CN110240582B - Flavone derivative with tumor cell inhibiting function and preparation method and application thereof - Google Patents
Flavone derivative with tumor cell inhibiting function and preparation method and application thereof Download PDFInfo
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- 150000002212 flavone derivatives Chemical class 0.000 title claims abstract description 23
- 210000004881 tumor cell Anatomy 0.000 title claims abstract description 14
- 230000002401 inhibitory effect Effects 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title abstract description 6
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N flavone Chemical group O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229930003944 flavone Natural products 0.000 claims abstract description 5
- 235000011949 flavones Nutrition 0.000 claims abstract description 5
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 claims abstract description 4
- 238000005859 coupling reaction Methods 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- -1 amine compound Chemical class 0.000 claims description 4
- XLEYFDVVXLMULC-UHFFFAOYSA-N 2',4',6'-trihydroxyacetophenone Chemical compound CC(=O)C1=C(O)C=C(O)C=C1O XLEYFDVVXLMULC-UHFFFAOYSA-N 0.000 claims description 3
- UYGBSRJODQHNLQ-UHFFFAOYSA-N 4-hydroxy-3,5-dimethylbenzaldehyde Chemical compound CC1=CC(C=O)=CC(C)=C1O UYGBSRJODQHNLQ-UHFFFAOYSA-N 0.000 claims description 3
- 230000000259 anti-tumor effect Effects 0.000 claims description 3
- FGPJTMCJNPRZGF-JXMROGBWSA-N (e)-1-(2-hydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one Chemical compound C1=CC(O)=CC=C1\C=C\C(=O)C1=CC=CC=C1O FGPJTMCJNPRZGF-JXMROGBWSA-N 0.000 claims description 2
- 238000005882 aldol condensation reaction Methods 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 claims description 2
- VVQIIIAZJXTLRE-QMMMGPOBSA-N (2s)-2-amino-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid Chemical group CC(C)(C)OC(=O)NCCCC[C@H](N)C(O)=O VVQIIIAZJXTLRE-QMMMGPOBSA-N 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims 1
- 238000006264 debenzylation reaction Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 230000005764 inhibitory process Effects 0.000 claims 1
- QVDXUKJJGUSGLS-ZCFIWIBFSA-N methyl (2r)-2-amino-4-methylpentanoate Chemical group COC(=O)[C@H](N)CC(C)C QVDXUKJJGUSGLS-ZCFIWIBFSA-N 0.000 claims 1
- CEMZBWPSKYISTN-YFKPBYRVSA-N methyl (2s)-2-amino-3-methylbutanoate Chemical group COC(=O)[C@@H](N)C(C)C CEMZBWPSKYISTN-YFKPBYRVSA-N 0.000 claims 1
- YXMMTUJDQTVJEN-WDSKDSINSA-N methyl (2s,3s)-2-amino-3-methylpentanoate Chemical group CC[C@H](C)[C@H](N)C(=O)OC YXMMTUJDQTVJEN-WDSKDSINSA-N 0.000 claims 1
- QVDXUKJJGUSGLS-LURJTMIESA-N methyl L-leucinate Chemical group COC(=O)[C@@H](N)CC(C)C QVDXUKJJGUSGLS-LURJTMIESA-N 0.000 claims 1
- 230000001028 anti-proliverative effect Effects 0.000 abstract description 7
- 239000002246 antineoplastic agent Substances 0.000 abstract description 4
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract description 3
- XADJWCRESPGUTB-UHFFFAOYSA-N apigenin Natural products C1=CC(O)=CC=C1C1=CC(=O)C2=CC(O)=C(O)C=C2O1 XADJWCRESPGUTB-UHFFFAOYSA-N 0.000 abstract description 2
- 235000008714 apigenin Nutrition 0.000 abstract description 2
- KZNIFHPLKGYRTM-UHFFFAOYSA-N apigenin Chemical compound C1=CC(O)=CC=C1C1=CC(=O)C2=C(O)C=C(O)C=C2O1 KZNIFHPLKGYRTM-UHFFFAOYSA-N 0.000 abstract description 2
- 229940117893 apigenin Drugs 0.000 abstract description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 abstract description 2
- 229960004316 cisplatin Drugs 0.000 abstract description 2
- 230000000118 anti-neoplastic effect Effects 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 150000002214 flavonoid derivatives Chemical class 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 108091005625 BRD4 Proteins 0.000 description 3
- 102100029895 Bromodomain-containing protein 4 Human genes 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 229930003935 flavonoid Natural products 0.000 description 3
- 150000002215 flavonoids Chemical class 0.000 description 3
- 235000017173 flavonoids Nutrition 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 108010077544 Chromatin Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 101001092185 Homo sapiens Regulator of cell cycle RGCC Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102100035542 Regulator of cell cycle RGCC Human genes 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 125000006278 bromobenzyl group Chemical group 0.000 description 1
- 125000006355 carbonyl methylene group Chemical group [H]C([H])([*:2])C([*:1])=O 0.000 description 1
- 230000006369 cell cycle progression Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000003483 chromatin Anatomy 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 150000002213 flavones Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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Abstract
Description
技术领域technical field
本发明属于有机合成领域，具体涉及一种具有抑制肿瘤细胞的黄酮衍生物及其制备方法与应用。The invention belongs to the field of organic synthesis, and specifically relates to a flavone derivative capable of inhibiting tumor cells, a preparation method and application thereof.
背景技术Background technique
癌症被认为是21世纪人口死亡的主要原因，也是提高预期寿命的最重要障碍。据估计，2018年全世界有1810万新病例和960万癌症死亡。这个数字随着时间的推移还将提高。目前的癌症治疗主要是手术、化疗和放射治疗，不能减少术后复发和转移，并显示出其局限性和缺点，如严重的副作用、不耐受性和耐药性增加。因此，开发一系列新的抗癌药物的需求正在增加。Cancer is considered to be the leading cause of death in the 21st century and the most important obstacle to increasing life expectancy. There were an estimated 18.1 million new cases and 9.6 million cancer deaths worldwide in 2018. This number will increase over time. Current cancer treatments are mainly surgery, chemotherapy, and radiotherapy, which cannot reduce postoperative recurrence and metastasis, and show their limitations and disadvantages, such as severe side effects, increased intolerance, and drug resistance. Therefore, the need to develop a series of new anticancer drugs is increasing.
黄酮类化合物是从植物和真菌中提取的多酚类次生代谢产物，具有多种生物活性，尤其是通过调节不同的靶点而具有抗癌活性。例如，一些研究报告黄酮靶向蛋白激酶(PKC)、坦克酶(TNKS)、酪氨酸激酶和环依赖性激酶。因此我们以黄酮为母体研究其抗肿瘤活性。专利WO2018112037A1报道以黄酮4’位羟基与各种烷烃反应生成醚类化合物对蛋白质(BRD4)具有很好的调控作用。而BRD4的一个显著特征是它与有丝分裂染色体的常染色区域有关。通过这种结合，该蛋白发挥其作为细胞周期从G2向M进展的调节器的作用，但也在G1向S转变的过程中发挥作用。也有人认为BRD4与染色质的联系对于细胞分裂过程中转录记忆的传递是重要的。Flavonoids are polyphenolic secondary metabolites extracted from plants and fungi that possess diverse biological activities, especially anticancer activity by modulating different targets. For example, several studies report that flavones target protein kinases (PKC), tank enzymes (TNKS), tyrosine kinases, and loop-dependent kinases. Therefore, we used flavonoids as the parent to study its antitumor activity. Patent WO2018112037A1 reported that the reaction of the 4' hydroxyl group of flavonoids with various alkanes to form ether compounds has a good regulatory effect on protein (BRD4). A striking feature of BRD4 is that it is associated with euchromatic regions of mitotic chromosomes. Through this binding, the protein exerts its role as a regulator of cell cycle progression from G2 to M, but also during the G1 to S transition. The association of BRD4 with chromatin has also been suggested to be important for the transmission of transcriptional memory during cell division.
