CN103086935B - Diphenyl selenide, diphenyl selenoxide, diphenyl selenone compounds and uses thereof - Google Patents
Diphenyl selenide, diphenyl selenoxide, diphenyl selenone compounds and uses thereof Download PDFInfo
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- 0 CC(Oc1cc(*(c(cc2OC)cc(OC)c2OC)=O)ccc1OC)=O Chemical compound CC(Oc1cc(*(c(cc2OC)cc(OC)c2OC)=O)ccc1OC)=O 0.000 description 1
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Abstract
The invention belongs to the technical field of medicine, and relates to diphenyl selenide, diphenyl selenoxide, diphenyl selenone compounds and related compounds thereof, wherein the structure is represented by the following formula. The present invention further provides pharmaceutically acceptable non-toxic salts and hydrates formed by the compounds represented by the structure formula, wherein the pharmaceutically acceptable non-toxic salts comprise salts formed by the derivatives and acids or bases. Pharmacological activity experiment results show that the derivatives have good tumor inhibition activity, and can be used as tumor cell proliferation inhibitors and tumor vascular disrupting agents to be used for antitumor drug preparation.
Description
Technical field
The invention belongs to medical art, relate to a kind of hexichol selenide, phenyl-selenide sulfoxide, phenyl-selenide sulfone compound and uses thereof, exactly, relate to this compounds and prepare the application in anti-tumor drug as tumor cell proliferation inhibitor and tumor vessel disrupting agent.
Background technology
Malignant tumour is the serious disease threatening human health and life, is the first lethal cause of disease in China.Find and find that treatment is the current key subjects faced with the new drug of prophylaxis of tumours.
Combretastatin A-4(CA-4) be from the willow of South Africa, be separated the cis-stilbene class natural product obtained, its chemical name be (
z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenol.CA-4 is tubulin polymerization inhibitor, and present very strong inhibition tumor cell propagation and tumor vessel destruction activity, its prodrug CA-4 phosphoric acid salt (CA-4P) enters three phase clinical investigation phase in the U.S..With CA-4 for lead compound designs, synthesizes the existing report in a large number of research of new active compound for anti tumor, but most CA-4 analogue exists or activity is not high enough or toxicity is comparatively large or synthesize the shortcomings such as more complicated.
Relevant report is see Pettit G. R., et al.
experientia,
1989, 45,209; Nam N.H.
current Medicinal Chemistry,
2003, 10,1697; Tron G.C., et al. Journal of Medicinal Chemistry,
2006, 49 (11), 3033-3044; Mousset C., et al.
bioorganic & Medicinal Chemistry Letters,
2008,18 (11), 3266-3271.
20th century the eighties, the World Health Organization approve: selenium, has obvious antitumor action.The antitumor action main manifestations of selenium is: selenium is the kill agent of tumour cell, and selenium is the energy block agent of tumour cell, and selenium is the drug effect toughener of antitumor drug.Comprise the hexichol selenide of CA-4 constitutional features, phenyl-selenide sulfoxide, phenyl-selenide sulfone compound and related compound thereof and have not yet to see report as the research of tumor cell proliferation inhibitor and tumor vessel disrupting agent.
Summary of the invention
Hexichol selenide, phenyl-selenide sulfoxide, phenyl-selenide sulfone compound, its structure is as follows:
X is selenium Se, selenoxide SeO, selenoxide water affixture Se (OH)
2and selenone SeO
2;
R
1~ R
3be C independently of one another
1~ C
6alkyl, C
1~ C
6alkyl oxygen base or halogen atom, and R
1~ R
3be asynchronously halogen, or adjacent two substituting groups can be-OCH
2o-thus form five-ring;
R
4~ R
8be hydrogen, C independently of one another
1~ C
6alkyl, C
1-C
6alkyl oxygen base, benzyloxy, hydroxyl, halogen atom, nitro, amino, C
1-C
6hydrocarbylamino, C
2-C
6dialkylamino, or adjacent two substituting groups can be-OCH
2o-thus form five-ring, or adjacent two substituting groups can be-CH=CH-CH=CH-thus formation six-ring.
Work as R
4~ R
8containing hydroxyl, amido, C
1-C
6during hydrocarbylamino, hydroxyl, amido, C
1-C
6hydrocarbylamino can with C
1-C
6in the saturated or human body such as unsaturated acid, phosphoric acid or glycine, 20 seed amino acids become ester or acid amides.
The preferred selenium of described X, selenoxide.
