CN103130631A - 1-substituted benzylidene-2-naphthyl ketone derivatives and preparation method and application thereof - Google Patents
1-substituted benzylidene-2-naphthyl ketone derivatives and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to novel derivatives of treatment for leukemia and a preparation method and application of the novel derivatives of the treatment for the leukemia, and particularly discloses the derivatives and acceptable salts on pharmacy disclosed in formula (I), the preparation method of the novel derivatives of the treatment for the leukemia comprises steps as below: enabling dimethoxynaphthalene and metallic sodium to flow in alcohol in a returning mode and generate 1-benzylidene-3,4-dihydro-2-naphthalenone after acidification; enabling the 1-benzylidene-3,4-dihydro-2-naphthalenone to be dissolved into dichloromethane to start a chemical reaction under the condition of being stirred at a room temperature and catalyzed by ethyl piperidine to generate 1-benzylidene-3,4-dihydro-2-naphthalenone; enabling the 1-benzylidene-3,4-dihydro-2-naphthalenone to be dissolved into 10% dichloromethane methanol solution, adding sodium borohydride, carrying out reduction, and the 1-substituted benzylidene-2-naphthyl ketone derivatives are obtained. The 1-substituted benzylidene-2-naphthyl ketone derivatives have a better effect of the treatment for the leukemia, can restrain tubulin, and can treat all kinds of cancers reactive in cytotoxic activity like breast cancer or colon cancer and cancers relevant with abnormal angiogenesis.
Description
Technical field
The present invention relates to medical technical field, be specifically related to a class 1-substituted benzene methylene radical-2-naphthalenone analog derivative, the invention still further relates to the preparation method of this compounds and the application in preparing antitumor drug thereof.
Background technology
Tumour, particularly malignant tumour, the serious threat mankind's health.According to estimates, the annual pathogenesis of cancer number of China approximately 2,600,000, dead 1,800,000, Past 30 Years China cancer mortality has increased by 80%, becomes first cause of the death of Chinese residents.Although antitumor drug is extend patient's survival time and improve its quality of life and made very large contribution, but most drug is cell toxicity medicament, it lacks selectivity can injure a large amount of normal cells, and resistance easily appears, so vascular targeting agents becomes study hotspot.
Tubulin is the important target of target treatment to tumor blood vessel.In three main drug binding sites of tubulin, the colchicine site is simple in structure because of the small volume of binding cavity and corresponding inhibitor, is more suitable for carrying out the research of micromolecular inhibitor than taxol site and vinealeucoblastine(VLB) site.
Summary of the invention
The object of the present invention is to provide a kind of antitumor, especially for the medicine of leukemia knurl strain.One class 1-substituted benzene methylene radical-2-naphthalenone analog derivative or its pharmacy acceptable salt and preparation method thereof and medicinal use are provided.
One aspect of the present invention has been to provide structure suc as formula the 1-substituted benzene methylene radical shown in (I)-2-naphthalenone analog derivative, or its pharmacy acceptable salt,
Wherein, substituent R
1being positioned at 5,6,7 or 8, can be monosubstituted, two replacements or polysubstituted, substituent R
1be selected from following groups a kind of, two or more: C
1-8straight or branched alkoxyl group, C
1-8straight or branched alkyl, halogen, methylene-dioxy, work as R
1for two or when polysubstituted, substituting group can be identical or different;
Preferably, substituent R
1for mono-substituted C
1-4the straight or branched alkoxyl group;
Preferred, substituent R
1for mono-substituted methoxyl group;
Most preferred, substituent R
1for 5-OCH
3, 6-OCH
3or 7-OCH
3;
Substituent R
2being positioned at 2 ', 3 ', 4 ', 5 ', 6 ', can be unsubstituted, mono-substituted, disubstituted or polysubstituted, described substituting group be selected from following groups a kind of, two or more: C
1-8straight or branched alkoxyl group, C
1-8straight or branched alkyl, C
1-8straight or branched haloalkyl, hydroxyl, halogen, nitro, cyano group, ester group, amide group, amino or the amino replaced, work as R
2for two or when polysubstituted, substituting group can be identical or different;
Preferably, substituent R
2be positioned at 2 ', 3 ', 4 ', 5 ' or 6 ', can be unsubstituted, mono-substituted, disubstituted or polysubstituted, described substituting group is selected from a kind of in following groups, two or more: methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, single methyl fluoride, difluoromethyl, trifluoromethyl, the monochloro methyl, dichloromethyl, trichloromethyl, single brooethyl, two brooethyls, trisbromomethyl, hydroxyl, fluorine, chlorine, bromine, iodine, nitro, cyano group, amino, methylamino, dimethylamino, ethylamino or propyl group amino, work as R
2for two or when polysubstituted, substituting group can be identical or different,
Preferred, substituent R
2be positioned at 2 ', 3 ', 4 ', 5 ' or 6 ', can be unsubstituted, mono-substituted, disubstituted or trisubstituted, described substituting group be selected from following groups a kind of, two or three: methoxyl group, methyl, the tertiary butyl, trifluoromethyl, hydroxyl, chlorine, bromine, nitro or dimethylamino, work as R
2during for two or three replacements, substituting group can be identical or different;
Further preferred, substituent R
2can be unsubstituted, mono-substituted, disubstituted or trisubstituted, described substituting group be selected from following groups a kind of, two or three: 2 '-OCH
3, 3 '-OCH
3, 4 '-OCH
3, 5 '-OCH
3, 3 '-OH, 4 '-OH, 4 '-CH
3, 4 '-C (CH
3)
3, 4 '-CF
3, 2 '-Cl, 3 '-Cl, 4 '-Cl, 6 '-Cl, 4 '-Br, 4 '-N (CH
3)
2or 4 '-NO
2, work as R
2during for two or three replacements, substituting group can be identical or different;
Most preferred, R
2can be not replace or replaced by following substituting group, described substituent R
2be selected from: 3 ', 4 ', 5 '-(OCH
3)
3, 2 ', 3 ', 4 '-(OCH
3)
3, 3 ', 4 '-(OCH
3)
2, 3 ', 5 '-(OCH
3)
2, 4 '-OCH
3, 3 '-OH, 4 '-OCH
3, 4 '-OH, 3 '-OCH
3, 4 '-CH
3, 4 '-C (CH
3)
3, 4 '-CF
3, 3 '-OH, 4 '-OH, 2 '-Cl, 4 '-Cl, 4 '-Br, 2 ', 4 '-(Cl)
2, 3 ', 4 '-(Cl)
2, 2 ', 6 '-(Cl)
2, 4 '-N (CH
3)
2or 4 '-NO
2.
Substituent X is: C=O, CHOR
3or C=NR
4, wherein, R
3represent hydrogen, acyl group, C
1-8straight or branched alkyl, substituted aryl.R
4represent hydrogen, acyl group, C
1-8straight or branched alkyl, substituted aryl; In further preferred embodiment of the present invention, R
3for H.
Preferably, substituent X is C=O or CHOH.
Wherein, in 1-substituted benzene methylene radical shown in described formula (I)-2-naphthalenone analog derivative, work as substituent R
1be the methoxyl group of 6 when monosubstituted, R
2can not be unsubstituted, and can not be 4 ' mono-substituted Br, CF
3, cyano group, nitro or methoxyl group, and can not be 3 ' mono-substituted Cl;
Except as otherwise noted, C of the present invention
1-8the straight or branched alkoxyl group refer to the alkoxyl group that contains 1-8 carbon atom, include but not limited to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy; Hexyloxy, heptan oxygen base or octyloxy;
Except as otherwise noted, C of the present invention
1-8the straight or branched alkyl refer to the alkyl that contains 1-8 carbon atom, include but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, hexyl, heptyl or octyl group;
Except as otherwise noted, term halogen is the haloid element substituting group, includes but not limited to fluorine, chlorine, bromine or iodine;
Described pharmacologically acceptable salts is inorganic acid salt, organic acid salt or amino acid salts.
Wherein the example of inorganic acid salt comprises: hydrochloride, vitriol, phosphoric acid salt, diphosphate, hydrobromate or nitrate;
Wherein the example of organic acid salt comprises: acetate, maleate, fumarate, tartrate, succinate, lactic acid salt, tosilate, salicylate, oxalate etc.;
Wherein the example of amino acid salts comprises: arginic acid salt, ornithine salt, lysine salt, leucine salt, Isoleucine salt, glycinate, cystine salt, cysteine salt, tyrosine salt, L-Ala salt, phenylalanine salt, Histidine salt, Serine salt, Threonine salt, methionine salt, tryptophane salt, glutaminate, aspartate, α-amino-isovaleric acid salt, methionine(Met) salt, proline salt or oxyproline salt.
Wherein, the term in the present invention " polysubstituted " and " multiple " refer to more than three kinds or three kinds, and what below occur is also identical meanings.
As one of further preferred embodiment of the present invention, 1-substituted benzene methylene radical-2-naphthalenone analog derivative or its pharmacologically acceptable salts shown in formula (I),
Wherein, substituent R
1for 5-OCH
3, 6-OCH
3or 7-OCH
3;
Wherein, substituent R
2being positioned at 2 ', 3 ', 4 ' or 5 ', can be mono-substituted, disubstituted or trisubstituted;
Work as R
2when monosubstituted, substituting group is selected from: 2 '-OCH
3, 3 '-OCH
3, 5 '-OCH
3, methyl, the tertiary butyl, hydroxyl, dimethylamino, 2 '-Cl or 4 '-Cl; Be preferably: 2 '-OCH
3, 3 '-OCH
3, 5 '-OCH
3, 3 '-OH, 4 '-OH, 4 '-CH
3, 4 '-C (CH
3)
3, 2 '-Cl, 4 '-Cl or 4 '-N (CH
3)
2;
Work as R
2during for two or three replacements, substituting group can be identical or different, and described substituting group is selected from two or three in following groups: methoxyl group, methyl, the tertiary butyl, hydroxyl, chlorine or dimethylamino; Preferred substituting group is selected from two or three: 2 '-OCH in following groups
3, 3 '-OCH
3, 4 '-OCH3,5 '-OCH
3, 3 '-OH, 4 '-OH, 4 '-CH
3, 4 '-C (CH
3)
3, 2 '-Cl, 3 '-Cl, 4 '-Cl or 4 '-N (CH
3)
2;
The X substituting group is C=O or CHOH.
As one of best embodiment, 1-substituted benzene methylene radical shown in formula of the present invention (I)-2-naphthalenone analog derivative is the particular compound as following table 1:
Table 1
The present invention also provides the preparation method of 1-substituted benzene methylene radical shown in above-mentioned formula (I)-2-naphthalenone analog derivative, and described method comprises the following steps:
(1) prepare 3,4-dihydro-2-naphthalenone
Dimethoxy-naphthalene and sodium Metal 99.5 are refluxed in ethanol, generate 3,4-dihydro-2-naphthalenone after acidifying;
(2) prepare 1-α-tolylene-3,4-dihydro-2-naphthalenone
3,4-dihydro-2-naphthalenone, phenyl aldehyde are dissolved in to methylene dichloride, and under the effect of catalytic amount acetyl piperidine, the stirring at room reaction, generate 1-α-tolylene-3,4-dihydro-2-naphthalenone;
(3) prepare 1-α-tolylene-1,2,3,4-tetrahydrochysene-2-naphthalene alcohol
By 1-α-tolylene-3,4-dihydro-2-naphthalenone, be dissolved in 10% dichloromethane methanol solution, adds sodium borohydride, and reduction generates 1-α-tolylene-1,2,3,4-tetrahydrochysene-2-naphthalene alcohol.
