CN107311846B - Gem difluoroethyl substituted stilbene and diphenylethane derivatives, and preparation method and application thereof - Google Patents
Gem difluoroethyl substituted stilbene and diphenylethane derivatives, and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a diphenyl ethylene and diphenyl ethane derivative substituted by difluoroethyl and a preparation method and application thereof. The invention carries out chemical structure modification on the 4 'position of the B aromatic ring of diphenylethane/alkene by using geminal difluoroethyl, and simultaneously modifies the 2' position of the B aromatic ring into substituents such as nitryl or amino, and the like, the geminal difluoroethyl substituted diphenylethylene and diphenylethane derivatives have stronger in-vitro antitumor activity, and the antitumor activity of the trans structure is better than that of the cis structure, and the introduction of fluorine atoms not only changes the physical property of the compound, but also enhances the in-vitro antitumor activity, and has better inhibiting effect on various tumor cells.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a gem-difluoroethyl substituted stilbene and diphenylethane derivative, a preparation method and application thereof.
Background
Combretastatin A-4(CA-4) is a stilbene compound isolated from the south Africa shrub willow bark combretaum caffrum by Pettit et al, which can specifically recognize and destroy tumor blood vessels, so that tumor cells do not obtain enough nutrients to be starved. By acting on the colchicine binding site, CA-4 is able to inhibit the polymerization of tubulin and thereby prevent tumor blood flow. However, CA-4 and its derivatives have many defects, such as poor water solubility, unstable cis-structure, no activity of trans-structure, etc., which greatly hinder clinical trials. Therefore, much research work has been done around the structural modification of CA-4 analogues for a long time. In most cases, only the part of the A ring is reserved in the modification of the CA-4 structure, and the connecting bridge and the B ring are modified. Erianin, chemical name is 3,4, 5-trimethoxy-3 '-hydroxy-4' -methoxy diphenylethane (code: MLS), is a natural diphenylethane active component extracted from noble Chinese medicinal material dendrobe, structurally has common structural characteristics with stilbene natural product Combretastatin A-4 (code: CA4, also called windmill), has common ring structure AB, and is equivalent to CA4 with hydrogenated vinyl bridge. Like CA4, erianin is a tubulin inhibitor and has strong tumor blood vessel targeted disruption effect, acting on colchicine binding site. In addition, the literature reports that the antitumor effect of erianin can also be related to the induction of tumor cell apoptosis by acting on telomerase. We found that the 4-ethoxy Erianin (EBT) obtained by replacing the methoxy group at the 4-position of the ring B of erianin with ethoxy group has significantly improved antitumor activity compared with erianin and CA4 (wufanhong et al, an ethoxy diphenylethane derivative, its preparation method and use, international publication No. US2012/0046492a1), and it was determined by molecular docking technology simulation that it has better effect with the binding site of microcosmic protein autumn alkaloid. Because the cis-trans isomer does not change, the related physicochemical properties are more stable than that of CA4, the preparation process of the compound is simpler and more convenient, the synthesis yield is obviously improved, and the raw material loss and the unit synthesis cost are greatly reduced (a preparation method of 3,4, 5-trimethoxy-3 '-hydroxy-4' -alkoxy diphenylethane, Chinese patent CN 103539642A).
In recent years, fluorine-containing drugs have a large specific gravity among clinical therapeutic drugs, and introduction of fluorine atoms or fluorine-containing groups into small molecule drugs is one of important strategies for improving pharmaceutical activity. Fluorine atoms have the largest element electronegativity and atomic radius close to that of hydrogen atoms, and after the fluorine atoms or fluorine-containing groups are introduced into small molecule drugs, the molecular volume of the small molecule drugs is hardly influenced, but the physical and chemical properties of the small molecule drugs, including electronic effect and stereoscopic effect, biological activity, pharmacokinetic property, metabolic stability, interaction force between ligand and target protein, selectivity and the like, can be obviously influenced, and the lipophilicity of the small molecule drugs can be enhanced, so that the small molecule drugs can more easily permeate cell membranes, and the biological activity is further improved.
Most of the CA-4 fluorine-containing compounds studied before are mono-fluorine substituted and trifluoromethyl substituted, and no report is found on the gem-difluoroethyl substituted stilbene and diphenylethane derivatives.
Disclosure of Invention
The invention aims to provide a diphenyl ethylene and diphenyl ethane derivative substituted by difluoroethyl and a preparation method and application thereof. The derivative of the invention has high anti-tumor activity and has a vascular targeting effect on tumors.
The technical scheme of the invention is specifically introduced as follows.
The invention provides a gem-difluoroethyl substituted stilbene and diphenylethane derivative, which has a structure shown in a general formula (I):
wherein:
dotted line- - -represents a bond or is absent;
r is hydrogen, hydroxyl, nitryl, amino, phosphate, sulfate, phosphorylcholine, or amino acid side chain and water-soluble ammonium salt thereof; preferably, R is hydrogen, hydroxy, nitro, amino, -OPO3Na2、-NHCOCHCH2NH2Or is-NHCOCHNH2CH2OH; further preferably, RIs hydrogen, hydroxyl, nitro or amino.