The pharmaceutically acceptable non-toxic salt that this compound also comprises hexichol selenide, phenyl-selenide sulfoxide, phenyl-selenide sulfone derivatives are formed and hydrate thereof.
The salt that the pharmaceutically acceptable non-toxic salt formed is formed with acid or alkali for this derivative; Described hydration number is the arbitrary integer in 0-16.
Described acid is selected from hydrochloric acid, sulfuric acid, Hydrogen bromide, phosphoric acid, acetic acid, toxilic acid, fumaric acid, citric acid, oxalic acid, tartrate, phenylformic acid, oxysuccinic acid.
Described alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, ammoniacal liquor, thanomin, triethylamine.
The present invention's preferred part of compounds structure is as follows:
Compound 1:
3,4,5-trimethoxyphenyl-4-aminomethyl phenyl selenide
Compound 2:
Two 3,4,5-trimethoxyphenyl selenides
Compound 3:
3,4,5-trimethoxyphenyl-rubigan selenide
Compound 4:
3,4,5-trimethoxyphenyl-p-methoxyphenyl selenide
Compound 5:
3,4,5-trimethoxyphenyl-1-naphthyl selenide
Compound 6:
3,4,5-trimethoxyphenyl-3-hydroxyl-4-p-methoxy-phenyl selenide
Compound 7:
3,4,5-trimethoxyphenyl-3-allyl group oxygen base-4-p-methoxy-phenyl selenide
Compound 8:
3,4,5-trimethoxyphenyl-3-acetoxyl group-4-p-methoxy-phenyl selenide
Compound 9:
3,4,5-trimethoxyphenyl-3-nitro-4-p-methoxy-phenyl selenide
Compound 10:
3,4,5-trimethoxyphenyl-3-amino-4-methoxyl phenyl selenide
Compound 11:
3,4,5-trimethoxyphenyl-3-acetylaminohydroxyphenylarsonic acid 4-p-methoxy-phenyl selenide
Compound 12
Chloro-4, the 5-Dimethoxyphenyl-3-nitro-4-p-methoxy-phenyl selenides of 3-
Compound 13
3,4,5-trimethoxyphenyl-3-Glycinylamino-4-p-methoxy-phenyl selenide
Compound 14:
3,4,5-trimethoxyphenyl-4-aminomethyl phenyl selenoxide
Compound 15:
3,4,5-trimethoxyphenyl-rubigan selenoxide
Compound 16:
3,4,5-trimethoxyphenyl-p-methoxyphenyl selenoxide
Compound 17:
3,4,5-trimethoxyphenyl-1-naphthyl selenoxide
Compound 18:
3,4,5-trimethoxyphenyl-3-allyl group oxygen base-4-p-methoxy-phenyl selenoxide
Compound 19:
3,4,5-trimethoxyphenyl-3-acetoxyl group-4-p-methoxy-phenyl selenoxide
Compound 20:
3,4,5-trimethoxyphenyl-3-amino-4-methoxyl phenyl selenoxide
Compound 21:
3,4,5-trimethoxyphenyl-3-nitro-4-p-methoxy-phenyl selenoxide
Compound 22:
3,4,5-trimethoxyphenyl-4-aminomethyl phenyl selenone
Compound 23:
3,4,5-trimethoxyphenyl-rubigan selenone
Compound 24:
3,4,5-trimethoxyphenyl-p-methoxyphenyl selenone
Compound 25:
3,4,5-trimethoxyphenyl-1-naphthyl selenone
Compound 26:
3,4,5-trimethoxyphenyl-3-allyl group oxygen base-4-p-methoxy-phenyl selenone
Compound 27:
3,4,5-trimethoxyphenyl-3-nitro-4-p-methoxy-phenyl selenone
Phenyl-selenide ether compound of the present invention can obtain according to following reaction scheme synthesis:
Method one: first synthesize selenophenol compounds negative ion
1. a kind of substituted-phenyl diazonium salt is obtained symmetrical hexichol diselenide compounds with containing the solution reaction of two selenium two negative ions, reductive agent obtains selenophenol compounds afterwards, then adds alkali and make selenophenol compounds negative ion.
2. a kind of halogeno-benzene and reactive magnesium are obtained corresponding phenyl grignard reagent, afterwards itself and elemental selenium are obtained by reacting selenophenol compounds negative ion.