The preparation method of the pharmaceutically acceptable salt of 1-substituted benzene methylene radical shown in formula (I)-2-naphthalenone analog derivative can be prepared according to this area ordinary method, for example with inorganic acid salt, organic acid salt or amino acid salts, under normal condition, is reacted and obtains.
The invention provides 1-substituted benzene methylene radical-2-naphthalenone analog derivative shown in formula (I) or its pharmacologically acceptable salts purposes for the preparation of the treatment leukemia medicament, the present invention also provides 1-substituted benzene methylene radical-2-naphthalenone analog derivative shown in formula (I) or the purposes of its pharmacologically acceptable salts in preparing the Antitubulin medicine.
The present invention is analyzed by the character to binding site in colchicine crystalline complex structure and is carried out docking simulation experiment, find that derivative shown in formula of the present invention (I) has tubulin and suppresses active, tumour cell can be blocked in mitosis metaphase, and verified that it has biological activity to kinds of tumor cells.
Application in the medicine of the cancer that further, the present invention also provides 1-substituted benzene methylene radical-2-naphthalenone analog derivative shown in formula (I) or its pharmacologically acceptable salts in the preparation treatment, cellular cytoxicity activity to be responded.
Further, the present invention also provides 1-substituted benzene methylene radical-2-naphthalenone analog derivative shown in formula (I) or its pharmacologically acceptable salts generating the application of the medicine of relevant disease for the preparation for the treatment of and abnormal vascular.
Further, the present invention also provides 1-substituted benzene methylene radical-2-naphthalenone analog derivative shown in formula (I) or the application of its pharmacologically acceptable salts in the medicine of preparation treatment tumor type disease.
Best, the invention provides 1-substituted benzene methylene radical-2-naphthalenone analog derivative shown in formula (I) or its pharmacologically acceptable salts in the application for the preparation of in treatment mammary cancer or colorectal carcinoma medicine.
In addition, the cancer that 1-substituted benzene methylene radical-2-naphthalenone analog derivative or its pharmacologically acceptable salts shown in formula of the present invention (I) also can be used for treatment includes but not limited to the cancer that the positions such as esophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lung, colon, mammary gland, uterus, uterine endometrium, ovary, prostate gland, testis, bladder, kidney, liver, pancreas, bone, reticular tissue, skin, eye, brain and central nervous system occur, and thyroid carcinoma, leukemia, Huo Jie king's evil and myelomatosis etc.
As one of preferred embodiment, the present invention also provides a kind of pharmaceutical composition, the carrier that described pharmaceutical composition comprises 1-substituted benzene methylene radical-2-naphthalenone analog derivative shown in described formula (I) or its pharmacy acceptable salt and pharmaceutically accepts.
Described pharmaceutical composition can be solid form or the pharmaceutical preparation of liquid form, and described pharmaceutical dosage form includes but not limited to tablet, capsule, powder agent, granule, suspensoid or injection.
Shown in formula of the present invention (I), 1-substituted benzene methylene radical-2-naphthalenone analog derivative or its pharmacologically acceptable salts have the leukemic activity of better treatment.
Evidence, shown in formula of the present invention (I), 1-substituted benzene methylene radical-2-naphthalenone analog derivative or its pharmacologically acceptable salts have better anti-leukocythemia liveness, especially for cem cell, its IC
50between 1nM-20 μ M.And derivative of the present invention also can be used for the treatment of multiple other various cancers diseases except the treatment leukemia.
The accompanying drawing explanation
Fig. 1: the period profile of the compound 1 of different concns and 16 pairs of HCT116 cells in experimental example 4;
Fig. 2: in experimental example 5, nude mice colo205 Transplanted cells knurl is with the administration time growth curve.
Embodiment
The present invention further sets forth the present invention by following examples and experimental example, but the present invention is not limited to this.
Embodiment 1:6-methoxyl group-3, the preparation of 4-dihydro-2-naphthalenone
By 2,6-dimethoxy-naphthalene (20g, 0.1mol) join in the dehydrated alcohol (200ml) of backflow, add the sodium Metal 99.5 silk (19g, 0.83mol) shredded, be back to sodium Metal 99.5 and all dissolve approximately 1 hour, be down to room temperature, drip hydrochloric acid (2M, 330ml) under water-bath and regulate PH=3, continue temperature rising reflux extremely clarification half an hour.Be down to room temperature, extract three times by ethyl acetate (50ml), concentrated water, then use ethyl acetate (50ml) to extract three times, merge organic phase, saturated common salt washing, anhydrous sodium sulfate drying.Through concentrated and molecular distillation, (boiling point 160-165 ℃ 10mmHg), through sherwood oil (60-90 ℃) recrystallization, obtains the white needles solid, yield 75%, fusing point 38-40 ℃ to obtain yellow oil.
Embodiment 2:(E)-6-methoxyl group-1-(3,4,5-trimethoxy α-tolylene)-3, the preparation of 4-dihydro-2-naphthalenone (1)
By 6-methoxyl group-3,4-dihydro-2-naphthalenone (1.76g, 10mmol), 3,4,5-TMB (1.96g, 10mmol) be dissolved in methylene dichloride (30ml), add 4A molecular sieve (3g), Glacial acetic acid (50mg), piperidines (50mg), stirring at room 8 hours, filter washing leaching cake, merge organic phase, washing (25ml), saturated common salt washing (25ml), anhydrous sodium sulfate drying, concentrated, (PE: EtOAc=10: 1), recrystallization obtains yellow crystals (1.68g, 47%) to column chromatography for separation.
m.p.102-103℃。
1H NMR(300MHz，CDCl3)δ7.49(s，1H)，7.44(d，J＝8.6Hz，1H)，6.80(d，J＝2.2Hz，1H)，6.72(s，2H)，6.64(dd，J＝8.6，2.2Hz，1H)，3.85(d，J＝13.9Hz，6H)，3.71(s，6H)，3.01(t，J＝6.4Hz，2H)，2.62(t，J＝6.4Hz，2H).
13C NMR(300MHz，CDCl3)δ201.78，159.42，152.91，140.23，138.68，133.21，132.59，130.60，130.46，124.86，112.73，111.81，106.86，60.89，55.93，55.25，36.98，28.05
HRMS：354.1467(target)，354.1466(found)。
Embodiment 3:(E)-6-methoxyl group-1-(3,4,5-trimethoxy α-tolylene)-1,2,3, the preparation of 4-tetrahydrochysene-2-naphthalene alcohol (16)
By (E)-6-methoxyl group-1-(3,4,5-trimethoxy α-tolylene)-3,4-dihydro-2-naphthalenone (2g, 5.6mmol), be dissolved in 10% dichloromethane methanol solution, add sodium borohydride, stirring at room 20 minutes, concentrated, washing, ethyl acetate extraction, saturated common salt washing, merge organic phase, concentrated, column chromatography for separation (PE: EtOAc=5: 1), recrystallization obtains white needle (1.7g, yield 85%), m.p.128 ℃
1H NMR(300MHz，CDCl
3)δ7.60(d，J＝9Hz，1H)，7.00(s，1H)，6.77-6.81(m，3H)，6.68(d，J＝2.7Hz，1H)，5.05(t，J＝2.44Hz，1H)，3.93(m，10H)，3.82(s，3H)，3.10-3.22(m，1H)，2.68-2.76(m，1H)，2.01-2.15(m，1H)，1.95-2.09(m，1H)
13C NMR(300MHz，CDCl
3)δ159.11，152.97，139.31，139.02，136.90，133.31，131.39，129.97，124.60，122.59，112.72，111.51，106.54，106.15，72.58，60.92，55.98，55.13，31.43，26.25
HRMS：356.1623(target)，379.1518(found，M+Na
+)
Embodiment 4:(E)-6-methoxyl group-1-(2,3,4-trimethoxy α-tolylene)-3, the preparation of 4-dihydro-2-naphthalenone (2)
With reference to embodiment 2, by 6-methoxyl group-3,4-dihydro-2-naphthalenone and the reaction of 2,3,4-TMB, can make (E)-6-methoxyl group-1-(2,3,4-trimethoxy α-tolylene)-3,4-dihydro-2-naphthalenone (2);
m.p.114℃；
1H NMR(300MHz，CDCl
