-dihydroxy isoflavone (3h)
The preparation method is similar to 3a, gets white solid 0.96g, yield 22.2%, mp:121-123 ℃.
1H-NMR (500MHz, DMSO-d
6) δ: 1.44-1.46 (m, 4H, CH
2CH
2), 1.73-1.76 (m, 2H, CH
2), 1.82-1.85 (m, 2H, CH
2), 3.53-3.56 (t, 2H, J=6.7Hz, BrCH
2), 4.08-4.11 (t, 2H, J=6.5Hz, CH
2O), 6.39 (d, 1H, J=2.2Hz, 6-H), 6.64 (d, 1H, J=2.2Hz, 8-H), 6.81-6.83 (dd, 2H, J=6.6,2.0Hz, 3 ', 5 '-H), 7.38-7.40 (dd, 2H, J=6.6,2.0Hz, 2 ', 6 '-H), 8.39 (s, 1H, 2-H), 9.56 (s, 1H, 4 '-OH), 12.94 (s, 1H, 5-OH) .IR (KBr) υ: 3433,2935,1663,1612,1574,1508,1292,1252,1169,1047,827cm
-1.
Embodiment 11
7-[3-(4-methylpiperazine-1-yl) propoxy-]-4 '-hydroxy-isoflavone (4a)
7-(3-bromine propoxy-)-4 '-hydroxy-isoflavone 263mg (0.7mmol), ethyl acetate 50mL, N methyl piperazine 700mg (7.0mmol), backflow 6h, post layer (chloroform: methyl alcohol=97: 3) separate, get white solid 240mg, yield 87.0%, mp:214～216 ℃.
1H-NMR(500MHz，DMSO-d
6)δ：1.89-1.92(m，2H，CH
2)，2.15(s，3H，CH
3)，2.32-2.44(m，10H，CH
2N(CH
2CH
2)
2N)，4.15-4.17(t，2H，J＝6.4Hz，CH
2O)，6.80-6.82(dd，2H，J＝6.6，2.0Hz，3’，5’-H)，7.05-7.07(dd，1H，J＝8.9，2.4Hz，6-H)，7.13(d，1H，J＝2.4Hz，8-H)，7.39-7.41(dd，2H，J＝6.6，2.0Hz，2’，6’-H)，8.01-8.03(d，1H，J＝8.9Hz，5-H)，8.35(s，1H，2-H)，9.50(s，1H，4’-OH).ESI-MS?m/z：395[M+H]
+.IR(KBr)υ：3441，3173，2698，1630，1516，1447，1223，829cm
-1.
Embodiment 12
7-[3-(4-benzyl diethylenediamine-1-yl) propoxy-]-4 '-hydroxy-isoflavone (4b)
The preparation method is similar to 4a, white solid 174mg, yield 52.9%, mp:137～140 ℃.
1H-NMR(300MHz，DMSO-d
6)δ：1.88-1.93(m，2H，CH
2)，2.38-2.43(m，10H，5×CH
2)，3.45(s，2H，CH
2)，4.13-4.17(t，2H，CH
2O)，6.80-6.83(d，2H，J＝8.4Hz，3’，5’-H)，7.05-7.08(dd，1H，J＝8.6，2.2Hz，6-H)，7.13-7.14(d，1H，J＝1.8Hz，8-H)，7.24-7.32(m，5H，C
6H
5)，7.39-7.42(d，2H，J＝8.4Hz，2’，6’-H)，8.00-8.03(d，1H，J＝8.6Hz，5-H)，8.36(s，1H，2-H).ESI-MS?m/z：471[M+H]
+.IR(KBr)υ：2814，2710，1626，1564，1443，1259，825，743，698cm
-1.
Embodiment 13
7-[3-(tetramethyleneimine-1-yl) propoxy-]-4 '-hydroxy-isoflavone (4c)
The preparation method is similar to 4a, yellow solid 110mg, yield 43.1%, mp:184～187 ℃.
1H-NMR(500MHz，DMSO-d
6)δ：1.71-1.78(m，4H，CH
2CH
2)，1.89-1.92(m，2H，CH
2)，2.84-3.22(m，6H，N(CH
2)
3)，4.14-4.17(t，2H，J＝6.4Hz，CH
2O)，6.80-6.82(dd，2H，J＝6.6，2.0Hz，3’，5’-H)，7.05-7.07(dd，1H，J＝8.6，2.2Hz，6-H)，7.13-7.14(d，1H，J＝2.2Hz，8-H)，7.39-7.41(dd，2H，J＝6.6，2.0Hz，2’，6’-H)，8.01～8.03(d，1H，J＝8.6Hz，5-H)，8.36(s，1H，2-H)，9.54(s，1H，4’-OH).ESI-MS?m/z：365[M+H]
+.IR(KBr)υ：3213，2943，2692，2617，1634，1566，1514，1445，1254，1221，829cm
-1.