发明内容Contents of the invention
本发明的目的是提供一种具有抑制肿瘤细胞的黄酮衍生物及其制备方法与应用。发明人通过应用偶联反应,以氨基取代物取代4’-OH，在黄酮骨架上合成具有含氮衍生物，通过引入氨基取代物调节黄酮衍生物与靶向蛋白的氢键作用，同时也可以调节其酯水分配系数，从而可以让黄酮衍生物具有相对较好的通过血脑屏障，起到制抑肿瘤细胞的作用。为实现上述目的所采用的具体的实验方案如下：The object of the present invention is to provide a kind of flavonoid derivatives capable of inhibiting tumor cells and its preparation method and application. The inventors use the coupling reaction to replace 4'-OH with amino substituents, synthesize nitrogen-containing derivatives on the flavone skeleton, and adjust the hydrogen bond between flavone derivatives and target proteins by introducing amino substituents, and also can By adjusting its ester-water partition coefficient, the flavonoid derivatives can pass through the blood-brain barrier relatively well and play a role in inhibiting tumor cells. The specific experimental scheme adopted to achieve the above-mentioned purpose is as follows:
一种具有抑制肿瘤细胞的黄酮衍生物,是应用偶联反应,以氨基取代物取代4’-OH，在黄酮骨架上合成具有含氮的衍生物，所述的黄酮衍生物的结构式为(I)：A kind of flavone derivative that can inhibit tumor cells is to apply coupling reaction, replace 4'-OH with amino substituent, synthesize nitrogen-containing derivative on flavone skeleton, the structural formula of described flavone derivative is (I ):
其结构式(I)中R为C1-C6的烷烃亚胺、氨基酸甲酯、氨基酸乙酯、取代苯亚胺、三氟甲磺酯基、苄氧基其中的一种，具体结构式为式(6-1)～式(6-14)所示化合物中的任意一种：In its structural formula (I), R is one of C 1 -C 6 alkane imine, amino acid methyl ester, amino acid ethyl ester, substituted phenylimine, triflate, benzyloxy, and the specific structural formula is the formula Any one of the compounds shown in (6-1) ~ formula (6-14):
上述具有抑制肿瘤细胞的黄酮衍生物的制备方法，合成路线包括步骤：The preparation method of the above-mentioned flavone derivatives capable of inhibiting tumor cells, the synthetic route includes steps:
合成步骤中首先对2,4,6-三羟基苯乙酮用甲基保护2和4位羟基得到化合物1a，用溴苄保护3,5-二甲基对羟基苯甲醛得合物2b；化合物1a和化合物2b在NaOH为碱的条件下通过羟醛缩合反应得查尔酮3；接着在I2催化的条件下氧化关环得到黄酮4；接着脱苄基保护得5，与三氟甲磺酰氯反应得到化合物6，然后以Pd化合物为催化剂、无水无氧的条件下与胺类化合物反应生成黄酮衍生物。In the synthesis steps, first, 2,4,6-trihydroxyacetophenone is protected with methyl group to obtain compound 1a, and 3,5-dimethyl p-hydroxybenzaldehyde is protected with bromobenzyl to obtain compound 2b; compound 1a and compound 2b were reacted by aldol condensation under the condition of NaOH as the base to obtain chalcone 3; followed by oxidative ring closure under the condition of I2 catalysis to obtain flavone 4; Compound 6 is obtained by acid chloride reaction, and then reacts with amine compounds under anhydrous and oxygen-free conditions using Pd compound as a catalyst to generate flavonoid derivatives.
所述黄酮衍生物应用到制备抗肿瘤的药物。The flavone derivatives are applied to the preparation of antitumor drugs.
有益效果：采用MTT法对该黄酮衍生物进行肿瘤细胞HEL和PC3的抗增殖活性研究，结果表明该黄酮衍生物对肿瘤细胞HEL和PC3的抗增殖活性好，比天然黄酮芹黄素的抗肿瘤活性高；与临床抗肿瘤药物顺铂抗增殖作用相近，抗肿瘤活性数据具体见表1。Beneficial effects: The anti-proliferation activity of the flavone derivatives on tumor cells HEL and PC3 was studied by MTT method, and the results showed that the anti-proliferation activities of the flavone derivatives on tumor cells HEL and PC3 were better than that of the natural flavone apigenin. High activity; the anti-proliferation effect of cisplatin is similar to that of the clinical anti-tumor drug, and the anti-tumor activity data are shown in Table 1.
表1：黄酮衍生物对肿瘤细胞HEL和PC3的抗增殖活性对比数据Table 1: Comparative data of antiproliferative activity of flavonoid derivatives on tumor cells HEL and PC3
具体实施方式Detailed ways
实施例1Example 1
(1)化合物1a的合成：在室温下，将2,4,6-三羟基苯乙酮1(1.0当量)和K2CO3(2.0当量)溶于丙酮中并在氮气保护下滴入Me2SO4(2.0eq)，升温至40℃，用TLC监测反应结束约4h，过滤反应，用丙酮洗涤3次。蒸发有机相得到1a，产率98％。(1) Synthesis of compound 1a: at room temperature, 2,4,6-trihydroxyacetophenone 1 (1.0 equiv) and K 2 CO 3 (2.0 equiv) were dissolved in acetone and dropped into Me 2 SO 4 (2.0eq), the temperature was raised to 40°C, and the reaction was monitored by TLC for about 4 hours. The reaction was filtered and washed 3 times with acetone. Evaporation of the organic phase afforded 1a in 98% yield.
(2)化合物2b的合成：把3,5-二甲基对羟基苯甲醛(6mmol,1.0eq),K2CO3(12mmol,2.0eq)溶于无水DMF(40mL)中，降温到0度。然后滴加BrBn(6.6mmol,1.1eq),滴完后，缓慢升温到室温。TLC监控反应，反应完后加入50mL水，EA20mL×3萃取,合并有机层，50mL水洗三次，饱和食盐水洗20mL洗三次，无水Na2SO4干燥，过虑，减压除去EA得化合物2b，产率95％。(2) Synthesis of compound 2b: Dissolve 3,5-dimethyl p-hydroxybenzaldehyde (6mmol, 1.0eq), K 2 CO 3 (12mmol, 2.0eq) in anhydrous DMF (40mL), cool to 0 Spend. Then BrBn (6.6mmol, 1.1eq) was added dropwise, and after the drop, the temperature was slowly raised to room temperature. The reaction was monitored by TLC. After the reaction, 50 mL of water was added, extracted with EA 20 mL×3, the organic layers were combined, washed three times with 50 mL of water, washed three times with 20 mL of saturated brine, dried over anhydrous Na 2 SO 4 , filtered, and EA was removed under reduced pressure to obtain compound 2b. The rate is 95%.
