CN107987004A - (hetero) aryl indole base selenide compounds - Google Patents
(hetero) aryl indole base selenide compounds Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The present invention provides a kind of (hetero) aryl indole base selenide compounds.Additionally provide the preparation method of such compound and its application in antitumor drug is prepared.Specific (hetero) aryl indole base selenide compounds provided by the invention are 3 arylseleno benzazolyl compounds, such compound particularly has significant inhibitory action with good antitumor activity to BGC823 cell line SGC 7901cell line, human oral cavity epithelial cancer cell line KB cell line, human fibrosarcoma cell's strain HT 1080cell line；Also, preparation method simple possible provided by the invention, yield and purity are higher.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of (hetero) aryl indole base selenide compounds, the present invention also relate to
And preparation method and its application in terms of anti-tumor drug is prepared of such compound.
Background technology
Numerous studies show that many Organic Selenium class compounds not only have antiviral, antitumor and treatment nervous system
The effect of aspect disease, but also make with pharmacology such as anti-inflammatory, anti-aging, prevention and cure of cardiovascular disease and prevention liver diseases
With.Such as Ebselen（Ebselen）And Selenazofurn（Selenium Zo furans）It is two generations for carrying out clinical research
Table medicine.
The organic selenide compounds of aryl, especially 3- arylselenos benzazolyl compounds all have well in multiple fields
Application potential and value, such as some compounds have the pharmacological activity such as antitumor, anti-inflammatory, antiviral in itself, while are also system
Other standby important intermediates with the medicine such as antitumor, anti-inflammatory, antiviral.
CN103641767A discloses a kind of substituted phenyl indole base selenide, selenoxide, selenone class compound and the structure
The pharmaceutically acceptable salt and its hydrate that formula compound is formed, these pharmaceutically acceptable salts include the derivative
The salt formed with acid.Pharmacological activity experiment results show that the analog derivative has preferable antitumor activity, thin available for tumour
Born of the same parents' antiblastic, has certain application in terms of anti-tumor drug is prepared.
CN103191121A discloses a kind of antitumor drug two (quinazoline -4- bases) diselenide or its is pharmaceutically acceptable
Salt, the compound or its pharmaceutically acceptable salt are especially non-small to treating and preventing various benign or malignant tumour
Cell lung cancer and breast cancer breast cancer cell have excellent proliferation inhibiting effect, show good active anticancer.
At present, the method that people have developed substantial amounts of synthesis selenide compound.
Vieira, Beatriz M et al.（“Sonochemistry: An efficient alternative to the
Synthesis of 3-selanylindoles using CuI as catalyst ", Ultrasonics
Sonochemistry, Volume: 27, Pages: 192-199, Journal）Disclose using ultrasonic wave using DMSO to be molten
Agent, under CuI catalysis, is reacted, the method for preparing 3- Organic Selenium benzazolyl compounds by ultrasonic excitation.
Azeredo, Juliano et al.（“. A Solvent- and Metal-Free Synthesis of 3-
Chalcogenyl-indoles Employing DMSO/I2 as an Eco-friendly Catalytic Oxidation
System ", Journal of Organic Chemistry, Volume: 79, Issue: 9, Pages: 4125-4130,
Journal）Disclose as follows with I2For catalyst, under conditions of solvent is not required for oxidant in DMSO, 3- aryl selenium Yin is prepared
The method of indole compound：
。
Alain Krief et al.（“Reaction of Organic Selenocyanates with Hydroxides:
The One-Pot Synthesis of Dialkyl Diselenides from Alkyl Bromides”,
Angew.Chem.Int.Ed.,2000,39(9),1669-1672）Disclose a kind of method for preparing aryl or the double selenides of alkyl：
R-Se-CN and M-OR ' react, and firstly generate R-Se-M, then R-Se-M and R-Se-CN react or with oxygen reaction and obtain
To R-Se-Se-R, wherein R is aryl or alkyl, and R ' is methyl or ethyl, and M is Na or K.
Devender Singh et al.（“Eco-friendly cross-coupling of diaryl diselenides
with aryl and alkyl bromides catalyzed by CuO nanopowder in ionic liquid”,
Green Chem.,2009,11,1521-1524）Aryl bromide or alkyl bromide are not disclosed in nanometer CuO powder and not
Under the catalysis of homo-ion liquid, with diphenyl disenenide ether（(PhSe)2）Generation coupling reaction, and obtain Aryl elemental selenium.
Camilo S.Freitas et al. (" Synthesis of diaryl selenides using
electrophilic selenium species and nucleophilic boron regents in ionic
Liquids ", Green Chem., 2011,13,2931-2938) in disclose electrophilicity compound Ar-Se-Cl (Br) with
Nucleophilic compound aryl boric acid (Ar1-B (OH) 2) or aromatic yl acid salt (Ar-BF3K) under ionic liquid-catalyzed, and
Obtain Aryl elemental selenium compound Ar-Se-Ar.