Embodiment 14
7-[4-(morpholine-4-yl) butoxy]-4 '-hydroxy-isoflavone (4d)
The preparation method is similar to 4a, gets white solid 200mg, yield 50.6%, mp:186-187 ℃.
1H-NMR (300MHz, DMSO-d
6) δ: 1.79-1.95 (m, 4H, CH
2CH
2), 2.49-2.51 (m, 6H, N (CH
2)
3), 3.55-3.59 (m, 4H, CH
2OCH
2), 4.15-4.19 (t, 2H, J=6.3Hz, CH
2O), 6.80-6.83 (dd, 2H, J=6.6,2.1Hz, 3 ', 5 '-H), and 7.05-7.09 (dd, 1H, J=8.8,2.3Hz, 6-H), 7.14-7.15 (d, 1H, J=2.3Hz, 8-H), 7.39-7.42 (dd, 2H, J=6.6,2.1Hz, 2 ', 6 '-H), 8.00-8.03 (d, 1H, J=8.8Hz, 5-H), 8.36 (s, 1H, 2-H), 9.52 (s, 1H, 4 '-OH) .ESI-MS m/z:396[M+H]
+.IR (KBr) υ: 3292,1630,1566,1510,1443,1261,1198,1103,1041,827cm
-1.
Embodiment 15
7-[4-(4-hydroxyethyl piperazine-1-yl) butoxy]-4 '-hydroxy-isoflavone (4e)
The preparation method is similar to 4a, gets canescence crystal 110mg, productive rate 25.1%, mp:181-183 ℃.
1H-NMR (500MHz, DMSO-d
6) δ: 1.63-1.80 (m, 2H, CH
2), 1.92-1.96 (m, 2H, CH
2), 2.35-2.95 (m, 12H, 6 * CH
2), 3.53-3.57 (t, 2H, CH
2O), 4.14-4.16 (t, 2H, J=6.2Hz, CH
2O), 4.55 (brs, 1H, OH), 6.80-6.82 (d, 2H, J=8.5Hz, 3 ', 5 '-H), 7.06-7.08 (dd, 1H, J=8.9,2.1Hz, 6-H), and 7.13-7.14 (d, 1H, J=2.1Hz, 8-H), 7.39-7.41 (d, 2H, J=8.5Hz, 2 ', 6 '-H), 8.01-8.03 (d, 1H, J=8.9Hz, 5-H), 8.36 (s, 1H, 2-H), 9.50 (s, 1H, 4 '-OH) .ESI-MS m/z:439[M+H]
+.IR (KBr) υ: 3389,3263,2826,1630,1566,1514,1447,1263,1200,1051,825cm
-1.
Embodiment 16
7-[5-(morpholine-4-yl) pentyloxy]-4 '-hydroxy-isoflavone (4f)
The preparation method is similar to 4a, gets white solid 160mg, yield 39.1%, mp:233-234 ℃.
1H-NMR (500MHz, DMSO-d
6) δ: 1.44-1.50 (m, 4H, CH
2CH
2), 1.76-1.79 (m, 2H, CH
2), 2.26-2.29 (t, 2H, J=7.0Hz, NCH
2), 2.33-2.34 (t, 4H, CH
2NCH
2), 3.55-3.57 (m, 4H, CH
2OCH
2), 4.12-4.14 (t, 2H, J=6.5Hz, CH
2O), 6.80-6.82 (dd, 2H, J=6.5,2.0Hz, 3 ', 5 '-H), and 7.05-7.07 (dd, 1H, J=9.0,2.0Hz, 6-H), 7.13 (d, 1H, J=2.0Hz, 8-H), 7.39-7.41 (dd, 2H, J=6.5,2.0Hz, 2 ', 6 '-H), 8.00-8.02 (d, 1H, J=9.0Hz, 5-H), 8.35 (s, 1H, 2-H), 9.50 (s, 1H, 4 '-OH) .ESI-MS m/z:410[M+H]
+.IR (KBr) υ: 3422,1630,1564,1514,1443,1256,1198,1103,1045,827cm
-1.
Embodiment 17
7-[5-(4-ethyl piperazidine-1-yl) pentyloxy]-4 '-hydroxy-isoflavone (4g)
The preparation method is similar to 4a, gets light yellow solid 120mg, yield 39.3%, mp:162-164 ℃.
1H-NMR (300MHz, DMSO-d
6) δ: 0.96-0.99 (t, 3H, CH
3), 1.45-1.51 (m, 4H, CH
2CH
2), 1.78-1.80 (m, 2H, CH
2), 2.36-2.41 (m, 12H, H
2CN (CH
2CH
2)
2NCH
2), 4.14-4.16 (t, 2H, CH
2O), 6.81-6.84 (dd, 2H, J=6.5,2.0Hz, 3 ', 5 '-H), and 7.08-7.12 (dd, 1H, J=8.8,2.0Hz, 6-H), 7.16 (d, 1H, J=2.0Hz, 8-H), 7.40-7.43 (dd, 2H, J=6.5,2.0Hz, 2 ', 6 '-H), 8.02-8.05 (d, 1H, J=8.8Hz, 5-H), 8.38 (s, 1H, 2-H), 9.55 (s, 1H, 4 '-OH) .ESI-MS m/z:437[M+H]
+.IR (KBr) υ: 3535,2945,1624,1512,1447,1246,1200,1173,833cm
-1.