The invention also provides a preparation method of the gem-difluoroethyl substituted stilbene and diphenylethane derivatives, which comprises the step of carrying out a Wittig reaction on 3,4, 5-trimethoxy benzyl bromide triphenyl phosphonium bromide and 4- (1, 1-difluoroethyl) benzaldehyde under the action of alkali to generate an olefin compound, or carrying out a Wittig reaction on 3,4, 5-trimethoxy benzyl bromide triphenyl phosphonium bromide and 4- (1, 1-difluoroethyl) -2 or 3-R substituted benzaldehyde under the action of alkali to generate an olefin compound. The synthetic route is shown as formula (II):
when the R functional group in the general formula (I) is an amino acid side chain, the R functional group is obtained by condensing a corresponding amino substance and an amino acid, and the synthesis equation is shown as the formula (III):
the invention further provides an application of the gem-difluoroethyl substituted stilbene and the diphenylethane derivatives in preparing a medicament for treating diseases caused by abnormal neovascularization; the diseases mainly comprise: rheumatic arthritis, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, psoriasis, rosacea, Kaposi's sarcoma, atopic keratitis, epidemic keratoconjunctivitis, neovascular glaucoma, bacterial ulcer, fungal ulcer, simple scar rash infection, herpes zoster infection, protozoan infection, mycobacterial infection, polyarteritis, sarcoidosis, scleritis, flushing, xerostomia arthritis syndrome, systemic lupus erythematosus, AIDS syndrome, syphilis.
The invention further provides application of the gem-difluoroethyl substituted stilbene and diphenylethane derivatives in preparing the tubulin aggregation inhibitor.
The invention further provides application of the gem-difluoroethyl substituted stilbene and diphenylethane derivatives in preparing a medicament which is used as an anti-tumor vascular damaging agent and has vascular targeting effect on various tumors. The various tumors include mainly: lung cancer, non-small cell lung cancer, liver cancer, pancreatic cancer, stomach cancer, bone cancer, esophageal cancer, breast cancer, prostate cancer, testicular cancer, colon cancer, ovarian cancer, bulbar carcinoma, cervical cancer, melanoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland cancer, sebaceous gland cancer, papillary carcinoma, papillary adenocarcinoma, cystic carcinoma, medullary carcinoma, bronchial cancer, osteocytic carcinoma, epithelial cancer, bile duct cancer, choriocarcinoma, embryonal carcinoma, seminoma, Wilms' cancer, glial cell carcinoma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, vocal cord neuroma, meningioma, neuroblastoma, retinoblastoma, neurofibroma, fibrosarcoma, fibroma, fibroadenoma, fibrochondroma, fibrocystic tumor, fibrocystic carcinoma, neuroblastoma, melanoma, and neuroblastoma, Fibroma, fibrosarcoma, myxosarcoma, mucinocytoma, mucinochondrocoma, mucinochondrocarcoma, mucinadenoma, mucinoblastoma, liposarcoma, lipoma, lipoadenoma, lipoblastoma, lipochondrosaoma, lipofibroma, lipohemangioma, mucinochinoma, chondrosarcoma, chondroma, chondromas, chordoma, chorioadenoma, chorioepithelioma, chorioblastoma, osteosarcoma, osteoblastoma, osteochondroma, angiosarcoma, angiolipoma, angiofibroma, angiolipoma, angioglioma, hemangioblastoma, angiofibroma, and other tumors, Angiolymphomas, angiolipoleiomyomas, angiomyolipomas, angiomyoneuromas, angiomyxomas, angioreticular endotheliomas, lymphangiosarcomas, lymphogranulomas, lymphangiomas, lymphomas, lymphomyxomas, lymphosarcomas, lymphangiofibromas, lymphocytomas, lymphoepitheliomas, lymphoblastomas, endotheliomas, endothelioblastomas, synoviomas, synovial sarcomas, mesotheliomas, connective tissue tumors, ewing's tumors, leiomyomas, leiomyosarcomas, rhabdomyosarcomas, rhabdomyomyxomas, acute lymphoid leukemias, acute myeloid leukemias, chronic diseased cells, polycythemia, lymphomas, multiple myeloma; preferably, the tumor is cervical cancer, colon cancer, non-small cell lung cancer, breast cancer or gastric cancer.
The invention relates to a pharmaceutical preparation of gem-difluoroethyl substituted stilbene and diphenylethane derivatives, which is selected from the following dosage forms: lyophilized powders, injections, liposomes, emulsions, microcapsules, suspensions or solutions for intravenous administration; granules, tablets, capsules or syrups for oral administration; or a suppository.
Compared with the prior art, the invention has the beneficial effects that: modifying the 4 'position of B aromatic ring of diphenylethane/alkene with gem-difluoroethyl, and modifying the 2' position into substituent such as nitro or amino; the diphenyl ethylene and diphenyl ethane derivatives substituted by the geminal difluoroethyl have stronger in-vitro anti-tumor activity, and the introduction of fluorine atoms not only changes the physical properties of the compounds, but also enhances the in-vitro anti-tumor activity and has better inhibition effect on various tumor cells.