Debasish Kundu et al.（ “Microwave-assisted reaction of aryl diazonium
fluoroborate and diaryl dichalcogenides in dimethyl carbonate:a general
procedure for the synthesis of unsymmetrical diaryl chalcogenides”,Green
Chem.,2012,14,2024-2030）In disclose under microwave radiation technology and Zn in the presence of, diazotising borofluoride (Ar-
N2BF4) and diaryl chalcogenide（Ar2X2, X=S, Se, Te）Reacted in dimethyl carbonate, so as to obtain asymmetric
Diaryl chalcogenide Ar1-X-Ar2.
Tanmay Chatterjee et al. "（Solvent-Controlled Hlao-Selective
Selenylationof Aryl Halides Catalyzed by Cu(II)Supported on Al2O3.A General
Protocol for the Synthesis of Unsymmetrical Organo Mono-and Bis-selenides”）It is public
Open under the effect of Cu- aluminium oxide, (R is aryl to R-X, vinyl, heteroaryl；X is halogen) and R '-Se-Se-R '
（R ' is aryl, alkyl, heteroaryl）Reaction, can obtain R-Se-R '.
CN104387311B discloses a kind of synthetic method of 3- arylselenos benzazolyl compounds, including in organic solvent with
Cupric oxide, cuprous iodide, cuprous bromide, stannous chloride etc. are used as catalyst, and in alkali（Such as cesium carbonate, potassium carbonate）In the presence of
Under, make halogenated aromatic compound and simple substance Se, Benzazole compounds reaction synthesis 3- arylseleno benzazolyl compounds.
CN103724246B discloses a kind of synthetic method of Aryl elemental selenium compound, and the synthetic method is with copper chemical combination
Thing is as catalyst, in the presence of oxidant and organic ligand, by arylboronic acid compound and elemental selenium in reaction dissolvent
(Se) react, and the Aryl elemental selenium compound is made in a step.
Malignant tumour is to threaten human health and the serious disease of life, is one of main lethal cause of disease in China.Find
New drug with discovery treatment and pre- preventing tumor is the hot research direction of our times.
The content of the invention
The object of the present invention is to provide a class formation is novel, there is the (hetero) aryl indole base selenide class of potential antitumor activity
Compound, and preparation method thereof.
In a first aspect, (hetero) aryl indole base selenide compounds and its pharmaceutically acceptable salt the present invention provides general formula Formulas I：
,
Wherein, R1Selected from H, C1~C6Alkyl, benzyl, phenyl and to Methyl benzenesulfonyl base；
R2Selected from H, C1~C6Alkyl, benzyl, phenyl and C1~C6Alkoxy carbonyl；
R3For H, halogen, cyano group, C1~C6Alkyl, C1~C6Alkoxy, C1~C6Alkoxyalkyl, phenyl, amino, benzyl, C1~C6Alkane
Benzyl, the C of base substitution1~C6Benzyl, benzyl, the C of amino substitution of alkoxy substitution1~C6Benzyl, two C of alkyl amino substitution1~
C6Benzyl, the C of alkyl amino substitution1~C6Benzyl, the benzyl or COR of nitro substitution of amide groups substitution4, wherein R4For C1~C6Alkane
Base, C1~C6Alkoxy, C1~C6Alkoxyalkyl, amino or benzyl；
R for phenyl, pyridine radicals, thienyl, benzyl, naphthyl, C1~C6Alkyl, C5~ C8Cycloalkyl or one or more
The phenyl of substituent substitution, pyridine radicals, thienyl, benzyl, the substituent is selected from C1~C6Alkyl, C1~C6Alkoxy, halogen,
Cyano group, nitro；Or two neighboring substituent is-OCH2O- is so as to form five-membered ring；Or two adjacent substituents for-
OCH2CH2O- is so as to form hexatomic ring.
In above-claimed cpd, it is preferable that the R1For H, C1~C6Alkyl or to Methyl benzenesulfonyl base；R2For H, C1~C6Alkyl or
C1~C6Alkoxy carbonyl；R3For H, phenyl, halogen, cyano group or C1~C6Alkoxy carbonyl group.
In above-claimed cpd, it is preferable that the R is phenyl, C1~C6Phenyl, the C of alkoxy substitution1~C6Alkyl-substituted benzene
Base, the phenyl of halogen substitution, phenyl, pyridine radicals, the C of cyano group substitution1~C6Alkoxy substitution pyridine radicals, thienyl, benzyl,
Naphthyl, C1~C6Alkyl, cyclohexyl, or。
On the other hand, the compound of Formula I, it is preferred that, the R is phenyl；R1For H or to Methyl benzenesulfonyl base；R2
For H, methyl, n-pentyl or methoxycarbonyl group；R3For H, methyl, phenyl or Cl.