(3)化合物3的合成：把1a(5mmol,1eq)和2b(5mmol,1eq)溶于40mL乙醇中，保持温度在室温，滴加40％NaOH(50mmol,10eq)水溶液。滴加完后，升温到40度，TLC监测反应，反应完后以1N HCl调节pH到酸性。过虑得固体，烘干，用乙醇重结晶得化合物3，产率70％。m.p.:120.6-121.4℃；1H NMR(400MHz,CDCl3)δ:(ppm)14.40(s,1H,OH),7.82(d,J＝15.6Hz,1H,C＝C-H),7.73(d,J＝15.6Hz,1H,C＝C-H),7.50(d,J＝6.8Hz,2H,Ar-H),7.37-7.45(m,3H,Ar-H),7.30(s,2H,Ar-H),6.12(d,J＝2.4Hz,1H,Ar-H),5.98(d,J＝2.4Hz,1H,Ar-H),4.85(s,2H,ArCH2),3.93(s,3H,OCH3),3.84(s,3H,OCH3),2.34(s,6H,ArCH3).13C NMR(100MHz,CDCl3)δ:(ppm)192.6,168.30,166.0,162.4,157.6,142.4,137.2,131.7,131.2,129.2,128.5,128.1,127.8,126.3,106.3,93.7,91.2,74.1,55.9,55.6,16.6.HRMS(ESI)calcd.C26H27O5,[M+H]+m/z:419.1853,found:417.1850。(3) Synthesis of compound 3: 1a (5mmol, 1eq) and 2b (5mmol, 1eq) were dissolved in 40mL ethanol, and the temperature was kept at room temperature, and 40% NaOH (50mmol, 10eq) aqueous solution was added dropwise. After the dropwise addition, the temperature was raised to 40°C, and the reaction was monitored by TLC. After the reaction, the pH was adjusted to be acidic with 1N HCl. The solid was obtained by filtration, dried, and recrystallized from ethanol to obtain compound 3 with a yield of 70%. mp: 120.6-121.4℃; 1 H NMR (400MHz, CDCl 3 ) δ: (ppm) 14.40(s, 1H, OH), 7.82(d, J=15.6Hz, 1H, C=CH), 7.73(d, J=15.6Hz, 1H, C=CH), 7.50(d, J=6.8Hz, 2H, Ar-H), 7.37-7.45(m, 3H, Ar-H), 7.30(s, 2H, Ar-H ), 6.12(d, J=2.4Hz, 1H, Ar-H), 5.98(d, J=2.4Hz, 1H, Ar-H), 4.85(s, 2H, ArCH 2 ), 3.93(s, 3H, OCH 3 ),3.84(s,3H,OCH 3 ),2.34(s,6H,ArCH 3 ). 13 C NMR(100MHz,CDCl 3 )δ:(ppm)192.6,168.30,166.0,162.4,157.6,142.4, 137.2, 131.7, 131.2, 129.2, 128.5, 128.1, 127.8, 126.3, 106.3, 93.7, 91.2, 74.1, 55.9, 55.6, 16.6. HRMS (ESI) calcd. C 26 H 27 O 5 ,[M+H] + m /z:419.1853,found:417.1850.
(4)化合物4的合成：取化合物3(2.4mmol,1eq)和碘(0.024mmol,0.01eq)于30mLDMSO中，加热到160度反应4h，降温到室温，把DMSO反应液到入冰水浴中，过滤得固体，因体用EA重结晶得到化合物4。产率72％,m.p.:208.1-209.2℃；1HNMR(400MHz,CDCl3)δ:(ppm)7.56(s,2H,Ar-H),7.50(d,J＝4.0Hz,2H,Ar-H),7.43(t,J＝4.0Hz,2H,Ar-H),7.39(t,J＝4.0Hz,1H,Ar-H),6.62(s,1H,C＝C-H),6.58(d,J＝1.2Hz,1H,Ar-H),6.37(d,J＝1.2Hz,1H,Ar-H),4.87(s,2H,ArCH2),3.96(s,3H,OCH3),3.93(s,3H,OCH3),2.37(s,6H,ArCH3).13C NMR(151MHz,CDCl3)δ:(ppm)177.7,164.0,160.9,160.7,159.9,158.5,137.1,132.0,128.6,128.2,127.9,127.0,126.7,109.2,108.5,96.1,92.8,74.2,56.4,55.8,16.7.HRMS(ESI)calcd.C26H25O5,[M+H]+m/z:417.1697,found:417.1695。(4) Synthesis of compound 4: Take compound 3 (2.4mmol, 1eq) and iodine (0.024mmol, 0.01eq) in 30mL of DMSO, heat to 160 degrees for 4 hours, cool down to room temperature, put the DMSO reaction solution into an ice-water bath , filtered to obtain a solid, which was recrystallized with EA to obtain compound 4. Yield 72%, mp: 208.1-209.2℃; 1 HNMR (400MHz, CDCl 3 ) δ: (ppm) 7.56(s, 2H, Ar-H), 7.50(d, J=4.0Hz, 2H, Ar-H ), 7.43(t, J=4.0Hz, 2H, Ar-H), 7.39(t, J=4.0Hz, 1H, Ar-H), 6.62(s, 1H, C=CH), 6.58(d, J =1.2Hz, 1H, Ar-H), 6.37(d, J=1.2Hz, 1H, Ar-H), 4.87(s, 2H, ArCH 2 ), 3.96(s, 3H, OCH 3 ), 3.93(s ,3H,OCH 3 ),2.37(s,6H,ArCH 3 ). 13 C NMR(151MHz,CDCl 3 )δ:(ppm)177.7,164.0,160.9,160.7,159.9,158.5,137.1,132.0,128.6,128.2 ,127.9,127.0,126.7,109.2,108.5,96.1,92.8,74.2,56.4,55.8,16.7.HRMS(ESI)calcd.C 26 H 25 O 5 ,[M+H] + m/z:417.1697,found: 417.1695.