Embodiment 18
7-[6-(4-methylpiperazine-1-yl) hexyloxy]-4 '-hydroxy-isoflavone (4h)
The preparation method is similar to 4a, gets shallow white solid 55mg, yield 18.0%, mp:201-202 ℃.
1H-NMR (300MHz, DMSO-d
6) δ: 1.44 (m, 6H, CH
2CH
2CH
2), 1.76 (m, 2H, CH
2), 2.14 (s, 3H, NCH
3), 2.25-2.31 (m, 10H, 5 * CH
2), 4.10-4.14 (t, 2H, J=6.4Hz, CH
2O), 6.80-6.83 (dd, 2H, J=6.6,2.1Hz, 3 ', 5 '-H), and 7.04-7.08 (dd, 1H, J=8.9,2.4Hz, 6-H), 7.13-7.14 (d, 1H, J=2.4Hz, 8-H), 7.39-7.42 (dd, 2H, J=6.6,2.1Hz, 2 ', 6 '-H), 8.00-8.03 (d, 1H, J=8.9Hz, 5-H), 8.36 (s, 1H, 2-H), 9.52 (s, 1H, 4 '-OH) .ESI-MS m/z:437[M+H]
+.IR (KBr) υ: 3418,3396,2934,1628,1564,1514,1447,1263,829cm
-1.
Embodiment 19
7-[6-(morpholine-4-yl) hexyloxy]-4 '-hydroxy-isoflavone (4i)
The preparation method is similar to 4a, gets white powder solid 90mg, yield 30.4%, mp:170-172 ℃.
1H-NMR (500MHz, DMSO-d
6) δ: 1.33-1.37 (m, 2H, CH
2), 1.42-1.47 (m, 4H, 2 * CH
2), 1.73-1.77 (m, 2H, CH
2), 2.24-2.27 (t, 2H, NCH
2), 2.32 (m, 4H, (CH
2)
2N), 3.54-3.56 (t, 4H, CH
2OCH
2), 4.11-4.13 (t, 2H, J=6.5Hz, CH
2O), 6.80-6.82 (dd, 2H, J=6.6,2.0Hz, 3 ', 5 '-H), and 7.05-7.07 (dd, 1H, J=8.9,2.3Hz, 6-H), 7.12-7.13 (d, 1H, J=2.3Hz, 8-H), 7.39-7.41 (d, 2H, J=6.6,2.0Hz, 2 ', 6 '-H), 8.00-8.02 (d, 1H, J=8.9Hz, 5-H), 8.35 (s, 1H, 2-H), 9.50 (s, 1H, 4 '-OH) .ESI-MS m/z:424[M+H]
+.IR (KBr) υ: 3420,1628,1564,1516,1445,1263,1200,1105,1043,829cm
-1.
Embodiment 20
7-[3-(tetramethyleneimine-1-yl) propoxy-]-5,4 '-dihydroxy isoflavone (4j)
The preparation method is similar to 4a, gets light yellow solid 290mg, yield 76.1%, mp:186-188 ℃.
1H-NMR(500MHz，DMSO-d
6)δ：1.70(m，4H，CH
2CH
2)，1.89(m，2H，CH
2)，2.45-2.52(m，6H，CH
2N(CH
2)
2)，4.14(t，2H，J＝6.2Hz，CH
2O)，6.41(d，1H，6-H)，6.65(d，1H，8-H)，6.82-6.85(d，2H，J＝8.2Hz，3’，5’-H)，7.38-7.41(d，2H，J＝8.2Hz，2’，6’-H)，8.41(s，1H，2-H)，9.59(s，1H)，12.92(s，1H).ESI-MS?m/z：382[M+H]
+。IR(KBr)υ：3418，3209，3089，1661，1610，1572，1512，1447，1258，1217，1182，1053，841cm
-1.
Embodiment 21
7-[3-(4-benzyl diethylenediamine-1-yl) propoxy-]-5,4 '-dihydroxy isoflavone (4k)
The preparation method is similar to 4a, gets white solid 60mg, yield 93.8%, mp:177-179 ℃.
1H-NMR (300MHz, DMSO-d
6) δ: 1.93-1.97 (m, 2H, CH
2), 2.55-2.58 (m, 10H, N (CH
2CH
2)
2NCH
2), 4.13-4.17 (t, 2H, J=6.0Hz, CH
2O), 3.56 (s, 2H, CH
2N), and 6.40-6.41 (d, 1H, J=2.2Hz, 6-H), 6.65-6.66 (d, 1H, J=2.2Hz, 8-H), 6.83-6.86 (d, 2H, J=8.6Hz, 3 ', 5 '-H), 7.28-7.36 (m, 5H, Ph), 7.39-7.42 (d, 2H, J=8.6Hz, 2 ', 6 '-H), 8.33 (s, 1H, 2-H), 9.61 (s, 1H, 4 '-OH), 12.96 (s, 1H, 5-OH) .ESI-MS m/z:487[M+H]
+.IR (KBr) υ: 3026,2945,2820,2710,1670,1609,1570,1514,1443,1367,1315,1286,1252,1209,1177,1151,1047,1003,933,814,744cm
-1.