In another embodiment, it is preferable that the R is the phenyl of methoxy substitution, 4-F- phenyl, 4- cvano-phenyls, 2,
5, -3,5-dimethylphenyl, pyridine radicals, 2- methoxypyridines base, 2- thienyls, 3- thienyls, naphthyl, methyl, cyclohexyl, benzyl
Or。
Most preferably, compound of Formula I of the present invention, it is：
。
The compound of the present invention further includes the pharmaceutically acceptable salt and its hydrate of its formation, these pharmaceutically may be used
The salt of receiving includes its salt formed with acid.The acid can be the inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and
The organic acids such as acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid, malic acid.
Second aspect of the present invention, additionally provides application of the compound in antitumor drug is prepared shown in general formula I.Wherein,
The tumour, include but not limited to it is further, cancer of pancreas, advanced solid tumor, ovarian neoplasm, non-small cell lung cancer, breast cancer,
Carcinoma of urinary bladder, cervical carcinoma, celiothelioma, the cancer of the esophagus, stomach cancer, colorectal cancer, liver cancer, cholangiocarcinoma, nasopharyngeal carcinoma, carcinoma of testis, lymthoma or head
Neck cancer；It is furthermore preferred that the cancer includes cancer of pancreas, advanced solid tumor, ovarian neoplasm, breast cancer.
Third aspect present invention, there is provided a kind of pharmaceutical composition, includes compound provided by the invention and at least one
Pharmaceutically acceptable excipient.The pharmaceutical composition can be administered by oral or parenteral, including intravenously administrable, skin
Lower administration, Intraperitoneal medication, intramuscular injection, inhalation, rectally and local administration（Such as oral cavity or sublingual administration）.
Wherein, the pharmaceutical composition for oral administration includes tablet, capsule, granule or supensoid agent；For what is taken orally
Tablet includes composition provided by the invention and is used as active ingredient, can also include the pharmaceutically useful excipient of one or more, such as
Diluent, disintegrant, adhesive, lubricant, sweetener, flavouring, pigment and preservative.When cornstarch and alginic acid conduct
During disintegrant, suitable inert diluent includes sodium carbonate, calcium carbonate, sodium phosphate, calcium phosphate and lactose.Adhesive includes starch
And gelatin, optional, lubricant is magnesium stearate, stearic acid or talcum powder.Optional, the tablet can also use single tristearin
Acid glyceride or glycerol distearate are coated, to delay absorption under one's belt.
Capsule for oral administration includes hard shell capsules and soft capsule, and wherein hard shell capsules include combination provided by the invention
Thing is as effective active composition and a kind of solid diluent；Soft capsule includes pharmaceutical composition provided by the invention as effectively living
Property component, with water or oil（Such as peanut oil, atoleine or olive oil）.
For the formulation suppository of rectally, the wherein matrix of suppository can be cocoa power oil or salicylate.
Dosage form for vagina administration is pessary, cotton balls, frost, gel, paste, foaming agent or spray, described
Preparation includes composition and conventional carrier known in the art containing active ingredient.
For being injected intravenously, the formulation of Intraperitoneal medication, subcutaneous administration and intramuscular administration when, composition provided by the invention
Usually sterile solution or sterile suspensions, and there is suitable pH value and osmotic pressure.The preparation of such preparation, can be according to ability
Conventional method prepares known to domain.
Fourth aspect present invention, there is provided a kind of preparation method of compound of Formula I, including：By heteroaromatic compounds II
Irradiated instead under blue LED lamp, preferably 400nm ~ 480nm, more preferably 450 nm LEDs lamps with symmetrical diselenide compound III
It should generate：
；
Wherein R1, R2, R3, R are as defined above.
Preferably, the preparation method of the compound of Formula I, including：By heteroaromatic compounds II and symmetrical diselenide
Compound III is irradiated under blue LED lamp and FIrPic（Double (4,6- difluorophenyl pyridinatos-N, C2) pyridinecarboxylics close iridium）It is existing
Under the conditions of react generation.
Wherein, the blue LED lamp refers to the LED light that wavelength is 400nm ~ 480nm, and optimal wavelength is the LED of 450nm
Lamp.
