CN103086935A - 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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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 technical field, relate to a kind of hexichol selenide, phenyl-selenide sulfoxide, phenyl-selenide sulfone compound and uses thereof, exactly, relate to this compounds and as tumor cell proliferation inhibitor and tumor vessel disrupting agent in the application aspect the preparation anti-tumor drug.
Background technology
Malignant tumour is the serious disease that threatens human health and life, is the first lethal cause of disease in China.Seek and find that treatment and the new drug of prophylaxis of tumours are the current key subjects that face.
Combretastatin A-4(CA-4) be to separate the cis-stilbene class natural product obtain from the willow of South Africa, its chemical name be (
Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenol.CA-4 is the tubulin polymerization inhibitor, presents very strong inhibition tumor cell propagation and tumor vessel and destroys activity, and its prodrug CA-4 phosphoric acid salt (CA-4P) enters the clinical study stage three phases in the U.S..For lead compound designs, the existing a large amount of reports of research of synthetic new active compound for anti tumor, but most CA-4 analogue exists or is active not high enough or toxicity is large or the shortcoming such as synthetic more complicated with CA-4.
Relevant report is referring to 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 ﹠amp; Medicinal Chemistry Letters,
2008,18 (11), 3266-3271.
20th century the eighties, World Health Organization approval: 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 blocker of tumour cell, and selenium is the drug effect toughener of antitumor drug.Hexichol selenide, phenyl-selenide sulfoxide, phenyl-selenide sulfone compound and the related compound thereof that comprises the CA-4 constitutional features has 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 not halogen simultaneously, perhaps two adjacent substituting groups can be-OCH
2Thereby O-consists of 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
6Alkyl is amino, C
2-C
6Dialkyl is amino, and perhaps two adjacent substituting groups can be-OCH
2Thereby O-consists of five-ring, thereby perhaps adjacent two substituting groups can consist of six-ring for-CH=CH-CH=CH-.
Work as R
4~ R
8Contain hydroxyl, amido, C
1-C
6When alkyl is amino, hydroxyl, amido, C
1-C
6Alkyl amino can with C
1-C
6Interior 20 seed amino acids of the saturated or human bodies such as unsaturated acid, phosphoric acid or glycine become ester or acid amides.
The preferred selenium of described X, selenoxide.
This compound also comprises hexichol selenide, phenyl-selenide sulfoxide, phenyl-selenide sulfone derivatives formed pharmaceutically acceptable non-toxic salt and hydrate thereof.
Formed pharmaceutically acceptable non-toxic salt is this derivative and acid or the formed salt of alkali; 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 preferred part of compounds structure of the present invention is as follows:
Compound 1:
3,4,5-trimethoxyphenyl-4-aminomethyl phenyl selenide
Compound 2:
Two 3,4,5-trimethoxyphenyl selenide
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
3-chloro-4,5-Dimethoxyphenyl-3-nitro-4-p-methoxy-phenyl selenide
Compound 13
3,4,5-trimethoxyphenyl-3-glycyl amino-4-methoxyl 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 is synthetic:
Method one: at first synthetic selenophenol compounds negative ion
1. a kind of substituted-phenyl diazonium salt and the solution reaction that contains two selenium two negative ions are obtained symmetrical hexichol diselenide compounds, reductive agent obtains the selenophenol compounds afterwards, then adds alkali to make selenophenol compounds negative ion.
2. a kind of halogeno-benzene and reactive magnesium are obtained corresponding phenyl grignard reagent, afterwards itself and the reaction of simple substance selenium are obtained selenophenol compounds negative ion.
