CN107987004B - Aryl indolyl selenoethers - Google Patents
Aryl indolyl selenoethers 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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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- 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
Abstract
The invention provides an aryl indolyl selenide compound. Also provides a preparation method of the compound and application of the compound in preparing antitumor drugs. The aryl indolyl selenide compounds provided by the invention are 3-aryl selenoindole compounds, which have good antitumor activity, and especially have significant inhibiting effect on human gastric adenocarcinoma cell line SGC-7901cell line, human oral epithelial cancer cell line KB cell line and human fibroma cell line HT-1080cell line; moreover, the preparation method provided by the invention is simple and feasible, and has high yield and purity.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an aryl indolyl selenide compound, a preparation method of the compound and application of the compound in preparing anti-tumor medicines.
Background
A large number of researches show that a plurality of organic selenium compounds not only have the effects of resisting virus and tumors and treating diseases in the aspect of nervous system, but also have the pharmacological effects of resisting inflammation and aging, preventing and treating cardiovascular diseases, preventing liver diseases and the like. For example, Ebselen and selezofurn are two representative drugs undergoing clinical research.
The aryl organic selenium ether compounds, especially the 3-aryl selenium indole compounds, have good application potential and value in a plurality of fields, for example, some compounds have pharmacological activities such as anti-tumor, anti-inflammatory and antiviral activities, and are also important intermediates for preparing other drugs with anti-tumor, anti-inflammatory and antiviral activities.
CN103641767A discloses substituted phenyl indolyl selenide, selenoxide, selenone compound, pharmaceutically acceptable salt formed by the compound with the structural formula and hydrate thereof, wherein the pharmaceutically acceptable salt comprises salt formed by the derivative and acid. Pharmacological activity test results show that the derivatives have good tumor inhibition activity, can be used as tumor cell proliferation inhibitors, and have certain application in the aspect of preparing anti-tumor medicaments.
CN103191121A discloses an antitumor drug bis (quinazolin-4-yl) diselenide or a pharmaceutically acceptable salt thereof, which has excellent proliferation inhibition effect on treating and preventing various benign or malignant tumors, particularly non-small cell lung cancer and breast cancer cells, and shows good anticancer activity.
At present, a large number of methods for synthesizing selenide compounds have been developed.
Vieira, Beatriz M et al ("Sonochhemistry: An organic alkaline to the synthesis of 3-selylindoles using CuI as a catalyst", Ultrasonics Sonochhemistry, Volume: 27, Pages: 192-.
Azeredo, Juliano et al (". A Solvent-and Metal-Free Synthesis of 3-Chalcogenyl-alcohols extrusion DMSO/I) 2 As an Eco-friendly Catalytic Oxidation System ", Journal of Organic Chemistry, Volume: 79, Issue: 9, Pages: 4125-4130, Journal) discloses the following as I 2 The method for preparing the 3-aryl selenium indole compound by taking DMSO as an oxidant without a solvent comprises the following steps:
alain Krief et al ("Reaction of Organic Selenocyanates with Hydroxides: The One-Point Synthesis of Dialkyl Diselenides from Alkyl amides", Angew. chem. int. Ed.,2000,39(9), 1669-: R-Se-CN reacts with M-OR 'to generate R-Se-M firstly, and then the R-Se-M reacts with the R-Se-CN OR reacts with oxygen to obtain R-Se-Se-R, wherein R is aryl OR alkyl, R' is methyl OR ethyl, and M is Na OR K.
Devender Singh et al ("Eco-friendly cross-linking of di-aryl and alkyl bromides with CuO nanopowder in ionic liquid", Green chem.,2009,11,1521- 2 ) Coupling reaction is carried out to obtain the aryl monoselenide.
Freetas et al ("Synthesis of aryl sugars using electrophoretic reactants in ionic liquids", Green chem.,2011,13,2931-2938) disclose electrophilic compounds Ar-Se-Cl (Br) and nucleophilic compounds aryl boronic acids (Ar1-B (OH)2) or aryl borates (Ar-BF 2938) 3 K) Under the catalysis of ionic liquid, the aryl monoselenide compound Ar-Se-Ar is obtained.
Debasish Kundu et al ("Microwave-assisted reaction of aryl diaryl fluoroborates and aryl dichalcogenides in dimethyl carbonates: a general procedure for the synthesis of acyclic diaryl carbonates", Green chem.,2012,14, 2024. sup. 2030) disclose diazotized fluoroborates (Ar-N-fluoroborates) with the aid of microwaves and in the presence of Zn 2 BF 4 ) With diarylchalcogenides (Ar) 2 X 2 X = S, Se, Te) in dimethyl carbonate to give the asymmetric diaryl chalcogenide Ar1-X-Ar 2.
