CN117586206A - Pterocarpus stilbene piperidine amide derivative, preparation method and medical application thereof - Google Patents
Pterocarpus stilbene piperidine amide derivative, preparation method and medical application thereof Download PDFInfo
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- CN117586206A CN117586206A CN202311468297.XA CN202311468297A CN117586206A CN 117586206 A CN117586206 A CN 117586206A CN 202311468297 A CN202311468297 A CN 202311468297A CN 117586206 A CN117586206 A CN 117586206A
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- pterostilbene
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- piperidine
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- -1 stilbene piperidine Chemical compound 0.000 title claims abstract description 88
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 235000009984 Pterocarpus indicus Nutrition 0.000 title description 2
- 241001446503 Pterocarpus Species 0.000 title 1
- VLEUZFDZJKSGMX-UHFFFAOYSA-N pterostilbene Natural products COC1=CC(OC)=CC(C=CC=2C=CC(O)=CC=2)=C1 VLEUZFDZJKSGMX-UHFFFAOYSA-N 0.000 claims abstract description 65
- VLEUZFDZJKSGMX-ONEGZZNKSA-N pterostilbene Chemical compound COC1=CC(OC)=CC(\C=C\C=2C=CC(O)=CC=2)=C1 VLEUZFDZJKSGMX-ONEGZZNKSA-N 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- 239000000243 solution Substances 0.000 claims description 41
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 30
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 150000001408 amides Chemical class 0.000 claims description 18
- 238000006482 condensation reaction Methods 0.000 claims description 18
- 239000000126 substance Substances 0.000 claims description 15
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 claims description 14
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 14
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 claims description 10
- 238000007254 oxidation reaction Methods 0.000 claims description 10
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 claims description 10
- 230000009471 action Effects 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- 238000009833 condensation Methods 0.000 claims description 9
- 230000005494 condensation Effects 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical class C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 8
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 7
- 239000007821 HATU Substances 0.000 claims description 7
- 150000001555 benzenes Chemical class 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 125000003172 aldehyde group Chemical group 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- YWUVOJJHVFLNJA-UHFFFAOYSA-N 2-fluoro-4-methoxyaniline Chemical compound COC1=CC=C(N)C(F)=C1 YWUVOJJHVFLNJA-UHFFFAOYSA-N 0.000 claims description 5
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 claims description 5
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 5
- LGDHZCLREKIGKJ-UHFFFAOYSA-N 3,4-dimethoxyaniline Chemical compound COC1=CC=C(N)C=C1OC LGDHZCLREKIGKJ-UHFFFAOYSA-N 0.000 claims description 5
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 5
- QZVQQUVWFIZUBQ-UHFFFAOYSA-N 3-fluoroaniline Chemical compound NC1=CC=CC(F)=C1 QZVQQUVWFIZUBQ-UHFFFAOYSA-N 0.000 claims description 5
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 5
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 claims description 5
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
- 229940041181 antineoplastic drug Drugs 0.000 claims description 5
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- ODGIMMLDVSWADK-UHFFFAOYSA-N 4-trifluoromethylaniline Chemical compound NC1=CC=C(C(F)(F)F)C=C1 ODGIMMLDVSWADK-UHFFFAOYSA-N 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical group [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 4
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 238000006266 etherification reaction Methods 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 239000000375 suspending agent Substances 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 239000004480 active ingredient Substances 0.000 claims 2
- 150000001412 amines Chemical class 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 230000005764 inhibitory process Effects 0.000 abstract description 6
- 210000004881 tumor cell Anatomy 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000004663 cell proliferation Effects 0.000 abstract description 2
- 230000000079 pharmacotherapeutic effect Effects 0.000 abstract description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 28
- 125000005504 styryl group Chemical group 0.000 description 19
- 239000007787 solid Substances 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 14
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 238000002835 absorbance Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 description 4
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 4
- 238000010609 cell counting kit-8 assay Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 235000021283 resveratrol Nutrition 0.000 description 4
- 229940016667 resveratrol Drugs 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
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- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
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- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
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- 244000086363 Pterocarpus indicus Species 0.000 description 1
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 235000003095 Vaccinium corymbosum Nutrition 0.000 description 1
- 240000000851 Vaccinium corymbosum Species 0.000 description 1
- 235000017537 Vaccinium myrtillus Nutrition 0.000 description 1
- 241000219094 Vitaceae Species 0.000 description 1
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- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 235000021014 blueberries Nutrition 0.000 description 1
- 239000012888 bovine serum Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
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- 150000002611 lead compounds Chemical class 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- SLFVYFOEHHLHDW-UHFFFAOYSA-N n-(trifluoromethyl)aniline Chemical compound FC(F)(F)NC1=CC=CC=C1 SLFVYFOEHHLHDW-UHFFFAOYSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention relates to pterostilbene piperidine amide derivatives, a preparation method and medical application thereof, and belongs to the fields of pharmaceutical chemistry and pharmacotherapeutics. The invention designs and synthesizes series of pterostilbene piperidine amide compounds with novel structures by taking pterostilbene as a raw material, and characterizes the structures of the pterostilbene piperidine amide compounds. The method for preparing the compounds has the characteristics of easily available raw materials, simple and convenient operation and high yield, and can rapidly synthesize target compounds. Compared with pterostilbene, the pterostilbene piperidine amide derivatives provided by the invention have a remarkable cell proliferation inhibition effect on tumor cells.
Description
Technical Field
The invention belongs to the fields of pharmaceutical chemistry and pharmacotherapeutics, and in particular relates to pterostilbene piperidine amide derivatives, a preparation method and medical application thereof.
Background
Malignant tumors seriously threaten the life and health of people. How to develop safe and effective anticancer drugs has been the focus of attention of medical researchers.