3)δ7.73(s，1H)，7.30(d，J＝8.4Hz，1H)，7.03(d，J＝8.7Hz，1H)，6.77(s，1H)，6.57(dd，J＝8.7，2.2Hz，1H)，6.47(d，J＝8.7Hz，1H)，3.90(d，6H)，3.85(s，6H)，2.99(t，J＝6.3Hz，2H)，2.62(t，J＝6.3Hz，2H)；
HRMS：354.1467(target)，354.1464(found，M
+)。
Embodiment 5:(E)-6-methoxyl group-1-(3,4-dimethoxy α-tolylene)-3, the preparation of 4-dihydro-2-naphthalenone (3)
With reference to embodiment 2, by 6-methoxyl group-3,4-dihydro-2-naphthalenone reacts with Veratraldehyde, can make (E)-6-methoxyl group-1-(3,4-dimethoxy α-tolylene)-3,4-dihydro-2-naphthalenone (3);
m.p.114℃；
1H NMR(300MHz，CDCl
3)δ7.52(s，1H)，7.42(d，J＝8.7Hz，1H)，7.07(d，J＝8.7，2.2Hz，1H)，7.03(s，1H)，6.76(d，J＝8.7Hz，1H)，6.62(dd，J＝8.4Hz，J＝2.2Hz，1H)，3.90(d，3H)，3.85(s，6H)，2.99(t，J＝6.3Hz，2H)，2.62(t，J＝6.3Hz，2H)；
HRMS：324.1362(target)，324.1361(found，M
+)。
Embodiment 6:(E)-6-methoxyl group-1-(3,5-dimethoxy α-tolylene)-3, the preparation of 4-dihydro-2-naphthalenone (4)
With reference to embodiment 2, by 6-methoxyl group-3,4-dihydro-2-naphthalenone and the reaction of 3,5-dimethoxy benzaldehyde, can make (E)-6-methoxyl group-1-(3,5-dimethoxy α-tolylene)-3,4-dihydro-2-naphthalenone (4);
m.p.126℃；
1H NMR(300MHz，CDCl
3)δ7.52(s，1H)，7.33(d，J＝8.7Hz，1H)，6.78(d，J＝2.4Hz，1H)，6.62(d，J＝8.7Hz，1H)，6.58(d，J＝8.7Hz，1H)，6.38(t，J＝2.4Hz，1H)，3.83(s，3H)，3.69(s，6H)，3.01(t，J＝6.3Hz，2H)，2.63(t，J＝6.3Hz，2H)；
HRMS：324.1362(target)，324.1363(found，M
+)。
Embodiment 7:(E)-6-methoxyl group-1-(3-hydroxyl-4-anisole methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (5)
With reference to embodiment 2, by 6-methoxyl group-3,4-dihydro-2-naphthalenone reacts with 3-hydroxyl-4-methoxybenzaldehyde, can make (E)-6-methoxyl group-1-(3-hydroxyl-4-anisole methylene radical)-3,4-dihydro-2-naphthalenone (5);
m.p.172℃；
1H NMR(300MHz，CDCl
3)δ7.50(s，1H)，7.38(d，J＝8.4Hz，1H)，7.06(d，J＝2.1Hz，1H)，7.01(dd，J＝8.7，2.1Hz，1H)，6.78(d，J＝21.Hz，1H)，6.76(d，J＝8.4Hz，1H)，6.62(dd，J＝8.7，2.7Hz，1H)，5.55(s，1H)，3.90(s，3H)，3.83(s，3H)，2.98(t，J＝6.3Hz，2H)，2.59(t，J＝6.3Hz，2H)；
HRMS：310.1205(target)，310.1204(found，M
+)。
Embodiment 8:(E)-6-methoxyl group-1-(3-methoxyl group-4-phenol methylene)-3, the preparation of 4-dihydro-2-naphthalenone (6)
With reference to embodiment 2, by 6-methoxyl group-3,4-dihydro-2-naphthalenone reacts with Vanillin, can make (E)-6-methoxyl group-1-(3-methoxyl group-4-phenol methylene)-3,4-dihydro-2-naphthalenone (6);
m.p.155℃；
1H NMR(300MHz，CDCl
3)δ7.53(s，1H)，7.45(d，J＝8.7Hz，1H)，7.06(s，1H)，7.02(s，1H)，6.83(s，1H)，6.80(s，1H)，6.63(dd，J＝8.7，2.7Hz，1H)，5.85(s，1H)，3.83(s，3H)，3.72(s，3H)，2.99(t，J＝6.6Hz，2H)，2.60(t，J＝6.6Hz，2H)；
HRMS：310.1205(target)，310.1206(found，M
+)。
Embodiment 9:(E)-6-methoxyl group-1-(4-phenol methylene)-3, the preparation of 4-dihydro-2-naphthalenone (7)
With reference to embodiment 2, by 6-methoxyl group-3,4-dihydro-2-naphthalenone reacts with the 4-hydroxy benzaldehyde, can make (E)-6-methoxyl group-1-(4-phenol methylene)-3,4-dihydro-2-naphthalenone (7);
m.p.148℃；
1H NMR(300MHz，CDCl
3)δ7.60(s，1H)，7.41(dd，J＝8.4，2.4Hz，1H)，7.30(d，J＝8.4Hz，1H)，6.77(dd，J＝8.1，2.7Hz，2H)，6.70(d，J＝2.7Hz，1H)，6.58(dd，J＝8.7，2H)，5.62(s，1H)3.88(s，3H)，3.83(s，3H)，3.00(t，J＝6.6Hz，2H)，2.61(t，J＝6.6Hz，2H)；
HRMS：280.1099(target)，280.1086(found，M
+)。
Embodiment 10:(E)-6-methoxyl group-1-(4-methylbenzene methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (8)
With reference to embodiment 2, by 6-methoxyl group-3,4-dihydro-2-naphthalenone reacts with the 4-tolyl aldehyde, can make (E)-6-methoxyl group-1-(4-methylbenzene methylene radical)-3,4-dihydro-2-naphthalenone (8);
m.p.120℃；
1H NMR(300MHz，CDCl
3)δ7.58(s，1H)，7.35(dd，J＝8.1，2.7Hz，3H)，7.07(d，J＝8.1Hz，2H)，6.80(d，J＝2.7Hz，1H)，6.60(dd，J＝8.7，2.7Hz，1H)，3.83(s，3H)，3.00(t，J＝6.3Hz，2H)，2.62(t，J＝6.3Hz，2H)，2.34(s，3H)；
HRMS：278.1307(target)，278.1307(found，M
+)。
Embodiment 11:(E)-6-methoxyl group-1-(4-dimethylamino α-tolylene)-3, the preparation of 4-dihydro-2-naphthalenone (9)
With reference to embodiment 2, by 6-methoxyl group-3,4-dihydro-2-naphthalenone reacts with the 4-dimethylaminobenzaldehyde, can make (E)-6-methoxyl group-1-(4-dimethylamino α-tolylene)-3,4-dihydro-2-naphthalenone (9);
m.p.130℃；
1H NMR(300MHz，CDCl
3)δ7.56(s，1H)，7.54(s，1H)，7.47(s，1H)，7.44(s，1H)，6.79(d，J＝2.7Hz，1H)，6.65(dd，J＝8.7，2.7Hz，1H)，6.58(d，J＝8.7Hz，2H)，3.84(s，3H)，3.00(s，6H)，2.96(t，J＝6.3Hz，2H)，2.57(t，J＝6.3Hz，2H)；
HRMS：307.1572(target)，307.1575(found，M
+)。
Embodiment 12:(E)-6-methoxyl group-1-(4-tert.-butylbenzene methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (10)
With reference to embodiment 2, by 6-methoxyl group-3,4-dihydro-2-naphthalenone and 4-tert.-butylbenzene formaldehyde reaction, can make (E)-6-methoxyl group-1-(4-tert.-butylbenzene methylene radical)-3,4-dihydro-2-naphthalenone (10);
m.p.148℃；
1H NMR(300MHz，CDCl
3)δ7.58(s，1H)，7.40(s，3H)，7.28(d，J＝6.6Hz，2H)，6.81(s，1H)，6.62(d，J＝8.4Hz，1H)，3.84(s，3H)，3.00(s，2H)，2.61(s，2H)；
HRMS：320.1776(target)，320.1775(found，M
+)。
Embodiment 13:(E)-6-methoxyl group-1-(4-chlorobenzene methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (11)
With reference to embodiment 2, by 6-methoxyl group-3,4-dihydro-2-naphthalenone reacts with the 4-chlorobenzaldehyde, can make (E)-6-methoxyl group-1-(4-chlorobenzene methylene radical)-3,4-dihydro-2-naphthalenone (11);
m.p.144℃；
1H NMR(300MHz，CDCl
3)δ7.43(s，1H)，7.31(d，J＝8.7Hz，2H)，7.22(d，J＝8.4Hz，2H)，7.21(d，8.7Hz，1H)，6.78(d，J＝2.7Hz，1H)，6.57(dd，J＝8.7，2.7Hz，1H)，3.83(s，3H)，2.99(t，J＝6.6Hz，2H)，2.62(t，J＝6.6Hz，2H)；
HRMS：298.0761(target)，298.0758(found，M
+)。
Embodiment 14:(E)-6-methoxyl group-1-(3-phenol methylene)-3, the preparation of 4-dihydro-2-naphthalenone (12)
With reference to embodiment 2, by 6-methoxyl group-3,4-dihydro-2-naphthalenone reacts with the 3-hydroxy benzaldehyde, can make (E)-6-methoxyl group-1-(3-phenol methylene)-3,4-dihydro-2-naphthalenone (12);
m.p.170℃；
1H NMR(300MHz，CDCl
3)δ7.54(s，1H)，7.30(d，J＝8.7Hz，1H)，7.15(t，J＝7.8Hz，1H)，7.00(d，J＝7.8Hz，1H)，6.92(s，1H)，6.78(d，J＝7.8Hz，2H)，6.59(dd，J＝8.7，2.7Hz，1H)，3.86(s，3H)，3.00(t，J＝6.3Hz，2H)，2.63(t，J＝6.3Hz，2H)；
HRMS：280.1099(target)，280.1036(found，M
+)。
Embodiment 15:(E)-6-methoxyl group-1-(2-chlorobenzene methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (13)
With reference to embodiment 2, by 6-methoxyl group-3,4-dihydro-2-naphthalenone reacts with the 2-chlorobenzaldehyde, can make (E)-6-methoxyl group-1-(2-chlorobenzene methylene radical)-3,4-dihydro-2-naphthalenone (13);
m.p.124℃；
1H NMR(300MHz，CDCl
3)δ7.63(s，1H)，7.38(d，J＝8.1Hz，1H)，7.24(m，2H)，7.18(m，2H)，6.56(dd，J＝8.4，2.4Hz，1H)，6.56(d，J＝2.4Hz，1H)，3.63(s，3H)，2.99(t，J＝6.3Hz，2H)，2.68(t，J＝6.3Hz，2H)；
HRMS：298.0761(target)，298.0754(found，M
+)。
Embodiment 16:(E)-6-methoxyl group-1-(2,4 dichloro benzene methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (14)
With reference to embodiment 2, by 6-methoxyl group-3,4-dihydro-2-naphthalenone and 2,4 dichloro benzene formaldehyde reaction, can make (E)-6-methoxyl group-1-(2,4 dichloro benzene methylene radical)-3,4-dihydro-2-naphthalenone (14);
m.p.124℃；
1H NMR(300MHz，CDCl
3)δ7.74(s，1H)，7.49(dd，J＝7.8，1.8Hz，1H)，7.42-7.47(m，1H)，7.39(s，1H)，7.32(d，J＝8.4Hz，1H)，7.20-7.25(m，1H)，6.61(dd，J＝8.7，2.4Hz，1H)，3.84(s，3H)，3.02(t，J＝6.6Hz，2H)，2.67(t，J＝6.6Hz，2H)；
HRMS：332.0371(target)，332.0370(found，M
+)。
Embodiment 17:(E)-6-methoxyl group-1-(3,4-dichlorobenzene methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (15)
With reference to embodiment 2, by 6-methoxyl group-3,4-dihydro-2-naphthalenone and the reaction of 3,4-dichlorobenzaldehyde, can make (E)-6-methoxyl group-1-(3,4-dichlorobenzene methylene radical)-3,4-dihydro-2-naphthalenone (15);
m.p.124℃；
1H NMR(300MHz，CDCl3)δ7.63(s，1H)，7.54(s，1H)，7.50(d，J＝8.4Hz，1H)，7.42(dd，J＝11.1，2.1Hz，2H)，6.99-7.07(m，1H)，6.78(s，1H)，3.86(s，3H)，3.04(t，J＝6.6Hz，2H)，2.62(t，J＝6.6Hz，2H)
HRMS：332.0371(target)，332.0374(found，M
+)。
Embodiment 18:(E)-7-methoxyl group-1-(3,4,5-trimethoxy α-tolylene)-3, the preparation of 4-dihydro-2-naphthalenone (17)
With reference to embodiment 2, by 7-methoxyl group-3,4-dihydro-2-naphthalenone reacts with 3,4,5-Trimethoxybenzaldehyde, can make (E)-7-methoxyl group-1-(3,4,5-trimethoxy α-tolylene)-3,4-dihydro-2-naphthalenone (17);