Tanmay Chatterjee et al "(Solvent-Controlled Hlao-Selective hydrogenation of Aryl Halides Catalyzed by Cu (II) Supported on Al2O3.A General Protocol for the Synthesis of asymmetric organic Mono-and Bis-selectides") disclose that R-X (R is Aryl, vinyl, heteroaryl; X is halogen) reacts with R '-Se-Se-R' (R 'is Aryl, alkyl, heteroaryl) under the action of Cu-alumina to obtain R-Se-R'.
CN104387311B discloses a method for synthesizing a 3-arylselenoindole compound, which comprises the steps of taking copper oxide, cuprous iodide, cuprous bromide, cuprous chloride and the like as catalysts in an organic solvent, and reacting a halogenated aryl compound with simple substance Se and indole compounds in the presence of alkali (such as cesium carbonate, potassium carbonate and the like) to synthesize the 3-arylselenoindole compound.
CN103724246B discloses a synthesis method of aryl monoselenide compound, which takes a copper compound as a catalyst, and reacts aryl boronic acid compound with elemental selenium (Se) in a reaction solvent in the presence of an oxidant and an organic ligand to prepare the aryl monoselenide compound in one step.
Malignant tumors are serious diseases threatening human health and life, and are one of the main lethal causes in China. The search and discovery of new drugs for treating and preventing tumors is a hot research direction in the world.
Disclosure of Invention
The invention aims to provide an arylindolyl selenide compound with a novel structure and potential anti-tumor activity and a preparation method thereof.
In a first aspect, the present invention provides arylindoylseleno ethers of the general formula I:
wherein R is 1 Selected from H, C 1 ~C 6 Alkyl, benzyl, phenyl and p-toluenesulfonyl;
R 2 selected from H, C 1 ~C 6 Alkyl, benzyl, phenyl and C 1 ~C 6 An alkoxycarbonyl group;
R 3 is H, halogen, cyano, C 1 ~C 6 Alkyl radical, C 1 ~C 6 Alkoxy radical, C 1 ~C 6 Alkoxyalkyl, phenyl, amino, benzyl, C 1 ~C 6 Alkyl-substituted benzyl, C 1 ~C 6 Alkoxy-substituted benzylRadical, amino-substituted benzyl, C 1 ~C 6 Alkylamino substituted benzyl, di-C 1 ~C 6 Alkylamino substituted benzyl, C 1 ~C 6 Amido-substituted benzyl, nitro-substituted benzyl or COR 4 Wherein R is 4 Is C 1 ~C 6 Alkyl radical, C 1 ~C 6 Alkoxy radical, C 1 ~C 6 Alkoxyalkyl, amino, or benzyl;
r is phenyl, pyridyl, thienyl, benzyl, naphthyl, C 1 ~C 6 Alkyl radical, C 5 ~ C 8 Or phenyl, pyridyl, thienyl, benzyl substituted with one or more substituents selected from C 1 ~C 6 Alkyl radical, C 1 ~C 6 Alkoxy, halogen, cyano, nitro; or two adjacent substituents are-OCH 2 O-thereby forming a five-membered ring; or two adjacent substituents are-OCH 2 CH 2 O-thereby forming a six-membered ring.
In the above compound, preferably, the R is 1 Is H, C 1 ~C 6 Alkyl or p-toluenesulfonyl; r 2 Is H, C 1 ~C 6 Alkyl or C 1 ~C 6 An alkoxycarbonyl group; r 3 Is H, phenyl, halogen, cyano or C 1 ~C 6 An alkoxycarbonyl group.
In the above compound, preferably, R is phenyl or C 1 ~C 6 Alkoxy-substituted phenyl, C 1 ~C 6 Alkyl-substituted phenyl, halogen-substituted phenyl, cyano-substituted phenyl, pyridyl, C 1 ~C 6 Alkoxy-substituted pyridyl, thienyl, benzyl, naphthyl, C 1 ~C 6 Alkyl, cyclohexyl, or
。
In another aspect, the compound of formula I, preferably, R is phenyl; r is 1 Is H or p-toluenesulfonyl; r is 2 Is H, methyl, n-pentyl or methoxycarbonyl; r 3 Is H, APhenyl or Cl.