Pterostilbene is a homolog of resveratrol, mainly from blueberries and grapes. The research shows that pterostilbene has small toxic and side effects and has various functions of resisting cancer, resisting oxidation, resisting inflammation, reducing blood fat and the like. Compared with resveratrol, the resveratrol has better antitumor activity because more two methoxy groups in the structure make the resveratrol have stronger fat solubility and stronger cell penetrating capacity. Pterostilbene has remarkable inhibition effect on proliferation of various tumor cells, and can inhibit proliferation of various cancers, including lung cancer, breast cancer, prostatic cancer, gastric cancer, colon cancer, pancreatic cancer, thyroid cancer, ovarian cancer, cervical cancer and the like.
However, pterostilbene has the defects of low bioavailability, poor stability, undefined target points and the like, and limits the clinical application and the medical value thereof. In addition, pterostilbene analogs have received great attention as promising multi-target anticancer agents. Therefore, pterostilbene is used as a lead compound, and the pharmaceutical chemical structure modification and transformation are adopted to improve the anticancer effect and improve the defects. Therefore, the development of a safe and effective novel pterostilbene antitumor drug has very important theoretical and practical significance.
Disclosure of Invention
Aiming at the problems, the invention provides a pterostilbene piperidine amide derivative, a preparation method and medical application thereof.
The first object of the present invention is to provide pterostilbene piperidine amide derivatives, wherein the chemical structural formula of the pterostilbene piperidine amide derivatives is shown in formula (1):
in formula I:
r is one of benzene, substituted benzene and cyclohexane.
Further, R is benzene, substituted benzene and cyclohexane. Including but not limited to one of phenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 3, 4-dimethoxyphenyl, 2-fluoro-4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl and cyclohexyl.
The second object of the present invention is to provide a method for preparing pterostilbene piperidine amide derivatives, comprising:
under the condition of anhydrous potassium carbonate, pterostilbene and ethyl bromoacetate undergo Williamson etherification reaction to obtain an intermediate 2;
dropwise adding phosphorus oxychloride into the solution of the intermediate 2 in ice bath, and stirring for reaction to obtain an intermediate 3;
under alkaline condition, intermediate 3 undergoes hydrolysis reaction to obtain intermediate 4;
the intermediate 4 and piperidine undergo a first amide condensation reaction under the action of a first condensation catalyst to obtain an intermediate 5;
the intermediate 5 and 2-methyl-2-butene are subjected to aldehyde oxidation reaction under the action of an oxidant to obtain an intermediate 6;
the intermediate 6 and the amino compound undergo a second amide condensation reaction under the action of a second condensation catalyst to obtain pterostilbene piperidine amide derivatives;
the synthetic route is as follows:
in formula I:
r is one of benzene, substituted benzene and cyclohexane.
Further, the reaction of pterostilbene and ethyl bromoacetate is a solution reaction, the solvent is acetonitrile, and the molar ratio of pterostilbene, anhydrous potassium carbonate and ethyl bromoacetate is 1:1-1.5:1-1.5.
Further, the solution of the intermediate 2 is DMF solution of the intermediate 2, and the mol ratio of the intermediate 2 to phosphorus oxychloride is 1:1.2-1.5.
Further, in the hydrolysis reaction, the solvent is ethanol solution with the mass fraction of 8-10%, and the dosage of the ethanol solution with the mass fraction of 8-10% is 4-5mL per millimole of intermediate 3; the base used was 10% sodium hydroxide solution by mass fraction, the amount of 10% sodium hydroxide solution by mass fraction being 2mL per millimole of intermediate 3.
Further, in the first amide condensation reaction, a reaction solvent is DMF; the first condensation catalyst is HATU and DIPEA, the molar ratio of the intermediate 4 to the piperidine to the HATU to the DIPEA is 1:1.2-1.4:1.5:1.5, and the temperature of the first amide condensation reaction is room temperature;
the aldehyde group oxidation reaction is a solution reaction, the solvent used is acetone, and the oxidant is NaClO 2 And NaH 2 PO 2 ·2H 2 O in water, said intermediate 5, 2-methyl-2-butene, naClO 2 、NaH 2 PO 2 ·2H 2 The molar ratio of O is 1:4-4.5:8:8, and the temperature of the aldehyde group oxidation reaction is room temperature;
the second amide condensation reaction is a solution reaction, the solvent used is DCM, and the second condensing agent is DMAP and EDC & HCl; the molar ratio of the intermediate 6, the amino compound, the DMAP and the EDC & HCl is 1:2-2.5:1.2:1.2, and the temperature of the second amide condensation reaction is room temperature.
Further, the amino compound is aniline, 4-methylaniline, 4-trifluoromethyl aniline, 4-methoxyaniline, 3, 4-dimethoxy aniline, 2-fluoro-4-methoxy aniline, 2-fluoro aniline, 3-fluoro aniline, 4-fluoro aniline, cyclohexane.
A third object of the present invention is to provide a pharmaceutical composition.
The pharmaceutical composition comprises pterostilbene piperidine amide derivatives prepared by the preparation method.
Further, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
Further, the pharmaceutical composition can be prepared into pharmaceutically acceptable dosage forms, such as tablets, dripping pills, capsules, powder, syrup, liquid, suspending agents, freeze-dried powder injection or injection and nano-preparations.
The fourth object of the invention is to provide the application of the pterostilbene piperidine amide derivatives or the pharmaceutical composition in preparing antitumor drugs.
The tumor comprises osteosarcoma, lung cancer, liver cancer, breast cancer and colon cancer.