(5)化合物5的合成：取化合物4(2.4mmol,1.0eq)和Pd/C 10％(0.24mmol,0.1eq)于50mL甲醇中，用氢所转换，通入氢气于室温下反应5h,补加50mL甲醇加热加回流后，趁热过滤得目标化合物5。产率95％，m.p.:185.3-186.2℃,1H NMR(600MHz,DMSO-d6)δ:(ppm)9.03(s,1H,OH),7.64(s,2H,Ar-H),6.84(d,J＝0.4Hz,1H,Ar-H),6.57(s,1H,C＝C-H),6.48(d,J＝1.2Hz,1H,Ar-H),3.9(s,3H,OCH3),3.82(s,3H,OCH3),2.24(s,6H,ArCH3).13C NMR(151MHz,DMSO-d6)δ:(ppm)176.1,164.0,160.8,160.6,159.6,157.0,126.7,125.2,121.7,108.7,106.6,96.7,93.7,56.5,56.4,17.1.HRMS(ESI)calcd.C19H19O5N,[M+H]+m/z:327.1227,found:327.1226。(5) Synthesis of compound 5: Take compound 4 (2.4mmol, 1.0eq) and Pd/C 10% (0.24mmol, 0.1eq) in 50mL of methanol, convert it with hydrogen, pass in hydrogen and react at room temperature for 5h, After adding 50 mL of methanol and heating to reflux, the target compound 5 was obtained by filtration while hot. Yield 95%, mp: 185.3-186.2℃, 1 H NMR (600MHz, DMSO-d 6 ) δ: (ppm) 9.03(s, 1 H, OH), 7.64(s, 2H, Ar-H), 6.84 (d, J=0.4Hz, 1H, Ar-H), 6.57(s, 1H, C=CH), 6.48(d, J=1.2Hz, 1H, Ar-H), 3.9(s, 3H, OCH 3 ),3.82(s,3H,OCH 3 ),2.24(s,6H,ArCH 3 ). 13 C NMR(151MHz,DMSO-d 6 )δ:(ppm)176.1,164.0,160.8,160.6,159.6,157.0, 126.7 , 125.2 , 121.7 , 108.7, 106.6, 96.7, 93.7, 56.5, 56.4, 17.1. HRMS ( ESI ) calcd.
(6)化合物6的合成：取化合物5(3mmol,1eq)和K2CO3(30mmol,10eq)于无水DMF中，氮气保护，加入过量的三氟甲磺酰氯，反应5h后，加入冰水50mL,20mL二氯甲烷萃取三次，合并有机层，20mL水洗有机层3次，饱和食盐水洗一次，有机层无水硫酸钠干燥，过滤减压除二氯甲烷得粗产品，粗产品经柱层析得纯品化合物6，产率60％，m.p.265.5-266.2℃:1HNMR(600MHz,CDCl3)δ:(ppm)7.60(s,2H,Ar-H),6.62(s,1H,C＝C-H),6.57(d,J＝2.4Hz,1H,Ar-H),6.37(d,J＝1.8Hz,1H,Ar-H),3.95(s,3H,OCH3),3.92(s,3H,OCH3),2.47(s,6H,CH3).13CNMR(151MHz,CDCl3)δ:(ppm)177.2,164.2,160.9,159.8,159.0,148.4,132.5,131.2,127.4,118.6(dd,J＝320.12,640.24,CF3)109.7,109.2,96.3,92.8,56.4,55.8,17.4.HRMS(ESI)calcd.C20H18O7F3S,[M+H]+m/z:459.0720,found:459.0721。(6) Synthesis of compound 6: take compound 5 (3mmol, 1eq) and K 2 CO 3 (30mmol, 10eq) in anhydrous DMF, nitrogen protection, add excess trifluoromethanesulfonyl chloride, react for 5h, add ice Extract with 50 mL of water and 20 mL of dichloromethane three times, combine the organic layers, wash the organic layer with 20 mL of water for three times, wash with saturated saline once, dry the organic layer with anhydrous sodium sulfate, filter and remove the dichloromethane under reduced pressure to obtain the crude product, and pass the crude product through the column layer Pure compound 6 was obtained with a yield of 60%, mp265.5-266.2℃: 1 HNMR (600MHz, CDCl 3 )δ: (ppm) 7.60(s, 2H, Ar-H), 6.62(s, 1H, C =CH),6.57(d,J=2.4Hz,1H,Ar-H),6.37(d,J=1.8Hz,1H,Ar-H),3.95(s,3H,OCH 3 ),3.92(s, 3H,OCH 3 ),2.47(s,6H,CH 3 ). 13 CNMR(151MHz,CDCl 3 )δ:(ppm)177.2,164.2,160.9,159.8,159.0,148.4,132.5,131.2,127.4,118.6(dd , J=320.12, 640.24, CF 3 ) 109.7, 109.2, 96.3, 92.8, 56.4, 55.8, 17.4. HRMS (ESI) calcd. C 20 H 18 O 7 F 3 S, [M+H] + m/z: 459.0720,found: 459.0721.
(7)化合物6-1～6-14的合成：取化合物乙酸钯(0.02mmol,0,01eq),BINAP(0.04mmol,0.2eq)，Cs2CO3,6(0.22mmol,2.2eq)和胺类(0.2mmol,1eq)于10mL无水甲苯中，在无水无氧条件下反应回流反应12h,降温到室温，直接柱层析得目标产物6-1～6-14。(7) Synthesis of compounds 6-1~6-14: take compounds palladium acetate (0.02mmol, 0,01eq), BINAP (0.04mmol, 0.2eq), Cs 2 CO 3 ,6 (0.22mmol, 2.2eq) and Amines (0.2mmol, 1eq) were reacted in 10mL of anhydrous toluene under anhydrous and anaerobic conditions under reflux for 12h, cooled to room temperature, and the target products 6-1~6-14 were obtained by direct column chromatography.
实施例2Example 2
为了进一步确认化合物结构的准确性，采用核磁共振对目标产物6-1-6-14化合物的进行核磁共振检测得出如下结果：In order to further confirm the accuracy of the compound structure, nuclear magnetic resonance was used to detect the target product 6-1-6-14 compound to obtain the following results:
化合物6-1:60％yield,m.p.:134.3-135.7℃,1HNMR(400MHz,CDCl3)δ:(ppm)7.49(s,2H,Ar-H),6.56(s,2H,Ar-H,C＝C-H),6.35(s,1H,Ar-H),4.26(s,1H,NH),3.94(s,5H,OCH3,COCH2),3.91(s,3H,OCH3),3.77(s,3H,OCH3),2.38(s,6H,ArCH3)；13C NMR(151MHz,CDCl3)δ:(ppm)177.7,172.4,163.8,161.1,160.8,159.9,148.9,127.6,126.8,123.7,109.2,107.4,96.0,92.8,56.4,55.7,52.4,49.3,19.1.HRMS(ESI)calcd.C22H24O6N,[M+H]+m/z:398.1598,found:398.1596。Compound 6-1: 60% yield, mp: 134.3-135.7℃, 1 HNMR (400MHz, CDCl 3 )δ: (ppm) 7.49(s, 2H, Ar-H), 6.56(s, 2H, Ar-H, C=CH), 6.35(s, 1H, Ar-H), 4.26(s, 1H, NH), 3.94(s, 5H, OCH 3 , COCH2), 3.91(s, 3H, OCH 3 ), 3.77(s ,3H,OCH 3 ),2.38(s,6H,ArCH 3 ); 13 C NMR (151MHz,CDCl 3 )δ:(ppm)177.7,172.4,163.8,161.1,160.8,159.9,148.9,127.6,126.8,123.7 , 109.2 , 107.4 , 96.0 , 92.8, 56.4, 55.7, 52.4 , 49.3, 19.1.