In another embodiment, preferably, R is methoxy-substituted phenyl, 4-F-phenyl, 4-cyano-phenyl, 2, 5-dimethylphenyl, pyridyl, 2-methoxypyridyl, 2-thienyl, 3-thienyl, naphthyl, methyl, cyclohexyl, benzyl or
。
Most preferably, the compounds of formula I according to the present invention are:
the compound also comprises pharmaceutically acceptable salts formed by the compound and hydrates thereof, and the pharmaceutically acceptable salts comprise salts formed by the compound and acid. The acid can be hydrochloric acid, inorganic acids such as sulfuric acid, phosphoric acid and hydrobromic acid, and organic acids such as acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid and malic acid.
In a second aspect, the invention also provides application of the compound shown in the general formula I in preparation of antitumor drugs. Wherein, the tumor includes but is not limited to pancreatic cancer, advanced solid tumor, ovarian tumor, non-small cell lung cancer, breast cancer, bladder cancer, cervical cancer, mesothelioma, esophageal cancer, gastric cancer, colorectal cancer, liver cancer, bile duct cancer, nasopharyngeal cancer, testicular cancer, lymphoma or head and neck cancer; more preferably, the cancer comprises pancreatic cancer, advanced solid tumors, ovarian tumors, breast cancer.
In a third aspect of the invention, there is provided a pharmaceutical composition comprising a compound provided herein and at least one pharmaceutically acceptable excipient. The pharmaceutical composition can be administered orally or parenterally, including intravenous, subcutaneous, intraperitoneal, intramuscular, inhalation, rectal, and topical (e.g., buccal or sublingual) administration.
Wherein, the pharmaceutical composition for oral administration comprises tablets, capsules, granules or suspensions; tablets for oral administration comprise the composition provided by the invention as active ingredient and may further comprise one or more pharmaceutically acceptable excipients, such as diluents, disintegrants, binders, lubricants, sweeteners, flavoring agents, pigments and preservatives. When corn starch and alginic acid are used as disintegrating agents, suitable inert diluents include sodium carbonate, calcium carbonate, sodium phosphate, calcium phosphate and lactose. The binder comprises starch and gelatin, and optionally the lubricant is magnesium stearate, stearic acid or talc. Optionally, the tablets may also be coated with glyceryl monostearate or glyceryl distearate to retard absorption in the stomach.
Capsules for oral administration include hard capsules and soft capsules, wherein the hard capsules comprise the composition provided by the present invention as an effective active ingredient and a solid diluent; soft capsules comprise the pharmaceutical composition provided by the present invention as an effective active ingredient, together with water or oil (such as peanut oil, liquid paraffin, or olive oil).
Suppositories in the form of preparations for rectal administration, where the base of the suppository may be cocoa butter or a salicylate.
Formulations for vaginal administration are in the form of pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing the active ingredient in association with such carriers as are known in the art to be conventional.
In the form of intravenous, intraperitoneal, subcutaneous and intramuscular administration, the compositions provided herein are typically sterile solutions or suspensions, and have appropriate pH and osmotic pressure. The preparation of the preparation can be prepared according to the conventional method known in the field.
In a fourth aspect of the present invention, there is provided a process for the preparation of a compound of formula I, comprising: the aromatic heterocyclic compound II and the symmetric diselenide compound III are irradiated and reacted under a blue LED lamp, preferably 400 nm-480 nm, more preferably 450nm LED lamps to generate:
wherein R1, R2, R3, R are as defined above.
Preferably, the preparation method of the compound of the general formula I comprises the following steps: the aromatic heterocyclic compound II and a symmetric diselenide compound III are irradiated under a blue LED lamp and react in the presence of FIrPic (bis (4, 6-difluorophenylpyridine-N, C2) pyridine formyl iridium).
The blue light LED lamp is an LED lamp with the wavelength of 400 nm-480 nm, and preferably an LED lamp with the wavelength of 450 nm.
Further, in the above method, preferably, the reaction molar ratio of the aromatic heterocyclic compound II to the symmetric diselenide compound III is 2: 1-2; more preferably 2:1.2, wherein the reaction molar ratio of the aromatic heterocyclic compound II to the symmetric diselenide compound III is 2: 1-2, preferably 2:1.2, and the molar ratio of the aromatic heterocyclic compound II to the FIrPic is 200-50: 1, preferably 50: 1. Preferably, the organic solvent is Dichloroethane (DCE), Dimethylsulfoxide (DMSO), N Dimethylformamide (DMF), Tetrahydrofuran (THF), dichloromethane, acetone, acetonitrile or a mixed solution thereof, and more preferably, the reaction solvent is anhydrous acetonitrile, DCE or acetone.