The invention has the beneficial effects that:
the invention designs and synthesizes a series of pterostilbene piperidine amide derivatives with novel structures, and characterizes the structures of the pterostilbene piperidine amide derivatives; the method for preparing the compounds has the characteristics of easily available raw materials, simple and convenient operation and high yield; meanwhile, the antitumor activity of the compounds is tested, and compared with pterostilbene, the pterostilbene piperidine amide derivatives provided by the invention have remarkable cell proliferation inhibition effect on tumor cells, and have the potential of being used as antitumor drugs for treating tumors.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objectives and other advantages of the invention may be realized and attained by the structure particularly pointed out in the written description and claims hereof as well as the appended drawings.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions of the prior art, the following description will briefly explain the drawings used in the embodiments or the description of the prior art, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 shows the chemical structural formula of pterostilbene amide derivatives according to embodiments of the present invention;
FIG. 2 shows a synthetic scheme of pterostilbene piperidine amide derivatives according to embodiments of the invention.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Figure 1 shows the chemical structural formula I of pterostilbene piperidine amide derivatives according to embodiments of the invention,
in formula I:
r is one of benzene, substituted benzene and cyclohexane.
In certain embodiments of the invention, R is one of phenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 3, 4-dimethoxyphenyl, 2-fluoro-4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, and cyclohexyl.
As shown in fig. 2, a preparation method of pterostilbene piperidine amide derivatives according to an embodiment of the present invention includes:
step a, under the condition of anhydrous potassium carbonate, pterostilbene and ethyl bromoacetate undergo Williamson etherification reaction to obtain an intermediate 2;
step b, dropwise adding phosphorus oxychloride into the solution of the intermediate 2 in an ice bath, and stirring for reaction to obtain an intermediate 3;
step c, under alkaline conditions, the intermediate 3 undergoes hydrolysis reaction to obtain an intermediate 4;
step d, performing a first amide condensation reaction on the intermediate 4 and piperidine under the action of a first condensation catalyst to obtain an intermediate 5;
step e, the intermediate 5 and the 2-methyl-2-butene are subjected to aldehyde oxidation reaction under the action of an oxidant to obtain an intermediate 6;
step f, performing a second amide condensation reaction on the intermediate 6 and the amino compound under the action of a second condensation catalyst to obtain pterostilbene piperidine amide derivatives;
in the step a, the reaction of pterostilbene and ethyl bromoacetate is a solution reaction, the solvent is acetonitrile, and the molar ratio of pterostilbene, anhydrous potassium carbonate and ethyl bromoacetate is 1:1-1.5:1-1.5.
In the step b, the mol ratio of the intermediate 2 to the phosphorus oxychloride is 1:1.2-1.5.
In the step c, the solvent used in the hydrolysis reaction is ethanol solution with the mass fraction of 8-10%, and the dosage of the ethanol solution with the mass fraction of 8-10% is 4-5mL per millimole of intermediate 3; the base used was 10% sodium hydroxide solution by mass fraction, the amount of 10% sodium hydroxide solution by mass fraction being 2mL per millimole of intermediate 3.
In the step d, in the first amide condensation reaction, a reaction solvent is DMF; the first condensation catalyst is HATU and DIPEA, the molar ratio of the piperidine to the intermediate 4 to the HATU to the DIPEA is 1.2-1.4:1:1.5:1.5, and the temperature of the first amide condensation reaction is room temperature.
In the step e, the aldehyde group oxidation reaction is a solution reaction, the solvent used is acetone, and the oxidant is NaClO 2 And NaH 2 PO 2 ·2H 2 O in water, said intermediate 5, 2-methyl-2-butene, naClO 2 、NaH 2 PO 2 ·2H 2 The molar ratio of O is 1:4-4.5:8:8, and the temperature of the aldehyde group oxidation reaction is room temperature.
In the step f, the second amide condensation reaction is a solution reaction, the solvent used is DCM, and the second condensing agent is DMAP and EDC & HCl; the molar ratio of the intermediate 6 to the amino compound to the DMAP to the EDC & HCl is 1:2-2.5:1.2:1.2, and the temperature of the second amide condensation reaction is room temperature;
wherein the amino compound is aniline, 4-methylaniline, 4-trifluoromethyl aniline, 4-methoxyaniline, 3, 4-dimethoxy aniline, 2-fluoro-4-methoxyaniline, 2-fluoroaniline, 3-fluoroaniline, 4-fluoroaniline, cyclohexylamine.
According to the above synthetic route, the specific amino compounds selected in step e are exemplified by the following synthetic examples of specific pterostilbene piperidine amide derivatives:
example 1
The amino compound is aniline, and the specific chemical structural formula of the obtained pterostilbene piperidine amide derivative is shown as follows:
the name is as follows: (E) -2, 4-dimethoxy-6- (4- (2-oxo-2- (piperidin-1-yl) ethoxy) styryl) -N-phenylbenzamide (hereinafter abbreviated as C-1)
The preparation method comprises the following steps:
a. pterostilbene (10.00 g,39.02 mmol) was added to a clean 250mL round bottom flask, 150mL acetonitrile was then added to the reaction flask, anhydrous potassium carbonate (5.39 g,39.02 mmol) and ethyl bromoacetate (9.77 g,58.52 mmol) were then added thereto, the reaction was stirred at 80℃for 20 hours, after which the TLC was monitored for substantial completion, the solvent was recovered under reduced pressure to dryness, then 150mL ethyl acetate was added, washed with water (60 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give a white product, intermediate 2. 1 HNMR(400MHz,CDCl 3 )δ7.44(d,J＝8.6Hz,2H),7.03(d,J＝16.2Hz,1H),6.94-6.88(m,3H),6.67-6.62(m,2H),6.38(s,1H),4.63(s,2H),4.28(q,J＝7.1Hz,2H),3.82(s,6H),1.30(t,J＝7.1Hz,3H). 13 CNMR(100MHz,CDCl 3 )δ168.8,160.9,157.5,139.5,130.9,128.4,127.8,127.1,114.8,104.3,99.7,65.4,61.4,55.3,14.2；ESI-HRMS(m/z):C 20 H 22 O 5 [M+H] + :calcd:343.1467；found:343.1529.