化合物6-2:55％yield,m.p.:192.7-193.3℃；1HNMR(400MHz,CDCl3)δ:(ppm)7.47((s,2H,Ar-H),6.55-6.56(m,1H,Ar-H,C＝C-H),6.34(d,J＝2.0Hz,1H,Ar-H),6.36(d,J＝2.0Hz,1H,Ar-H),4.10-4.15(m,1H,NHCH),3.93(s,3H,OCH3),3.90(s,3H,OCH3),3.61(s,3H,OCH3),2.36(s,6H,ArCH3),1.61-1.80(m,3H,CH2CH),0.97(t,J＝7.2Hz,6H,CH3)；13C NMR(100MHz,CDCl3)δ:(ppm)177.7,175.1,163.7,161.0,160.8,159.8,147.4,128.1,126.8,123.8,109.2,107.4,95.9,92.7,57.7,56.3,55.7,51.9,43.6,l 24.9,22.8,22.5,19.2.HRMS(ESI)calcd.C26H32O6N,[M+H]+m/z:454.2224,found:454.2223。Compound 6-2: 55% yield, mp: 192.7-193.3℃; 1 HNMR (400MHz, CDCl 3 ) δ: (ppm) 7.47 ((s, 2H, Ar-H), 6.55-6.56 (m, 1H, Ar -H, C=CH), 6.34(d, J=2.0Hz, 1H, Ar-H), 6.36(d, J=2.0Hz, 1H, Ar-H), 4.10-4.15(m, 1H, NH CH ),3.93(s,3H,OCH 3 ),3.90(s,3H,OCH 3 ),3.61(s,3H,OCH 3 ),2.36(s,6H,ArCH 3 ),1.61-1.80(m,3H, CH 2 CH), 0.97 (t, J=7.2Hz, 6H, CH 3 ); 13 C NMR (100MHz, CDCl 3 ) δ: (ppm) 177.7, 175.1, 163.7, 161.0, 160.8, 159.8, 147.4, 128.1, 126.8, 123.8, 109.2, 107.4, 95.9, 92.7, 57.7, 56.3, 55.7, 51.9, 43.6, l 24.9, 22.8, 22.5, 19.2. HRMS (ESI) calcd. C 26 H 32 O 6 N, [M+H] + m/z:454.2224,found:454.2223.
化合物6-3:59％yield；m.p.:166.1-167.4℃；1HNMR(400MHz,CDCl3)δ:(ppm)7.47((s,2H,Ar-H),6.57(s,1H,C＝C-H),6.56(d,J＝2.0Hz,1H,Ar-H),6.35(d,J＝2.0Hz,1H,Ar-H),4.13(t,J＝6.8Hz,1H,NHCH),3.93(s,3H,OCH3),3.90(s,3H,OCH3),3.61(s,3H,OCH3),2.37(s,6H,ArCH3),1.60-1.77(m,3H,CH2CH),0.98(t,J＝7.2Hz,6H,CH3)；13C NMR(100MHz,CDCl3)δ:(ppm)177.7,175.1,163.8,161.1,160.7,159.8,147.4,128.1,126.9,123.8,109.1,107.3,95.9,92.7,57.7,56.3,55.7,51.8,43.6,24.9,22.8,22.5,19.2.HRMS(ESI)calcd.C26H32O6N,[M+H]+m/z:454.2224,found:454.2223。Compound 6-3: 59% yield; mp: 166.1-167.4°C; 1 HNMR (400MHz, CDCl 3 ) δ: (ppm) 7.47((s, 2H, Ar-H), 6.57(s, 1H, C=CH ),6.56(d,J=2.0Hz,1H,Ar-H),6.35(d,J=2.0Hz,1H,Ar-H),4.13(t,J=6.8Hz,1H,NH CH ),3.93 (s,3H,OCH 3 ),3.90(s,3H,OCH 3 ),3.61(s,3H,OCH 3 ),2.37(s,6H,ArCH 3 ),1.60-1.77(m,3H,CH 2 CH ), 0.98 (t, J=7.2Hz, 6H, CH 3 ); 13 C NMR (100MHz, CDCl 3 ) δ: (ppm) 177.7, 175.1, 163.8, 161.1, 160.7, 159.8, 147.4, 128.1, 126.9, 123.8 , 109.1,107.3,95.9,92.7,57.7,56.3,55.7,51.8,43.6,24.9,22.8,22.5,19.2.HRMS (ESI) calcd.C26H32O6N , [ M+H] + m/z :454.2224,found:454.2223.
化合物6-4:40％yield,m.p.:142.0-143.1℃,1HNMR(400MHz,CDCl3)δ::7.49(s,2H,Ar-H),6.56-6.57(m,2H,Ar-H,C＝C-H),6.36(d,J＝4.0Hz,1H,Ar-H),4.26(s,1H,NH),3.96-4.09(m,1H,NHCH),3.94(s,3H,OCH3),3.91(s,3H,OCH3),3.66(s,3H,OCH3),2.64(t,J＝8.0Hz,CHCH2 ),2.39(s,6H,ArCH3),2.09(s,3H,SCH3),2.00-2.12(m,2H,SCH2)；13C NMR(100MHz,CDCl3)δ:177.7,174.4,163.8,161.0,160.7,159.8,147.1,128.2,126.8,123.9,109.1,107.2,95.9,92.7,57.8,56.3,55.7,52.1,30.1,29.6,19.2,15.4.HRMS(ESI)calcd.C25H30O6NS,[M+H]+m/z:472.1788,found:472.1791。Compound 6-4: 40% yield, mp: 142.0-143.1℃, 1 HNMR (400MHz, CDCl 3 )δ::7.49(s, 2H, Ar-H), 6.56-6.57(m, 2H, Ar-H, C=CH), 6.36(d, J=4.0Hz, 1H, Ar-H), 4.26(s, 1H, NH), 3.96-4.09(m, 1H, NH CH ), 3.94(s, 3H, OCH 3 ),3.91(s,3H,OCH 3 ),3.66(s,3H,OCH 3 ),2.64(t,J=8.0Hz,CH CH 2 ),2.39(s,6H,ArCH 3 ),2.09(s, 3H, SCH 3 ), 2.00-2.12 (m, 2H, SCH 2 ); 13 C NMR (100MHz, CDCl 3 ) δ: 177.7, 174.4, 163.8, 161.0, 160.7, 159.8, 147.1, 128.2, 126.8, 123.9, 109.1 , 107.2, 95.9, 92.7, 57.8, 56.3, 55.7, 52.1, 30.1, 29.6, 19.2, 15.4. HRMS (ESI) calcd. C 25 H 30 O 6 NS, [M+H] + m/z: 472.1788, found :472.1791.