Further, in the above method, it is preferred that the heteroaromatic compounds II and symmetrical diselenide compound III's
It is 2 to react molar ratio:1~2；More preferably 2:1.2, wherein, the heteroaromatic compounds II and symmetrical diselenide compound
The reaction molar ratio of III is 2:1 ~ 2, preferably 2:The molar ratio of 1.2, the heteroaromatic compounds II and FIrPic are 200 ~ 50:
1, preferably 50:1.It is preferred that the organic solvent is dichloroethanes (DCE), and dimethyl sulfoxide (DMSO) (DMSO), N, N dimethyl formyl
Amine (DMF), tetrahydrofuran (THF), dichloromethane, acetone, acetonitrile or its mixed solution, more preferably described reaction dissolvent are
Anhydrous acetonitrile, DCE or acetone.
In another preferred embodiment, the above method can operate as follows：By heteroaromatic compounds II, right
Claim diselenide III, and FIrPic solvents are in organic solvent（Such as anhydrous acetonitrile, dichloroethanes, acetone or its mixed solution）
In, wherein, heteroaromatic compounds II and symmetrical diselenide III to react molar ratio as 2:1 ~ 2, preferably 2:1.2, heteroaromatic
The reaction molar ratio of compound II and FIrPic are 200 ~ 50:1, preferably 50:1, transparent glass tube is placed in, in blue LED lamp
Lower irradiation.With thin layer plate chromatography（TLC）Extent of reaction is detected, after heteroaromatic compounds II is wholly absent, decompression removes solvent,
Residue preparation column chromatography（As silica gel for filling, washing and dehydrating integrated machine is petroleum ether and ethyl acetate）Separation, you can obtain pure
Unsymmetrical selenides compound I.
The (hetero) aryl indole base selenide compounds and its pharmaceutically acceptable salt of general formula I provided by the invention have good resist
Tumor promotion, particularly to BGC823 cell line SGC-7901cell line, human oral cavity epithelial cancer cell line KB cell
Line has significant inhibitory action；Also, preparation method simple possible provided by the invention, yield and purity are higher.
Specific embodiment
Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments and
Purpose is only used for enumerating the present invention, not forms any type of any restriction to the real protection scope of the present invention, more non-to incite somebody to action
Protection scope of the present invention is confined to this.
In the following embodiments, each abbreviation refers to following concrete meaning：
Me：Methyl；MeO：Methoxyl group；Ph：Phenyl；Bn：Benzyl；FIrPic structural formulas are as follows：
。
Agents useful for same of the present invention is commercially available.
Embodiment 1：The preparation of compound 1
By heteroaromatic compounds A（0.2mmol）, symmetrical diselenide B（0.12 mmol）Solvent is placed in 2mL anhydrous acetonitriles
Bright glass tube, under air conditions, irradiates under the LED light of wavelength 450nm.Period detects extent of reaction with thin layer plate chromatography,
After heteroaromatic compounds 1a is wholly absent, decompression removes solvent, and residue is with preparing pillar layer separation（Silica gel is filling, is washed
De- agent is petroleum ether and ethyl acetate）, you can obtain pure unsymmetrical selenides compound 1, yield 93%, purity（HPLC）：
99.3%。
Nuclear magnetic data：1H NMR (400 MHz, (CD3)2SO): δ 11.46 (brs, 1H), 7.64 (d, J=2.8
Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.21-7.18 (m, 2H), 6.91 (d, J=2.4 Hz, 1H),
6.83-6.76 (m, 3H) 3.71 (s, 3H), 3.66 (s, 3H) ppm. 13C NMR (100 MHz, (CD3)2SO):
δ 158.0, 154.2, 132.7, 131.5, 130.7, 130.2, 123.2, 114.9, 112.9, 112.0,
100.7, 96.1, 55.3, 55.1 ppm。
Embodiment 2：The preparation of compound 2 ~ 11
In addition to using corresponding raw material, with the identical method prepare compound 2 ~ 11 of embodiment 1：
1H NMR (400 MHz, (CD3)2SO): δ 11.55 (brs, 1H), 7.67 (d, J=2.4 Hz, 1H),
7.41 (d, J=8.8 Hz, 1H), 7.08(t, J=7.8 Hz, 1H), 6.88 (d, J=2.4 Hz, 1H), 6.84
(d, J=2.4 Hz, 1H), 6.82 (d, J=2.8 Hz, 1H), 6.73-6.67 (m, 3H), 3.70 (s, 3H),
3.62 (s, 3H) ppm。
13 32δ 159.7, 154.3, 135.2, 133.4, 131.6, 130.3, 129.9, 120.2, 113.8,
113.0, 112.2, 110.9, 100.6, 94.5, 55.3, 54.9 ppm。
Yield 90%, purity（HPLC）：99.1%.