b. Weighing intermediate 2 (12.00 g,35.05 mmol) and adding into a clean 250mL round bottom flask, then adding 135mL of LDMF into the round bottom flask, cooling to below 0deg.C in ice-salt bath, slowly dropwise adding phosphorus oxychloride (8.06 g,52.57 mmol), stirring at room temperature for reaction after dropwise addition, TLC monitoring reaction, and slowly adding the reaction solution after the reaction is finishedSlowly dripping into ice water, and adding NaHCO 3 After the pH of the reaction solution was adjusted to be slightly alkaline, the crude product was obtained by suction filtration and purified by column chromatography (DCM: PE=3:1) to obtain a yellowish green solid, intermediate 3. 1 HNMR(600MHz,CDCl 3 )δ10.52(s,1H),8.06(d,J＝16.2Hz,1H),7.50(d,J＝8.6Hz,2H),7.00-6.89(m,3H),6.73(s,1H),6.39(s,1H),4.64(s,2H),4.28(q,J＝7.1Hz,2H),3.91(s,3H),3.89(s,3H),1.31(t,J＝7.1Hz,3H). 13 CNMR(100MHz,CDCl 3 )δ190.6,168.8,165.0,164.5,157.7,142.9,131.78,131.0,128.4,126.1,116.0,114.8,103.4,96.9,65.4,61.4,55.8,55.5,14.2；ESI-HRMS(m/z):C 21 H 22 O 6 [M+H] + :calcd:371.1416；found:371.1490.
c. Adding intermediate 3 (6.60 g,17.82 mmol) into a clean 100mL round-bottom flask, then adding 20mL of 10% ethanol, then adding 36mL of 10% sodium hydroxide solution, stirring at 50 ℃ for reaction for 2h, adding 20mL of ice water after the reaction is finished, adjusting the pH to be acidic by 3mol/L HCl, and carrying out suction filtration to obtain 5.74g of dark yellow solid, namely intermediate 3; 1 HNMR(400MHz,CDCl 3 )δ10.53(s,1H),8.08(d,J＝16.0Hz,1H),7.53(d,J＝8.7Hz,2H),7.00-6.90(m,4H),6.74(s,1H),6.40(s,1H),4.71(s,2H),3.93(s,3H),3.91(s,3H). 13 CNMR(100MHz,DMSO-d6)δ194.9,175.3,170.0,169.7,163.0,146.9,137.1,135.3,133.2,129.8,120.3,120.0,108.7,102.6,69.6,61.4,60.9；ESI-HRMS(m/z):C 20 H 22 O 5 [M+H] + :calcd:343.1103；found:343.1166.
d. piperidine (993.0. Mu.L, 10.53 mmol) was added to a clean 25mL round bottom flask, followed by 1mL of LDMF, then sequentially added with intermediate 3 (1.00 g,5.85 mmol), HATU (3.34 g,8.78 mmol), DIPEA (1.14 g,8.78 mmol), stirring at room temperature for reaction, TLC monitoring the reaction, after the reaction was completed, a proper amount of water was added dropwise to the reaction solution, solids precipitated, and the filter cake was directly filtered by suction, recovered and dried to give 1.08g of yellow solid, intermediate 5, in 90.32% yield. 1 H NMR(400MHz,CDCl 3 )δ10.52(s,1H),8.05(d,J＝16.2Hz,1H),7.50(d,J＝8.5Hz,2H),6.99-6.91(m,3H),6.74(s,1H),6.39(s,1H),4.70(s,2H),3.92(s,3H),3.90(s,3H),3.56(t,J＝8.0Hz,2H),3.50(t,J＝8.0Hz,2H),1.66-1.54(m,6H). 13 C NMR(100MHz,CDCl 3 )δ190.7,166.0,165.0,164.5,157.9,143.1,131.9,130.8,128.4,126.0,116.1,114.8,103.3,97.0,67.8,55.9,55.6,46.5,43.3,26.5,25.5,24.4；ESI-HRMS(m/z):C 24 H 27 NO 6 [M+H] + :calcd:410.1923；found:410.1958.
e. Intermediate 5 (4.00 g,9.77 mmol) was added to a clean 50mL round bottom flask followed by 30mL of acetone and 2-methyl-2-butene (3.215 mL,39.10 mmol) followed by NaClO 2 (7.07 g,78.20 mmol) and NaH 2 PO 2 ·2H 2 O (10.95 g,78.20 mmol) in water (30 mL), the reaction mixture was stirred for 1h, 30mL of water was added after the completion of the reaction, extracted with EA (3X 30 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give the crude product, which was purified by column chromatography (DCM: meOH=30:1) to give a white solid, intermediate 6. 1 H NMR(400MHz,DMSO-d6)δ7.43(d,J＝8.4Hz,2H),7.21(d,J＝16.2Hz,1H),7.01-6.86(m,4H),6.49(s,1H),4.81(s,2H),3.83(s,3H),3.75(s,3H),3.44-3.39(m,4H),1.61-1.43(m,6H). 13 CNMR(100MHz,CDCl3)δ170.5,165.2,165.2,163.2,162.0,140.3,135.1,134.9,132.8,128.6,120.1,105.6,103.0,102.0,71.3,60.8,60.6,50.4,47.3,31.1,30.5,29.1；ESI-HRMS(m/z):C 24 H 27 NO 5 [M+H] + :calcd:426.1872；found:426.1900.