3. a kind of halogeno-benzene is obtained by reacting corresponding lithium aryl at low temperatures to n-Butyl Lithium, afterwards itself and elemental selenium is obtained by reacting selenophenol compounds negative ion
Then by selenophenol compounds negative ion in alkaline aqueous solution, at 0 degree Celsius, the phenyldiazonium salt compounds that slowly drips under the condition that keeps reaction system alkalescence, dropwise rear continuation reaction 2 hours.Adjustment reaction system is slightly acidic, and add ethyl acetate and stir, cross to filter and do not allow thing, be extracted with ethyl acetate, organic layer saturated nacl aqueous solution washs and uses anhydrous sodium sulfate drying.Steam through Rotary Evaporators and desolventize, obtain product through column chromatographic isolation and purification.Yield 40-90%
Method two: by 2 of symmetrical hexichol diselenide compounds, the phenylboronic acid compound of 3 equivalents, the cuprous bromide of 0.1 equivalent and 0.1 equivalent, 2 '-dipyridyl adds in reaction flask, add the dimethyl sulfoxide (DMSO) of 4 times amount again: water is the mixed solvent of 2:1, react 12 hours under 100 degrees Celsius.Poured into by reaction solution in large water gaging, extraction into ethyl acetate, organic layer saturated nacl aqueous solution washs and uses anhydrous sodium sulfate drying.Steam through Rotary Evaporators and desolventize, obtain product through column chromatographic isolation and purification.Yield 70% ~ 96%.（Nobukazu Taniguchi
J. Org. Chem.2007, 72(4), 1241-1245）。
Wherein, R
4~ R
8in can by corresponding R containing the phenyl-selenide ether compound of hydroxyl
4~ R
8in prepare through removing allyl reaction containing the compound of allyloxy, go the reagent of allyl group base to be titanium tetrachloride, or remove ethanoyl or acryl in the basic conditions for the compound containing ethanoyl or acryl.
Phenyl-selenide sulfoxide compound of the present invention can obtain according to following reaction scheme synthesis:
Be dissolved in organic solution by phenyl-selenide ether compound, use and oxidizingly obtain phenyl-selenide sulfoxide, be extracted with ethyl acetate afterwards, organic layer saturated nacl aqueous solution washs and uses anhydrous sodium sulfate drying.Steam through Rotary Evaporators and desolventize, obtain product through column chromatographic isolation and purification.Yield 70% ~ 99%.
Wherein, R
4~ R
8in can by corresponding R containing the phenyl-selenide sulfoxide compound of hydroxyl
4~ R
8in prepare through removing allyl reaction containing the compound of allyloxy, go the reagent of allyl group base to be titanium tetrachloride, or remove ethanoyl or acryl in the basic conditions for the compound containing ethanoyl or acryl.
Phenyl-selenide sulfone derivatives of the present invention can obtain according to following reaction scheme synthesis:
Be dissolved in organic solution by phenyl-selenide ether compound, use and oxidizingly obtain hexichol selenone, be extracted with ethyl acetate afterwards, organic layer saturated nacl aqueous solution washs and uses anhydrous sodium sulfate drying.Steam through Rotary Evaporators and desolventize, obtain product through column chromatographic isolation and purification.Yield 40% ~ 95%.
Wherein, R
4~ R
8in can by corresponding R containing the phenyl-selenide sulfone derivatives of hydroxyl
4~ R
8in prepare through removing allyl reaction containing the compound of allyloxy, go the reagent of allyl group base to be titanium tetrachloride, or remove ethanoyl or acryl in the basic conditions for the compound containing ethanoyl or acryl.
Embodiment
To contribute to understanding the present invention by following example, but content of the present invention is not limited to example.
Agents useful for same of the present invention is commercially available, and nuclear magnetic resonance spectrum is measured by AVANCE-400, Bruker ARX-300 fourier transform NMR spectrometer, and mass spectrum is measured by Brukee Esqure 2000 type mass spectrograph.
embodiment 1:the preparation (compound 1) of 3,4,5-trimethoxyphenyl-4-aminomethyl phenyl selenide
Be dissolved in anhydrous THF by 3,4,5-trimethoxy hexichol diselenide 1g, the tetrahydrochysene lithium reactive aluminum adding 0.77g obtains 3,4,5-trimethoxy selenophenol for 1 hour.P-nethoxyaniline 0.25g is added in another reaction flask, adds the concentrated hydrochloric acid of 0.5ml, stirring and dissolving, under 0 degree Celsius, add Sodium Nitrite 0.14g, react 30 minutes.Under 0 degree Celsius, add 30ml water by obtained selenophenol solution afterwards, and add 3g salt of wormwood, under 0 degree Celsius, slowly drip obtained diazonium salt solution.Dropwise rear reaction 2 hours.Acidification reaction liquid afterwards, and be extracted with ethyl acetate, organic layer saturated sodium-chloride water solution washs, and separate organic layer and with anhydrous sodium sulphate or anhydrous magnesium sulfate drying, after removing solvent under reduced pressure, obtain compound 1 through column chromatography for separation, yield is 70%.