1H NMR (400 MHz, (CD3)2SO): δ 11.58 (brs, 1H), 7.63 (d, J=2.4 Hz, 1H),
7.43 (d, J=8.8Hz, 1H), 7.10-7.06 (m, 1H), 6.94 (dd, J=8.2 Hz, 1H), 6.85-6.81
(m, 2H), 7.68-7.64 (m, 1H), 6.50-6.47 (m, 1H), 3.88 (s, 3H), 3.68 (s, 3H)
ppm. 13C NMR (100 MHz, (CD3)2SO): δ 155.6, 154.3, 133.8, 131.8, 130.6, 127.0,
126.3, 122.8, 121.3, 113.0, 112.2, 110.5, 100.5, 92.5, 55.7, 55.3 ppm。
Yield 87%, purity（HPLC）：99.2%.
Yield 90%, MS (ESI):[M+H]=334.04.
1H NMR (400 MHz, (CD3)2SO): δ 11.43 (brs, 1H), 7.65 (d, J=2.8 Hz, 1H),
7.47 (dd, J=5.2 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.23 (dd, J=3.6 Hz, 1H),
7.06 (d, J=2.4 Hz, 1H), 6.94 (dd, J=5.2 Hz, 1H), 6.82 (dd, J=8.8 Hz, 1H),
3.77 (s, 3H) ppm. 13C NMR (100 MHz, (CD3)2SO): δ 154.2, 132.3, 132.0, 131.2,
129.7, 128.0, 127.5, 112.8, 112.1, 100.7, 97.8, 55.3 ppm。
Yield 81%.
1 32 δ 11.43 (brs, 1H), 7.64 (d, J=2.8 Hz, 1H), 7.47 (dd, J=5.2 Hz,
1H), 7.37 (d, J=8.8 Hz, 1H), 7.22 (dd, J=2.8 Hz, 1H), 6.95 (d, J=2.8 Hz, 1H),
6.93 (dd, J=4.8 Hz, 1H), 6.82 (dd, J=8.8 Hz, 1H), 3.73 (s, 3H) ppm. 13C NMR
(100 MHz, (CD3)2SO): δ 154.1, 132.3, 131.4, 130.0, 129.8, 127.0, 126.2, 122.9,
112.8, 112.0, 100.6, 95.9, 55.3 ppm。
Yield 75%.
1 32 δ 11.5 (brs, 1H), 7.67 (d, J=2.4 Hz, 1H) 7.39 (d, J=8.8 Hz, 1H),
6.91 (d, J=2.4 Hz, 1H), 6.84 (dd, J=8.8 Hz, 1H), 6.76-6.75 (m, 3H), 5.93 (s,
2H), 3.72 (s, 3H) ppm. 13C NMR (100 MHz, (CD3)2SO): δ 154.2, 147.9, 146.0,
133.0, 131.5, 130.2, 125.0, 122.2, 112.9, 112.1, 109.5, 109.0, 101.0, 1006,
95.8, 55.3 ppm。
Yield 90%, purity（HPLC）：99.1%.
1H NMR (400 MHz, (CD3)2SO): δ 11.64 (brs, 1H), 8.27 (d, J=8.4 Hz, 1H),
7.92 (d, J=8.0 Hz, 1H), 7.77 (d, J=2.8 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.63
(t, J=7.2 Hz, 1H), 7.56 (t, J=7.2 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.22 (t, J
=7.8 Hz, 1H), 7.10 (d, J=6.8 Hz, 1H), 6.88-6.83 (m, 2H), 3.64 (s, 3H) pp.13CNMR (100 MHz, (CD3)2SO): δ 154.6, 133.8, 132.6, 132.1, 132.0, 130.7, 128.9,
126.9, 126.7, 126.5, 126.4, 125.5, 113.5, 112.6, 100.9, 94.1, 55.6 ppm。
Yield 85%, purity（HPLC）：99.1%.
1H NMR (400 MHz, (CD3)2SO): δ 11.22 (brs, 1H), 7.31 (d, J=8.8Hz, 1H), 7.25
(d, J=2.4 Hz, 1H), 7.20-7.12 (m, 3H), 7.07-7.05 (m, 2H), 6.84 (d, J=2.4 Hz,
1H), 6.77 (dd, J=8.8 Hz, 1H), 3.86 (s, 2H), 3.72 (s, 3H) ppm. 13CNMR (100 MHz,
(CD3)2SO): δ153.9,140.0, 132.0, 131.2, 130.5, 128.1, 126.3, 112.5, 111.9,
100.5, 96.2, 55.2, 31.8 ppm。
Yield 67%.
1 32 δ 11.20 (brs, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H),
7.00 (d, J=2.4 Hz, 1H), 6.80 (dd, J=8.8 Hz, 1H), 3.79 (s, 3H), 2.12(s, 3H)
ppm. 13CNMR (100 MHz, (CD3)2SO): δ153.9, 131.3, 130.7, 130.0, 112.6, 111.9,
100.6, 97.1, 55.3, 8.9 ppm。
Yield 77%.