3. a kind of halogeno-benzene and n-Butyl Lithium are reacted at low temperatures and obtain corresponding lithium aryl, afterwards itself and the reaction of simple substance selenium are obtained selenophenol compounds negative ion
Then with selenophenol compounds negative ion in alkaline aqueous solution, 0 degree centigrade, keep the Arenediazonium salts compounds that slowly drips under the condition of reaction system alkalescence, dropwise rear continuation reaction 2 hours.The conditioned reaction system is slightly acidic, adds ethyl acetate to stir, and removes by filter not tolerantly, uses ethyl acetate extraction, and organic layer washs and use anhydrous sodium sulfate drying with saturated nacl aqueous solution.Desolventize through the Rotary Evaporators steaming, obtain product through column chromatographic isolation and purification.Yield 40-90%
Method two: with 2 of the cuprous bromide of the phenylo boric acid compounds of symmetrical hexichol diselenide compounds, 3 equivalents, 0.1 equivalent and 0.1 equivalent, 2 '-dipyridyl adds in reaction flask, the dimethyl sulfoxide (DMSO) that adds again 4 times of amounts: water is the mixed solvent of 2:1, and reaction is 12 hours under 100 degrees centigrade.Reaction solution is poured in large water gaging, and ethyl acetate extraction, organic layer wash and use anhydrous sodium sulfate drying with saturated nacl aqueous solution.Desolventize through the Rotary Evaporators steaming, 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 contain the phenyl-selenide ether compound of hydroxyl can be by corresponding R
4～R
8In contain allyloxy compound through going the allyl reaction preparation, the reagent that removes the allyl group base is titanium tetrachloride, perhaps removes ethanoyl or acryl for the compound that contains ethanoyl or acryl under alkaline condition.
Phenyl-selenide sulfoxide compound of the present invention can obtain according to following reaction scheme is synthetic:
The phenyl-selenide ether compound is dissolved in organic solution, uses the oxygenant oxidation to obtain the phenyl-selenide sulfoxide, use afterwards ethyl acetate extraction, organic layer washs and uses anhydrous sodium sulfate drying with saturated nacl aqueous solution.Desolventize through the Rotary Evaporators steaming, obtain product through column chromatographic isolation and purification.Yield 70%～99%.
Wherein, R
4～R
8In contain the phenyl-selenide sulfoxide compound of hydroxyl can be by corresponding R
4～R
8In contain allyloxy compound through going the allyl reaction preparation, the reagent that removes the allyl group base is titanium tetrachloride, perhaps removes ethanoyl or acryl for the compound that contains ethanoyl or acryl under alkaline condition.
Phenyl-selenide sulfone derivatives of the present invention can obtain according to following reaction scheme is synthetic:
The phenyl-selenide ether compound is dissolved in organic solution, uses the oxygenant oxidation to obtain the hexichol selenone, use afterwards ethyl acetate extraction, organic layer washs and uses anhydrous sodium sulfate drying with saturated nacl aqueous solution.Desolventize through the Rotary Evaporators steaming, obtain product through column chromatographic isolation and purification.Yield 40%～95%.
Wherein, R
4～R
8In contain the phenyl-selenide sulfone derivatives of hydroxyl can be by corresponding R
4～R
8In contain allyloxy compound through going the allyl reaction preparation, the reagent that removes the allyl group base is titanium tetrachloride, perhaps removes ethanoyl or acryl for the compound that contains ethanoyl or acryl under alkaline condition.
Embodiment
To help to understand 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 spectrographs.
Embodiment 1:The preparation (compound 1) of 3,4,5-trimethoxyphenyl-4-aminomethyl phenyl selenide
3,4,5-trimethoxy hexichol diselenide 1g is dissolved in anhydrous THF, adds the tetrahydrochysene lithium reactive aluminum of 0.77g to obtain 3,4,5-trimethoxy selenophenol in 1 hour.P-nethoxyaniline 0.25g is added in another reaction flask, add the concentrated hydrochloric acid of 0.5ml, stirring and dissolving adds Sodium Nitrite 0.14g under 0 degree centigrade, reacts 30 minutes.To add 30ml water in prepared selenophenol solution afterwards under 0 degree centigrade, and add 3g salt of wormwood, slowly drip the diazonium salt solution that makes under 0 degree centigrade.Dropwised afterreaction 2 hours.Acidification reaction liquid afterwards, and use ethyl acetate extraction, organic layer washs with saturated sodium-chloride water solution, tells organic layer and with anhydrous sodium sulphate or anhydrous magnesium sulfate drying, after removing solvent under reduced pressure, obtains compound 1 through column chromatography for separation, and 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:Two 3,4, the preparation of 5-trimethoxyphenyl selenide (compound 2)
Except using corresponding raw material, prepare compound 2 with the identical method of embodiment 1, yield is 80%.ESI?m/z?437.1[M+Na]
+
Embodiment 3:The preparation of 3,4,5-trimethoxyphenyl-rubigan selenide (compound 3)
Except using corresponding raw material, prepare compound 3 with the identical method of embodiment 1, 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 of 3,4,5-trimethoxyphenyl-p-methoxyphenyl selenide (compound 4)