f. Aniline (44.7 mg,0.48 mol) was added to a clean 25mL round bottom flask, then 1mL of LDCM was added, then intermediate 6 (0.10 g,0.24 mmol), DMAP (34.48 mg,0.28 mmol) and EDC. HCl (54.09 mg,0.28 mmol) were added sequentially, the reaction was stirred at room temperature, the TLC monitored the reaction, after the reaction was completed, a saturated NaCl solution was added thereto for washing twice, and the organic layer, anhydrous Na, was recovered 2 SO 4 Drying and concentrating under reduced pressure to obtain a crude product. After purification on a silica gel column (DCM: meoh=120:1), 44.00mg of a white solid was obtained in 37.41% yield. 1 H NMR(400MHz,CDCl 3 )δ7.68-7.59(m,3H),7.42-7.34(m,4H),7.14(t,J＝7.4Hz,1H),7.03(d,J＝16.1Hz,1H),6.90(d,J＝8.5Hz,2H),6.81(d,J＝2.1Hz,1H),6.43(d,J＝2.1Hz,1H),4.68(s,2H),3.90(s,3H),3.85(s,3H),3.57-3.47(m,4H),1.67-1.57(m,6H). 13 C NMR(100MHz,CDCl 3 )δ166.1,165.5,161.5,158.0,158.0,138.7,138.3,131.0,130.6,129.1,128.4,124.4,124.2,119.9,118.8,114.9,101.7,97.9,77.4,77.1,76.8,67.9,56.1,55.7,46.6,43.4,26.6,25.6,24.5；ESI-HRMS(m/z):C 30 H 32 N 2 O 5 [M+H] + :calcd:501.2389；found:501.2415.
Example 2
The amino compound is 4-methylaniline, and the specific chemical structural formula of the obtained pterostilbene piperidine amide derivative is shown as follows:
the name is as follows: (E) -2, 4-dimethoxy-6- (4- (2-oxo-2- (piperidin-1-yl) ethoxy) styryl) -N- (p-tolyl) benzamide (hereinafter referred to as C-2)
The preparation method comprises the following steps:
the procedure used in example 1 was repeated except that p-methylaniline was used instead of aniline in step f to give the objective product E) -2, 4-dimethoxy-6- (4- (2-oxo-2- (piperidin-1-yl) ethoxy) styryl) -N- (p-tolyl) benzamide as a white solid, 44.48mg, yield 36.78%. 1 H NMR(400MHz,CDCl 3 )δ7.53(d,J＝8.2Hz,2H),7.38(d,J＝8.4Hz,2H),7.23-7.13(m,3H),7.01(d,J＝16.0Hz,1H),6.89(d,J＝8.4Hz,2H),6.80(d,J＝1.2Hz,1H),6.41(d,J＝1.5Hz,1H),4.66(s,2H),3.89(s,3H),3.83(s,3H),3.56-3.46(m,4H),2.34(s,3H),1.65-1.53(m,6H). 13 C NMR(100MHz,CDCl 3 )δ165.3,164.7,160.6,157.3,157.2,137.8,135.0,133.3,130.2,129.8,128.8,127.6,123.4,119.3,118.2,114.1,100.8,97.1,76.7,76.4,76.0,67.1,55.3,54.9,45.8,42.6,25.8,24.9,23.8,20.3；ESI-HRMS(m/z):C 31 H 34 N 2 O 5 [M+H] + :calcd:515.2546；found:515.2563.
Example 3
The amino compound is trifluoromethyl aniline, and the specific chemical structural formula of the obtained pterostilbene piperidine amide derivative is shown as follows:
the name is as follows: (E) -2, 4-dimethoxy-6- (4- (2-oxo-2- (piperidin-1-yl) ethoxy) styryl) -N- (4- (trifluoromethyl) phenyl) benzamide (hereinafter abbreviated as C-3)
The preparation method comprises the following steps:
the procedure of example 1 was followed except that p-trifluoromethylaniline was used instead of aniline in step d to give the desired product E) -2, 4-dimethoxy-6- (4- (2-oxo-2- (piperidin-1-yl) ethoxy) styryl) -N- (4- (trifluoromethyl) phenyl) benzamide as a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.71(d,J＝8.3Hz,1H),7.54(d,J＝8.3Hz,1H),7.35-7.30(m,2H),6.96(d,J＝5.1Hz,1H),6.93-6.80(m,4H),6.77-6.64(m,2H),6.35(d,J＝16.0Hz,1H),4.60(s,2H),3.84(s,3H),3.81(s,3H),3.51-3.46(m,2H),3.44-3.38(m,2H),1.54(d,J＝20.2Hz,6H). 13 C NMR(100MHz,CDCl 3 )δ167.1,164.5,160.0,156.7,156.5,136.2,129.6,128.9,126.6,122.1,114.2,113.3,99.7,96.3,75.9,75.5,75.2,66.2,54.5,54.0,45.0,41.8,25.0,24.1,23.0；ESI-HRMS(m/z):C 31 H 31 F 3 N 2 O 5 [M+H] + :calcd:569.2263；found:569.2288.
Example 4
The amino compound is p-methoxyaniline, and the specific chemical structural formula of the obtained pterostilbene piperidine amide derivative is shown as follows:
the name is as follows: (E) -2, 4-dimethoxy-N- (4-methoxyphenyl) -6- (4- (2-oxo-2- (piperidin-1-yl) ethoxy) styryl) benzamide (hereinafter abbreviated as C-4)
The preparation method comprises the following steps:
the procedure of example 1 was followed except that p-methoxyaniline was used in place of aniline in step f to give (E) -2, 4-dimethoxy-N- (4-methoxyphenyl) -6- (4- (2-oxo-2- (piperidin-1-yl) ethoxy) styryl) benzamide as a target product as a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.60-7.53(m,3H),7.39(d,J＝8.6Hz,2H),7.22(s,1H),7.01(d,J＝16.1Hz,1H),6.90(dd,J＝8.9,2.9Hz,4H),6.80(d,J＝2.1Hz,1H),6.42(d,J＝2.1Hz,1H),4.67(s,2H),3.89(s,3H),3.84(s,3H),3.81(s,3H),3.56-3.46(m,4H),1.63(q,J＝5.9,5.3Hz,6H). 13 C NMR(100MHz,CDCl 3 )δ166.0,165.4,161.3,158.0,158.0,156.4,138.5,131.5,130.8,130.6,128.3,124.2,121.7,114.8,114.2,101.5,97.8,77.4,77.1,76.8,67.7,56.1,55.6,46.5,43.3,26.5,25.6,24.5；ESI-HRMS(m/z):C 31 H 34 N 2 O 6 [M+H] + :calcd:531.2495；found:531.2518.