1 32 δ 11.26 (brs, 1H), 7.41 (d, J=2.4 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H),
7.01 (d, J=8.4 Hz, 1H), 6.79 (dd, J=8.6 Hz, 1H), 3.77 (s, 3H), 2.96-2.89 (m,
1H), 1.90-1.86 (m, 2H), 1.66-1.61 (m, 2H), 1.50-1.46 (m, 2H), 1.40-1.36 (m,
3H) ppm. 13CNMR (100 MHz, (CD3)2SO): δ 153.9, 132.6, 131.4, 131.3, 112.5,
111.6, 101.1, 94.9, 55.3, 42.0, 33.9, 26.2, 25.2 ppm。
Yield 70%.
Embodiment 3：The preparation of compound 12
By heteroaromatic compounds C（0.2mmol）, symmetrical diselenide D（0.12mmol）, FIrPic (0.004 mmol) is molten
Agent is placed in transparent glass tube in 20 mL anhydrous acetonitriles, under air conditions, is irradiated under blue LED lamp.Period lamellae
Chromatography detects extent of reaction, and after heteroaromatic compounds I is wholly absent, decompression removes solvent, residue preparation column chromatography point
From（Silica gel is filling, and washing and dehydrating integrated machine is petroleum ether:Ethyl acetate=30:1 isocratic elution.）, you can obtain pure asymmetric selenium
Ether compound 12, yield 91%.
1 32 δ 11.58 (brs, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.34 (d, J=7.6 Hz, 1H),
7.15-7.16 (m, 6H), 7.05-7.00 (m, 1H), 2.87 (t, J=7.6 Hz, 2H), 1.67-1.60 (m,
2H), 1.24-1.15 (m, 6H), 0.78 (t, J=7.0 Hz, 3H) ppm. 13CNMR (100 MHz, (CD3)2SO): δ 145.9, 136.1, 133.9, 130.5, 129.0, 127.7, 125.3, 121.3, 119.8, 118.5,
111.3, 93.3, 30.9, 29.1, 28.2, 26.7, 21.9, 13.8 ppm。
Embodiment 4：The preparation of compound 13,14
Except using in addition to corresponding raw material, with the identical method prepare compound 13,14 of embodiment 1,：
1H NMR (400 MHz, (CD3)2SO): δ 11.90 (brs, 1H), 7.84 (d, J=2.4 Hz, 1H),
7.53 (d, J=8.8 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.20-7.10 (m, 6H) ppm. 13CNMR
(100 MHz, (CD3)2SO): δ 135.2, 134.6, 133.3, 130.9, 129.2, 128.2, 128.1, 125.8,
124.9, 122.1, 118.0, 113.9, 94.8 ppm。
Yield 84%.
1 32 δ 7.50 (d, J=8.4 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.19-7.04 (m,
7H), 3.78 (s, 3H), 2.53 (s, 3H) ppm. 13CNMR (100 MHz, (CD3)2SO): δ 143.1,
137.1, 133.7, 129.8, 129.1, 127.9, 125.5, 121.4, 120.1, 118.6, 109.8, 93.5,
30.4, 11.6 ppm。
Yield 83%.
Embodiment 5：The preparation of compound 15 ~ 18
In addition to using corresponding raw material, with the identical method prepare compound 20`23 of embodiment 1：
1H NMR (400 MHz, (CD3)2SO): δ 11.55 (brs, 1H), 7.69 (d, J=2.8 Hz, 1H),
7.24-7.20 (m, 2H), 7.06-7.01 (m, 2H), 6.89 (d, J=2.4 Hz, 1H), 6.84 (dd, J=8.8
Hz, 1H), 3.71 (s, 3H) ppm. 13C NMR (100 MHz, (CD3)2SO): δ 162.0 (d, J=241 Hz),
154.3, 133.2, 131.6, 130.3, 130.2, 130.1, 128.6(d, J=2 Hz), 116.2 (d, J=21
Hz), 113.0 (d, J=79 Hz), 100.5, 95.0, 55.3 ppm。
Yield 83%.
1 32 δ 11.69 (brs, 1H), 7.73 (d, J=2.8 Hz, 1H), 7.59 (d, J=8.4 Hz, 2H),
7.44 (d, J=8.4Hz, 1H) 7.28-7.26 (m, 2H), 6.87 (d, J=2.4 Hz, 1H), 6.85 (dd, J=
10.2 Hz, 1H), 3.69 (s, 3H) ppm. 13C NMR (100 MHz, (CD3)2SO): δ 154.5, 142.6,
133.8, 132.4, 131.7, 129.9, 127.9, 118.9, 113.2, 112.4, 107.7, 100.2, 92.9,
55.3 ppm。
Yield 78%.