Biconjugate methoxyl group hexichol diselenide 0.74g is put into the 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, heating is 12 hours under 100 degrees centigrade, reaction solution is poured in large water gaging afterwards, and use ethyl acetate extraction, organic layer washs with saturated sodium-chloride water solution, tells 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 put into an iodine add 15 times of amount anhydrous tetrahydro furans under nitrogen protection, stirs and drips 1-naphthalene bromide 0.42g, question response causes controls rate of addition afterwards, and the maintenance reaction flask is no more than 50 degrees centigrade.50 degrees centigrade of reactions 1 hour, add afterwards selenium powder 0.2g after dropwising, reacted 2 hours, and add 1.68g salt of wormwood, slowly drip the diazonium salt solution that makes under 0 degree centigrade.Dropwised afterreaction 2 hours.Acidification reaction liquid afterwards, and use ethyl acetate extraction, organic layer washs with saturated sodium-chloride water solution, tells organic layer and with anhydrous sodium sulphate or anhydrous magnesium sulfate drying, after removing solvent under reduced pressure, obtains compound 5 through column chromatography for separation, and 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 identical method of embodiment 1, 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 identical method of embodiment 1, 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
With 0.86g compound 7, be dissolved in methylene dichloride, add the 1.15g titanium tetrachloride to stir under 0 degree centigrade 5 minutes, use afterwards dichloromethane extraction, organic layer washs with saturated sodium-chloride water solution, tell 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 is 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 identical method of embodiment 1, 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
The 3.08g ferrous sulfate is put into flask, add water dissolution, then add 2.70g ammoniacal liquor, add afterwards 0.75g compound 9, refluxed 30 minutes, filtered while hot, filter cake ethyl acetate rinse.Filtrate is used ethyl acetate extraction, and organic layer washs with saturated sodium-chloride water solution, tells organic layer and with anhydrous sodium sulphate or anhydrous magnesium sulfate drying, after removing solvent under reduced pressure, obtains compound 10 through column chromatography for separation, and 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 the methylene dichloride dissolving, add 0.24g triethylamine, 0.19g Acetyl Chloride 98Min., stirred 30 minutes, use afterwards dichloromethane extraction, organic layer washs with saturated sodium-chloride water solution, tells 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 12:3-chloro-4, the preparation (compound 12) of 5-Dimethoxyphenyl-3-nitro-4-p-methoxy-phenyl selenide
Except using corresponding raw material, prepare compound 12 with the identical method of embodiment 1, 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-glycyl amino-4-methoxyl phenyl selenide
0.6g compound 10 is put into reaction flask, add the methylene dichloride dissolving, add 0.48g Fmoc-glycine, 0.34g DCC, 0.11g HOBT in another reaction flask, reaction is 30 minutes under 0 degree centigrade, filter afterwards, will fill the reaction flask of compound 10 filtrate adding, and add 0.02g DMAP, room temperature reaction 24 hours, add afterwards piperidines 0.13g, reacted 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
0.5g compound 1 is dissolved in methyl alcohol, adds the 0.10g hydrogen peroxide, stirred 4 hours, the 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 of 3,4,5-trimethoxyphenyl-rubigan selenoxide (compound 13)
Except using corresponding raw material, prepare compound 13 with the identical method of embodiment 12, 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 of 3,4,5-trimethoxyphenyl-p-methoxyphenyl selenoxide (compound 14)
Except using corresponding raw material, prepare compound 14 with the identical method of embodiment 12, 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 identical method of embodiment 12, 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 identical method of embodiment 12, 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 identical method of embodiment 12, 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 identical method of embodiment 12, yield is 89%.ESI?m/z?428.2[M+H]
?+,?450.2[M+Na]
+。
Embodiment 21:The preparation of 3,4,5-trimethoxyphenyl-phenyl selenoxide (compound 19)
Except using corresponding raw material, prepare compound 19 with the identical method of embodiment 12, 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
0.5g compound 1 is dissolved in methyl alcohol, adds the 0.4g hydrogen peroxide, reflux stirred 4 hours, and the 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 of 3,4,5-trimethoxyphenyl-rubigan selenone (compound 21)
Compound 13 (0.5g) is dissolved in methyl alcohol, adds the 0.4g hydrogen peroxide, reflux stirred 4 hours, and the 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 identical method of embodiment 20, 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 identical method of embodiment 20, 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 identical method of embodiment 20, 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 identical method of embodiment 20, 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 are as follows: wherein, and the positive control experiment group of clinical antitumor drug cis-platinum commonly used.