1H-NMR(300M, CDCl
3), δ7.37(2H, d, J=8.10), 7.10(2H, d, J=8.10), 6.70(2H, s), 3.83(3H, s), 3.79(6H, s), 3.37(3H, s), ESI m/z 339.3[M+H]
+, 361.1[M+Na]
+。
embodiment 2:the preparation (compound 2) of two 3,4,5-trimethoxyphenyl selenides
Except using corresponding raw material, prepare compound 2 with the method that embodiment 1 is identical, yield is 80%.ESI m/z 437.1[M+Na]
+
embodiment 3:the preparation (compound 3) of 3,4,5-trimethoxyphenyl-rubigan selenide
Except using corresponding raw material, prepare compound 3 with the method that embodiment 1 is identical, yield is 86%.
1H-NMR(300M, CDCl
3), δ7.33(2H, d, J=8.62), 7.23(2H, d, J=8.62), 6.74(2H, s), 3.85(3H, s), 3.81(6H, s), ESI m/z 359.2[M+H]
+, 381.2[M+Na]
+。
embodiment 4:the preparation (compound 4) of 3,4,5-trimethoxyphenyl-p-methoxyphenyl selenide
Biconjugate methoxyl group hexichol diselenide 0.74g is put into 100ml flask, add 3,4,5-trimethoxy phenylo boric acid 1.27g, cuprous bromide 0.03g, 2,2 '-dipyridyl 0.03g, dimethyl sulfoxide (DMSO): water is the solvent 5ml of 2:1, heat 12 hours under 100 degrees Celsius, afterwards reaction solution is poured in large water gaging, and be extracted with ethyl acetate, organic layer saturated sodium-chloride water solution washs, and separates organic layer and with anhydrous sodium sulphate or anhydrous magnesium sulfate drying, after removing solvent under reduced pressure, obtain compound 4 through column chromatography for separation, yield is 85%.
1H-NMR(300M, CDCl
3), δ7.50(2H, d, J=8.76), 6.88(2H, d, J=8.76), 6.63(2H, s), 3.83(6H, s), 3.79(6H, s), ESI m/z 377, 1[M+Na]
+
embodiment 5:3,4,5-trimethoxyphenyl-1-naphthyl selenide (compound 5)
0.07g magnesium powder is put into flask, then puts into an iodine and add 15 times amount anhydrous tetrahydro furans under nitrogen protection, stir and drip 1-naphthalene bromide 0.42g, question response controls rate of addition after causing, and keeps reaction flask to be no more than 50 degrees Celsius.50 degrees Celsius of reactions 1 hour after dropwising, add selenium powder 0.2g afterwards, react 2 hours, and add 1.68g salt of wormwood, under 0 degree Celsius, slowly drip obtained diazonium salt solution.Dropwise rear reaction 2 hours.Acidification reaction liquid afterwards, and be extracted with ethyl acetate, organic layer saturated sodium-chloride water solution washs, and separate organic layer and with anhydrous sodium sulphate or anhydrous magnesium sulfate drying, after removing solvent under reduced pressure, obtain compound 5 through column chromatography for separation, yield is 65%.
1H-NMR(300M, CDCl
3), δ8.31(1H, d, J=7.63), 7.82(2H, m), 7.66(2H, d, J=6.96), 7.51(2H, m), 7.36(1H, t, J=7.62), 6.67(2H, s, ), 3.81(3H, s), 3.70(6H, s)。
embodiment 6:the preparation (compound 6) of 3,4,5-trimethoxyphenyl-3-hydroxyl-4-p-methoxy-phenyl selenide
Except using corresponding raw material, prepare compound 6 with the method that embodiment 1 is identical, yield is 40%.