1 32 δ 11.25 (brs, 1H), 7.47 (d, J=2.8 Hz, 1H), 7.30 (d, 8.4 Hz, 1H),
7.11-7.04 (m, 3H), 6.75-6.72 (m, 2H), 3.66 (s, 3H), 2.56 (s, 6H) ppm. 13C NMR
(100 MHz, (CD3)2SO): δ 153.7, 141.8, 132.0, 131.2, 130.8, 129.9, 128.0, 127.7,
112.6, 111.6, 100.7, 97.0, 55.0, 24.1 ppm。
Yield 83%.
18
Embodiment 6：The preparation of compound 18
In addition to using corresponding raw material, with the identical method prepare compound 18 of embodiment 3：
1H NMR (400 MHz, (CD3)2SO): δ 11.55 (brs, 1H), 7.68 (d, J=2.8 Hz, 1H),
7.43-7.34 (m, 3H), 7.32-7.28 (m, 2H), 7.27 (d, J=5.2 Hz, 1H), 7.17-7.09 (m,
5H), 6.99 (d, J=2,4 Hz, 1H), 6.92 (dd, J=4.8 Hz, 1H), 5.03 (s, 3H) ppm. 13CNMR
(100 MHz, (CD3)2SO): δ 153.2, 137.5, 133.8, 133.4, 131.7, 130.3, 129.1, 128.3,
128.2, 127.6, 125.6, 112.9, 112.8, 102.2, 94.7, 69.7 ppm。
Embodiment 7：The anti tumor activity in vitro test of the compound of the present invention
External activity test method and result are as follows：
Wherein, clinical common antitumor drug adriamycin is selected（ADM）For positive control experiment group.
Antitumor activity body outer screening test -1
Using using tetrazolium（micoculture tetrozolium,MTT）Reduction method research the compounds of this invention 1 ~ 24 with
10 μ g/mL dosage are to cell line BGC823 cell line SGC-7901cell line, human oral cavity epithelial cancer cell line KB cell
The inhibitory action of line, human fibrosarcoma cell strain HT-1080cell line, when action time is respectively 72 small, the present inventionization
Inhibiting rate of the compound 1 ~ 21 with 10 μ g/mL dosage to above-mentioned three kinds of tumour growths（%）As shown in table 1.
Table 1, the inhibiting rate with 10 μ g/mL dosage to above-mentioned three kinds of tumour growths（%）：
Embodiment 8：Antitumor activity test in the animal body of the compound of the present invention
Selection the compounds of this invention 1, compound 2, compound 7, compound 11, compound 15 and compound 21 have carried out animal body
Interior antitumor activity test, model used are mouse S-180 sarcoma models, and positive control medicine is clinical common antineoplastic
Thing fluorouracil（Fluorouracil）.
Experimental method：18-22 grams of female KM mouse and the S-180 knurl kinds of well-grown 7-11 days are selected, by knurl
Cell suspension is made in tissue, and it is subcutaneous to be seeded to right side of mice armpit, the cell of about 1.0-2.0 × 106/only, when inoculation 24 is small after with
Machine divides cage, continuous 7 days of intraperitoneal injection.Animal is put to death when 24 is small after drug withdrawal, is weighed, knurl weight, each group is calculated and is averaged knurl weight,
Tumor control rate is obtained as follows and is carried outtExamine.
Tumor control rate=[(blank control group be averaged knurl weight-treatment group be averaged knurl weight)/(blank control group be averaged knurl weight)]
× 100%
Experimental result is shown in Table -2.
Table 2
Other of the invention compounds use similar experimental study its to antitumor activity in animal body, find chemical combination of the present invention
Thing 3`6 and 8 ~ 10 and 20 ~ 21 pairs of mouse tumor inhibiting rates reach more than 68%, and compound 12`14 suppresses mouse tumor
Rate is in the range of 65% ~ 69%.
Embodiment 9：Acute toxicity preliminary test in the animal body of the compound of the present invention
Selection compound 1, compound 2, compound 7, compound 11, compound 15 and compound 21 have carried out acute in animal body
Toxotest.Each 10 of 18-22 grams of female KM mouse is selected, respectively intraperitoneal injection compound 1, compound 2, chemical combination
After thing 7,21 each 500mg/kg of compound 11, compound 15 and compound, there is autogenic movement suppression, writhing, and weight is increased
The suppression of length, food ration, water intake, but have no dead mouse.It is discontinued after a few days, surviving animals recover normal.Intraperitoneal administration
LD50 values are more than 500mg/kg.