Embodiment 22
7-[4-(4-methylpiperazine-1-yl) butoxy]-5,4 '-dihydroxy isoflavone (4l)
The preparation method is similar to 4a, gets little yellow solid 165mg, yield 48.7%, mp144-146 ℃.
1H-NMR (500MHz, DMSO-d
6) δ: 1.54-1.57 (m, 2H, CH
2), 1.72-1.77 (m, 2H, CH
2), 2.14 (s, 3H, CH
3), 2.29-2.33 (m, 10H, N (CH
2CH
2)
2NCH
2), 4.09-4.12 (t, 2H, CH
2O), 6.39 (d, 1H, J=2.0Hz, 6-H), 6.64 (d, 1H, J=2.0Hz, 8-H), 6.82-6.84 (d, 2H, J=8.5Hz, 3 ', 5 '-H), 7.38-7.40 (d, 2H, J=8.5Hz, 2 ', 6 '-H), 8.39 (s, 1H, 2-H), 9.56 (s, H, 4 '-OH), 12.93 (s, 1H, 5-OH) .ESI-MS m/z:425[M+H]
+.IR (KBr) υ: 3444,2945,2792,2677,1663,1614,1582,1514,1460,1383,1285,1248,1198,1149,1045,1006,825,784cm
-1.
Embodiment 23
7-[4-(4-ethyl piperazidine-1-yl) butoxy]-5,4 '-dihydroxy isoflavone (4m)
The preparation method is similar to 4a, gets little yellow solid 190mg, yield 54.2%, mp:168-170 ℃.
1H-NMR(500MHz，DMSO-d
6)δ：0.96-0.99(t，3H，CH
3)，1.54-1.59(m，2H，CH
2)，1.72-1.76(m，2H，CH
2)，2.27-2.36(m，12H，CH
2N(CH
2CH
2)
2NCH
2)，4.10-4.14(t，2H，J＝6.6Hz，CH
2O)，6.39(d，1H，J＝2.2Hz，6-H)，6.64(d，1H，J＝2.2Hz，8-H)，6.82-6.84(dd，2H，J＝6.5，2.2Hz，3’，5’-H)，7.38-7.40(dd，2H，J＝6.5，2.2Hz，2’，6’-H)，8.39(s，1H，2-H)，9.56(s，1H，4’-OH)，12.94(s，1H，5-OH).ESI-MS?m/z：439[M+H]
+.IR(KBr)υ：3533，3364，1661，1610，1574，1514，1445，，1379，1312，1248，1178，1155，1043，839cm
-1.
Embodiment 24
7-[4-(tetramethyleneimine-1-yl) butoxy]-5,4 '-dihydroxy isoflavone (4n)
The preparation method is similar to 4a, gets white solid 150mg, yield 47.5%, mp:230-231 ℃.
1H-NMR(300MHz，DMSO-d
6)δ：1.80(m，4H，CH
2CH
2)，1.91(m，4H，CH
2CH
2)，3.02-3.52(m，6H，CH
2N(CH
2)
2)，4.14(t，2H，CH
2O)，6.43(d，1H，6-H)，6.67(d，1H，8-H)，6.82-6.85(d，2H，J＝8.2Hz，3’，5’-H)，7.38-7.41(d，2H，J＝8.2Hz，2’，6’-H)，8.42(s，1H，2-H)，9.60(s，1H，4’-OH)，12.96(s，1H，5-OH).ESI-MS?m/z：396[M+H]
+.IR(KBr)υ：3196，2949，2698，1663，1612，1580，1514，1443，1312，1256，1207，1177，1053，841，820cm
-1.
Embodiment 25
7-[5-(4-methylpiperazine-1-yl) pentyloxy]-5,4 '-dihydroxy isoflavone (4o)
The preparation method is similar to 4a, white solid 40mg, yield 76.5%, mp:138～141 ℃.
1H-NMR(500MHz，DMSO-d
6)δ：1.41-1.49(m，4H，CH
2CH
2)，1.73-1.77(m，2H，CH
2)，2.21(s，3H，CH
3)，2.28-2.46(m，10H，N(CH
2CH
2)
2NCH
2)，4.08-4.11(t，2H，J＝6.6Hz，CH
2O)，6.39(d，1H，J＝2.0Hz，6-H)，6.64(d，1H，J＝2.0Hz，8-H)，6.81-6.83(d，2H，J＝8.5Hz，3’，5’-H)，7.38-7.40(d，2H，J＝8.5Hz，2’，6’-H)，8.39(s，1H，2-H)，9.57(s，1H，4’-OH)，12.92(s，1H，5-OH).ESI-MS?m/z：439[M+H]
+.IR(KBr)υ：3491，2945，2812，2691，1661，1612，1574，1512，1452，1373，1310，1281，1248，1155，1043，1005，833，785cm
-1.