化合物6-5:45％yield,m.p.:151.3-153.4；1HNMR(600MHz,CDCl3)δ:7.43(s,2H,Ar-H),6.53(s,1H,C＝C-H),6.52(d,J＝1.8Hz,1H,Ar-H),6.30(d,J＝2.4Hz,Ar-H),4.01-4.05(m,2H,NHCH),3.90(s,3H,OCH3),3.86(s,3H,OCH3),3.60(s,3H,OCH3),2.34(s,6H,ArCH3),1.78-1.85(m,1H,CH3 CH),1.68-1.72(m,1H,CH3CH2),1.51-1.59(m,1H,CH3CH2),0.90-0.97(m,6H,CHCH3 ,CH2 CH3 ),13C NMR(151MHz,CDCl3)δ:(ppm)177.8,174.2,163.8,161.2,160.8,159.8,147.5,127.8,126.97,123.45,109.15,107.22,,95.98,92.76,63.24,56.33,55.73,51.65,39.0,25.9,19.3,15.2,11.7.HRMS(ESI)calcd.C26H32O6N,[M+H]+m/z:454.2224,found:454.2225。Compound 6-5: 45% yield, mp: 151.3-153.4; 1 HNMR (600MHz, CDCl 3 ) δ: 7.43(s, 2H, Ar-H), 6.53(s, 1H, C=CH), 6.52(d , J=1.8Hz, 1H, Ar-H), 6.30(d, J=2.4Hz, Ar-H), 4.01-4.05(m, 2H, NHCH ), 3.90(s, 3H, OCH 3 ), 3.86( s,3H,OCH 3 ),3.60(s,3H,OCH 3 ),2.34(s,6H,ArCH 3 ),1.78-1.85(m,1H,CH 3 CH ),1.68-1.72(m,1H,CH 3 CH 2 ),1.51-1.59(m,1H,CH 3 CH 2 ),0.90-0.97(m,6H,CH CH 3 ,CH 2 CH 3 ), 13 C NMR(151MHz,CDCl 3 )δ:(ppm ) 177.8, 174.2, 163.8, 161.2, 160.8, 159.8, 147.5, 127.8, 126.97, 123.45, 109.15, 107.22, 95.98, 92.76, 63.24, 56.33, 55.73, 51.65, 19.0, 23.2 ESI) calcd. C 26 H 32 O 6 N, [M+H] + m/z: 454.2224, found: 454.2225.
化合物6-6:55％yield；m.p.172.6-173.3℃；1HNMR(400MHz,CDCl3)δ:(ppm)7.47(s,2H,Ar-H),6.55-6.56(m,2H,Ar-H,C＝C-H),6.34(d,J＝2.0Hz,1H,Ar-H),4.03-4.06(m,1H,COCH),3.94(s,3H,OCH3),3.90(s,3H,OCH3),3.62(s,3H,OCH3),2.37(s,6H,ArCH3),2.04-2.12(m,1H,(CH3)2CH),1.13(d,J＝7.2Hz,3H,CH3),1.01(d,J＝7.2Hz,3H,CH3).13CNMR(100MHz,CDCl3)δ:(ppm)177.7,174.3,163.7,161.1,160.7,159.8,147.4,127.8,126.9,123.5,109.2,107.3,95.9,92.7,64.5,56.3,55.7,51.7,32.2,19.3,18.9,18.7.HRMS(ESI)calcd.C25H30O6N,[M+H]+m/z:440.2068,found:440.2065。Compound 6-6: 55% yield; mp172.6-173.3℃; 1 HNMR (400MHz, CDCl 3 ) δ: (ppm) 7.47(s, 2H, Ar-H), 6.55-6.56(m, 2H, Ar- H,C=CH),6.34(d,J=2.0Hz,1H,Ar-H),4.03-4.06(m,1H,COCH),3.94(s,3H,OCH 3 ),3.90(s,3H, OCH 3 ), 3.62(s, 3H, OCH 3 ), 2.37(s, 6H, ArCH 3 ), 2.04-2.12(m, 1H, (CH 3 ) 2 CH), 1.13(d, J=7.2Hz, 3H , CH 3 ), 1.01 (d, J=7.2Hz, 3H, CH 3 ). 13 CNMR (100MHz, CDCl 3 ) δ: (ppm) 177.7, 174.3, 163.7, 161.1, 160.7, 159.8, 147.4, 127.8, 126.9 ,123.5,109.2,107.3,95.9,92.7,64.5,56.3,55.7,51.7,32.2,19.3,18.9,18.7.HRMS(ESI)calcd.C 25 H 30 O 6 N,[M+H] + m/z :440.2068,found:440.2065.
化合物6-7:53％yield；m.p.:166.8-168.4℃；1HNMR(400MHz,CDCl3)δ:(ppm)7.47(s,2H,Ar-H),6.55-6.56(m,2H,Ar-H,C＝C-H),6.35(d,J＝2.4Hz,1H,Ar-H),4.03-4.06(m,1H,NHCH),3.94(s,3H,OCH3),3.92(s,3H,OCH3),3.62(s,3H,OCH3),2.37(s,6H,ArCH3),2.04-2.12(m,1H,(CH3)2 CH),1.13(d,J＝7.2Hz,CH3),1.01(d,J＝7.2Hz,CH3).13C NMR(100MHz,CDCl3)δ:(ppm)177.7,174.3,163.7,161.1,160.7,159.8,147.4,127.8,126.9,123.5,109.0,107.3,95.9,92.7,64.5,56.3,55.7,51.7,32.2,19.2,18.9,18.7.HRMS(ESI)calcd.C25H30O6N,[M+H]+m/z:440.2068,found:440.2066。Compound 6-7: 53% yield; mp: 166.8-168.4℃; 1 HNMR (400MHz, CDCl 3 ) δ: (ppm) 7.47 (s, 2H, Ar-H), 6.55-6.56 (m, 2H, Ar- H,C=CH),6.35(d,J=2.4Hz,1H,Ar-H),4.03-4.06(m,1H,NH CH ),3.94(s,3H,OCH 3 ),3.92(s,3H ,OCH 3 ),3.62(s,3H,OCH 3 ),2.37(s,6H,ArCH 3 ),2.04-2.12(m,1H,(CH 3 ) 2 CH ),1.13(d,J＝7.2Hz, CH 3 ), 1.01 (d, J=7.2Hz, CH 3 ). 13 C NMR (100MHz, CDCl 3 ) δ: (ppm) 177.7, 174.3, 163.7, 161.1, 160.7, 159.8, 147.4, 127.8, 126.9, 123.5 ,109.0,107.3,95.9,92.7,64.5,56.3,55.7,51.7,32.2,19.2,18.9,18.7.HRMS(ESI)calcd.C 25 H 30 O 6 N,[M+H] + m/z:440.2068 ,found: 440.2066.
化合物6-8:55％yield,m.p.183.2-184.0；1HNMR(600MHz,CDCl3)δ:(ppm)7.49(s,2H,Ar-H),6.58(s,1H,C＝C-H),6.56(d,J＝1.8Hz,1H,Ar-H),6.35(d,J＝2.4Hz,1H,Ar-H),4.15(dd,J＝6.6,13.8Hz,1H,COCH),3.94(s,3H,OCH3),3.90(s,3H,OCH3),3.69((s,3H,OCH3),2.37(s,6H,ArCH3),1.42(d,J＝7.2Hz,3H,CH3).13C NMR(151MHz,CDCl3)δ:(ppm)177.8,175.5,163.9,161.2,160.9,159.9,147.4,128.5,126.9,124.0,109.2,107.5,96.0,92.8,56.4,55.8,54.7,52.2,19.9,19.2.HRMS(ESI)calcd.C23H26O6N,[M+H]+m/z:412.1755,found:4121753。Compound 6-8: 55% yield, mp183.2-184.0; 1 HNMR (600MHz, CDCl 3 ) δ: (ppm) 7.49 (s, 2H, Ar-H), 6.58 (s, 1H, C=CH), 6.56(d, J=1.8Hz, 1H, Ar-H), 6.35(d, J=2.4Hz, 1H, Ar-H), 4.15(dd, J=6.6, 13.8Hz, 1H, COCH), 3.94( s,3H,OCH 3 ),3.90(s,3H,OCH 3 ),3.69((s,3H,OCH 3 ),2.37(s,6H,ArCH 3 ),1.42(d,J＝7.2Hz,3H, CH 3 ). 13 C NMR (151MHz, CDCl 3 ) δ: (ppm) 177.8, 175.5, 163.9, 161.2, 160.9, 159.9, 147.4, 128.5, 126.9, 124.0, 109.2, 107.5, 96.0, 92.8, 56.4, 55.8, 54.7, 52.2, 19.9, 19.2. HRMS (ESI) calcd. C 23 H 26 O 6 N, [M+H] + m/z: 412.1755, found: 4121753.