Detailed Description
The following examples are merely illustrative of the implementation of the embodiments, including but not limited to the conditions therein. The compounds of the present invention can be prepared according to the general scheme described below using appropriate materials as starting materials and are specifically exemplified by the following examples. Of course, various known reasonable variations of the conditions and methods of the exemplary compound preparation procedures in the examples can also be used to prepare these compounds. The analytical test instruments and conditions described, unless otherwise indicated: the HRMS high resolution mass spectrum is determined by SolanX-70FT-MS, H-NMR nuclear magnetic hydrogen spectrum Volan III 500M or Agilent 400NMR or Bruker AMX-400 nuclear magnetic resonance instrument of Bruker company, and the test solvent is CDCl3。
Example 14 Synthesis of- (1, 1-difluoro) ethylbenzaldehyde
The method comprises the following steps: preparation of methyl 4- (1, 1-difluoroethyl) benzoate
Methyl 4-acetylbenzoate (5.00g,28.06mmol) was dissolved in 40mL anhydrous CH2Cl2Into a sealed tube, N2Protecting, slowly adding DAST (diethylaminosulfur trifluoride) (12mL,3.4eq) dropwise at-40 deg.C, heating in oil bath at 60 deg.C for 24 hr, cooling to below 0 deg.C, and adding saturated NaHCO3Quenching the reaction with aqueous solution, CH2Cl2Extraction, combination of organic phases, concentration and column chromatography of EA: PE: 1:150 gave 3.30g of a white solid in 59% yield. Mp 35.2-35.7 ℃.1H NMR(CDCl3,500MHz):δ1.92(t,3H,J＝18.0Hz),3.93(s,3H),7.57(d,2H,J＝8.0Hz),8.09(d,2H,J＝8.0Hz).13C NMR(CDCl3,125MHz):δ166.3,142.6142.4,142.2,131.4,129.8,124.7,123.8,121.4,119.5,52.27,26.1,25.9,25.6.19F NMR(CDCl3,470MHz):δ-88.70.MS(m/z):200(M+).ESI-HRMS(m/z):calculated for C10H10F2O2(M+H)+:201.0727,found:201.6502.
Step two: preparation of 4- (1, 1-difluoroethyl) benzyl alcohol
LAH (lithium aluminum hydride) (1.00g, 26.4mmol, 3eq) is dissolved in 50mL THF, stirred for 3h at 60 ℃ in an oil bath, then the reaction system is cooled to below 0 ℃, 8mL THF solution of 4- (1, 1-difluoroethyl) methyl benzoate (1.76g, 8.8mmol) is slowly dripped into a reaction bottle, and after the dripping is finished, the temperature is raised to 100 ℃ for reflux reaction for 2 h. Stopping heating, cooling the reaction system to below 0 ℃, and adding saturated NaH2PO4Quenching the solution, extracting with EA, mixing the organic phases, and adding anhydrous Na2SO4Drying, filtration, concentration and spin-drying gave 1.50g of 4- (1, 1-difluoroethyl) benzyl alcohol as a yellow liquid in 99% yield.1H NMR(CDCl3,500MHz):δ1.90(t,3H,J＝18.0Hz),2.40(s,1H),4.67(s,2H),7.37(d,2H,J＝8.0Hz),7.48(d,2H,J＝8.5Hz).13C NMR(CDCl3,125MHz):δ142.5,137.7,137.4,137.2,126.9,124.9,123.7,121.8,119.9,64.6,26.1,25.9,25.7.19F NMR(CDCl3,470MHz):δ-87.22.MS(m/z):172(M+).ESI-HRMS(m/z):calculated for C9H10F2O(M+H)+:173.0788,found:173.3046.
Step three: preparation of 4- (1, 1-difluoroethyl) benzaldehyde
4- (1, 1-Difluoroethyl) benzyl alcohol (1.93g,11.21mmol) was dissolved in 50mL of anhydrous CH2Cl2To this was added PCC (pyridinium chlorochromate) (3.63g,16.82mmol,1.5eq), N2Protecting, stirring at room temperature for 1h, detecting by TLC tracking till the reaction is complete, adding saturated NaCl aqueous solution, and adding saturated NaHCO3Washing with water solution to colorless, extracting with ethyl acetate, and extracting with anhydrous Na2SO4Drying, filtration, concentration and spin-drying gave 1.55g of a white solid in 81% yield. Mp 165.8-166.3 ℃.1H NMR(CDCl3,500MHz):δ1.95(t,3H,J＝18.0Hz),7.63(d,2H,J＝8.0Hz),8.18(d,2H,J＝8.0Hz),10.07(s,1H).13C NMR(CDCl3,125MHz):δ191.6,171.1,143.4,130.5,124.9,123.2,121.3,119.4,26.2,25.9,25.7.19F NMR(CDCl3,470MHz):δ-88.92.MS(m/z):170(M+).ESI-HRMS(m/z):calculated for C9H8F2O(M+H)+:171.0621,found:171.2190.