Embodiment 26
7-[5-(4-benzyl diethylenediamine-1-yl) pentyloxy]-5,4 '-dihydroxy isoflavone (4p)
The preparation method is similar to 4a, gets white solid 60mg, yield 95.2%, mp:120-122 ℃.
1H-NMR (500MHz, DMSO-d
6) δ: 1.41-1.50 (m, 4H, CH
2CH
2), 1.72-1.75 (m, 2H, CH
2), 2.32-2.38 (m, 10H, N (CH
2CH
2)
2NCH
2), 4.08-4.10 (t, 2H, J=6.5Hz, CH
2O), 3.45 (s, 2H, CH
2N), 6.39 (d, 1H, J=2.2Hz, 6-H), 6.64 (d, 1H, J=2.2Hz, 8-H), 6.81-6.83 (d, 2H, J=8.6Hz, 3 ', 5 '-H), 7.27-7.34 (m, 5H, Ph), 7.38-7.40 (d, 2H, J=8.6Hz, 2 ', 6 '-H), 8.39 (s, 1H, 2-H), 9.57 (s, 1H, 4 '-OH), 12.94 (s, 1H, 5-OH) .ESI-MS m/z:515[M+H]
+.IR (KBr) υ: 3304,3109,2943,2831,1664,1612,1570,1512,1448,1292,1256,1155,831,741cm
-1.
Embodiment 27
7-[6-(morpholine-4-yl) hexyloxy]-5,4 '-dihydroxy isoflavone (4q)
The preparation method is similar to 4a, gets white solid 130mg, yield 42.3%, mp:156-158 ℃.
1H-NMR(500MHz，DMSO-d
6)δ：1.33-1.36(m，2H，CH
2)，1.39-1.45(m，4H，2×CH
2)，1.71-1.74(m，2H，CH
2)，2.24-2.32(t，6H，N(CH
2)
3)，3.54-3.56(t，4H，CH
2OCH
2)，4.07-4.10(t，2H，J＝6.4Hz，CH
2O)，6.38(d，1H，J＝2.1Hz，6-H)，6.63(d，1H，J＝2.1Hz，8-H)，6.81-6.83(d，2H，J＝8.6，3’，5’-H)，7.38-7.40(d，2H，J＝8.6，2’，6’-H)，8.39(s，1H，2-H)，9.57(s，1H，4’-OH)，12.93(s，1H，5-OH).ESI-MS?m/z：440[M+H]
+.IR(KBr)υ：2957，2885，2833，1632，1514，1468，1437，1385，1277，1236，1171，1130，1038，989，881，824，770cm-1。
Embodiment 28
7-[6-(4-methylpiperazine-1-yl) hexyloxy]-5,4 '-dihydroxy isoflavone (4r)
The preparation method is similar to 4a, gets little yellow solid 115mg, yield 36.4%, mp:182-184 ℃.
1H-NMR (300MHz, DMSO-d
6) δ: 1.25-1.44 (m, 6H, CH
2CH
2CH
2), 1.72-1.74 (m, 2H, CH
2), 2.15 (s, 3H, CH
3), 2.22-2.32 (m, 10H, N (CH
2CH
2)
2NCH
2), 4.08-4.12 (t, 2H, J=6.0Hz, CH
2O), and 6.40-6.41 (d, 1H, J=2.0Hz, 6-H), 6.65-6.66 (d, 1H, J=2.0Hz, 8-H), 6.83-6.86 (d, 2H, J=8.4Hz, 3 ', 5 '-H), 7.39-7.42 (d, 2H, J=8.4Hz, 2 ', 6 '-H), 8.42 (s, 1H, 2-H), 9.61 (s, 1H, 4 '-OH), 12.96 (s, 1H, 5-OH) .ESI-MS m/z:453[M+H]
+.IR (KBr) υ: 2932,1651,1612,1576,1512,1462,1445,1383,1306,1248,1205,1151,1045,839cm
-1.
Embodiment 29
7-[6-(4-ethyl piperazidine-1-yl) hexyloxy]-5,4 '-dihydroxy isoflavone (4s)
The preparation method is similar to 4a, gets little yellow solid 190mg, yield 58.2%, mp:164-166 ℃.
1H-NMR(300MHz，DMSO-d
6)δ：1.00-1.03(t，3H，CH
3)，1.31-1.36(m，2H，CH
2)，1.39-1.47(m，4H，2×CH
2)，1.70-1.76(m，2H，CH
2)，2.36-2.47(m，2H，CH
2)，2.36-2.47(m，12H，CH
2N(CH
2CH
2)
2NCH
2)，4.07-4.10(t，2H，J＝6.4Hz，CH
2O)，6.38(d，1H，J＝2.1Hz，6-H)，6.638(d，1H，J＝2.1Hz，8-H)，6.82-6.84(d，2H，J＝8.5Hz，3’，5’-H)，7.38-7.40(d，2H，J＝8.5Hz，2’，6’-H)，8.390(s，1H，2-H)，9.57(s，1H，4’-OH)，12.94(s，1H，5-OH)。ESI-MS?m/z：467[M+H]
+.IR(KBr)υ：3354，3090，1653，1612，1576，1514，1468，1441，1377，1308，1248，1200，1151，1045，837cm
-1.