In another preferred embodiment, the above process may be operated as follows: the preparation method comprises the following steps of (1) putting an aromatic heterocyclic compound II, a symmetrical diselenide III and a FIrPic solvent in an organic solvent (such as anhydrous acetonitrile, dichloroethane, acetone or a mixed solution thereof), wherein the reaction molar ratio of the aromatic heterocyclic compound II to the symmetrical diselenide III is 2: 1-2, preferably 2:1.2, and the reaction molar ratio of the aromatic heterocyclic compound II to the FIrPic is 200-50: 1, preferably 50:1, placing the mixture in a transparent glass tube, and irradiating the transparent glass tube under a blue LED lamp. Detecting reaction progress by thin layer plate chromatography (TLC), removing solvent under reduced pressure after the aromatic heterocyclic compound II disappears completely, and separating the residue by preparative column chromatography (such as silica gel as filler, and washing and dehydrating machine such as petroleum ether and ethyl acetate) to obtain pure asymmetric selenide compound I.
The aryl indolyl selenide compounds with the general formula I and the pharmaceutically acceptable salts thereof have good anti-tumor activity, and especially have obvious inhibition effect on human gastric adenocarcinoma cell strain SGC-7901cell line and human oral epithelial carcinoma cell strain KB cell line; moreover, the preparation method provided by the invention is simple and feasible, and has high yield and purity.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The present invention is described in detail below with reference to specific examples, but the use and purpose of these exemplary embodiments are merely to exemplify the present invention, and do not set forth any limitation on the actual scope of the present invention in any form, and the scope of the present invention is not limited thereto.
In the following examples, each abbreviation refers to the following specific meaning:
me: a methyl group; MeO: a methoxy group; ph: a phenyl group; bn: a benzyl group; the FIrPic structural formula is as follows:
the reagents used in the present invention are all commercially available.
Example 1: preparation of Compound 1
The heteroaromatic compound A (0.2 mmol) and the symmetric diselenide B (0.12 mmol) are placed in 2mL of anhydrous acetonitrile in a transparent glass tube and irradiated under an LED lamp with the wavelength of 450nm under the air condition. During the reaction, thin-layer plate chromatography is used for detecting the reaction progress, after the aromatic heterocyclic compound 1a completely disappears, the solvent is removed under reduced pressure, and the residue is separated by preparative column chromatography (silica gel is used as filling, and eluent is petroleum ether and ethyl acetate), so that the pure asymmetric selenide compound 1 can be obtained, the yield is 93%, and the purity (HPLC): 99.3 percent.
Nuclear magnetic data: 1 H NMR (400 MHz, (CD 3 ) 2 SO): 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. 13 C NMR (100 MHz, (CD 3 ) 2 SO): 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。
example 2: preparation of Compounds 2 to 11
Compounds 2 to 11 were prepared in the same manner as in example 1, except that the corresponding starting materials were used:
1 H NMR (400 MHz, (CD 3 ) 2 SO): 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 32 δ 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 percent.
1 H NMR (400 MHz, (CD 3 ) 2 SO): 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. 13 C NMR (100 MHz, (CD 3 ) 2 SO): 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 percent.
Yield 90%, ms (esi) [ < M + H ] = 334.04.
1 H NMR (400 MHz, (CD 3 ) 2 SO): 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. 13 C NMR (100 MHz, (CD 3 ) 2 SO): 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。
The yield thereof was found to be 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. 13 C NMR (100 MHz, (CD 3 ) 2 SO): 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。
The yield thereof was found to be 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. 13 C NMR (100 MHz, (CD 3 ) 2 SO): 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 percent.
1 H NMR (400 MHz, (CD 3 ) 2 SO): 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. 13 CNMR (100 MHz, (CD 3 ) 2 SO): 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 percent.
1 H NMR (400 MHz, (CD 3 ) 2 SO): 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. 13 CNMR (100 MHz, (CD 3 ) 2 SO): 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。
The yield thereof was found to be 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. 13 CNMR (100 MHz, (CD 3 ) 2 SO): δ153.9, 131.3, 130.7, 130.0, 112.6, 111.9, 100.6, 97.1, 55.3, 8.9 ppm。
The yield thereof was found to be 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. 13 CNMR (100 MHz, (CD 3 ) 2 SO): 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。
The yield thereof was found to be 70%.