Example 2 preparation of (Z/E) -3,4, 5-trimethoxy-4' - (1, 1-difluoroethyl) stilbene
N2Under protection, 3,4, 5-trimethoxy benzyl bromide triphenyl phosphonium bromide (3.08g, 5.88mmol) is suspended in 50mL of anhydrous THF solution, n-butyl lithium (4.5mL, 7.06mmol, 1.2eq) is slowly added dropwise at-30 ℃ and then reacted for 1h, then a THF solution (5mL) of 4- (1, 1-difluoroethyl) benzaldehyde (1.00g, 5.88mmol) is slowly added dropwise into the reaction system and the temperature is raised to room temperature for reaction for 12h overnight. The reaction is finishedCooling the system to below-5 deg.C, adding saturated NaCl water solution, EA extracting, mixing organic phases, and anhydrous Na2SO4Drying, filtration, concentration and column chromatography gave 1.20g of oil as a cis-trans mixture in 64% yield (Z: E ═ 4: 1). Further column chromatography separation is carried out to obtain pure cis-trans isomers.
(Z) -3,4, 5-trimethoxy-4' - (1, 1-difluoroethyl) stilbene
White oil Z-isomer:1H NMR(CDCl3,500MHz):δ1.89(t,3H,J＝18.0Hz),3.64(s,6H),3.83(s,3H),6.42(s,2H),6.56(d,1H,J＝12.0Hz),6.59(d,1H,J＝12.0Hz),7.33(d,2H,J＝8.0Hz),7.40(d,2H,J＝8.0Hz).13C NMR(CDCl3,125MHz):δ153.0,139.1,137.5,137.0,136.9,136.6,132.1,131.3,129.0,124.6,123.6,121.7,119.8,106.2,60.9,55.8,26.0,25.8,25.5.19F NMR(CDCl3,470MHz):δ-87.37.MS(m/z):334(M+).ESI-HRMS(m/z):calculated for C19H20F2O3(M+H)+:335.1459,found:335.1453.
(E) -3,4, 5-trimethoxy-4' - (1, 1-difluoroethyl) stilbene
White solid E-isomer Mp:142.4-143.1 ℃.1H NMR(CDCl3,500MHz):δ1.94(t,3H,J＝18.0Hz),3.88(s,3H),3.92(s,6H),6.75(s,2H),7.01(d,1H,J＝16.0Hz),7.08(d,1H,J＝16.0Hz),7.49(d,2H,J＝8.0Hz),7.54(d,2H,J＝8.0Hz).13C NMR(CDCl3,125MHz):δ153.5,138.7,138.4,137.1,132.7,130.0,127.1,126.4,125.1,123.7,121.8,119.9,103.9,61.0,56.2,26.1,25.9,25.6.19F NMR(CDCl3,470MHz):δ-87.22.MS(m/z):334(M+).ESI-HRMS(m/z):calculated for C19H20F2O3(M+H)+:335.1459,found:335.1453.
Example 33 preparation of 4, 5-trimethoxy-4' - (1, 1-difluoroethyl) diphenylethane
Will (Z-E) -3,4, 5-trimethoxy-4' - (1, 1-difluoroethyl) stilbene (1.20g, 3.6mmol) was dissolved in 30mL ethanol and Pd/C (0.10g,0.9mmol), H2The reaction mixture was stirred overnight at room temperature, Pd/C was removed by filtration after the reaction was complete, and the solvent was dried by spinning to give 1.10g of a white solid with a yield of 90%. Mp is 60.1-60.7 ℃.1H NMR(CDCl3,500MHz):δ1.91(t,3H,J＝18.0Hz),2.86(m,2H),2.94(m,2H),3.82(d,9H,J＝10.0Hz),6.34(s,2H),7.22(d,2H,J＝7.5Hz),7.42(d,2H,J＝7.5Hz).13C NMR(CDCl3,125MHz):δ153.1,143.3,137.1,136.3,136.2,135.9,135.7,128.6,124.7,124.6,124.6,123.8,121.9,120.0,105.5,60.9,56.1,38.1,37.7,26.1,25.9,25.6.19F NMR(CDCl3,470MHz):δ-86.84.MS(m/z):336(M+).ESI-HRMS(m/z):calculated for C19H22F2O3(M+H)+:337.1615,found:337.1610.
Example Synthesis of 44- (1, 1-difluoro) ethyl-2-nitrobenzaldehyde
The method comprises the following steps: preparation of 4- (1, 1-difluoro) ethyl-2-nitrotoluene
4-methyl-3-nitroacetophenone (5.00g,27.91mmol) was dissolved in 40mL of anhydrous CH2Cl2Into a sealed tube, N2Protecting, slowly adding DAST (diethylaminosulfur trifluoride) (12mL,3.4eq) dropwise at-40 deg.C, heating in oil bath at 60 deg.C for 24 hr, cooling to below 0 deg.C, and adding saturated NaHCO3Quenching the reaction with aqueous solution, CH2Cl2Extraction, combination of organic phases, concentration and column chromatography of EA: PE: 1:150 gave 5.20g of a pale yellow liquid in 93% yield.1H NMR(CDCl3,500MHz):δ1.95(t,3H,J＝18.0Hz),2.63(s,3H),7.43(d,1H,J＝8.0Hz),7.64(d,1H,J＝7.5Hz),8.11(s,1H).13C NMR(CDCl3,125MHz):δ149.1,137.7,137.5,137.3,135.2,133.3,129.0,122.6,121.2,120.7,118.8,25.9,25.6,25.4,20.2.19F NMR(CDCl3,470MHz):δ-87.80.MS(m/z):201(M+).ESI-HRMS(m/z):calculated for C9H9F2NO2(M+K)+:240.0238,found:240.1427.