Embodiment 30
7,4 '-two (2, the 3-glycidoxy) isoflavones (5a)
Daidzein 2.54g (10mmol), dehydrated alcohol 200ml, heating for dissolving, add salt of wormwood 1.6g (11.6mmol), a small amount of potassiumiodide, epoxy chloropropane 10g (108mmol), backflow 3h, filtered while hot, cooling, separate out crystallization, get white solid 2.3g, crude product post layer (chloroform: methyl alcohol=97: 3) separate, get white solid 1.24g, yield 40.0%, mp:128-131 ℃.
Embodiment 31
7,4 '-two [2, the 3-glycidoxy]-5-hydroxy-isoflavones (5b)
The preparation method is similar to 5a, gets little yellow solid 1.64g, yield 42.9%, mp:116-119 ℃.
Embodiment 32
7,4 '-two (2-hydroxyl-3-isopropylamino propoxy-) isoflavones (6a)
7,4 '-two (2, the 3-glycidoxy) isoflavones 930mg (3mmol), dehydrated alcohol 60ml, heating for dissolving adds Isopropylamine 530mg (9mmol), backflow 2h, the filtering white solid, filtrate concentrates, post layer (chloroform: methyl alcohol=10: 1) separate, get yellow solid 940mg, yield 76.6%, mp:42-44 ℃ of .1.05-1.06 (d, 12H, J=6.0Hz, 4 * CH
3), 2.67-2.69 (m, 6H, 2 * CHNCH
2), 3.94-4.17 (m, 6H, 2 * OCHCH
2O), 7.00-7.02 (d, 2H, J=8.8Hz, 3 ', 5 '-H), 7.09-7.11 (dd, 1H, J=8.9,2.3Hz, 6-H), 7.17 (d, 1H, J=2.3Hz, 8-H), 7.52-7.54 (d, 2H, J=8.8Hz, 2 ', 6 '-H), 8.03-8.05 (d, 1H, J=8.9Hz, 5-H), 8.41 (s, 1H, 2-H) .ESI-MS m/z:485[M+H]
+.IR (KBr) υ: 3373,3296,2964,1628,1568,1510,1443,1375,1254,1178,1103,1041,887,831cm
-1.
Embodiment 33
7,4 '-two (the amino propoxy-of 2-hydroxyl-uncle's 3-fourth) isoflavones (6b)
The preparation method is similar to 6a, gets light yellow solid 400mg, yield 20.9%, mp:58-60 ℃.
1H-NMR (500MHz, DMSO-d
6) δ: 1.10 (s, 18H, 6 * CH
3), 2.68-2.78 (m, 4H, 2 * NCH
2), 3.93-4.09 (m, 6H, 2 * OCHCH
2O), 7.00-7.02 (d, 2H, J=8.5Hz, 3 ', 5 '-H), 7.09-7.12 (dd, 1H, J=9.0,2.0Hz, 6-H), and 7.17-7.18 (d, 1H, J=2.0Hz, 8-H), 7.52-7.54 (d, 2H, J=8.5Hz, 2 ', 6 '-H), 8.03-8.05 (d, 1H, J=9.0Hz, 5-H), 8.42 (s, 1H, 2-H) .ESI-MS m/z:513[M+H]
+.IR (KBr) υ: 3379,2964,1624,1566,1510,1443,1369,1252,1198,1099,1032,885,833cm
-1.
Embodiment 34
7,4 '-two [2-hydroxyl-3-(4-methylpiperazine-1-yl) propoxy-] isoflavones (6c)
The preparation method is similar to 6a, gets light yellow solid 330mg, yield 20.1%, mp:153-156 ℃.
1H-NMR (500MHz, DMSO-d
6) δ: 2.15 (s, 6H, 2 * CH
3), 2.28-2.48 (m, 20H, 2 * N (CH
2CH
2)
2NCH
2), 3.88-4.16 (m, 6H, 2 * OCHCH
2O), 4.81 (s, 1H, OH), 4.91 (s, 1H, OH), 6.99-7.01 (dd, 2H, J=6.7,2.1Hz, 3 ', 5 '-H), and 7.08-7.10 (dd, 1H, J=8.9,2.4Hz, 6-H), 7.16 (d, 1H, J=2.4Hz, 8-H), 7.51-7.53 (dd, 2H, J=6.7,2.1Hz, 2 ', 6 '-H), 8.02-8.04 (d, 1H, J=8.9Hz, 5-H), 8.41 (s, 1H, 2-H) .ESI-MS m/z:567[M+H]
+.IR (KBr) υ: 3414,2799,1628,1566,1510,1445,1288,1252,1173,883,824cm
-1.