m.p.123℃；
1H NMR(300MHz，CDCl
3)δ7.56(s，1H)，7.07(m，2H)，6.78(d，J＝8.7Hz，1H)，6.69(s，2H)，3.90(d，6H)，3.69(s，6H)，3.08(t，J＝6.3Hz，2H)，2.57(t，J＝6.3Hz，2H)；
HRMS：354.1467(target)，354.1469(found，M
+)。
Embodiment 19:(E)-7-methoxyl group-1-(2,3,4-trimethoxy α-tolylene)-3, the preparation of 4-dihydro-2-naphthalenone (18)
With reference to embodiment 2, by 7-methoxyl group-3,4-dihydro-2-naphthalenone and the reaction of 2,3,4-TMB, can make (E)-7-methoxyl group-1-(2,3,4-trimethoxy α-tolylene)-3,4-dihydro-2-naphthalenone (18);
m.p.78℃；
1H NMR(300MHz，CDCl
3)δ7.60(s，1H)，6.96(m，1H)，6.87(d，J＝2.4Hz，1H)，6.73(s，1H)，6.68(dd，J＝8.7，2.4Hz，1H)，6.50(d，J＝8.4Hz，1H)，3.92(d，6H)，3.73(s，6H)，2.99(t，J＝6.3Hz，2H)，2.61(t，J＝6.3Hz，2H)；
HRMS：354.1467(target)，354.1466(found，M
+)。
Embodiment 20:(E)-7-methoxyl group-1-(3,4-dimethoxy α-tolylene)-3, the preparation of 4-dihydro-2-naphthalenone (19)
With reference to embodiment 2, by 7-methoxyl group-3,4-dihydro-2-naphthalenone reacts with Veratraldehyde, can make (E)-7-methoxyl group-1-(3,4-dimethoxy α-tolylene)-3,4-dihydro-2-naphthalenone (19);
m.p.115℃；
1H NMR(300MHz，CDCl
3)δ7.61(s，1H)，7.06(m，4H)，6.78(d，J＝8.4Hz，2H)，3.89(s，6H)，3.64(s，3H)，3.07(t，J＝6.3Hz，2H)，2.56(t，J＝6.3Hz，2H)；
HRMS：324.1362(target)，324.1364(found，M
+)。
Embodiment 21:(E)-7-methoxyl group-1-(3,5-dimethoxy α-tolylene)-3, the preparation of 4-dihydro-2-naphthalenone (20)
With reference to embodiment 2, by 7-methoxyl group-3,4-dihydro-2-naphthalenone and the reaction of 3,5-dimethoxy benzaldehyde, can make (E)-7-methoxyl group-1-(3,5-dimethoxy α-tolylene)-3,4-dihydro-2-naphthalenone (20);
m.p.127℃；
1H NMR(300MHz，CDCl
3)δ7.59(s，1H)，7.01(m，2H)，6.78(dd，J＝6.62.4Hz，1H)，6.54(s，2H)，6.39(t，J＝2.2Hz，1H)，3.87(s，3H)，3.67(s，6H)，3.08(t，J＝6.6Hz，2H)，2.58(t，J＝6.6Hz，2H)；
HRMS：324.1362(target)，324.1381(found，M
+)。
Embodiment 22:(E)-7-methoxyl group-1-(4-anisole methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (21)
With reference to embodiment 2, by 7-methoxyl group-3,4-dihydro-2-naphthalenone reacts with 3-hydroxyl-4-methoxybenzaldehyde, can make (E)-7-methoxyl group-1-(3-hydroxyl-4-anisole methylene radical)-3,4-dihydro-2-naphthalenone (21);
m.p.180℃；
1H NMR(300MHz，CDCl
3)δ7.57(s，1H)，7.05(d，J＝7.8Hz，2H)，7.02(dd，J＝7.82.4Hz，2H)，6.97(dd，J＝8.1，2.1Hz，1H)，6.76(dd，J＝8.4，2.7Hz，2H)，5.61(s，1H)，3.89(s，3H)，3.87(s，3H)，3.05(t，J＝6.6Hz，2H)，2.54(t，J＝6.6Hz，2H)；
HRMS：310.1205(target)，310.1204(found，M
+)。
Embodiment 23:(E)-7-methoxyl group-1-(3-methoxyl group-4-phenol methylene)-3, the preparation of 4-dihydro-2-naphthalenone (22)
With reference to embodiment 2, by 7-methoxyl group-3,4-dihydro-2-naphthalenone reacts with Vanillin, can make (E)-7-methoxyl group-1-(3-methoxyl group-4-phenol methylene)-3,4-dihydro-2-naphthalenone (22);
m.p.162℃；
1H NMR(300MHz，CDCl
3)δ7.60(s，1H)，7.11(d，J＝7.8Hz，1H)，7.02(d，J＝7.8，2.1Hz，2H)，6.99(s，1H)，6.80(dd，J＝8.1，2.1Hz，2H)，6.00(m，1H)，3.88(s，3H)，3.67(s，3H)，3.06(t，J＝6.3Hz，2H)，2.55(t，J＝6.3Hz，2H)；
HRMS：310.1205(target)，310.1209(found，M
+)。
Embodiment 24:(E)-7-methoxyl group-1-α-tolylene-3, the preparation of 4-dihydro-2-naphthalenone (23)
With reference to embodiment 2, by 7-methoxyl group-3,4-dihydro-2-naphthalenone reacts with phenyl aldehyde, can make (E)-7-methoxyl group-1-α-tolylene-3,4-dihydro-2-naphthalenone (23);
m.p.120℃；
1H NMR(300MHz，CDCl
3)δ7.71(s，1H)，7.34(dd，J＝2.4Hz，2H)，7.23-7.27(m，3H)，6.98(d，J＝7.8Hz，1H)，6.92(d，J＝7.8Hz，1H)，6.79(d，J＝7.8Hz，1H)，3.88(s，3H)，3.10(t，J＝6.3Hz，2H)，2.58(t，J＝6.3Hz，2H)；
HRMS：264.1150(target)，264.1151(found，M
+)。
Embodiment 25:(E)-7-methoxyl group-1-(4-anisole methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (24)
With reference to embodiment 2, by 7-methoxyl group-3,4-dihydro-2-naphthalenone reacts with 4-methoxybenzaldehyde, can make (E)-7-methoxyl group-1-(4-anisole methylene radical)-3,4-dihydro-2-naphthalenone (24);
m.p.128℃；
1H NMR(300MHz，CDCl
3)δ7.64(s，1H)，7.40(d，J＝8.4Hz，2H)，6.98-7.07(q，2H)，6.77(d，J＝8.7Hz，2H)，6.76(s，1H)，3.88(s，3H)，3.85(s，3H)，3.07(t，J＝6.3Hz，2H)，2.56(t，J＝6.3Hz，2H)；
HRMS：294.1256(target)，294.1254(found，M
+)。
Embodiment 26:(E)-7-methoxyl group-1-(4-phenol methylene)-3, the preparation of 4-dihydro-2-naphthalenone (25)
With reference to embodiment 2, by 7-methoxyl group-3,4-dihydro-2-naphthalenone reacts with the 4-hydroxy benzaldehyde, can make (E)-7-methoxyl group-1-(4-phenol methylene)-3,4-dihydro-2-naphthalenone (25);
m.p.153℃；
1H NMR(300MHz，CDCl
3)δ7.63(s，1H)，7.35(d，J＝8.4Hz，2H)，7.04(m，2H)，6.78(d，J＝7.2Hz，1H)，6.73(d，J＝8.4Hz，2H)，5.58(s，1H)，3.88(s，3H)，3.06(t，J＝6.3Hz，2H)，2.56(t，J＝6.3Hz，2H)；
HRMS：280.1099(target)，280.1119(found，M
+)。
Embodiment 27:(E)-7-methoxyl group-1-(4-methylbenzene methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (26)
With reference to embodiment 2, by 7-methoxyl group-3,4-dihydro-2-naphthalenone reacts with the 4-tolyl aldehyde, can make (E)-7-methoxyl group-1-(4-methylbenzene methylene radical)-3,4-dihydro-2-naphthalenone (26);
m.p.162℃；
1H NMR(300MHz，CDCl
3)δ7.67(s，1H)，7.32(d，J＝7.8Hz，2H)，7.06(d，J＝8.1Hz，2H)，6.99(d，J＝4.5Hz，2H)，6.78(t，J＝4.5Hz，1H)，3.89(s，3H)，3.08(t，J＝6.6Hz，2H)，2.57(t，J＝6.6Hz，2H)，2.34(s，3H)；
HRMS：278.1307(target)，278.1306(found，M
+)。
Embodiment 28:(E)-7-methoxyl group-1-(4-oil of mirbane methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (27)
With reference to embodiment 2, by 7-methoxyl group-3,4-dihydro-2-naphthalenone and 4-nitrobenzoyl aldehyde reaction, can make (E)-7-methoxyl group-1-(4-oil of mirbane methylene radical)-3,4-dihydro-2-naphthalenone (27);
m.p.156℃；
1H NMR(300MHz，CDCl
3)δ8.10(d，J＝11.1Hz，2H)，7.62(s，1H)，7.48(d，J＝11.1Hz，2H)，6.98(t，J＝8.1Hz，1H)，6.82(d，J＝7.5Hz，1H)，6.72(d，J＝7.5Hz，1H)，3.88(s，3H)，3.11(t，J＝6.6Hz，2H)，2.65(t，J＝6.6Hz，2H)；
HRMS：309.1001(target)，309.1004(found，M
+)。
Embodiment 29:(E)-7-methoxyl group-1-(4-trifluoromethyl α-tolylene)-3, the preparation of 4-dihydro-2-naphthalenone (28)
With reference to embodiment 2, by 7-methoxyl group-3,4-dihydro-2-naphthalenone reacts with the 4-trifluoromethylated benzaldehyde, can make (E)-7-methoxyl group-1-(4-trifluoromethyl α-tolylene)-3,4-dihydro-2-naphthalenone (28);
m.p.150℃；
1H NMR(300MHz，CDCl
3)δ7.63(s，1H)，7.62(d，J＝8.4Hz，2H)，7.48(d，J＝8.1Hz，2H)7.09(d，J＝8.4Hz，1H)，6.95(s，1H)，6.67(d，J＝2.7Hz，1H)，3.62(s，3H)，3.05(t，J＝6.3Hz，2H)，2.62(t，J＝6.3Hz，2H)；
HRMS：332.1024(target)，332.1028(found，M
+)。
Embodiment 30:(E)-7-methoxyl group-1-(4-dimethylamino α-tolylene)-3, the preparation of 4-dihydro-2-naphthalenone (29)
With reference to embodiment 2, by 7-methoxyl group-3,4-dihydro-2-naphthalenone reacts with the 4-dimethylaminobenzaldehyde, can make (E)-7-methoxyl group-1-(4-dimethylamino α-tolylene)-3,4-dihydro-2-naphthalenone (29);
m.p.98℃；
1H NMR(300MHz，CDCl
3)δ7.63(s，1H)，7.56(d，J＝8.1Hz，2H)，7.37(d，J＝7.8Hz，1H)，6.79(d，J＝2.7Hz，1H)，6.65(dd，J＝8.7，2.7Hz，3H)，3.92(s，3H)，3.12(s，6H)，3.06(t，J＝6.3Hz，2H)，2.53(t，J＝6.3Hz，2H)；
HRMS：307.1572(target)，307.1589(found，M
+)。
Embodiment 31:(E)-7-methoxyl group-1-(4-tert.-butylbenzene methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (30)
With reference to embodiment 2, by 7-methoxyl group-3,4-dihydro-2-naphthalenone and 4-tert.-butylbenzene formaldehyde reaction, can make (E)-7-methoxyl group-1-(4-tert.-butylbenzene methylene radical)-3,4-dihydro-2-naphthalenone (30);
m.p.152℃；
1H NMR(300MHz，CDCl
3)δ7.66(s，1H)，7.38(d，J＝8.4Hz，2H)，7.27(d，J＝8.4Hz，2H)，7.02(d，J＝7.8Hz，2H)，6.80(d，J＝7.5Hz，1H)，3.89(s，3H)，3.08(t，J＝6.6Hz，2H)，2.57(t，J＝6.6Hz，2H)，1.31(s，9H)；
HRMS：320.1776(target)，320.1779(found，M
+)。
Embodiment 32:(E)-7-methoxyl group-1-(4-bromobenzene methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (31)
With reference to embodiment 2, by 7-methoxyl group-3,4-dihydro-2-naphthalenone reacts with the 4-bromobenzaldehyde, can make (E)-7-methoxyl group-1-(4-bromobenzene methylene radical)-3,4-dihydro-2-naphthalenone (31);
m.p.132℃；
1H NMR(300MHz，CDCl