Step two: preparation of 4- (1, 1-difluoroethyl) -2-nitrobromotoluene
4- (1, 1-Difluoroethyl) -2-nitrotoluene (5.20g, 25.85mmol), NBS (N-bromosuccinimide) (5.52g, 31.02mmol, 1.2eq), BPO (benzoyl peroxide) (1.00g) and 100mL CCL4The mixture was mixed into a flask and stirred under reflux for 12 h. Cooling the reaction solution to room temperature, adding saturated NaCl aqueous solution for washing, EA extracting, combining organic phases, and anhydrous Na2SO4Drying, filtering, concentrating, adding petroleum ether four times the amount of the remaining liquid, placing in a refrigerator for recrystallization, and filtering to obtain 4.45g of white solid with a yield of 61%. Mp 81.0-81.7 ℃.1H NMR(CDCl3,500MHz):δ1.97(t,3H,J＝18.0Hz),4.84(s,2H),7.67(d,1H,J＝8.0Hz),7.75(d,1H,J＝8.0Hz),8.18(s,1H).13C NMR(CDCl3,125MHz):δ147.9,140.3,140.0,139.8,134.3,138.1,129.8,122.3,122.1,120.4,118.5,29.6,28.0,25.9,25.7,25.4.19F NMR(CDCl3,470MHz):δ-88.38.MS(m/z):280(M+).ESI-HRMS(m/z):calculated for C9H8BrF2NO2(M+H)+:281.9764,found:281.0254.
Step three: preparation of 4- (1, 1-difluoroethyl) -2-nitrobenzyl alcohol
4- (1, 1-Difluoroethyl) -2-nitrobromotoluene (3.11g, 11.11mmol) and CaCO3(5.56g, 55.55mmol, 5eq) was suspended in 80mL of a mixed solvent of 1, 4-dioxane-H2Heating to 90 ℃ in O (1:1) and reacting for 12 h. Cooling the reaction solution to room temperature, adding saturated NaCl aqueous solution for washing, EA extracting, combining organic phases, and anhydrous Na2SO4Drying, filtering, concentrating and column chromatography to isolate EA: PE ═ 1:10, yielding 1.30g of red solid in 54% yield. Mp is 51.8-52.4 deg.C.1H NMR(CDCl3,500MHz):δ1.99(t,3H,J＝18.0Hz),5.07(s,2H),7.84(d,1H,J＝8.0Hz),7.90(d,1H,J＝8.0Hz),8.27(s,1H).13C NMR(CDCl3,125MHz):δ147.3,139.1,138.9,138.6,138.5,130.0,122.5,121.5,120.6,118.7,61.9,25.9,25.7,25.4.19F NMR(CDCl3,470MHz):δ-88.10.MS(m/z):217(M+).ESI-HRMS(m/z):calculated for C9H9F2NO3(M+K)+:256.0188,found:256.9813.
Step four: preparation of 4- (1, 1-difluoroethyl) -2-nitrobenzaldehyde
4- (1, 1-Difluoroethyl) -2-nitrobenzyl alcohol (1.00g,4.6mmol) was dissolved in 30mL of anhydrous CH2Cl2To this was added PCC (pyridinium chlorochromate) (1.50g,6.9mmol,1.5eq), N2Protecting, stirring at room temperature for 12h, detecting by TLC tracking till the reaction is complete, adding saturated NaCl aqueous solution, and adding saturated NaHCO3Washing with water solution to colorless, extracting with ethyl acetate, and extracting with anhydrous Na2SO4Drying, filtering, concentrating, and column chromatography to separate EA, PE 1:70 to obtain light yellow solid 0.78g, 79% yield.1H NMR(CDCl3,500MHz):δ1.99(t,3H,J＝18.0Hz),7.92(d,1H,J＝8.0Hz),8.00(d,1H,J＝7.5Hz),8.23(s,1H),10.40(s,1H).13C NMR(CDCl3,125MHz):δ187.5,149.4,143.9,143.6,143.4,132.2,130.3,122.3,121.1,120.3,118.4,25.5,25.3,25.1.19F NMR(CDCl3,470MHz):δ-88.93.MS(m/z):215(M+).ESI-HRMS(m/z):calculated for C9H7F2NO3(M+Na)+:238.0292,found:238.0296.
EXAMPLE 5 preparation of (Z/E) -3,4, 5-trimethoxy-2 '-nitro-4' - (1, 1-difluoroethyl) stilbene
N2Under protection, 3,4, 5-trimethoxy benzyl bromide triphenyl phosphonium bromide (1.90g, 3.6mmol) is suspended in 20mL of anhydrous THF solution, n-butyl lithium (2.7mL, 4.3mmol, 1.2eq) is slowly added dropwise at-30 ℃ and then reacted for 1h, then a THF solution (10mL) of 2-nitro-4-gem-difluorobenzaldehyde (0.78g, 3.6mmol) is slowly added dropwise into the reaction system and the reaction system is warmed to room temperature for 12h overnight. Cooling the system to below-5 ℃ after the reaction is finished, adding saturated NaCl aqueous solution, EA extracting, combining organic phases and anhydrous Na2SO4Drying, filtration, concentration and column chromatography gave 0.98g of a cis-trans mixture as a yellow oil in 72% yield (Z: E ═ 3: 1). Further column chromatography separation is carried out to obtain pure cis-trans isomers.