化合物6-9:10％yield,m.p.:123.3-124.0℃；1HNMR(600MHz,CDCl3)δ:(ppm)7.47(s,2H,Ar-H),6.56(s,1H,C＝C-H),6.55(d,J＝2.4Hz,1H,Ar-H),6.35(d,J＝2.4Hz,1H,Ar-H),4.14(s,1H),3.94(s,3H,OCH3),3.90(s,3H,OCH3),3.69(s,3H,OCH3),3.65(s,3H,OCH3),2.49-2.55(m,2H,CHCH2 ),2.36(s,6H,ArCH3),2.10-2.14(m,2H,COCH2).13C NMR(151MHz,CDCl3)δ:(ppm)177.8,174.4,173.2,163.9,161.1,160.9,159.9,147.1,128.4,127.0,124.1,109.3,107.6,96.0,92.8,58.3,56.4,55.8,52.2,51.9,30.1,28.8,19.2.HRMS(ESI)calcd.C26H30O8N,[M+H]+m/z:484.1966,found:484.1959。Compound 6-9: 10% yield, mp: 123.3-124.0℃; 1 HNMR (600MHz, CDCl 3 )δ: (ppm) 7.47(s, 2H, Ar-H), 6.56(s, 1H, C=CH) ,6.55(d,J=2.4Hz,1H,Ar-H),6.35(d,J=2.4Hz,1H,Ar-H),4.14(s,1H),3.94(s,3H,OCH 3 ), 3.90(s,3H,OCH 3 ),3.69(s,3H,OCH 3 ),3.65(s,3H,OCH 3 ),2.49-2.55(m,2H,CH CH 2 ),2.36(s,6H,ArCH 3 ),2.10-2.14(m,2H,COCH 2 ). 13 C NMR(151MHz,CDCl 3 )δ:(ppm)177.8,174.4,173.2,163.9,161.1,160.9,159.9,147.1,128.4,127.0,124.1 ,109.3,107.6,96.0,92.8,58.3,56.4,55.8,52.2,51.9,30.1,28.8,19.2.HRMS(ESI)calcd.C 26 H 30 O 8 N,[M+H] + m/z:484.1966 ,found: 484.1959.
化合物6-10:60％yield,m.p.:174.1-175.9℃；1HNMR(400MHz,CDCl3)δ:(ppm)7.46(s,2H,Ar-H),7.25-7.32(m,3H,Ar-H),7.14(d,J＝7.2Hz,Ar-H),6.57(s,1H,C＝C-H),6.56(d,J＝2.4Hz,1H,Ar-H),6.35(d,J＝2.0Hz,1H,Ar-H),4.34(t,J＝6.4Hz,1H,COCH),3.93(s,3H,OCH3),3.90(s,3H,OCH3),3.60(s,3H,COOCH3),3.10(m,2H,ArCH2),2.23(s,6H,ArCH3).13C NMR(100MHz,CDCl3)δ:(ppm)177.7,174.1,163.8,161.0,160.7,159.8,147.1,136.1,129.3,128.4,128.1,127.0,126.8,123.7,109.1,107.3,96.0,92.7,60.2,56.3,55.7,51.9,40.0,19.1.HRMS(ESI)calcd.C29H30O6N,[M+H]+m/z:488.2068,found:488.2068。Compound 6-10: 60% yield, mp: 174.1-175.9℃; 1 HNMR (400MHz, CDCl 3 ) δ: (ppm) 7.46 (s, 2H, Ar-H), 7.25-7.32 (m, 3H, Ar- H), 7.14(d, J=7.2Hz, Ar-H), 6.57(s, 1H, C=CH), 6.56(d, J=2.4Hz, 1H, Ar-H), 6.35(d, J= 2.0Hz,1H,Ar-H),4.34(t,J＝6.4Hz,1H,COCH),3.93(s,3H,OCH 3 ),3.90(s,3H,OCH 3 ),3.60(s,3H, COOCH 3 ),3.10(m,2H,ArCH 2 ),2.23(s,6H,ArCH 3 ). 13 C NMR(100MHz,CDCl 3 )δ:(ppm)177.7,174.1,163.8,161.0,160.7,159.8, 147.1, 136.1, 129.3, 128.4, 128.1, 127.0, 126.8, 123.7, 109.1, 107.3, 96.0, 92.7, 60.2, 56.3, 55.7, 51.9, 40.0, 19.1. HRMS (ESI) calcd. C 29 H 30 O 6 N, [M+H] + m/z:488.2068,found:488.2068.