3)δ7.57(s，1H)，7.38(d，J＝8.7Hz，2H)，7.25(d，J＝8.4Hz，2H)，6.98(t，J＝8.1Hz，1H)，6.87(d，J＝7.8Hz，1H)，6.79(d，J＝8.1Hz，1H)，3.88(s，3H)，3.08(t，J＝6.6Hz，2H)，2.56(t，J＝6.6Hz，2H)；
HRMS：342.0255(target)，342.0258(found，M
+)。
Embodiment 33:(E)-7-methoxyl group-1-(4-chlorobenzene methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (32)
With reference to embodiment 2, by 7-methoxyl group-3,4-dihydro-2-naphthalenone reacts with the 4-chlorobenzaldehyde, can make (E)-7-methoxyl group-1-(4-chlorobenzene methylene radical)-3,4-dihydro-2-naphthalenone (32);
m.p.150℃；
1H NMR(300MHz，CDCl
3)δ7.59(s，1H)，7.32(d，J＝8.4Hz，2H)，7.21(d，J＝8.4Hz，2H)，6.99(t，J＝8.1Hz，1H)，6.88(d，J＝8.1Hz，1H)，6.79(d，J＝8.1Hz，1H)，3.88(s，3H)，3.08(t，J＝6.3Hz，2H)，2.57(t，J＝6.3Hz，2H)；
HRMS：299.0839(target)，299.0832(found，M+H
+)。
Embodiment 34:(E)-7-methoxyl group-1-(3-phenol methylene)-3, the preparation of 4-dihydro-2-naphthalenone (33)
With reference to embodiment 2, by 7-methoxyl group-3,4-dihydro-2-naphthalenone reacts with the 3-hydroxy benzaldehyde, can make (E)-7-methoxyl group-1-(3-phenol methylene)-3,4-dihydro-2-naphthalenone (33);
m.p.162℃；
1H NMR(300MHz，CDCl
3)δ7.63(s，1H)，7.14(t，J＝8.4Hz，1H)，7.00(d，J＝8.4Hz，1H)，6.96(m，2H)6.89(s，1H)，6.77(m，2H)，5.22(s，1H)，3.88(s，3H)，3.08(t，J＝6.3Hz，2H)，2.58(t，J＝6.3Hz，2H)；
HRMS：280.1099(target)，280.1102(found，M
+)。
Embodiment 35:(E)-7-methoxyl group-1-(2-chlorobenzene methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (34)
With reference to embodiment 2, by 7-methoxyl group-3,4-dihydro-2-naphthalenone reacts with the 2-chlorobenzaldehyde, can make (E)-7-methoxyl group-1-(2-chlorobenzene methylene radical)-3,4-dihydro-2-naphthalenone (34);
m.p.126℃；
1H NMR(300MHz，CDCl
3)δ7.78(s，1H)，7.38(d，J＝8.4Hz，1H)，7.12(d，J＝7.8Hz，1H)，7.04(dd，J＝8.1，2.4Hz，2H)，6.96(s，1H)，6.76(m，1H)，6.56(m，1H)，3.76(s，3H)，3.09(t，J＝6.6Hz，2H)，2.63(t，J＝6.6Hz，2H)；
HRMS：298.0761(target)，298.0760(found，M
+)。
Embodiment 36:(E)-7-methoxyl group-1-(2,4 dichloro benzene methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (35)
With reference to embodiment 2, by 7-methoxyl group-3,4-dihydro-2-naphthalenone and 2,4 dichloro benzene formaldehyde reaction, can make (E)-7-methoxyl group-1-(2,4 dichloro benzene methylene radical)-3,4-dihydro-2-naphthalenone (35);
m.p.126℃；
1H NMR(300MHz，CDCl
3)δ7.45(s，1H)，7.31(d，J＝7.8Hz，1H)，7.22(dd，J＝8.1，1.5Hz，1H)，7.15(s，1H)，7.09(d，J＝8.4Hz，1H)，6.58(m，1H)，3.80(s，3H)，3.01(t，J＝6.3Hz，2H)，2.58(t，J＝6.3Hz，2H)；
HRMS：332.0371(target)，332.0370(found，M
+)。
Embodiment 37:(E)-7-methoxyl group-1-(3,4-dichlorobenzene methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (36)
With reference to embodiment 2, by 7-methoxyl group-3,4-dihydro-2-naphthalenone and the reaction of 3,4-dichlorobenzaldehyde, can make (E)-7-methoxyl group-1-(3,4-dichlorobenzene methylene radical)-3,4-dihydro-2-naphthalenone (36);
m.p.126℃；
1H NMR(300MHz，CDCl
3)δ7.52(s，1H)，7.37(s，1H)，7.23(dd，J＝7.8，2.4Hz，1H)，7.05(dd，J＝8.4，2.4Hz，1H)，6.89(d，J＝8.1Hz，1H)，7.02(dd，J＝8.4，1.8Hz，1H)，6.89(d，J＝7.8Hz，1H)，3.88(s，3H)，3.09(t，J＝6.3Hz，2H)，2.64(t，J＝6.3Hz，2H)；
HRMS：332.0371(target)，332.0370(found，M
+)。
Embodiment 38:(E)-7-methoxyl group-1-(3,4,5-trimethoxy α-tolylene)-1,2,3, the preparation of 4-tetrahydrochysene-2-naphthalene alcohol (37)
With reference to embodiment 3, compound 17 is reacted with sodium borohydride, can make (E)-7-methoxyl group-1-(3,4,5-trimethoxy α-tolylene)-1,2,3,4-tetrahydrochysene-2-naphthalene alcohol (37);
m.p.150℃；
1H NMR(300MHz，CDCl
3)δ7.57(d，J＝8.7Hz，1H)，7.00(s，1H)，6.79(m，3H)，6.68(dd，J＝8.4，2.7Hz，1H)，5.05(s，1H)，3.92(s，10H)，3.82(s，3H)，3.12(m，1H)，2.68(m，1H)，2.15(m，1H)，1.95(m，1H)
HRMS：356.1623(target)，379.1619(found，M+Na
+)。
Embodiment 39:(E)-5-methoxyl group-1-(3,4,5-trimethoxy α-tolylene)-3, the preparation of 4-dihydro-2-naphthalenone (38)
With reference to embodiment 2, by 5-methoxyl group-3,4-dihydro-2-naphthalenone reacts with 3,4,5-Trimethoxybenzaldehyde, can make (E)-5-methoxyl group-1-(3,4,5-trimethoxy α-tolylene)-3,4-dihydro-2-naphthalenone (38);
m.p.115℃；
1H NMR(300MHz，CDCl
3)δ7.58(s，1H)，7.18(d，J＝8.4Hz，1H)，7.00(s，1H)，6.78(dd，J＝8.4，2.7Hz，1H)，6.73(s，2H)，3.86(s，3H)，3.70(s，6H)，3.56(s，3H)，2.98(t，J＝6.6Hz，2H)，2.60(t，J＝6.6Hz，2H)；
HRMS：354.1467(target)，354.1466(found，M
+)。
Embodiment 40:(E)-5-methoxyl group-1-(2,3,4-trimethoxy α-tolylene)-3, the preparation of 4-dihydro-2-naphthalenone (39)
With reference to embodiment 2, by 5-methoxyl group-3,4-dihydro-2-naphthalenone and the reaction of 2,3,4-TMB, can make (E)-5-methoxyl group-1-(2,3,4-trimethoxy α-tolylene)-3,4-dihydro-2-naphthalenone (39);
m.p.120℃；
1H NMR(300MHz，CDCl
3)δ7.84(s，1H)，7.16(d，J＝8.4Hz，1H)，7.06(d，J＝9Hz，1H)，6.89(d，J＝2.4Hz，1H)，6.75(dd，J＝8.7，2.7Hz，1H)，6.50(d，J＝8.7Hz，1H)，3.92(s，3H)，3.88(s，3H)，3.85(s，3H)，3.53(s，3H)，2.97(t，J＝6.3Hz，2H)，2.62(t，J＝6.3Hz，2H)；
HRMS：354.1467(target)，354.1464(found，M
+)。
Embodiment 41:(E)-5-methoxyl group-1-(3,4-dimethoxy α-tolylene)-3, the preparation of 4-dihydro-2-naphthalenone (40)
With reference to embodiment 2, by 5-methoxyl group-3,4-dihydro-2-naphthalenone reacts with Veratraldehyde, can make (E)-5-methoxyl group-1-(3,4-dimethoxy α-tolylene)-3,4-dihydro-2-naphthalenone (40);
m.p.86℃；
1H NMR(300MHz，CDCl
3)δ7.62(s，1H)，7.28(d，J＝8.4Hz，1H)，7.00(dd，J＝8.4，2.4Hz，1H)，6.95(s，1H)，6.68(d，J＝2.4Hz，2H)，6.62(dd，J＝8.7，2.4Hz，1H)，3.85(s，6H)，3.63(s，3H)，2.92(t，J＝6.3Hz，2H)，2.61(t，J＝6.3Hz，2H)；
HRMS：324.1362(target)，324.136(found，M
+)。
Embodiment 42:(E)-5-methoxyl group-1-(3,5-dimethoxy α-tolylene)-3, the preparation of 4-dihydro-2-naphthalenone (41)
With reference to embodiment 2, by 5-methoxyl group-3,4-dihydro-2-naphthalenone and the reaction of 3,5-dimethoxy benzaldehyde, can make (E)-5-methoxyl group-1-(3,5-dimethoxy α-tolylene)-3,4-dihydro-2-naphthalenone (41);
m.p.127℃；
1H NMR(300MHz，CDCl3)δ7.62(s，1H)，7.17(d，J＝8.4Hz，1H)，6.91(d，J＝2.4Hz，1H)，6.77(dd，J＝8.4，2.7Hz，1H)，6.58(d，J＝2.1Hz，2H)，6.39(t，J＝2.1Hz，1H)，3.68(s，6H)，3.53(s，3H)，2.99(t，J＝6.3Hz，2H)，2.62(t，J＝6.3Hz，2H)；
HRMS：324.1362(target)，324.1365(found，M
+)。
Embodiment 43:(E)-5-methoxyl group-1-(4-methoxyl group-3-phenol methylene)-3, the preparation of 4-dihydro-2-naphthalenone (42)
With reference to embodiment 2, by 5-methoxyl group-3,4-dihydro-2-naphthalenone reacts with 3-hydroxyl-4-methoxybenzaldehyde, can make (E)-5-methoxyl group-1-(3-hydroxyl-4-anisole methylene radical)-3,4-dihydro-2-naphthalenone (42);
m.p.172℃；
1H NMR(300MHz，CDCl
3)δ7.59(s，1H)，7.16(d，J＝7.6Hz，2H)，7.11(s，1H)，7.01(s，2H)，6.77(d，J＝7.8Hz，2H)，5.71(s，1H)，3.89(s，3H)，3.57(s，3H)，2.95(s，1H)，2.59(s，3H)；
HRMS：310.1205(target)，310.1211(found，M
+)。
Embodiment 44:(E)-5-methoxyl group-1-(3-methoxyl group-4-phenol methylene)-3, the preparation of 4-dihydro-2-naphthalenone (43)
With reference to embodiment 2, by 5-methoxyl group-3,4-dihydro-2-naphthalenone reacts with Vanillin, can make (E)-5-methoxyl group-1-(3-methoxyl group-4-phenol methylene)-3,4-dihydro-2-naphthalenone (43);
m.p.158℃；
1H NMR(300MHz，CDCl
3)δ7.60(s，1H)，7.18(d，J＝8.4Hz，1H)，7.09(s，1H)，7.04(t，J＝2.7Hz，2H)，6.83(d，J＝8.4Hz，1H)，6.76(dd，J＝8.4，2.7Hz，1H)，5.97(s，1H)，3.71(s，3H)，3.64(s，3H)，2.96(t，J＝6.3Hz，2H)，2.60(t，J＝6.3Hz，2H)；
HRMS：310.1205(target)，310.1209(found，M
+)。
Embodiment 45:(E)-5-methoxyl group-1-α-tolylene-3, the preparation of 4-dihydro-2-naphthalenone (44)
With reference to embodiment 2, by 5-methoxyl group-3,4-dihydro-2-naphthalenone reacts with phenyl aldehyde, can make (E)-5-methoxyl group-1-α-tolylene-3,4-dihydro-2-naphthalenone (44);
m.p.112℃；
1H NMR(300MHz，CDCl
3)δ7.71(s，1H)，7.41-7.44(q，2H)，7.28(t，3H)，7.17(d，J＝8.4Hz，1H)，6.83(s，1H)，6.77(dd，J＝8.4，2.4Hz，1H)，3.45(s，3H)，2.99(t，J＝6.3Hz，2H)，2.62(t，J＝6.3Hz，2H)；
HRMS：264.1150(target)，264.1152(found，M
+)。
Embodiment 46:(E)-5-methoxyl group-1-(4-anisole methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (45)
With reference to embodiment 2, by 7-methoxyl group-3,4-dihydro-2-naphthalenone reacts with 4-methoxybenzaldehyde, can make (E)-5-methoxyl group-1-(4-anisole methylene radical)-3,4-dihydro-2-naphthalenone (45);
m.p.108℃；
1H NMR(300MHz，CDCl