1H-NMR(300M, CDCl
3), δ6.75-7.12(3H, m), 6.70(2H, s), 3.92(3H, s), 3.83(3H, s), 3.80(6H, s)。
embodiment 7:the preparation (compound 7) of 3,4,5-trimethoxyphenyl-3-allyl group oxygen base-4-p-methoxy-phenyl selenide
Except using corresponding raw material, prepare compound 7 with the method that embodiment 1 is identical, yield is 60%.ESI m/z 411.1[M+H]
+, 433.1[M+Na]
+。
embodiment 8:the preparation (compound 8) of 3,4,5-trimethoxyphenyl-3-acetoxyl group-4-p-methoxy-phenyl selenide
By 0.86g compound 7, be dissolved in methylene dichloride, under 0 degree Celsius, add 1.15g titanium tetrachloride stir 5 minutes, use dichloromethane extraction afterwards, organic layer saturated sodium-chloride water solution washs, separate organic layer and with anhydrous sodium sulphate or anhydrous magnesium sulfate drying, 0.19g Acetyl Chloride 98Min., 0.24g triethylamine are added reaction system, and reaction 2h, after removing solvent under reduced pressure, obtain compound 8 through column chromatography for separation, yield is 79%.ESI m/z 413.1[M+H]
+, 435.1[M+Na]
+
embodiment 9:the preparation (compound 9) of 3,4,5-trimethoxyphenyl-3-nitro-4-p-methoxy-phenyl selenide
Except using corresponding raw material, prepare compound 9 with the method that embodiment 1 is identical, yield is 88%.ESI m/z 400.1[M+H]
+, 422.1[M+Na]
+。
embodiment 10:the preparation (compound 10) of 3,4,5-trimethoxyphenyl-3-amino-4-methoxyl phenyl selenide
3.08g ferrous sulfate is put into flask, adds water dissolution, then add 2.70g ammoniacal liquor, add 0.75g compound 9 afterwards, reflux 30 minutes, filtered while hot, filter cake ethyl acetate rinse.Filtrate is extracted with ethyl acetate, and organic layer saturated sodium-chloride water solution washs, and separate organic layer and with anhydrous sodium sulphate or anhydrous magnesium sulfate drying, after removing solvent under reduced pressure, obtain compound 10 through column chromatography for separation, yield is 85%.ESI m/z 370.1[M+H]
+, 392.1[M+Na]
+。
embodiment 11:the preparation (compound 11) of 3,4,5-trimethoxyphenyl-3-acetylaminohydroxyphenylarsonic acid 4-p-methoxy-phenyl selenide
0.79g compound 10 is put into reaction flask, add methylene dichloride to dissolve, add 0.24g triethylamine, 0.19g Acetyl Chloride 98Min., stir 30 minutes, use dichloromethane extraction afterwards, organic layer saturated sodium-chloride water solution washs, and separates organic layer and with anhydrous sodium sulphate or anhydrous magnesium sulfate drying, after removing solvent under reduced pressure, obtain compound 11 through column chromatography for separation, yield is 85%.ESI m/z 412.2[M+H]
+, 434.2[M+Na]
+。
embodiment 12:the preparation (compound 12) of chloro-4, the 5-Dimethoxyphenyl-3-nitro-4-p-methoxy-phenyl selenides of 3-
Except using corresponding raw material, prepare compound 12 with the method that embodiment 1 is identical, yield is 63%.ESI m/z 404.1[M+H]
+, 426.1[M+Na]
+。
embodiment 13:the preparation (compound 13) of 3,4,5-trimethoxyphenyl-3-Glycinylamino-4-p-methoxy-phenyl selenide
0.6g compound 10 is put into reaction flask, adds methylene dichloride and dissolve, in another reaction flask, add 0.48g Fmoc-glycine, 0.34g DCC, 0.11g HOBT, react 30 minutes under 0 degree Celsius, filter afterwards, is filled the reaction flask of compound 10 filtrate adding, and add 0.02g DMAP, room temperature reaction 24 hours, add piperidines 0.13g afterwards, react 30 minutes, after removing solvent under reduced pressure, obtain compound 11 through column chromatography for separation, yield is 85%.ESI m/z 427.2[M+H]
+, 449.2[M+Na]
+。
embodiment 14:the preparation (compound 12) of 3,4,5-trimethoxyphenyl-4-aminomethyl phenyl selenoxide
Be dissolved in methyl alcohol by 0.5g compound 1, add 0.10g hydrogen peroxide, stir 4 hours, evaporated under reduced pressure solvent, obtains product 12 through column chromatographic isolation and purification.Yield 96%.