Claims (11)
1. the (hetero) aryl indole base selenide compounds and its pharmaceutically acceptable salt of general formula I：
,
Wherein, R1Selected from H, C1~C6Alkyl, benzyl, phenyl and to Methyl benzenesulfonyl base；
R2Selected from H, C1~C6Alkyl, benzyl, phenyl and C1~C6Alkoxy carbonyl；
R3For H, halogen, cyano group, C1~C6Alkyl, C1~C6Alkoxy, C1~C6Alkoxyalkyl, phenyl, amino, benzyl, C1~C6Alkane
Benzyl, the C of base substitution1~C6Benzyl, benzyl, the C of amino substitution of alkoxy substitution1~C6Benzyl, two C of alkyl amino substitution1~
C6Benzyl, the C of alkyl amino substitution1~C6Benzyl, the benzyl or COR of nitro substitution of amide groups substitution4, wherein R4For C1~C6Alkane
Base, C1~C6Alkoxy, C1~C6Alkoxyalkyl, amino or benzyl；
R for phenyl, pyridine radicals, thienyl, benzyl, carbazyl, naphthyl, C1~C6Alkyl, C5~C8Cycloalkyl or by one or
The phenyl of multiple substituents substitution, pyridine radicals, thienyl, benzyl, the substituent is selected from C1~C6Alkyl, C1~C6Alkoxy,
Halogen, cyano group, nitro；Or two neighboring substituent is-OCH2O- is so as to form five-membered ring；Or two adjacent substituents
For-OCH2CH2O- is so as to form hexatomic ring.
2. compound according to claim 1, it is characterised in that the R1For H, C1~C6Alkyl or to Methyl benzenesulfonyl base；R2
For H, C1~C6Alkyl or C1~C6Alkoxy carbonyl；R3For H, phenyl, halogen, cyano group or C1~C6Alkoxy carbonyl group.
3. compound according to claim 2, it is characterised in that the R is phenyl, C1~C6Phenyl, the C of alkoxy substitution1~
C6Alkyl-substituted phenyl, the phenyl of halogen substitution, phenyl, pyridine radicals, the C of cyano group substitution1~C6The pyridine radicals of alkoxy substitution,
Thienyl, benzyl, carbazyl, naphthyl, C1~C6Alkyl, cyclohexyl, or。
4. compound according to claim 1, it is characterised in that the R is phenyl；R1For H or to Methyl benzenesulfonyl base；R2
For H, methyl, n-pentyl or methoxycarbonyl group；R3For H, methyl, phenyl or Cl.
5. compound according to claim 1, it is characterised in that the R is phenyl, 4-F- phenyl, the 4- of methoxy substitution
Cvano-phenyl, 2,5, -3,5-dimethylphenyl, pyridine radicals, 2- methoxypyridines base, 2- thienyls, 3- thienyls, naphthyl, first
Base, cyclohexyl, benzyl or。
6. according to any one of claim 1 ~ 5 compound, it is：
。
7. compound according to claim 6, it is characterised in that the pharmaceutically acceptable salt is formed for the analog derivative and acid
Salt, the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid, malic acid.
8. the purposes of any one of a kind of claim 1 ~ 6 compound, it is characterised in that be used to prepare antitumor drug.
9. a kind of pharmaceutical composition, pharmaceutically acceptable comprising claim 1 ~ 7 any one of them compound and at least one
Excipient.
10. the preparation method of compound described in a kind of claim 1, including：By heteroaromatic compounds II and symmetrical diselenide
Compound III irradiates reaction generation under blue LED lamp：
；
Wherein R1, R2, R3, R are as defined above.
11. method according to claim 10, it is characterised in that the heteroaromatic compounds II and symmetrical diselenide chemical combination
Thing III reactions production compound I is in FIrPic（Double (4,6- difluorophenyl pyridinatos-N, C2) pyridinecarboxylics close iridium）It is existing
Under the conditions of carry out.
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|---|---|---|---|---|
| CN103641767A (en) * | 2013-11-22 | 2014-03-19 | 沈阳药科大学 | Substituted phenylindolyl selenide, selenoxide, selenone and application as tumor cell proliferation inhibitor |
| CN104387311A (en) * | 2014-12-03 | 2015-03-04 | 温州大学 | Synthetic method of 3-arylselanyl indole compound |
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| CN103641767A (en) * | 2013-11-22 | 2014-03-19 | 沈阳药科大学 | Substituted phenylindolyl selenide, selenoxide, selenone and application as tumor cell proliferation inhibitor |
| CN104387311A (en) * | 2014-12-03 | 2015-03-04 | 温州大学 | Synthetic method of 3-arylselanyl indole compound |
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| CN111848488A (en) * | 2020-06-19 | 2020-10-30 | 温州医科大学 | Method for synthesizing 3-selenoindole derivative |
| CN111848488B (en) * | 2020-06-19 | 2022-12-27 | 温州医科大学 | Method for synthesizing 3-selenoindole derivative |
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