3)δ7.65(s，1H)，7.46(d，J＝7.2Hz，2H)，7.18(d，J＝8.1Hz，1H)，6.99(s，1H)，6.81(d，J＝7.8Hz，2H)，6.76(s，1H)，3.82(s，3H)，3.55(s，3H)，2.96(s，2H)，2.60(s，2H)；
HRMS：294.1256(target)，294.1255(found，M
+)。
Embodiment 47:(E)-5-methoxyl group-1-(4-phenol methylene)-3, the preparation of 4-dihydro-2-naphthalenone (46)
With reference to embodiment 2, by 5-methoxyl group-3,4-dihydro-2-naphthalenone reacts with the 4-hydroxy benzaldehyde, can make (E)-5-methoxyl group-1-(4-phenol methylene)-3,4-dihydro-2-naphthalenone (46);
m.p.150℃，
1H NMR(300MHz，CDCl
3)δ7.62(s，1H)，7.35(d，J＝8.4Hz，2H)，7.08(m，2H)，6.82(d，J＝7.2Hz，2H)，6.73(m，1H)，5.50(s，1H)，3.82(s，3H)，2.99(t，J＝6.3Hz，2H)，2.59(t，J＝6.3Hz，2H)；
HRMS：280.1099(target)，280.1098(found，M
+)。
Embodiment 48:(E)-5-methoxyl group-1-(4-methylbenzene methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (47)
With reference to embodiment 2, by 5-methoxyl group-3,4-dihydro-2-naphthalenone reacts with the 4-tolyl aldehyde, can make (E)-5-methoxyl group-1-(4-methylbenzene methylene radical)-3,4-dihydro-2-naphthalenone (47);
m.p.106℃；
1H NMR(300MHz，CDCl
3)δ7.68(s，1H)，7.36(d，J＝8.1Hz，2H)，7.18(d，J＝8.4Hz，1H)，7.08(d，J＝8.1Hz，2H)，6.92(s，1H)，6.77(dd，J＝8.4，2.7Hz，1H)，6.83(dd，J＝8.4Hz，J＝2.2Hz，1H)，3.52(s，3H)，2.98(t，J＝6.6Hz，2H)，2.61(t，J＝6.6Hz，2H)，2.34(s，3H)；
HRMS：278.1307(target)，278.1330(found，M
+)。
Embodiment 49:(E)-5-methoxyl group-1-(4-oil of mirbane methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (48)
With reference to embodiment 2, by 5-methoxyl group-3,4-dihydro-2-naphthalenone and 4-nitrobenzoyl aldehyde reaction, can make (E)-5-methoxyl group-1-(4-oil of mirbane methylene radical)-3,4-dihydro-2-naphthalenone (48);
m.p.133℃；
1H NMR(300MHz，CDCl
3)δ8.15(d，J＝9Hz，2H)，7.65(s，1H)，7.56(d，J＝8.4Hz，2H)，7.27(s，1H)，7.24(d，J＝9Hz，1H)，6.83(dd，J＝8.4Hz，J＝2.2Hz，1H)，3.51(s，3H)，3.03(t，J＝6.3Hz，2H)，2.66(t，J＝6.3Hz，2H)；
HRMS：309.1001(target)，309.0998(found，M
+)。
Embodiment 50:(E)-5-methoxyl group-1-(4-trifluoromethyl α-tolylene)-3, the preparation of 4-dihydro-2-naphthalenone (49)
With reference to embodiment 2, by 5-methoxyl group-3,4-dihydro-2-naphthalenone reacts with the 4-trifluoromethylated benzaldehyde, can make (E)-5-methoxyl group-1-(4-trifluoromethyl α-tolylene)-3,4-dihydro-2-naphthalenone (49);
m.p.130℃；
1H NMR(300MHz，CDCl
3)δ7.66(s，1H)，7.52(q，4H)，7.19(d，J＝8.4Hz，1H)，6.78(dd，J＝8.4，1.8Hz，1H)，6.67(d，J＝2.1Hz，1H)，3.43(s，3H)，3.00(t，J＝6.3Hz，2H)，2.63(t，J＝6.3Hz，2H)；
HRMS：332.1024(target)，332.1021(found，M
+)。
Embodiment 51:(E)-5-methoxyl group-1-(4-dimethylamino α-tolylene)-3, the preparation of 4-dihydro-2-naphthalenone (50)
With reference to embodiment 2, by 5-methoxyl group-3,4-dihydro-2-naphthalenone reacts with the 4-dimethylaminobenzaldehyde, can make (E)-5-methoxyl group-1-(4-dimethylamino α-tolylene)-3,4-dihydro-2-naphthalenone (50);
m.p.119℃；
1H NMR(300MHz，CDCl
3)δ7.57(s，1H)，7.23(d，J＝8.1Hz，2H)，7.14(d，J＝8.4Hz，2H)，6.76(dd，J＝8.1，2.4Hz，1H)，6.56(d，J＝2.7Hz，2H)，3.68(s，3H)，3.10(s，6H)，2.89(t，J＝6.3Hz，1H)，2.65(t，J＝6.3Hz，1H)；
HRMS：307.1572(target)，307.1576(found，M
+)。
Embodiment 52:(E)-5-methoxyl group-1-(4-tert.-butylbenzene methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (51)
With reference to embodiment 2, by 5-methoxyl group-3,4-dihydro-2-naphthalenone and 4-tert.-butylbenzene formaldehyde reaction, can make (E)-5-methoxyl group-1-(4-tert.-butylbenzene methylene radical)-3,4-dihydro-2-naphthalenone (51);
m.p.142℃；
1H NMR(300MHz，CDCl
3)δ7.70(s，1H)，7.43(d，J＝8.1Hz，1H)，7.40(d，J＝8.4Hz，2H)，7.31(d，J＝8.4Hz，2H)，7.16(d，J＝8.4Hz，1H)，6.89(d，J＝2.7Hz，1H)，6.77(dd，J＝8.4，2.7Hz，1H)，3.47(s，3H)，2.98(t，J＝6.6Hz，1H)，2.62(t，J＝6.6Hz，1H)，1.31(s，9H)；
HRMS：320.1776(target)，320.1778(found，M
+)。
Embodiment 53:(E)-5-methoxyl group-1-(4-bromobenzene methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (52)
With reference to embodiment 2, by 5-methoxyl group-3,4-dihydro-2-naphthalenone reacts with the 4-bromobenzaldehyde, can make (E)-5-methoxyl group-1-(4-bromobenzene methylene radical)-3,4-dihydro-2-naphthalenone (52);
m.p.128℃；
1H NMR(300MHz，CDCl
3)δ7.55(s，1H)，7.42(d，J＝8.7Hz，2H)，7.36(s，1H)，7.30(s，1H)，7.07(d，J＝8.7Hz，2H)，7.00(dd，J＝8.4Hz，J＝2.2Hz，1H)，3.51(s，3H)，3.05(t，J＝6.3Hz，2H)，2.59(t，J＝6.3Hz，2H)；
HRMS：342.0255(target)，342.0257(found，M
+)。
Embodiment 54:(E)-5-methoxyl group-1-(4-chlorobenzene methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (53)
With reference to embodiment 2, by 5-methoxyl group-3,4-dihydro-2-naphthalenone reacts with the 4-chlorobenzaldehyde, can make (E)-5-methoxyl group-1-(4-chlorobenzene methylene radical)-3,4-dihydro-2-naphthalenone (53);
m.p.142℃；
1H NMR(300MHz，CDCl
3)δ7.62(s，1H)，7.39(d，J＝8.7Hz，2H)，7.28(d，J＝8.4Hz，1H)，6.89(d，J＝8.7Hz，2H)，6.84(dd，J＝8.4，J＝2.4Hz，1H)，6.79(d，J＝8.4Hz，1H)，3.52(s，3H)，3.00(t，J＝6.3Hz，2H)，2.58(t，J＝6.3Hz，2H)；
HRMS：299.0839(target)，299.0835(found，M
+)。
Embodiment 55:(E)-5-methoxyl group-1-(2-chlorobenzene methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (54)
With reference to embodiment 2, by 5-methoxyl group-3,4-dihydro-2-naphthalenone reacts with the 2-chlorobenzaldehyde, can make (E)-5-methoxyl group-1-(2-chlorobenzene methylene radical)-3,4-dihydro-2-naphthalenone (54);
m.p.98℃；
1H NMR(300MHz，CDCl
3)δ7.83(s，1H)，7.43(d，J＝8.1Hz，1H)，7.23(m，2H)，7.14(m，2H)，6.76(dd，J＝8.1，2.4Hz，1H)，6.56(d，J＝2.7Hz，1H)，3.40(s，3H)，3.00(t，J＝6.3Hz，2H)，2.66(t，J＝6.3Hz，2H)；
HRMS：298.0761(target)，298.0783(found，M
+)。
Embodiment 56:(E)-5-methoxyl group-1-(2,4 dichloro benzene methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (55)
With reference to embodiment 2, by 5-methoxyl group-3,4-dihydro-2-naphthalenone and 2,4 dichloro benzene formaldehyde reaction, can make (E)-5-methoxyl group-1-(2,4 dichloro benzene methylene radical)-3,4-dihydro-2-naphthalenone (55);
m.p.120℃；
1H NMR(300MHz，CDCl
3)δ7.73(s，1H)，7.31(dd，J＝8.4，1.8Hz，1H)，7.18(d，J＝8.4Hz，1H)，7.11(d，J＝8.4Hz，1H)，6.89(dd，J＝8.4，2.7Hz，1H)6.77(dd，J＝8.1，2.4Hz，1H)，6.56(d，J＝2.7Hz，1H)，3.48(s，3H)，3.02(t，J＝6.6Hz，2H)，2.65(t，J＝6.6Hz，2H)；
HRMS：332.0371(target)，332.0368(found，M
+)。
Embodiment 57:(E)-5-methoxyl group-1-(3,4-dichlorobenzene methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (56)
With reference to embodiment 2, by 5-methoxyl group-3,4-dihydro-2-naphthalenone and the reaction of 3,4-dichlorobenzaldehyde, can make (E)-5-methoxyl group-1-(3,4-dichlorobenzene methylene radical)-3,4-dihydro-2-naphthalenone (56);
m.p.120℃；
1H NMR(300MHz，CDCl
3)δ7.54(s，1H)，7.35(s，1H)，7.22(m，2H)，7.08(m，2H)，6.68(m，1H)，3.69(s，3H)，2.96(t，J＝6.3Hz，1H)，2.67(t，J＝6.3Hz，1H)；
HRMS：332.0371(target)，332.0370(found，M
+)。
Embodiment 58:(E)-5-methoxyl group-1-(2,6-dichlorobenzene methylene radical)-3, the preparation of 4-dihydro-2-naphthalenone (57)
With reference to embodiment 2, by 5-methoxyl group-3,4-dihydro-2-naphthalenone and the reaction of 2,6-dichlorobenzaldehyde, can make (E)-5-methoxyl group-1-(2,6-dichlorobenzene methylene radical)-3,4-dihydro-2-naphthalenone (57);
m.p.120℃，
1H NMR(300MHz，CDCl
3)δ7.57(s，1H)，7.31(d，J＝8.4Hz，2H)，7.20(d，J＝7.2Hz，1H)，7.14(d，J＝8.7Hz，1H)，6.74(dd，J＝8.4，2.7Hz，1H)，6.30(d，J＝2.7Hz，1H)，3.36(s，3H)，2.99(t，J＝6.3Hz，1H)，2.69(t，J＝6.3Hz，1H)；
HRMS：332.0371(target)，332.0372(found，M
+)。
Embodiment 59:(E)-5-methoxyl group-1-(3,4,5-trimethoxy α-tolylene)-1,2,3, the preparation of 4-tetrahydrochysene-2-naphthalene alcohol (58)
With reference to embodiment 3, compound 38 is reacted with sodium borohydride, can make (E)-5-methoxyl group-1-(3,4,5-trimethoxy α-tolylene)-1,2,3,4-tetrahydrochysene-2-naphthalene alcohol (58);
m.p.135℃，
1H NMR(300MHz，CDCl
3)δ7.19(d，J＝2.4Hz，1H)，7.10(s，1H)，7.06(s，1H)，6.82(m，3H)，5.06(s，1H)，3.90(s，7H)，3.84(s，6H)，3.09(m，1H)，2.70(m，1H)，2.11(m，1H)，1.93(m，1H)；
HRMS：356.1623(target)，379.1624(found，M
+)。
Experimental example 1: to the cytotoxicity of cem cell strain
One, experiment material and method:
1, experiment material
(1) experimental cell strain
This experiment has adopted the cell strain of CEM (human leukemia cell) as the screening object, and this JEG-3 is provided by Shanghai Institute of Pharmaceutical Industry's Pharmacology Lab.