1H-NMR(300M, CDCl
3), δ7.58(2H, d, J=8.10), 7.23(2H, d, J=8.10), 6.92(2H, s), 3.87(3H, s), 3.84(6H, s), 2.37(3H, s)。
embodiment 15:the preparation (compound 13) of 3,4,5-trimethoxyphenyl-rubigan selenoxide
Except using corresponding raw material, prepare compound 13 with the method that embodiment 12 is identical, yield is 90%.
1H-NMR(300M, CDCl
3), δ7.66(2H, d, J=8.29), 7.50(2H, d, J=8.29), 6.92(2H, s), 3.90(6H, s), 3.85(3H, s)。
embodiment 16:the preparation (compound 14) of 3,4,5-trimethoxyphenyl-p-methoxyphenyl selenoxide
Except using corresponding raw material, prepare compound 14 with the method that embodiment 12 is identical, yield is 94%.
1H-NMR(300M, CDCl
3), δ7.57(2H, d, J=8.55), 6.96(2H, d, J=8.55), 6.89(2H, s), 3.84(6H, s), 3.81(3H, s), 3.78(3H, s), ESI m/z 371.2[M+H]
+, 393.1[M+Na]
+。
embodiment 17:the preparation (compound 15) of 3,4,5-trimethoxyphenyl-1-naphthyl selenoxide
Except using corresponding raw material, prepare compound 15 with the method that embodiment 12 is identical, yield is 93%.
1H-NMR(300M, CDCl
3), δ8.26(1H, d, J=6.96), 8.19(1H, m), 7.98(2H, m), 7.63(3H, m), 7.36(2H, s), 3.8(9H, s)。
embodiment 18:the preparation (compound 16) of 3,4,5-trimethoxyphenyl-3-allyl group oxygen base-4-p-methoxy-phenyl selenoxide
Except using corresponding raw material, prepare compound 16 with the method that embodiment 12 is identical, yield is 90%.ESI m/z 427.1[M+H]
+, 449.1[M+Na]
+。
embodiment 19:the preparation (compound 17) of 3,4,5-trimethoxyphenyl-3-acetoxyl group-4-p-methoxy-phenyl selenoxide
Except using corresponding raw material, prepare compound 17 with the method that embodiment 12 is identical, yield is 88%.ESI m/z 429.1[M+H]
+, 45.1[M+Na]
+
embodiment 20:the preparation (compound 18) of 3,4,5-trimethoxyphenyl-3-acetylaminohydroxyphenylarsonic acid 4-p-methoxy-phenyl selenoxide
Except using corresponding raw material, prepare compound 18 with the method that embodiment 12 is identical, yield is 89%.ESI m/z 428.2[M+H]
+, 450.2[M+Na]
+。
embodiment 21:the preparation (compound 19) of 3,4,5-trimethoxyphenyl-phenyl selenoxide
Except using corresponding raw material, prepare compound 19 with the method that embodiment 12 is identical, yield is 96%.ESI m/z 341.0[M+H]
+。
embodiment 22:the preparation (compound 20) of 3,4,5-trimethoxyphenyl-4-aminomethyl phenyl selenone
Be dissolved in methyl alcohol by 0.5g compound 1, add 0.4g hydrogen peroxide, reflux stirs 4 hours, and evaporated under reduced pressure solvent obtains compound 20 through column chromatographic isolation and purification, and yield is 85%.
1H-NMR(300M, CDCl
3), δ7.86(2H, d, J=8.21), 7.41(2H, d, J=8.21), 7.19(2H, s), 3.91(3H, s), 3.89(6H, s), 2.44(3H, s)。
embodiment 23:the preparation (compound 21) of 3,4,5-trimethoxyphenyl-rubigan selenone
Be dissolved in methyl alcohol by compound 13 (0.5g), add 0.4g hydrogen peroxide, reflux stirs 4 hours, and evaporated under reduced pressure solvent obtains compound 21 through column chromatographic isolation and purification, yield 87%.
1H-NMR(300M, CDCl
3), δ7.92(2H, d, J=8.62), 7.60(2H, d, J=8.63), 7.18(2H, s), 3.92(6H, s), 3.89(3H, s)。
embodiment 24:3,4,5-trimethoxyphenyl-p-methoxyphenyl selenone (compound 10)
Except using corresponding raw material, prepare compound 22 with the method that embodiment 20 is identical, yield is 76%.