(Z) -3,4, 5-trimethoxy-2 '-nitro-4' - (1, 1-difluoroethyl) stilbene
Yellow oil Z-isomer:1H NMR(CDCl3,500MHz):δ1.96(t,3H,J＝18.0Hz),3.61(s,6H),3.83(s,3H),6.24(s,2H),6.75(d,1H,J＝12.0Hz),6.88(d,1H,J＝12.0Hz),7.44(d,1H,J＝8.0Hz),7.60(d,1H,J＝8.0Hz),8.24(s,1H).13C NMR(CDCl3,125MHz):δ153.0,148.3,138.8,138.6,138.3,138.0,135.3,133.1,132.8,130.8,129.0,124.9,122.4,121.1,120.5,118.5,106.5,60.9,55.8,29.7,25.8,25.5,25.3.19F NMR(CDCl3,470MHz):δ-87.98.MS(m/z):379(M+).ESI-HRMS(m/z):calculated for C19H19F2NO5(M+H)+:380.1310,found:380.1309.
(E) -3,4, 5-trimethoxy-2 '-nitro-4' - (1, 1-difluoroethyl) stilbene
Yellow solid E-isomer Mp:93.2-93.8 ℃.1H NMR(CDCl3,500MHz):δ1.99(t,3H,J＝18.0Hz),3.92(d,9H,J＝17.0Hz),6.78(s,2H),7.08(d,1H,J＝16.0Hz),7.50(d,1H,J＝16.0Hz),7.74(d,1H,J＝8.0Hz),7.84(d,1H,J＝8.0Hz),8.11(s,1H).13C NMR(CDCl3,125MHz):δ153.5,147.7,139.2,138.1,135.1,134.3,131.8,129.1,128.5,122.5,121.9,121.5,120.6,104.4,61.0,56.2,29.7,25.9,25.7,25.4.19F NMR(CDCl3,470MHz):δ-87.94.MS(m/z):379(M+).ESI-HRMS(m/z):calculated for C19H19F2NO5(M+H)+:380.1310,found:380.1309.
EXAMPLE 6 preparation of (Z) -3,4, 5-trimethoxy-2 '-amino-4' - (1, 1-difluoroethyl) stilbene
Reacting (Z) -3,4, 5-trimethoxy-2 '-nitro-4' - (1, 1-difluoroethyl) stilbene (0.50g, 1.32mmol), zinc powder (0.95g, 14.52mmol, 11eq), glacial acetic acid (20mL) were mixed in a single-neck flask, stirred at room temperature, reacted for 2h, checked by TLC for completion, and saturated NaHCO was added3Aqueous solution, EA extraction, combined organic phases, anhydrous Na2SO4Drying, filtering, concentrating and column chromatography to isolate EA: PE 1:15, which is 0.20g of red oil with 43% yield.1H NMR(CDCl3,500MHz):δ1.87(t,3H,J＝18.0Hz),3.60(s,6H),3.81(s,3H),6.43(s,2H),6.47(d,1H,J＝12.0Hz),6.60(d,1H,J＝12.0Hz),6.85(d,2H,J＝7.5Hz),7.15(d,1H,J＝8.0Hz).13C NMR(CDCl3,125MHz):δ152.8,143.9,138.6,138.4,138.2,137.7,132.5,131.7,129.8,125.1,124.6,123.6,121.7,119.8,114.4,111.3,106.0,60.8,55.7,26.0,25.8,25.5.19F NMR(CDCl3,470MHz):δ-87.63.MS(m/z):349(M+).ESI-HRMS(m/z):calculated for C19H21F2NO3(M+H)+:350.1568,found:350.1564.
Example 7 preparation of (E) -3,4, 5-trimethoxy-2 '-amino-4' - (1, 1-difluoroethyl) stilbene
Mixing (E) -3,4, 5-trimethoxy-2 '-nitro-4' - (1, 1-difluoroethyl) stilbene (0.50g, 1.32mmol), zinc powder (0.95g, 14.52mmol, 11eq), glacial acetic acid (20mL) into a single-neck flask, stirring at room temperature, reacting for 2h, detecting the reaction completion by TLC, adding saturated NaHCO3Aqueous solution, EA extraction, combined organic phases, anhydrous Na2SO4Drying, filtering, concentrating and column chromatography to isolate EA: PE 1:10, which gave 0.38g of red solid in 82% yield. Mp is 96.3-96.9 ℃.1H NMR(CDCl3,500MHz):δ1.90(t,3H,J＝18.0Hz),3.87(s,3H),3.91(s,6H),6.73(s,2H),6.87(s,1H),6.92(d,1H,J＝7.0Hz),6.94(d,1H,J＝16.0Hz),7.03(d,1H,J＝16.0Hz),7.41(d,1H,J＝8.0Hz).13C NMR(CDCl3,125MHz):δ153.5,143.8,138.4,133.0,131.5,127.4,125.1,123.6,122.9,121.7,119.8,115.4,112.4,103.8,61.0,56.2,26.1,25.9,25.6.19F NMR(CDCl3,470MHz):δ-87.65.MS(m/z):349(M+).ESI-HRMS(m/z):calculated for C19H21F2NO3(M+H)+:350.1568,found:350.1567.