Example 3: preparation of Compound 12
The heteroaromatic compound C (0.2 mmol), the symmetric diselenide D (0.12 mmol) and the FIrPic (0.004 mmol) are placed in a transparent glass tube in 20 mL of anhydrous acetonitrile and irradiated under a blue LED lamp under the air condition. During the reaction, the reaction progress is detected by thin-layer plate chromatography, after the aromatic heterocyclic compound I completely disappears, the solvent is removed under reduced pressure, and the residue is separated by preparative column chromatography (silica gel is used as a filler, and a washing and dehydrating machine is petroleum ether: ethyl acetate =30:1 isocratic elution.) to obtain the pure asymmetric selenide compound 12 with the yield of 91 percent.
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. 13 CNMR (100 MHz, (CD 3 ) 2 SO): 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。
Example 4: preparation of Compounds 13, 14
Compounds 13, 14 were prepared in the same manner as in example 1, except that the corresponding starting materials were used:
1 H NMR (400 MHz, (CD 3 ) 2 SO): 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. 13 CNMR (100 MHz, (CD 3 ) 2 SO): 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。
the yield thereof was found to be 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. 13 CNMR (100 MHz, (CD 3 ) 2 SO): 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。
The yield thereof was found to be 83%.
Example 5: preparation of Compounds 15 to 18
Compound 20' 23 was prepared in the same manner as in example 1, except that the corresponding starting materials were used:
1 H NMR (400 MHz, (CD 3 ) 2 SO): 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. 13 C NMR (100 MHz, (CD 3 ) 2 SO): 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。
the yield thereof was found to be 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. 13 C NMR (100 MHz, (CD 3 ) 2 SO): 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。
The yield thereof was found to be 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. 13 C NMR (100 MHz, (CD 3 ) 2 SO): 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。
The yield thereof was found to be 83%.
18
Example 6: preparation of Compound 18
Compound 18 was prepared in the same manner as in example 3, except that the corresponding starting materials were used:
1 H NMR (400 MHz, (CD 3 ) 2 SO): 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. 13 CNMR (100 MHz, (CD 3 ) 2 SO): 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。
example 7: in vitro antitumor Activity test of Compounds of the invention
In vitro activity test methods and results are as follows:
wherein, the common clinical antitumor drug Adriamycin (ADM) is selected as a positive control experimental group.
In vitro screening test for antitumor Activity-1
The inhibition effects of the compounds 1 to 24 on cell strains, namely human gastric adenocarcinoma cell strains SGC-7901cell line, human oral epithelial cancer cell strains KB cell line and human fibrosarcoma cell strains HT-1080cell line, are researched by adopting a tetrazolium salt (MTT) reduction method, wherein the dosage of 10 mu g/mL is used for inhibiting the growth of the three tumors, the action time is 72 hours, and the inhibition rates (%) of the compounds 1 to 21 on the growth of the three tumors are shown in Table 1, wherein the dosage of 10 mu g/mL is used for inhibiting the growth of the three tumors.
Table 1, inhibition (%) of the growth of the above three tumors at a dose of 10 μ g/mL:
example 8: in vivo anti-tumor Activity testing of Compounds of the invention in animals
The compound 1, the compound 2, the compound 7, the compound 11, the compound 15 and the compound 21 are selected to carry out in-vivo anti-tumor activity test on animals, the used model is a mouse S-180 sarcoma model, and the positive control drug is clinical common anti-tumor drug Fluorouracil (Fluorouracil).
The experimental method comprises the following steps: selecting 18-22 g female Kunming mice and S-180 tumor species with good growth for 7-11 days, preparing tumor tissue into cell suspension, inoculating the cell suspension to the subcutaneous part of the right axilla of the mouse, about 1.0-2.0 multiplied by 106 cells/mouse, randomly distributing cages after 24 hours of inoculation, and carrying out intraperitoneal injection for continuous 7 days. Killing the animals 24 hours after drug withdrawal, weighing the weight and tumor weight, calculating the average tumor weight of each group, calculating the tumor inhibition rate according to the following formula, and carrying outtAnd (6) checking.
Tumor inhibition rate = [ (average tumor weight in control blank-average tumor weight in treatment blank)/(average tumor weight in control blank) ] × 100%
The results are shown in Table-2.
TABLE 2
The other compounds of the invention are subjected to similar experimental study on the antitumor activity in an animal body, and the results show that the inhibition rates of the compounds 3 '6, 8-10 and 20-21 of the invention on the mouse tumor are all higher than 68%, and the inhibition rate of the compound 12' 14 on the mouse tumor is within the range of 65-69%.