Example 5
The amino compound is 3, 4-dimethoxy aniline, and the specific chemical structural formula of the obtained pterostilbene piperidine amide derivative is shown as follows:
the name is as follows: (E) -N- (3, 4-dimethoxyphenyl) -2, 4-dimethoxy-6- (4- (2-oxo-2- (piperidin-1-yl) ethoxy) styryl) benzamide (hereinafter abbreviated as C-5)
The preparation method comprises the following steps:
the preparation was carried out in the same manner as in example 1 except that 3, 4-dimethoxyaniline was used in place of aniline in step f to give the desired product (E) -N- (3, 4-dimethoxyphenyl) -2, 4-dimethoxy-6- (4- (2-oxo-2- (piperidin-1-yl) ethoxy) styryl) benzamide as a purple solid. 1 H NMR(400MHz,CDCl 3 )δ7.52(d,J＝1.6Hz,2H),7.40(d,J＝8.6Hz,2H),7.22(d,J＝16.1Hz,1H),7.03(d,J＝16.1Hz,1H),6.97(dd,J＝8.6,2.1Hz,1H),6.90(d,J＝8.6Hz,2H),6.84(d,J＝8.6Hz,1H),6.80(d,J＝1.8Hz,1H),6.43(d,J＝1.4Hz,1H),4.68(s,2H),3.92(s,3H),3.90(s,3H),3.88(s,3H),3.85(s,3H),3.56–3.47(m,4H),1.68–1.55(m,6H). 13 C NMR(100MHz,CDCl 3 )δ165.9,165.3,161.3,157.9,157.9,149.0,145.8,138.4,131.9,130.9,130.4,128.2,124.0,118.8,114.7,111.7,111.3,104.7,101.5,97.7,77.3,77.0,76.7,67.7,56.1,56.0,56.0,55.5,46.4,43.2,26.4,25.5,24.4；ESI-HRMS(m/z):C 32 H 36 N 2 O 7 [M+H] + :calcd:561.2601；found:561.2636.
Example 6
The amino compound is 2-fluoro-4-methoxyaniline, and the specific chemical structural formula of the obtained pterostilbene piperidine amide derivative is shown as follows:
the name is as follows: (E) -N- (2-fluoro-4-methoxyphenyl) -2, 4-dimethoxy-6- (4- (2-oxo-2- (piperidin-1-yl) ethoxy) styryl) benzamide (hereinafter abbreviated as C-6)
The preparation method comprises the following steps:
the preparation was carried out in the same manner as in example 1 except that 2-fluoro-4-methoxyaniline was used in place of aniline in step f to give the desired product E) -N- (2-fluoro-4-methoxyphenyl) -2, 4-dimethoxy-6- (4- (2-oxo-2- (piperidin-1-yl) ethoxy) styryl) benzamide as a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.85–7.77(m,1H),7.42(d,J＝8.6Hz,2H),7.31(d,J＝16.1Hz,1H),7.01(d,J＝16.0Hz,1H),6.92(d,J＝8.7Hz,2H),6.81(d,J＝1.9Hz,1H),6.76–6.70(m,2H),6.43(d,J＝1.9Hz,1H),4.69(s,2H),3.90(s,3H),3.86(s,3H),3.81(s,3H),3.57–3.47(m,4H),1.69–1.55(m,6H). 13 C NMR(100MHz,CDCl 3 )δ165.8,164.9,161.2,157.8,157.7,156.4,156.3,138.9,130.6,128.0,124.2,123.0,119.4,117.8,114.5,109.1,101.7,101.6,101.4,97.5,77.1,76.8,76.5,67.6,55.8,55.5,55.3,46.2,43.0,26.2,25.3,24.6；ESI-HRMS(m/z):C 31 H 33 FN 2 O 6 [M+H] + :calcd:549.2401；found:549.2422.
Example 7
The amino compound is 2-fluoroaniline, and the specific chemical structural formula of the obtained pterostilbene piperidine amide derivative is shown as follows:
the name is as follows: (E) -N- (2-fluorophenyl) -2, 4-dimethoxy-6- (4- (2-oxo-2- (piperidin-1-yl) ethoxy) styryl) benzamide (hereinafter abbreviated as C-7)
The preparation method comprises the following steps:
the preparation was carried out in the same manner as in example 1 except that 2-fluoroaniline was used instead of aniline in step f to obtain the desired product (E) -N- (2-fluorophenyl) -2, 4-dimethoxy-6- (4- (2-oxo-2- (piperidin-1-yl) ethoxy) styryl) benzamide as a white solid. 1 H NMR(400MHz,CDCl 3 )δ8.03–7.99(m,1H),7.35(d,J＝8.7Hz,2H),7.25(d,J＝16.1Hz,1H),7.16–7.09(m,2H),7.04–6.99(m,2H),6.85(d,J＝8.7Hz,2H),6.75(d,J＝2.0Hz,1H),6.37(d,J＝2.0Hz,1H),4.61(s,2H),3.84(s,3H),3.80(s,3H),3.50–3.47(m,2H),3.42(d,J＝5.2Hz,2H),1.61–1.51(m,6H). 13 C NMR(100MHz,CDCl 3 )δ165.4,165.4,161.0,160.9,157.6,157.3,138.9,137.1,130.5,130.3,130.0,129.9,127.7,127.6,123.9,123.1,121.3,114.2,114.2,101.6,100.6,97.1,76.8,76.5,76.1,67.2,55.4,55.0,45.9,42.7,25.9,25.0,23.9；ESI-HRMS(m/z):C 30 H 31 FN 2 O 5 [M+H] + :calcd:519.2295；found:519.2314.