化合物6-11:60％yield；m.p.:92.4-94.4℃；1HNMR(600MHz,CDCl3)δ:(ppm)7.44(s,2H,Ar-H),6.52-6.53(m,2H,Ar-H,C＝C-H),6.31(d,J＝1.8Hz,1H,Ar-H),4.61(s,1H,NH),4.05-4.07(m,1H,NHCH),4.0(br,1H,CONH),3.90(s,3H,OCH3),3.87(s,3H,OCH3),3.62(s,3H,OCH3),3.08-3.10(m,2H,CONHCH2 ),2.33(s,6H,CH3),1.76-1.79(m,2H,COCHCH2 ),1.36-1.51(m,4H,CH2CH2),1.40(s,9H,C(CH3)3)；13C NMR(151MHz,CDCl3)δ:(ppm)177.7,174.8,163.8,161.1,160.8,159.8,156.0,147.4,128.2,126.9,123.8,109.2,107.4,96.0,92.8,79.1,59.0,56.4,55.7,52.0,40.2,33.7,29.9,28.4,22.8,19.21.HRMS(ESI)calcd.C31H41O8N2,[M+H]+m/z:569.2857,found:569.2856。Compound 6-11: 60% yield; mp: 92.4-94.4℃; 1 HNMR (600MHz, CDCl 3 ) δ: (ppm) 7.44 (s, 2H, Ar-H), 6.52-6.53 (m, 2H, Ar- H,C=CH),6.31(d,J=1.8Hz,1H,Ar-H),4.61(s,1H,NH),4.05-4.07(m,1H,NH CH ),4.0(br,1H, CONH),3.90(s,3H,OCH 3 ),3.87(s,3H,OCH 3 ),3.62(s,3H,OCH 3 ),3.08-3.10(m,2H,CONH CH 2 ),2.33(s, 6H, CH 3 ), 1.76-1.79 (m, 2H, COCH CH 2 ), 1.36-1.51 (m, 4H, CH 2 CH 2 ), 1.40 (s, 9H, C(CH 3 ) 3 ); 13 C NMR (151MHz, CDCl 3 )δ: (ppm) 177.7, 174.8, 163.8, 161.1, 160.8, 159.8, 156.0, 147.4, 128.2, 126.9, 123.8, 109.2, 107.4, 96.0, 92.8, 79.1, 59.0, 56.4, 55.0.7, 5 . _ _ _ _
化合物6-12:62％yield；m.p.:151.5-152.6℃；1HNMR(600MHz,CDCl3)δ:(ppm)7.49(s,2H,Ar-H),6.54(s,2H,Ar-H,C＝C-H),6.32(d,J＝1.6Hz,1H,Ar-H),3.91(s,3H,OCH3),3.88(s,3H,OCH3),3.09(t,J＝7.2Hz,2H,NHCH2 ),2.31(s,6H,ArCH3),1.54-1.60(m,2H,CH3 CH2),0.96(t,J＝7.2Hz,3H,CH3)；13C NMR(151MHz,CDCl3)δ:(ppm)177.8,163.8,161.3,160.8,159.9,149.7,127.5,126.8,122.8,109.2,107.1,96.0,92.8,56.4,55.7,49.9,24.4,19.2,11.5.HRMS(ESI)calcd.C22H26O4N,[M+H]+m/z:368.1856,found:368.1856。Compound 6-12: 62% yield; mp: 151.5-152.6°C; 1 HNMR (600MHz, CDCl 3 ) δ: (ppm) 7.49 (s, 2H, Ar-H), 6.54 (s, 2H, Ar-H, C=CH), 6.32(d, J=1.6Hz, 1H, Ar-H), 3.91(s, 3H, OCH 3 ), 3.88(s, 3H, OCH 3 ), 3.09(t, J=7.2Hz, 2H, NH CH 2 ), 2.31 (s, 6H, ArCH 3 ), 1.54-1.60 (m, 2H, CH 3 CH 2 ) , 0.96 (t, J=7.2Hz, 3H, CH 3 ); 13 C NMR ( ( ESI) calcd. C 22 H 26 O 4 N, [M+H] + m/z: 368.1856, found: 368.1856.
化合物6-13:70％yield,m.p.:143.9-145.2℃；1HNMR(600MHz,CDCl3)δ:(ppm)7.47(s,2H,Ar-H),6.55-6.56(m,2H,Ar-H,C＝C-H),6.34(d,J＝2.4Hz,Ar-H),3.93(s,3H,OCH3),3.90(s,3H,OCH3),3.14(t,J＝7.2Hz,2H,NHCH2 ),2.32(s,6H,ArCH3),1.53-1.58(m,2H,CH2),1.37-1.43(m,2H,CH2),0.94(t,J＝7.8Hz,CH3)；13C NMR(151MHz,CDCl3)δ:(ppm)177.8,163.8,161.3,160.8,159.9,149.8,127.5,126.8,122.8,109.3,107.1,96.0,92.8,56.4,55.7,47.8,33.4,20.2,19.3,13.9.HRMS(ESI)calcd.C23H28O4N,[M+H]+m/z:382.2013,found:382.2012。Compound 6-13: 70% yield, mp: 143.9-145.2℃; 1 HNMR (600MHz, CDCl 3 ) δ: (ppm) 7.47 (s, 2H, Ar-H), 6.55-6.56 (m, 2H, Ar- H,C=CH),6.34(d,J=2.4Hz,Ar-H),3.93(s,3H,OCH 3 ),3.90(s,3H,OCH 3 ),3.14(t,J=7.2Hz, 2H,NH CH 2 ),2.32(s,6H,ArCH 3 ),1.53-1.58(m,2H,CH 2 ),1.37-1.43(m,2H,CH 2 ),0.94(t,J=7.8Hz, CH 3 ); 13 C NMR (151MHz, CDCl 3 ) δ: (ppm) 177.8, 163.8, 161.3, 160.8, 159.9, 149.8, 127.5, 126.8, 122.8, 109.3, 107.1, 96.0, 92.8, 56.4, 55.7, 47.8, 33.4, 20.2, 19.3, 13.9. HRMS (ESI) calcd. C 23 H 28 O 4 N, [M+H] + m/z: 382.2013, found: 382.2012.
化合物6-14:70％yield,m.p.:125.9-130.1℃；1HNMR(600MHz,CDCl3)δ:(ppm)7.61(s,2H,Ar-H),7.05-7.08(m,1H,Ar-H),6.87(t,J＝4.2Hz,1H),6.70-6.73(m,1H,Ar-H),6.63(s,1H,C＝CH),6.57(d,J＝2.4Hz,Ar-H),6.36(d,J＝2.4Hz,Ar-H),6.23-6.26(m,1H,Ar-H),5.45(s,1H,NH),3.94(s,3H,OCH3),3.91(s,3H,OCH3),2.26(s,6H,ArCH3),13C NMR(151MHz,CDCl3)δ:(ppm)177.7,164.1,160.9,160.6,159.9,151.8(d,J＝293.64Hz),140.5,136.0,133.5(d,J＝11.02Hz),128.5,126.3,124.4(d,J＝3.47Hz),118.6(d,J＝6.64Hz),115.0(d,J＝18.42Hz),113.9(d,J＝1.96Hz),109.2,108.6,96.2,92.8,56.4,55.8,18.6.HRMS(ESI)calcd.C25H23O4NF,[M+H]+m/z:420.1606,found:420.1603。Compound 6-14: 70% yield, mp: 125.9-130.1℃; 1 HNMR (600MHz, CDCl 3 ) δ: (ppm) 7.61 (s, 2H, Ar-H), 7.05-7.08 (m, 1H, Ar- H), 6.87(t, J=4.2Hz, 1H), 6.70-6.73(m, 1H, Ar-H), 6.63(s, 1H, C=CH), 6.57(d, J=2.4Hz, Ar- H), 6.36(d, J=2.4Hz, Ar-H), 6.23-6.26(m, 1H, Ar-H), 5.45(s, 1H, NH), 3.94(s, 3H, OCH 3 ), 3.91 (s,3H,OCH 3 ),2.26(s,6H,ArCH 3 ), 13 C NMR (151MHz,CDCl 3 )δ:(ppm)177.7,164.1,160.9,160.6,159.9,151.8(d,J＝293.64 Hz), 140.5, 136.0, 133.5(d, J=11.02Hz), 128.5, 126.3, 124.4(d, J=3.47Hz), 118.6(d, J=6.64Hz), 115.0(d, J=18.42Hz) ,113.9(d,J＝1.96Hz),109.2,108.6,96.2,92.8,56.4,55.8,18.6.HRMS(ESI)calcd.C 25 H 23 O 4 NF,[M+H] + m/z:420.1606 ,found: 420.1603.
上述实施例仅仅是为清楚地说明所作的举例，而并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。The above-mentioned embodiments are only examples for clear description, and are not intended to limit the implementation. For those of ordinary skill in the art, other changes or changes in different forms can be made on the basis of the above description. It is not necessary and impossible to exhaustively list all the implementation manners here. And the obvious changes or changes derived therefrom are still within the scope of protection of the present invention.
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