1H-NMR(300M, CDCl
3), δ7.90(2H, d, J=9.04), 7.17(2H, s), 7.07(2H, d, J=9.04), 3.91(6H, s), 3.89(3H, s), 3.87(3H, s)。
embodiment 25:3,4,5-trimethoxyphenyl-1-naphthyl selenone (compound 23)
Except using corresponding raw material, prepare compound 23 with the method that embodiment 20 is identical, yield is 81%.
1H-NMR(300M, CDCl
3), δ8.77(1H, d, J=8.29), 8.45(1H, d, J=7.30), 8.18(1H, d, J=8.29), 7.99(1H, m), 7.66(3H, m), 7.25(2H, s, ), 3.88(9H, s)。
embodiment 26:the preparation (compound 24) of 3,4,5-trimethoxyphenyl-3-allyl group oxygen base-4-p-methoxy-phenyl selenone
Except using corresponding raw material, prepare compound 24 with the method that embodiment 20 is identical, yield is 88%.ESI m/z 443.1[M+H]
+, 465.1[M+Na]
+。
embodiment 27:3,4,5-trimethoxyphenyl-phenyl selenone (compound 25)
Except using corresponding raw material, prepare compound 25 with the method that embodiment 20 is identical, yield is 83%.ESI m/z 356.0[M+H]
+。
embodiment 28:the anti tumor activity in vitro test of compound of the present invention
External activity testing method and result as follows: wherein, clinical conventional antitumor drug cis-platinum is positive control experiment group.
Anti-tumor activity body outer screening test:
Screening method: tetrazolium (micoculture tetrozolium, MTT) reduction method
Cell strain: people's cancer of the stomach glandular cell strain SGC-7901 cell line
Action time: 72 h
Under each compound 10 μ g/mL dosage to the inhibiting rate of tumor growth in Table-1.
Anti-tumor activity body outer screening test-2
Screening method: tetrazolium (micoculture tetrozolium, MTT) reduction method
Cell strain: human oral epidermoid carcinoma cell strain KB cell line
Action time: 72 h
Each compound 10 μ g/mL to the inhibiting rate of tumor growth in Table-1.
Anti-tumor activity body outer screening test 3
Screening method: tetrazolium (micoculture tetrozolium, MTT) reduction method
Cell strain: human fibrosarcoma cell's strain HT-1080 cell line
Action time: 72 h
Each compound 10 μ g/mL to the inhibiting rate of tumor growth in Table-1.
Table-1
Claims (7)
1. hexichol selenide, phenyl-selenide sulfoxide, phenyl-selenide sulfone compound, its structure is as follows:
X is selenium Se, selenoxide SeO, selenone SeO
2;
R
1, R
2, R
3be C simultaneously
1~ C
6alkyl oxygen base;
R
4for hydrogen;
R
5be hydrogen, C independently
1-C
6alkyl oxygen base, hydroxyl, nitro, amino, C
1-C
6hydrocarbylamino, C
2-C
6dialkylamino;
R
6be hydrogen, C independently
1~ C
6alkyl, C
1-C
6alkyl oxygen base, halogen atom;
R
7, R
8be hydrogen, C independently
1-C
6alkyl oxygen base, or two substituting groups can be-CH=CH-CH=CH-thus form six-ring;
Work as R
5containing hydroxyl, amino, C
1-C
6during hydrocarbylamino, hydroxyl, amino, C
1-C
6hydrocarbylamino and C
1-C
6in saturated or unsaturated acid, phosphoric acid or glycine are anthropoid, 20 seed amino acids become ester or acid amides.
2. hexichol selenide according to claim 1, phenyl-selenide sulfoxide, phenyl-selenide sulfone compound, is characterized in that the preferred selenium of described X, selenoxide.
3. hexichol selenide according to claim 1, phenyl-selenide sulfoxide, phenyl-selenide sulfone compound, is characterized in that: the pharmaceutically acceptable non-toxic salt that this compound also comprises hexichol selenide, phenyl-selenide sulfoxide, phenyl-selenide sulfone compound are formed.
4. hexichol selenide according to claim 3, phenyl-selenide sulfoxide, phenyl-selenide sulfone compound, is characterized in that: the salt that the pharmaceutically acceptable non-toxic salt formed is formed with acid or alkali for this compound.
5. hexichol selenide according to claim 4, phenyl-selenide sulfoxide, phenyl-selenide sulfone compound, is characterized in that: described acid is selected from hydrochloric acid, sulfuric acid, Hydrogen bromide, phosphoric acid, acetic acid, toxilic acid, fumaric acid, citric acid, oxalic acid, tartrate, phenylformic acid, oxysuccinic acid; Described alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, ammoniacal liquor, thanomin, triethylamine.