Example 9: preliminary in vivo acute toxicity testing of Compounds of the invention in animals
Compound 1, compound 2, compound 7, compound 11, compound 15, and compound 21 were selected for acute toxicity testing in animals. After 10 female Kunming mice with 18-22 g are respectively subjected to intraperitoneal injection and administration of 500mg/kg of each of compound 1, compound 2, compound 7, compound 11, compound 15 and compound 21, spontaneous exercise inhibition and writhing occur, and the inhibition on weight gain, food intake and water intake is realized, but the mice do not die. After several days of drug withdrawal, the surviving animals returned to normal. The LD50 value of the intraperitoneal administration is more than 500 mg/kg.
Claims (6)
1. A method for preparing aryl indole selenide compounds of general formula I or pharmaceutically acceptable salts thereof comprises the following steps: the aromatic heterocyclic compound II and the symmetric diselenide compound III are irradiated and reacted under a blue LED lamp to generate the compound I, and the reaction of the aromatic heterocyclic compound II and the symmetric diselenide compound III is carried out under the condition that FIrPic exists:
wherein the FIrPic has the following structure:
wherein R is 1 Selected from H, C 1 ～C 6 Alkyl, benzyl, phenyl and p-toluenesulfonyl;
R 2 selected from H, C 1 ～C 6 Alkyl, benzyl, phenyl and C 1 ～C 6 An alkoxycarbonyl group;
R 3 is H, halogen, cyano, C 1 ～C 6 Alkyl radical, C 1 ～C 6 Alkoxy radical, C 1 ～C 6 Alkoxy-substituted alkyl, phenyl, amino, benzyl, C 1 ～C 6 Alkyl-substituted benzyl, C 1 ～C 6 Alkoxy-substituted benzyl, amino-substituted benzyl, C 1 ～C 6 Alkylamino substituted benzyl, di (C) 1 ～C 6 Alkylamino) substituted benzyl, C 1 ～C 6 Amido-substituted benzyl, nitro-substituted benzyl or COR 4 ；
R 4 Is C 1 ～C 6 Alkyl radical, C 1 ～C 6 Alkoxy radical, C 1 ～C 6 Alkoxy substituted alkyl, amino, or benzyl;
r is phenyl, pyridyl, thienyl, benzyl, carbazolyl, naphthyl, C 1 ～C 6 Alkyl radical, C 5 ～C 8 Or phenyl, pyridyl, thienyl, benzyl substituted with one or more substituents selected from C 1 ～C 6 Alkyl radical, C 1 ～C 6 Alkoxy, halogen, cyano, nitro; or two adjacent substituents are-OCH 2 O-thereby forming a five-membered ring; or two adjacent substituents are-OCH 2 CH 2 O-thereby forming a six-membered ring.
2. The method of claim 1, wherein R is 1 Is H, C 1 ～C 6 Alkyl or p-toluenesulfonyl; r 2 Is H, C 1 ～C 6 Alkyl or C 1 ～C 6 An alkoxycarbonyl group; r 3 Is H, phenyl, halogen, cyano or C 1 ～C 6 An alkoxycarbonyl group.
3. The method of claim 2, wherein R is phenyl, C 1 ～C 6 Alkoxy-substituted phenyl, C 1 ～C 6 Alkyl-substituted phenyl, halogen-substituted phenyl, cyano-substituted phenyl, pyridyl, C 1 ～C 6 Alkoxy-substituted pyridyl, thienyl, benzyl, carbazolyl, naphthyl, C 1 ～C 6 Alkyl, cyclohexyl, or
4. The method of claim 1, wherein R is phenyl; r 1 Is H or p-toluenesulfonyl; r 2 Is H, methyl, n-pentyl or methoxycarbonyl; r 3 Is H, methyl, phenyl or Cl.
5. The method of claim 1, wherein R is methoxy-substituted phenyl, 4-F-phenyl, 4-cyano-phenyl, 2, 5-dimethylphenyl, pyridyl, 2-methoxypyridyl, 2-thienyl, 3-thienyl, naphthyl, methyl, cyclohexyl, benzyl, or
6. The method of claim 1, wherein the arylindosylselenoethers of formula I are selected from the group consisting of:
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| Visible Light Photocatalyzed Direct Conversion of Aryl-/Heteroarylamines to Selenides at Room Temperature;Debasish Kundu等;《Organic Letters》;20140221;第16卷(第6期);10-11 * |
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