Embodiment 35
7,4 '-two [2-hydroxyl-3-(4-hydroxyethyl piperazine-1-yl) propoxy-] isoflavones (6d)
The preparation method is similar to 6a, gets white particulate solid 380mg, yield 43.2%, mp:168-171 ℃.
1H-NMR (500MHz, DMSO-d
6) δ: 2.37-2.47 (m, 24H, 2 * CH
2N (CH
2CH
2)
2NCH
2), 3.46-3.49 (t, 4H, 2 * OCH
2), 3.88-4.17 (m, 6H, 2 * OCHCH
2O), and 4.30-4.32 (t, 2H, 2 * OH), 4.80-4.81 (d, 1H, OH), 4.90-4.91 (d, 1H, OH), 6.99-7.01 (dd, 2H, J=6.7,2.0Hz, 3 ', 5 '-H), 7.08-7.10 (dd, 1H, J=8.9,2.4Hz, 6-H), 7.16 (d, 1H, J=2.4Hz, 8-H), 7.51-7.53 (dd, 2H, J=6.7,2.0Hz, 2 ', 6 '-H), 8.02-8.04 (d, 1H, J=8.9Hz, 5-H), 8.41 (s, 1H, 2-H) .ESI-MS m/z:627[M+H]
+.IR (KBr) υ: 3369,2818,1628,1566,1510,1445,1258,1045,1005,881,829cm
-1.
Embodiment 36
7,4 '-two (hydroxyl-3-diethylin propoxy-) isoflavones (6e)
The preparation method is similar to 6a, gets light yellow solid 170mg, yield 22.2%, mp:84-87 ℃.
1H-NMR (300MHz, DMSO-d
6) δ: 0.94-0.99 (t, 12H, 4 * CH
3), 2.44-2.55 (m, 12H, 2 * N (CH
2)
3), 3.89-4.18 (m, 6H, 2 * OCHCH
2O), 4.85 (brs, 2H, 2 * OH), 6.98-7.01 (d, 2H, J=8.8Hz, 3 ', 5 '-H), 7.07-7.11 (dd, 1H, J=8.9,2.4Hz, 6-H), 7.15-7.16 (d, 1H, J=2.4Hz, 8-H), 7.50-7.53 (d, 2H, J=8.8Hz, 2 ', 6 '-H), 8.02-8.05 (d, 1H, J=8.9Hz, 5-H), 8.42 (s, 1H, 2-H) .ESI-MS m/z:513[M+H]
+.IR (KBr) υ: 3391,2966,2926,1630,1566,1508,1443,1377,1256,1196,1178,1099,1038,831cm
-1.
Embodiment 37
7,4 '-two [2-hydroxyl-3-(morpholine-4-yl) propoxy-]-5-hydroxy-isoflavones (6f)
The preparation method is similar to 6a, gets light yellow solid 280mg, yield 33.8%, mp147-149 ℃.
1H-NMR(500MHz，DMSO-d
6)δ：2.39-2.48(m，12H，2×N(CH
2)
3)，3.56-3.58(m，8H，2×O(CH
2)
2)，3.91-4.14(m，6H，2×OCHCH
2O)，4.86(d，1H，OH)，4.94(d，1H，OH)，6.43(d，1H，J＝2.3Hz，6-H)，6.67(d，1H，J＝2.3Hz，8-H)，7.01-7.03(d，2H，J＝8.9Hz，3’，5’-H)，7.50-7.52(d，2H，J＝8.9Hz，2’，6’-H)，8.44(s，1H，2-H)，12.91(s，1H，5-OH)。ESI-MS?m/z：541[M+H]+。IR(KBr)υ：3424，2881，2808，1689，1611，1573，1514，1290，1248，1184，1115，836cm-1。
Embodiment 38
7,4 '-two [2-hydroxyl-3-(piperidines-1-yl) propoxy-]-5-hydroxy-isoflavones (6g)
The preparation method is similar to 6a, gets little yellow solid 160mg, yield 18.7%, mp140-143 ℃.
1H-NMR(500MHz，DMSO-d
6)δ：1.41(m，4H，2×CH
2)，1.54(m，8H，4×CH
2)，2.50(m，12H，2×N(CH
2)
3)，3.93-4.13(m，6H，2×OCHCH
2O)，4.96(d，2H，2×OH)，6.43(d，1H，6-H)，6.67(d，1H，8-H)，7.01-7.03(d，2H，J＝8.3Hz，3’，5’-H)，7.50-7.52(d，2H，J＝8.3Hz，2’，6’-H)，8.45(s，1H，2-H)，12.91(s，1H，5-OH)。ESI-MS?m/z：553[M+H]
+。IR(KBr)υ：3385，2881，1665，1576，1512，1443，1248，1182，1043，831cm
-1。
Claims (7)
1. the compound or its pharmacy acceptable salt that lead to formula I:
Wherein Q represents hydrogen, hydroxyl, chlorine, bromine, iodine, amino, nitro.