Example 8
The amino compound is 3-fluoroaniline, and the specific chemical structural formula of the obtained pterostilbene piperidine amide derivative is shown as follows:
the name is as follows: (E) -N- (3-fluorophenyl) -2, 4-dimethoxy-6- (4- (2-oxo-2- (piperidin-1-yl) ethoxy) styryl) benzamide (hereinafter abbreviated as C-8)
The preparation method comprises the following steps:
the procedure used in example 1 was repeated except that 3-fluoroaniline was used instead of aniline in step d to give (E) -N- (3-fluorophenyl) -2, 4-dimethoxy-6- (4- (2-oxo-2- (piperidin-1-yl) ethoxy) styryl) benzamide as a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.73–7.65(m,2H),7.40(d,J＝8.6Hz,2H),7.22(d,J＝6.2Hz,2H),7.02(d,J＝15.9Hz,1H),6.91(d,J＝8.6Hz,2H),6.86–6.81(m,2H),6.43(d,J＝1.7Hz,1H),4.68(s,2H),3.90(s,3H),3.85(s,3H),3.56–3.48(m,4H),1.67–1.58(m,6H). 13 C NMR(100MHz,CDCl 3 )δ165.9,165.4,161.8,161.5,158.0,157.9,139.8,138.9,131.0,130.4,130.1,130.0,128.2,124.0,118.1,114.9,114.8,111.0,107.4,107.1,101.8,97.7,77.3,77.0,76.7,67.7,56.0,55.5,46.4,43.2,26.425.5,24.4；ESI-HRMS(m/z):C 30 H 31 FN 2 O 5 [M+H] + :calcd:519.2295；found:519.2320.
Example 9
The amino compound is 4-fluoroaniline, and the specific chemical structural formula of the obtained pterostilbene piperidine amide derivative is shown as follows:
the name is as follows: (E) -N- (4-fluorophenyl) -2, 4-dimethoxy-6- (4- (2-oxo-2- (piperidin-1-yl) ethoxy) styryl) benzamide (hereinafter abbreviated as C-9)
The preparation method comprises the following steps:
the procedure used in example 1 was repeated except that 4-fluoroaniline was used instead of aniline in step f to give (E) -N- (4-fluorophenyl) -2, 4-dimethoxy-6- (4- (2-oxo-2- (piperidin-1-yl) ethoxy) styryl) benzamide as a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.62–7.59(m,2H),7.40(d,J＝8.3Hz,2H),7.08–7.04(m,2H),7.00–6.90(m,4H),6.81(d,J＝1.3Hz,1H),6.43(d,J＝2.1Hz,1H),4.68(s,2H),3.90(s,3H),3.85(s,3H),3.55–3.49(m,4H),1.67–1.62(m,6H). 13 C NMR(100MHz,d-DMSO)δ165.6,161.1,159.6,158.5,157.8,157.3,136.6,136.3,136.3,130.9,130.0,128.4,128.0,123.0,121.4,121.3,120.5,115.8,115.6,115.4,101.1,98.3,66.4,56.2,56.0,45.6,42.6,40.5,40.3,40.1,39.9,39.7,39.5,39.3,26.4,25.7,24.4；ESI-HRMS(m/z):C 30 H 31 FN 2 O 5 [M+H] + :calcd:519.2295；found:519.2321.
Example 10
The amino compound is cyclohexylamine, and the specific chemical structural formula of the obtained pterostilbene piperidine amide derivative is shown as follows:
the name is as follows: (E) -N-cyclohexyl-2, 4-dimethoxy-6- (4- (2-oxo-2- (piperidin-1-yl) ethoxy) styryl) benzamide (hereinafter referred to as C-10)
The preparation method comprises the following steps:
the procedure of example 1 was repeated except that cyclohexylamine was used instead of aniline in step f to give (E) -N-cyclohexyl-2, 4-dimethoxy-6- (4- (2-oxo-2- (piperidin-1-yl) ethoxy) styryl) benzamide as a target product as a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.34(d,J＝8.6Hz,2H),7.06(d,J＝16.2Hz,1H),6.92(d,J＝16.2Hz,1H),6.86(d,J＝8.6Hz,2H),6.68(d,J＝1.8Hz,1H),6.30(d,J＝1.8Hz,1H),4.63(s,2H),3.80(s,3H),3.74(s,3H),3.52-3.48(m,2H),3.44-3.40(m,2H),2.00-1.95(m,2H),1.67-1.52(m,8H),1.38-1.33(m,2H),1.19-1.12(m,4H). 13 C NMR(100MHz,CDCl 3 )δ165.7,165.1,160.0,157.0,156.8,136.6,129.7,129.5,127.2,123.1,118.6,113.9,100.1,96.9,76.5,76.1,75.8,66.8,55.0,54.6,47.6,45.6,42.4,32.2,28.8,28.8,25.6,24.7,23.9,23.5,21.8；ESI-HRMS(m/z):C 30 H 38 N 2 O 5 [M+H] + :calcd:507.2859；found:507.2877.
Example 11: evaluation of antitumor Activity
Determination of in vitro anti-tumor Activity by CCK-8 method
The inhibition rate of pterostilbene derivatives on human lung cancer cells A549, human liver cancer cells HepG2, colon cancer cells HCT116 and human osteosarcoma cells U-2OS is determined by using a CCK-8 (CellCounting kit-8) method.