The 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
Inhibiting rate to tumor growth under each compound 10 μ g/mL dosage sees 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 see Table-1 to the inhibiting rate of tumor growth.
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 see Table-1 to the inhibiting rate of tumor growth.
Table-1
Claims (10)
1. 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 not halogen simultaneously, perhaps two adjacent substituting groups can be-OCH
2Thereby O-consists of 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
6Alkyl is amino, C
2-C
6Dialkyl is amino, and perhaps two adjacent substituting groups can be-OCH
2Thereby O-consists of five-ring, thereby perhaps adjacent two substituting groups can consist of six-ring for-CH=CH-CH=CH-;
Work as R
4~ R
8Contain hydroxyl, amido, C
1-C
6When alkyl is amino, hydroxyl, amido, C
1-C
6Alkyl amino can with C
1-C
6Interior 20 seed amino acids of the saturated or human bodies such as unsaturated acid, phosphoric acid or glycine 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, it is characterized in that: this compound also comprises hexichol selenide, phenyl-selenide sulfoxide, phenyl-selenide sulfone derivatives formed pharmaceutically acceptable non-toxic salt and hydrate thereof.
4. hexichol selenide according to claim 3, phenyl-selenide sulfoxide, phenyl-selenide sulfone compound, it is characterized in that: formed pharmaceutically acceptable non-toxic salt is this derivative and acid or the formed salt of alkali; Described hydration number is the arbitrary integer in 0-16.
5. hexichol selenide according to claim 4, phenyl-selenide sulfoxide, phenyl-selenide sulfone compound, it 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. the preparation method of a hexichol selenide as claimed in claim 1, phenyl-selenide sulfoxide, phenyl-selenide sulfone compound is characterized in that:
The synthetic method of described phenyl-selenide ether compound is as follows:
1) at first prepare selenophenol compounds negative ion, its preparation method can have following three kinds: 1. a kind of substituted-phenyl diazonium salt and the solution reaction that contains two selenium two negative ions are obtained symmetrical hexichol diselenide compounds, use afterwards reductive agent to obtain the selenophenol compounds in organic solvent, then add alkali to make selenophenol compounds negative ion; 2. a kind of halogeno-benzene and reactive magnesium are obtained corresponding phenyl grignard reagent, afterwards itself and the reaction of simple substance selenium are obtained selenophenol compounds negative ion; 3. a kind of halogeno-benzene and n-Butyl Lithium are reacted at low temperatures and obtain corresponding lithium aryl, afterwards itself and the reaction of simple substance selenium are obtained selenophenol compounds negative ion;
With the selenophenol compounds negative ion and the reaction of substituted-phenyl diazonium salt that prepare, make corresponding phenyl-selenide ether compound afterwards;
2) by 1) in the symmetrical hexichol diselenide compounds and the phenylo boric acid compounds that prepare react under the catalysis of mantoquita or cuprous salt, make corresponding phenyl-selenide ether compound.
7. the preparation method of a hexichol selenide as claimed in claim 1, phenyl-selenide sulfoxide, phenyl-selenide sulfone compound, it is characterized in that: the synthetic method of described phenyl-selenide sulfoxide compound is as follows:
Use oxygenant in solvent the phenyl-selenide ether compound of above-mentioned preparation, control reaction conditions, oxidable is corresponding phenyl-selenide sulfoxide compound.