R
1Expression H ,-(CH
2)
nNR
3R
4Or-CH
2CHOHCH
2NR
5R
6, n=1-6; R
2Expression H ,-CH
2CHOHCH
2NR
5R
6Or-CH
2CHOHCH
2NR
7R
8NR
3R
4, NR
5R
6And NR
7R
8Represent various amino respectively, represent morpholinyl, pyrrolidyl, piperidyl and various substituted piperazinyl especially.
2. the compound of claim 1 or its pharmacy acceptable salt, wherein Q represents hydrogen, hydroxyl, chlorine, bromine, iodine, amino, nitro.
3. the compound of claim 1 or its pharmacy acceptable salt are following arbitrary compound or its pharmacy acceptable salt:
7-[3-(4-methylpiperazine-1-yl) propoxy-]-4 '-hydroxy-isoflavone (4a);
7-[3-(4-benzyl diethylenediamine-1-yl) propoxy-]-4 '-hydroxy-isoflavone (4b);
7-[3-(tetramethyleneimine-1-yl) propoxy-]-4 '-hydroxy-isoflavone (4c);
7-[4-(morpholine-4-yl) butoxy]-4 '-hydroxy-isoflavone (4d);
7-[4-(4-hydroxyethyl piperazine-1-yl) butoxy]-4 '-hydroxy-isoflavone (4e);
7-[5-(morpholine-4-yl) pentyloxy]-4 '-hydroxy-isoflavone (4f);
7-[5-(4-ethyl piperazidine-1-yl) pentyloxy]-4 '-hydroxy-isoflavone (4g);
7-[6-(4-methylpiperazine-1-yl) hexyloxy]-4 '-hydroxy-isoflavone (4h);
7-[6-(morpholine-4-yl) hexyloxy]-4 '-hydroxy-isoflavone (4i);
7-[3-(tetramethyleneimine-1-yl) propoxy-]-5,4 '-dihydroxy isoflavone (4j);
7-[3-(4-benzyl diethylenediamine-1-yl) propoxy-]-5,4 '-dihydroxy isoflavone (4k);
7-[4-(4-methylpiperazine-1-yl) butoxy]-5,4 '-dihydroxy isoflavone (4l);
7-[4-(4-ethyl piperazidine-1-yl) butoxy]-5,4 '-dihydroxy isoflavone (4m);
7-[4-(tetramethyleneimine-1-yl) butoxy]-5,4 '-dihydroxy isoflavone (4n);
7-[5-(4-methylpiperazine-1-yl) pentyloxy]-5,4 '-dihydroxy isoflavone (4o);
7-[5-(4-benzyl diethylenediamine-1-yl) pentyloxy]-5,4 '-dihydroxy isoflavone (4p);
7-[6-(morpholine-4-yl) hexyloxy]-5,4 '-dihydroxy isoflavone (4q);
7-[6-(4-methylpiperazine-1-yl) hexyloxy]-5,4 '-dihydroxy isoflavone (4r);
7-[6-(4-ethyl piperazidine-1-yl) hexyloxy]-5,4 '-dihydroxy isoflavone (4s);
7,4 '-two (2-hydroxyl-3-isopropylamino propoxy-) isoflavones (6a);
7,4 '-two (the amino propoxy-of 2-hydroxyl-uncle's 3-fourth) isoflavones (6b);
7,4 '-two [2-hydroxyl-3-(4-methylpiperazine-1-yl) propoxy-] isoflavones (6c);
7,4 '-two [2-hydroxyl-3-(4-hydroxyethyl piperazine-1-yl) propoxy-] isoflavones (6d);
7,4 '-two (2-hydroxyl-3-diethylin propoxy-) isoflavones (6e);
7,4 '-two [2-hydroxyl-3-(morpholine-4-yl) propoxy-]-5-hydroxy-isoflavones (6f);
7,4 '-two [2-hydroxyl-3-(piperidines-1-yl) propoxy-]-5-hydroxy-isoflavones (6g);
4. the compound of claim 1 or its pharmacy acceptable salt, wherein pharmacy acceptable salt comprises the acid salt of logical formula I compound and following acid formation: hydrochloric acid, Hydrogen bromide, sulfuric acid, citric acid, tartrate, phosphoric acid, lactic acid, acetate, toxilic acid or Phenylsulfonic acid.
5. pharmaceutical composition wherein contains logical formula I compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of claim 1.
6. the logical formula I compound of claim 1 or its pharmacy acceptable salt are in preparation is used for preventing or treatment and selective estrogen receptor are regulated the medicine of diseases associated purposes.
7. the purposes of claim 6 is mammary cancer, ovarian cancer, endometriosis, artery smooth cell hyperplasia, carcinoma of endometrium, prostate cancer, osteoporosis, female climacteric syndrome and atherosclerosis with selective estrogen receptor adjusting diseases associated wherein.
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