EXAMPLE 83 preparation of 4, 5-trimethoxy-2 '-nitro-4' - (1, 1-difluoroethyl) diphenylethane
(Z/E) -3,4, 5-trimethoxy-2 '-nitro-4' - (1, 1-difluoroethyl) stilbene (1.00g, 2.64mmol) was dissolved in 30mL of ethanol, and Pd/C (0.10g,0.9mmol), H2The reaction mixture was stirred overnight at room temperature, Pd/C was removed by filtration after the reaction was complete, and the solvent was dried by spinning to give 0.46g of a red solid with a yield of 46%. Mp is 87.9-88.5 ℃.1H NMR(CDCl3,500MHz):δ1.88(t,3H,J＝18.0Hz),2.79(m,2H),2.87(m,2H),3.80(s,6H),3.83(s,3H),6.34(s,2H),6.81(s,1H),6.85(d,1H,J＝8.0Hz),7.05(d,1H,J＝8.0Hz).13C NMR(CDCl3,125MHz):δ153.2,143.9,137.3,137.1,136.4,129.8,127.6,123.7,121.8,120.0 115.3,112.0,105.4,60.9,56.1,35.6,33.1,26.1,25.9,25.6.19F NMR(CDCl3,470MHz):δ-87.21.MS(m/z):381(M+).ESI-HRMS(m/z):calculated for C19H21F2NO5(M+H)+:382.1466,found:382.1831.
Example 93 preparation of 4, 5-trimethoxy-2 '-amino-4' - (1, 1-difluoroethyl) diphenylethane
(Z/E) -3,4, 5-trimethoxy-2 '-nitro-4' - (1, 1-difluoroethyl) stilbene (1.00g, 2.64mmol) was dissolved in 30mL of ethanol, and Pd/C (0.10g,0.9mmol), H2The reaction mixture was stirred overnight at room temperature, Pd/C was removed by filtration after the reaction was completed, and the solvent was dried by spinning to obtain 0.37g of a red liquid with a yield of 40%.1H NMR(CDCl3,500MHz):δ1.90(t,3H,J＝18.0Hz),2.76(t,2H,J＝6.5Hz),2.87(t,2H,J＝6.5Hz),3.08(dd,2H,J＝6.5Hz,J＝7.0Hz),3.81(d,9H,J＝19.0Hz),6.31(s,2H),6.71(s,2H),6.81(d,1H,J＝7.5Hz),7.06(d,1H,J＝6.5Hz).13C NMR(CDCl3,125MHz):δ153.2,146.2,137.6,137.3,137.2,136.5,129.0,126.9,124.1,122.2,120.3,113.1,106.3,105.5,60.8,56.1,38.5,35.7,32.9,26.2,25.9,25.7.19F NMR(CDCl3,470MHz):δ-87.05.MS(m/z):351(M+).ESI-HRMS(m/z):calculated for C19H23F2NO3(M+Na)+:374.1544,found:374.1960.
Example 103 preparation of 4, 5-trimethoxy-2 '- (aminoacetyl hydrochloride) amino 4' - (1, 1-difluoro) ethyl-diphenylethane
Dissolving (Z, E) -3,4, 5-trimethoxy-2 '-amino-4' - (1, 1-difluoro) ethyl-stilbene (0.50g,1.42mmol) and boc-glycine (1.5mmol) in 10mL of anhydrous dichloromethane, adding DCC (2.0mmol), stirring at an excessive room temperature overnight, adding water for quenching, filtering with diatomite to remove insoluble substances, spin-drying the filtrate, dissolving in diethyl ether again, adding 2N hydrogen chloride diethyl ether solution for deprotection, separating out solids, stirring at the room temperature for 1h, detecting the reaction by TLC, and filtering to obtain a white solid, wherein the white solid is 0.57g, and the yield is 90%.
Example 15 MTT assay for testing Compounds for anti-tumor Activity on various tumor cells
1. Test method
Culturing cells in RPMI 1640 culture medium containing 200mL/L fetal calf serum to keep the cells in logarithmic growth phase, inoculating the cells to a 96-well plate, wherein the density of the cells is 4-8 multiplied by 104Adding drugs into the mixture at 37 ℃ for 24 hours of pre-culture, setting 6 concentrations for the drugs, setting 3 multiple holes for each drug, continuously acting for 48 hours, throwing off culture solution, air-drying, adding ice cold 500g/L trichloroacetic acid 50 muL (final concentration is 100g/L) into each hole, fixing for 60min, washing for 4-5 times with deionized water, drying, adding SRB 100 muL 4g/L into each hole, acting for 30min, and lightly washing with acetic acid 10mL/L4 times, spin-drying, adding 10mmol Tris base 200 μ L per well, shaking, mixing well, shaking for 5min on a plate oscillator, measuring A value in an enzyme-linked immunosorbent assay detector, adjusting to zero with blank control, using wavelength of 490nm, tumor inhibition rate (%) (average value of A value in drug-free cell control well-average value of A value in drug-free cell control well)/average value of A value in drug-free cell control well x 100%, positive control is (Z) -3,4, 5-trimethoxy-3 '-hydroxy-4' -methoxystilbene (CA-4), calculating IC by Logit method according to inhibition rate of drug on cell growth at different concentrations50The value is obtained. Cell lines: hela cell strain, HCT-116 cell strain, A549 cell strain, MCF-7 cell strain and MKN45 cell strain.