8. the preparation method of a hexichol selenide as claimed in claim 1, phenyl-selenide sulfoxide, phenyl-selenide sulfone compound, it is characterized in that: the synthetic method of described phenyl-selenide sulfone compound is as follows:
Use oxygenant in solvent hexichol selenide or the phenyl-selenide sulfoxide of above-mentioned preparation, control reaction conditions, oxidable is corresponding phenyl-selenide sulfone compound;
R
4-R
8In be the compound of phenolic hydroxyl group, can benzyloxy or allyloxy compound remove benzyl or allyl-based protection prepares by containing accordingly, the reagent of removing protecting group is titanium tetrachloride, aluminum chloride, boron trifluoride, boron trichloride, boron tribromide etc.; Perhaps, prepared by the compound that contains accordingly acetoxyl group, propionyloxy or acryloxy, the reagent that removes above-mentioned protecting group is acid or alkali;
R
4-R
8In be amino compound, can be by also preparation originally of the compound that contains accordingly nitro, reductive agent or method of reducing comprise tetrahydrochysene lithium aluminium, sodium borohydride, vat powder, ferrous sulfate, iron protochloride, Pd/C catalytic hydrogenation, use Raney Ni catalytic hydrogenation etc.
9. the preparation method of according to claim 7 or 8 described hexichol selenides, phenyl-selenide sulfoxide, phenyl-selenide sulfone compound, it is characterized in that: described oxygenant is selected from hydrogen peroxide, benzoyl hydroperoxide, metachloroperbenzoic acid, Peracetic Acid, peroxy tert-butyl alcohol, Potassium Persulphate, ozone, potassium bichromate, potassium permanganate, clorox, Textone, sodium periodate, pyridinium chloro-chromate, pyridinium dichromate; Described solvent is selected from water, methyl alcohol, ethanol, tetrahydrofuran (THF), chloroform, methylene dichloride, ethyl acetate or their arbitrary proportion mixture.
10. any one described hexichol selenide of claim 1-7, phenyl-selenide sulfoxide, the application of phenyl-selenide sulfone compound in the preparation antitumor drug.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103601684A (en) * | 2013-11-29 | 2014-02-26 | 沈阳药科大学 | 5-arylselenobenzimidazole compound and application thereof |
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| CN105175299A (en) * | 2014-05-26 | 2015-12-23 | 赢创德固赛有限公司 | Method For The Preparation Of 2,2'selenobiarylethers Or 4,4'selenobiarylethers Using Selenium Dioxide |
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| CN110804028A (en) * | 2019-11-14 | 2020-02-18 | 中山万远新药研发有限公司 | Piperazinyl substituted diaryl sulfoxide compound and composition and application thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1305458A (en) * | 1998-06-12 | 2001-07-25 | 盖尔德马研究及发展公司 | Diarylselenide compounds and their use in human or veterinary medicine and in cosmetics |
| WO2004047925A2 (en) * | 2002-11-22 | 2004-06-10 | Exeter Antioxidant Therapeutics Limited | Therapeutic oxidation catalysts |
| CN1613852A (en) * | 2003-11-06 | 2005-05-11 | 华东理工大学 | Cesium triazoleamide compounds and their preparation and use |
| CN101891736A (en) * | 2010-06-30 | 2010-11-24 | 天津理工大学 | 1,3,4-thiadiazole (oxadiazole) derivatives based on benzoisoselenothiazolidone structure, and preparation and application thereof |
-
2011
- 2011-10-28 CN CN201110332812.2A patent/CN103086935B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1305458A (en) * | 1998-06-12 | 2001-07-25 | 盖尔德马研究及发展公司 | Diarylselenide compounds and their use in human or veterinary medicine and in cosmetics |
| WO2004047925A2 (en) * | 2002-11-22 | 2004-06-10 | Exeter Antioxidant Therapeutics Limited | Therapeutic oxidation catalysts |
| CN1613852A (en) * | 2003-11-06 | 2005-05-11 | 华东理工大学 | Cesium triazoleamide compounds and their preparation and use |
| CN101891736A (en) * | 2010-06-30 | 2010-11-24 | 天津理工大学 | 1,3,4-thiadiazole (oxadiazole) derivatives based on benzoisoselenothiazolidone structure, and preparation and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| 王敏等: "铜盐催化芳基硼酸在离子液体中与二硒(啼)醚的偶联反应", 《第十三届全国金属有机化学学术讨论会论文集》 * |
| 田丰收等: "二硒醚的合成进展", 《化学试剂》 * |
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| CN110804028A (en) * | 2019-11-14 | 2020-02-18 | 中山万远新药研发有限公司 | Piperazinyl substituted diaryl sulfoxide compound and composition and application thereof |
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