(2) nutrient solution is that RPMI1640+15%NBS+ is two anti-.Full-automatic microplate reader model used is: WellscanMK-2, production firm: Labsystems.Import 96 well culture plates etc.
2, test method
Anti tumor activity in vitro adopts mtt assay
Sample preparation: after dissolving with DMSO (Merck), add PBS (-) to be made into solution or the uniform suspension of 1000 μ g/ml, then use PBS (-) dilution containing DMSO.
Nutrient solution: RPMI1640+15%NBS+ is two anti-.
Experimental procedure is as follows:
In 96 well culture plates, to add concentration be 4～5 * 10 in every hole
4the cell suspension 100 μ l of individual/ml, put 37 ℃, in the 5%CO2 incubator.After 24h, add sample liquid, 10 μ l/ holes, establish two multiple holes, and 37 ℃, 5%CO2 effect 72h.Every hole adds the MTT solution 20 μ l of 5mg/ml, after effect 4h, adds lysate, and 100 μ l/ holes, put in incubator, after dissolving, by the full-automatic microplate reader of MK-2, surveys the 570nmOD value.
Two, experimental result
The in-vitro multiplication restraining effect of table 1 target compound to human leukemia cell CEM
Experimental result shows, compound 1-58 has the effect of obvious inhibition cem cell strain, after the compounds of this invention is introduced methoxyl group on the different positions of naphthalene nucleus, the restraining effect of cells in vitro propagation all is significantly increased.This result shows that the compounds of this invention has the leukemic effect of better treatment.
Experimental example 2: to the cytotoxicity of HCT116, MDA-MB-435 cell strain
One, experiment material and method:
1, experiment material
(1) experimental cell strain
This experiment has adopted the cell strain of human colon cancer cell, human breast cancer cell as the screening object, and this JEG-3 provides by Shanghai Institute of Pharmaceutical Industry's Pharmacology Lab.
1) HCT116 (human colon cancer cell)
2) MDA-MB-435 (human breast cancer cell)
(2) nutrient solution is that RPMI1640+15%NBS+ is two anti-.Full-automatic microplate reader model used is: WellscanMK-2, production firm: Labsystems.Import 96 well culture plates etc.
2, test method
Anti tumor activity in vitro adopts mtt assay.
Sample preparation: after dissolving with DMSO (Merck), add PBS (-) to be made into solution or the uniform suspension of 1000 μ g/ml, then use PBS (-) dilution containing DMSO.
Nutrient solution: RPMI1640+15%NBS+ is two anti-.
Experimental procedure is as follows:
In 96 well culture plates, to add concentration be 4～5 * 10 in every hole
4the cell suspension 100 μ l of individual/ml, put 37 ℃, 5%CO
2in incubator.After 24h, add sample liquid, 10 μ l/ holes, establish two multiple holes, and 37 ℃, 5%CO
2effect 72h.Every hole adds the MTT solution 20 μ l of 5mg/ml, after effect 4h, adds lysate, and 100 μ l/ holes, put in incubator, after dissolving, by the full-automatic microplate reader of MK-2, surveys the 570nmOD value.
Two, experimental result
The in-vitro multiplication restraining effect of table 2 target compound to MDA-MB-435 and HCT116
Experimental result shows, target compound of the present invention not only has obvious restraining effect to human leukemia cell CEM, human colon cancer cell HCT116 and human breast cancer cell MDA-MB-435 are also had to good In-vitro Inhibitory Effect, and this result shows that the compounds of this invention has the effect for the treatment of colorectal carcinoma and mammary cancer.
Experimental example 3: suppress the tubulin polymerization experiment
One, experiment material and method:
1, experiment material
(1) tubulin
This experiment has adopted the ox tubulin as screening object, manufacturer: Cytoskeleton.
(2) damping fluid
General Tubulin Buffer:80mM PIPES pH=6.9,2mM MgCl2,0.5mMEGTA, manufacturer: Cytoskeleton.
Tubulin Glycerol Buffer:60%glycerol, manufacturer: Cytoskeleton.
GTP:100mM, manufacturer: Cytoskeleton
Full-automatic microplate reader model used is: Synergy 4, production firm: BioTek.Import 96 hole half area culture plates etc.
2, test method
The employing literature method (Cell Biochemistry and Biophysics, 2003,38:1-21), and tubulin kit method (CytoDYNAMIX Screen 03).
Sample preparation: after dissolving with DMSO (Merck), add damping fluid to be made into solution or the uniform suspension of respective concentration, then dilute with damping fluid.
Experimental procedure is as follows:
In 96 well culture plates, to add respective concentration be testing compound 10 μ l in every hole, puts in 37 ℃ of microplate reader, after 2min, adds the tubulin liquid of 3mg/ml, and 100 μ l/ holes, establish two multiple holes, 37 ℃, and effect 1h, per minute is surveyed the 340nmOD value.
Two, experimental result
Table 3 compound suppresses the effect of tubulin polymerization
| Compound | R 1 | X | R 2 | IC 50(μM) |
| 1 | 6-OCH 3 | C＝O | 3’，4’，5’-(OCH 3) 3 | 3.93 |
| 2 | 6-OCH 3 | C＝O | 2’，3’，4’-(OCH 3) 3 | 25.78 |
| 3 | 6-OCH 3 | C＝O | 3’，4’-(OCH 3) 2 | 6.42 |
| 4 | 6-OCH 3 | C＝O | 3’，5’-(OCH 3) 2 | 6.88 |
| 5 | 6-OCH 3 | C＝O | 3’-OH，4’-OCH 3 | ＞40 |
| 6 | 6-OCH 3 | C＝O | 4’-OH，3’-OCH 3 | ＞40 |
| 16 | 6-OCH 3 | CHOH | 3’，4’，5’-(OCH 3) 3 | 2.47 |
| 17 | 7-OCH 3 | C＝O | 3’，4’，5’-(OCH 3) 3 | 9.63 |
| 37 | 7-OCH 3 | CHOH | 3’，4’，5’-(OCH 3) 3 | 6.42 |
| 38 | 5-OCH 3 | C＝O | 3’，4’，5’-(OCH 3) 3 | ＞10 |
| 58 | 5-OCH 3 | CHOH | 3’，4’，5’-(OCH 3) 3 | ＞10 |
Experimental result shows, above-claimed cpd all has the effect of certain inhibition tubulin polymerization, can be used as antitumor drug and is furtherd investigate.
Experimental example 4: flow cytometer detects the cell cycle
The HCT116 cell that the phase of taking the logarithm grows is with 1 * 10
6cell count is inoculated in culturing bottle, in 12 orifice plates.After cell attachment, add respectively the compound 1 of 0.2 μ M, 2 μ M and by the compound 16 of 0.04 μ M, 0.4 μ M, after continuing function cells 24h, the collecting cell suspension, adjust cell density, the centrifugal nutrient solution that discards, 70% cold ethanol is fixed, 4 ℃ of PI secretly dye 30min, with flow cytometer, detect the cell cycle.Referring to Fig. 1
As shown in the figure, flow cytometry shows compound 1 and the compound 16 of different concns, can affect the distribution of HCT116 cell cycle in effect after 24 hours, with the solvent control group, compare, S phase cell proportion reduces, and G2/M phase cell proportion increases, be arrested in the G2/M phase, and there were significant differences (P<0.05), and inducing cell presents typical apoptosis form, inducing apoptosis peak.
Experimental example 5: Colorectal Carcinoma in Nude Mice transplanted tumor experiment in body
Get well-grown colo205 transplanted tumor, cut into the even fritter of about 3mm size under aseptic condition, with one of the right armpit subcutaneous vaccination of every mouse of trochar, be divided at random 5 groups, be respectively: 1) negative control group (5%Glu); 2) compound 1, the 12.5mg/kg group; 3) compound 1, the 25mg/kg group; 4) compound 1, the 50mg/kg group.Inoculate and again divide into groups according to tumor size after 8 days, eliminate the excessive and too small animal of tumour, every group of tumor average volume is basically identical, starts by above scheme administration, and the tail vein is injected 5 times continuously, and the administration volume is the 0.5ml/20g body weight.Within every 4 days, survey major diameter (a), the minor axis (b) of knurl piece with digimatic calipers, gross tumor volume (tumor volume, TV) calculation formula is: TV=1/2 * a * b
2, relative tumour volume (relative tumor volume, RTV) calculation formula is: RTV=Vt/Vo, Vo during for minute cage (do) measure the gained gross tumor volume, the gross tumor volume of Vt when measuring each time.Inoculate and put to death animal after 28 days, dissect and get the knurl piece.The evaluation index of anti-tumor activity is tumour inhibiting rate (%): (1-T
rTV/ C
rTV) * 100%, and carry out the T check.
Experimental result:
The growth-inhibiting effect of 1 pair of nude mice colo205 transplanted tumor of compound
Each gross tumor volume size variation of organizing experimental mouse has notable difference (seeing accompanying drawing 2).Calculate heavily respectively and respectively organize knurl volume inhibiting rate and the heavy inhibiting rate of knurl according to 20 days experimental mouse gross tumor volume sizes after administration and knurl, the results are shown in accompanying drawing 2.
The impact of table 4 compound 1 on the growth-inhibiting effect of nude mice colo205 transplanted tumor
With compare:
*p<0.05,
*p<0.01
To sum up, 1-substituted benzene methylene radical of the present invention-2-naphthalenone analog derivative has certain antitumor action, especially the human leukemia cem cell is had to significant inhibition proliferation function.What be worth particularly pointing out is, colchicine site for tubulin, the compounds of this invention has shown the restraining effect to tubulin polymerization, for further investigation with develop new Antitubulin and opened up new approach and direction, simultaneously for further exploitation is efficient, the antitumor drug of low toxicity, high specificity lays a good foundation.