6. hexichol selenide, phenyl-selenide sulfoxide, phenyl-selenide sulfone compound, be selected from
Compound 1:
3,4,5-trimethoxyphenyl-4-aminomethyl phenyl selenide
Compound 2:
Two 3,4,5-trimethoxyphenyl selenides
Compound 3:
3,4,5-trimethoxyphenyl-rubigan selenide
Compound 4:
3,4,5-trimethoxyphenyl-p-methoxyphenyl selenide
Compound 5:
3,4,5-trimethoxyphenyl-1-naphthyl selenide
Compound 6:
3,4,5-trimethoxyphenyl-3-hydroxyl-4-p-methoxy-phenyl selenide
Compound 7:
3,4,5-trimethoxyphenyl-3-allyl group oxygen base-4-p-methoxy-phenyl selenide
Compound 8:
3,4,5-trimethoxyphenyl-3-acetoxyl group-4-p-methoxy-phenyl selenide
Compound 9:
3,4,5-trimethoxyphenyl-3-nitro-4-p-methoxy-phenyl selenide
Compound 10:
3,4,5-trimethoxyphenyl-3-amino-4-methoxyl phenyl selenide
Compound 11:
3,4,5-trimethoxyphenyl-3-acetylaminohydroxyphenylarsonic acid 4-p-methoxy-phenyl selenide
Compound 12
Chloro-4, the 5-Dimethoxyphenyl-3-nitro-4-p-methoxy-phenyl selenides of 3-
Compound 13
3,4,5-trimethoxyphenyl-3-Glycinylamino-4-p-methoxy-phenyl selenide
Compound 14:
3,4,5-trimethoxyphenyl-4-aminomethyl phenyl selenoxide
Compound 15:
3,4,5-trimethoxyphenyl-rubigan selenoxide
Compound 16:
3,4,5-trimethoxyphenyl-p-methoxyphenyl selenoxide
Compound 17:
3,4,5-trimethoxyphenyl-1-naphthyl selenoxide
Compound 18:
3,4,5-trimethoxyphenyl-3-allyl group oxygen base-4-p-methoxy-phenyl selenoxide
Compound 19:
3,4,5-trimethoxyphenyl-3-acetoxyl group-4-p-methoxy-phenyl selenoxide
Compound 20:
3,4,5-trimethoxyphenyl-3-amino-4-methoxyl phenyl selenoxide
Compound 21:
3,4,5-trimethoxyphenyl-3-nitro-4-p-methoxy-phenyl selenoxide
Compound 22:
3,4,5-trimethoxyphenyl-4-aminomethyl phenyl selenone
Compound 23
3,4,5-trimethoxyphenyl-rubigan selenone
Compound 24:
3,4,5-trimethoxyphenyl-p-methoxyphenyl selenone
Compound 25:
3,4,5-trimethoxyphenyl-1-naphthyl selenone
Compound 26:
3,4,5-trimethoxyphenyl-3-allyl group oxygen base-4-p-methoxy-phenyl selenone
Compound 27:
3,4,5-trimethoxyphenyl-3-nitro-4-p-methoxy-phenyl selenone.
7. the hexichol selenide of claim 1-6 described in any one, phenyl-selenide sulfoxide, phenyl-selenide sulfone compound are preparing the application in antitumor drug.
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| CN103724246B (en) * | 2013-12-04 | 2015-04-08 | 温州大学 | Aryl elemental selenium compound synthesis method |
| DE102014209974A1 (en) * | 2014-05-26 | 2015-12-17 | Evonik Degussa Gmbh | Process for the preparation of 2,2'-selenobiaryl ether using selenium dioxide |
| CN106496087B (en) * | 2016-09-12 | 2018-01-23 | 广西师范大学 | A kind of method by the decarboxylation coupling reaction one pot process compound of class containing selenium |
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| CN106866480B (en) * | 2017-04-06 | 2019-03-22 | 盐城工学院 | Polycyclic virtue selenide analog derivative and preparation method thereof |
| CN110804028B (en) * | 2019-11-14 | 2020-07-31 | 中山万远新药研发有限公司 | Piperazinyl substituted diaryl sulfoxide compound and composition and application thereof |
| CN114246867B (en) * | 2020-09-24 | 2023-07-04 | 中国科学院大连化学物理研究所 | Application of monoseleno ether compound in preparation of anti-coronavirus medicine and medicine |
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