2. Test results
TABLE 1 evaluation of antitumor Activity of the Compounds of the examples in vitro against various tumor cell lines (MTT method)
| Number of | Hela(μML) |
| CA-4 | 0.27 |
| I-1 | 0.37 |
| I-2 | 0.24 |
| I-3 | 0.11 |
| I-4 | / |
| I-5 | 0.34 |
| I-6 | 0.19 |
| I-7 | 0.0067 |
| I-8 | 0.13 |
| I-19 | 0.46 |
| I-10 | 0.05 |
TABLE 2 evaluation of antitumor Activity of the Compounds of the examples in vitro against various tumor cell lines (MTT method)
The positive control substance for the anti-tumor activity test of the compound on the general formula (I) is (Z) -3,4, 5-trimethoxy-3 '-hydroxy-4' -methoxystilbene (CA-4), and the evaluation result of the drug effect is summarized as follows: :
the result of the evaluation of the antitumor activity of the tumor cells cultured in vitro shows that the fluorine-containing analogue of CA-4 has wide inhibitory activity on Hela cells, and the activity value of the compounds is not much different from that of the control drug CA-4, especially the IC of the compound 750IC's with values of 0.0067. mu.M less than CA-4, respectively50The value (0.27. mu.M) indicates that the introduction of two fluorine atoms in the B ring of the CA-4 structure effectively improves the antitumor activity of the compound. Analysis of the activity of the 4-geminally difluoro-substituted CA-4 analogues revealed that the trans compounds also have better activity and comparable activity to the cis structure, e.g. IC of compounds 1 and 250Value divisionIC of 0.37 and 0.24. mu.M, respectively, Compounds 6 and 750The values were 0.19 and 0.0067. mu.M, respectively, even though no IC could be detected in the cis-structure50Values, as for compound 4.
We further evaluate the compound 7 with the best inhibitory activity on Hela cells, and the experimental results show that the compound 7 also has stronger inhibitory activity on human gastric cancer cells MKN45, human lung cancer cells A549, human breast cancer cells MCF-7 and human colon cancer cells HCT-116, the inhibitory activity on various tumor cell strains is obviously superior to that of CA4 under the same condition, the compound shows broad-spectrum anti-tumor activity, and has certain selectivity on Hela cells and HCT-116 cells, and the IC is IC50The values were 0.0067. mu.M and 0.063. mu.M, respectively.
The activity data show that the in vitro anti-tumor activity of the gem-difluoro ethyl substituted diphenylethane and stilbene derivatives is obviously superior to that of a known positive control compound CA4, and the compound has good application and development prospects.
It should be noted that the above examples have illustrated some compounds of the present invention, but are not limited to the above examples, and those skilled in the art can make various equivalent changes and substitutions without departing from the spirit of the present invention, and these equivalent changes and substitutions should be included in the scope defined by the claims of the present application.
Claims (5)
1. A gem-difluoroethyl substituted trans-stilbene and diphenylethane derivative, characterized in that it has the structure of formula (I):
wherein:
dotted line- - -represents a bond or is absent;
r is hydroxyl, nitro or amino.
2. The process for preparing trans-stilbene and diphenylethane derivatives with difluoroethyl substituent as claimed in claim 1, which comprises the step of Wittig reacting 3,4, 5-trimethoxy benzyl bromide triphenyl phosphonium bromide and 4- (1, 1-difluoroethyl) benzaldehyde under the action of alkali to generate olefin compounds, or Wittig reacting 3,4, 5-trimethoxy benzyl bromide triphenyl phosphonium bromide and 2-or 3-substituted 4- (1, 1-difluoroethyl) benzaldehyde under the action of alkali to generate olefin compounds, wherein the synthesis reaction equation is as follows:
3. use of the gem-difluoroethyl-substituted trans-stilbene and diphenylethane derivatives of claim 1 in the manufacture of a medicament for the treatment of diseases caused by abnormal neovascularization.
4. Use of the gem-difluoroethyl-substituted trans-stilbene and diphenylethane derivatives of claim 1 in the preparation of tubulin aggregation inhibitors.
5. Use of the gem-difluoroethyl-substituted trans-stilbene and diphenylethane derivatives of claim 1 in the preparation of a medicament having vascular targeting effects on tumors as an anti-tumor vascular damaging agent; wherein: the tumor is cervical cancer, colon cancer, non-small cell lung cancer, breast cancer or gastric cancer.
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