Claims (21)
1. 1-substituted benzene methylene radical-2-naphthalenone analog derivative or its pharmacy acceptable salt shown in formula (I),
Wherein, substituent R
1being positioned at 5,6,7,8, is single, double or polysubstituted, substituent R
1be selected from following groups a kind of, two or more: C
1-8straight or branched alkoxyl group, C
1-8straight or branched alkyl, halogen, methylene-dioxy, work as R
1for two or when polysubstituted, substituting group can be identical or different;
Substituent R
2being positioned at 2 ', 3 ', 4 ', 5 ', 6 ', can be unsubstituted, mono-substituted, disubstituted or polysubstituted, described substituting group be selected from following groups a kind of, two or more: C
1-8straight or branched alkoxyl group, C
1-8straight or branched alkyl, C
1-8straight or branched haloalkyl, hydroxyl, halogen, nitro, cyano group, ester group, amide group, amino or the amino replaced, work as R
2for two or when polysubstituted, substituting group can be identical or different;
Substituent X is: C=O, CHOR
3or C=NR
4, wherein, R
3represent hydrogen, acyl group, C
1-8straight or branched alkyl, substituted aryl; R
4represent hydrogen, acyl group, C
1-8straight or branched alkyl, substituted aryl;
Wherein, work as substituent R
1be the methoxyl group of 6 when monosubstituted, R
2can not be unsubstituted, and can not be 4 ' mono-substituted Br, CF
3, cyano group, nitro or methoxyl group, and can not be 3 ' mono-substituted Cl;
Described pharmacy acceptable salt is inorganic acid salt, organic acid salt or amino acid salts.
2. 1-substituted benzene methylene radical according to claim 1-2-naphthalenone analog derivative, is characterized in that described substituent R
1for mono-substituted C
1-4the straight or branched alkoxyl group.
3. 1-substituted benzene methylene radical according to claim 2-2-naphthalenone analog derivative, is characterized in that described substituent R
1for mono-substituted methoxyl group.
4. 1-substituted benzene methylene radical according to claim 3-2-naphthalenone analog derivative, is characterized in that described substituent R
1for 5-OCH
3, 6-OCH
3or 7-OCH
3.
5. according to the described 1-substituted benzene methylene radical of claim 1-4 any one-2-naphthalenone analog derivative, it is characterized in that described substituent R
2be positioned at 2 ', 3 ', 4 ', 5 ' or 6 ', can be unsubstituted, mono-substituted, disubstituted or polysubstituted, described substituting group is selected from a kind of in following groups, two or more: methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, single methyl fluoride, difluoromethyl, trifluoromethyl, the monochloro methyl, dichloromethyl, trichloromethyl, single brooethyl, two brooethyls, trisbromomethyl, hydroxyl, fluorine, chlorine, bromine, iodine, nitro, cyano group, amino, methylamino, dimethylamino, ethylamino or propyl group amino, work as R
2for two or when polysubstituted, substituting group can be identical or different.
6. 1-substituted benzene methylene radical according to claim 5-2-naphthalenone analog derivative, is characterized in that substituent R
2be positioned at 2 ', 3 ', 4 ', 5 ' or 6 ', can be unsubstituted, mono-substituted, disubstituted or trisubstituted, described substituting group be selected from following groups a kind of, two or three: methoxyl group, methyl, the tertiary butyl, trifluoromethyl, hydroxyl, chlorine, bromine, nitro or dimethylamino, work as R
2during for two or three replacements, substituting group can be identical or different.
7. 1-substituted benzene methylene radical according to claim 6-2-naphthalenone analog derivative, is characterized in that substituent R
2can be unsubstituted, mono-substituted, disubstituted or trisubstituted, described substituting group be selected from following groups a kind of, two or three: 2 '-OCH
3, 3 '-OCH
3, 4 '-OCH
3, 5 '-OCH
3, 3 '-OH, 4 '-OH, 4 '-CH
3, 4 '-C (CH
3)
3, 4 '-CF
3, 2 '-Cl, 3 '-Cl, 4 '-Cl, 6 '-Cl, 4 '-Br, 4 '-N (CH
3)
2or 4 '-NO
2, work as R
2during for two or three replacements, substituting group can be identical or different.
8. 1-substituted benzene methylene radical according to claim 7-2-naphthalenone analog derivative, is characterized in that substituent R
2be selected from: 3 ', 4 ', 5 '-(OCH
3)
3, 2 ', 3 ', 4 '-(OCH
3)
3, 3 ', 4 '-(OCH
3)
2, 3 ', 5 '-(OCH
3)
2, 4 '-OCH
3, 3 '-OH, 4 '-OCH
3, 4 '-OH, 3 '-OCH
3, 4 '-CH
3, 4 '-C (CH
3)
3, 4 '-CF
3, 3 '-OH, 4 '-OH, 2 '-Cl, 4 '-Cl, 4 '-Br, 2 ', 4 '-(Cl)
2, 3 ', 4 '-(Cl)
2, 2 ', 6 '-(Cl)
2, 4 '-N (CH
3)
2or 4 '-NO
2.
9. according to the described 1-substituted benzene methylene radical of claim 1-8 any one-2-naphthalenone analog derivative, it is characterized in that, described substituent X is C=O or CHOH.
10. according to the described 1-substituted benzene methylene radical of claim 1-9 any one-2-naphthalenone analog derivative, it is characterized in that, wherein inorganic acid salt is: hydrochloride, vitriol, phosphoric acid salt, diphosphate, hydrobromate or nitrate; Wherein organic acid salt is: acetate, maleate, fumarate, tartrate, succinate, lactic acid salt, tosilate, salicylate, oxalate; Wherein amino acid salts is: arginic acid salt, ornithine salt, lysine salt, leucine salt, Isoleucine salt, glycinate, cystine salt, cysteine salt, tyrosine salt, L-Ala salt, phenylalanine salt, Histidine salt, Serine salt, Threonine salt, methionine salt, tryptophane salt, glutaminate, aspartate, α-amino-isovaleric acid salt, methionine(Met) salt, proline salt or oxyproline salt.
11. the 1-substituted benzene methylene radical shown in formula (I)-2-naphthalenone analog derivative or its pharmacologically acceptable salts,
Wherein, substituent R
1for 5-OCH
3, 6-OCH
3or 7-OCH
3;
Wherein, substituent R
2being positioned at 2 ', 3 ', 4 ' or 5 ', can be mono-substituted, disubstituted or trisubstituted;
Work as R
2when monosubstituted, substituting group is selected from: 2 '-OCH
3, 3 '-OCH
3, 5 '-OCH
3, methyl, the tertiary butyl, hydroxyl, dimethylamino, 2 '-Cl or 4 '-Cl;
Work as R
2during for two or three replacements, substituting group can be identical or different, and described substituting group is selected from two or three in following groups: methoxyl group, methyl, the tertiary butyl, hydroxyl, chlorine or dimethylamino;
The X substituting group is C=O or CHOH.
12. 1-substituted benzene methylene radical according to claim 11-2-naphthalenone analog derivative, wherein R
2for monosubstituted, substituting group is selected from: 2 '-OCH
3, 3 '-OCH
3, 5 '-OCH
3, 3 '-OH, 4 '-OH, 4 '-CH
3, 4 '-C (CH
3)
3, 2 '-Cl, 4 '-Cl or 4 '-N (CH
3)
2.
13. 1-substituted benzene methylene radical according to claim 11-2-naphthalenone analog derivative, wherein R
2for two or three replacements, substituting group can be identical or different, and described substituting group is selected from two or three: 2 '-OCH in following groups
3, 3 '-OCH
3, 4 '-OCH3,5 '-OCH
3, 3 '-OH, 4 '-OH, 4 '-CH
3, 4 '-C (CH
3)
3, 2 '-Cl, 3 '-Cl, 4 '-Cl or 4 '-N (CH
3)
2.
14. 1-substituted benzene methylene radical according to claim 1-2-naphthalenone analog derivative is characterized in that 1-substituted benzene methylene radical shown in described formula (I)-2-naphthalenone analog derivative is following compound:
15. the preparation method of the 1-substituted benzene methylene radical shown in the described formula of claim 1-14 any one (I)-2-naphthalenone analog derivative, is characterized in that, said method comprising the steps of:
(1) prepare 3,4-dihydro-2-naphthalenone
Dimethoxy-naphthalene and sodium Metal 99.5 are refluxed in ethanol, generate 3,4-dihydro-2-naphthalenone after acidifying;
(2) prepare 1-α-tolylene-3,4-dihydro-2-naphthalenone
3,4-dihydro-2-naphthalenone, phenyl aldehyde are dissolved in to methylene dichloride, and under the effect of catalytic amount acetyl piperidine, the stirring at room reaction, generate 1-α-tolylene-3,4-dihydro-2-naphthalenone;
(3) prepare 1-α-tolylene-1,2,3,4-tetrahydrochysene-2-naphthalene alcohol
By 1-α-tolylene-3,4-dihydro-2-naphthalenone, be dissolved in 10% dichloromethane methanol solution, adds sodium borohydride, and reduction generates 1-α-tolylene-1,2,3,4-tetrahydrochysene-2-naphthalene alcohol.
16. according to 1-substituted benzene methylene radical-2-naphthalenone analog derivative shown in the described formula of the arbitrary claim of above-mentioned 1-14 (I) or the application of its pharmacologically acceptable salts in preparing the Antitubulin medicine.
17. the application in preparing the medicine for the treatment of the cancer that cellular cytoxicity activity is responded according to 1-substituted benzene methylene radical-2-naphthalenone analog derivative shown in the described formula of the arbitrary claim of above-mentioned 1-14 (I) or its pharmacologically acceptable salts.
18. the application in the medicine that generates relevant disease for the preparation for the treatment of and abnormal vascular according to 1-substituted benzene methylene radical-2-naphthalenone analog derivative shown in the described formula of the arbitrary claim of above-mentioned 1-14 (I) or its pharmacologically acceptable salts.
19. according to 1-substituted benzene methylene radical-2-naphthalenone analog derivative shown in the described formula of the arbitrary claim of above-mentioned 1-14 (I) or its pharmacologically acceptable salts in the application for the preparation of in treatment mammary cancer or colorectal carcinoma medicine.
20. a pharmaceutical composition, the carrier that contains 1-substituted benzene methylene radical-2-naphthalenone analog derivative shown in the described formula of claim 1-14 any one (I) or its pharmacy acceptable salt and pharmaceutically accept.
21. pharmaceutical composition according to claim 20, is characterized in that, described pharmaceutical composition is tablet, capsule or injection.
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| CN108299169A (en) * | 2018-02-02 | 2018-07-20 | 南京杰运医药科技有限公司 | The synthetic method of the chloro- 3,4- dihydros -2H-1- naphthalenones of 6- |
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| CN109541237A (en) * | 2018-12-28 | 2019-03-29 | 吴江近岸蛋白质科技有限公司 | The Determination of biological activity method of fibronectin |
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| CN108299169A (en) * | 2018-02-02 | 2018-07-20 | 南京杰运医药科技有限公司 | The synthetic method of the chloro- 3,4- dihydros -2H-1- naphthalenones of 6- |
| CN108299169B (en) * | 2018-02-02 | 2021-04-30 | 南京杰运医药科技有限公司 | Synthesis method of 6-chloro-3, 4-dihydro-2H-1-naphthalenone |
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