4 human tumor cells were stored in a 5% CO2 cell incubator at 37℃with RPMI-1640 medium containing 10% fetal bovine serum (BI), 100U/mL penicillin and 0.1mg/mL streptomycin; after the cells reach the logarithmic phase, starting to collect the cells and counting the number, diluting the cells to a proper density, and inoculating the cells into a 96-well plate; the inoculation number of the adherent cells is 5000/hole, and the inoculation number of the suspension cells is 8000/holeCovering the edge hole with PBS, and culturing in incubator (37 deg.C, 5% CO 2 ) Overnight; preparing stock solutions of the compound to be tested and the positive medicine with the concentration of 100 mu M into solution to be tested with different concentrations by using cell culture solution according to a gradient dilution method. 100 μl of the solution to be tested was added to each well, 5 concentrations of each compound were set, and 3 multiplex wells were set for each concentration. The blank without cells, the negative control without drug, and the medium of the same volume were added for control. After adding the drugs (C-1, C-2-C-10, pterostilbene, 5-FU) thereto, the medium was returned to the incubator, and the culture was continued at 37℃in a 5% CO2 cell incubator for 48 hours. Then, 10. Mu.L of CCK-8 solution was added to each well, and the mixture was incubated under the same conditions for about 2 hours. Finally, the absorbance at 450nm (OD value) was measured with a microplate reader. Each set of experiments was repeated three times, each independent of the other.
The inhibition rate of cell growth was calculated according to the following formula:
growth inhibition = (1-survival) ×100% = [1- (OD experiment-OD void)/(OD control-OD void) ]×100% (OD experiment represents absorbance of test drug group, OD control represents absorbance of control group, OD blank represents absorbance of blank group).
Half maximal Inhibitory Concentration (IC) 50 ) Defined as the drug concentration at which 50% of the tumor cells survived. Based on the measured absorbance (OD value), the resulting inhibition was calculated and then IC was fitted using Origin 50 Values.
Measured IC 50 The values are shown in Table 1.
TABLE 1
From Table 1, it is clear that the inhibitory activity of compound C-1 against tumor cells of A549, hepG2, HCT116 and U-2OS was stronger than that of pterostilbene and 5-FU.
Although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims (11)
1. The pterostilbene piperidine amide derivative is characterized in that the chemical structural formula of the pterostilbene piperidine amide derivative is shown as the formula (1):
in formula I:
r is one of benzene, substituted benzene and cyclohexane.
2. The pterostilbene piperidine amide derivative according to claim 1, wherein R is benzene, substituted benzene, or cyclohexane. Including but not limited to one of phenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 3, 4-dimethoxyphenyl, 2-fluoro-4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl and cyclohexyl.
3. A method for preparing pterostilbene piperidine amide derivatives, which is characterized in that the pterostilbene piperidine amide derivatives according to any one of claims 1-2 are prepared, comprising:
under the condition of anhydrous potassium carbonate, pterostilbene and ethyl bromoacetate undergo Williamson etherification reaction to obtain an intermediate 2;
dropwise adding phosphorus oxychloride into the solution of the intermediate 2 in ice bath, and stirring for reaction to obtain an intermediate 3;
under alkaline condition, intermediate 3 undergoes hydrolysis reaction to obtain intermediate 4;
the intermediate 4 and piperidine undergo a first amide condensation reaction under the action of a first condensation catalyst to obtain an intermediate 5;
the intermediate 5 and 2-methyl-2-butene are subjected to aldehyde oxidation reaction under the action of an oxidant to obtain an intermediate 6;
the intermediate 6 and the amino compound undergo a second amide condensation reaction under the action of a second condensation catalyst to obtain pterostilbene piperidine amide derivatives;
the synthetic route is as follows:
in formula I:
r is one of benzene, substituted benzene and cyclohexane.
4. The method for preparing pterostilbene piperidine amide derivatives according to claim 3, wherein the pterostilbene and ethyl bromoacetate are reacted in solution, the solvent is acetonitrile, and the molar ratio of pterostilbene, anhydrous potassium carbonate and ethyl bromoacetate is 1:1-1.5:1-1.5.
5. The method for preparing pterostilbene piperidine amide derivatives according to claim 3, wherein the solution of intermediate 2 is DMF solution of intermediate 2, and the molar ratio of intermediate 2 to phosphorus oxychloride is 1:1.2-1.5.
6. The method for producing pterostilbene piperidine amide derivatives according to claim 3, wherein the solvent used in the hydrolysis reaction is 8-10% by mass of an ethanol solution, and the amount of the ethanol solution of 8-10% by mass is 4-5mL per mmol of intermediate 3; the base used was 10% sodium hydroxide solution by mass fraction, the amount of 10% sodium hydroxide solution by mass fraction being 2mL per millimole of intermediate 3.
7. The method for producing pterostilbene piperidine amide derivatives according to claim 3, wherein in the first amide condensation reaction, the reaction solvent is DMF; the first condensation catalyst is HATU and DIPEA, the molar ratio of the intermediate 4 to the piperidine to the HATU to the DIPEA is 1:1.2-1.4:1.5:1.5, and the temperature of the first amide condensation reaction is room temperature;
the aldehyde group oxidation reaction is a solution reaction, the solvent used is acetone, and the oxidant is NaClO 2 And NaH 2 PO 2 ·2H 2 O in water, said intermediate 5, 2-methyl-2-butene, naClO 2 、NaH 2 PO 2 ·2H 2 The molar ratio of O is 1:4-4.5:8:8, and the temperature of the aldehyde group oxidation reaction is room temperature;
the second amide condensation reaction is a solution reaction, the solvent used is DCM, and the second condensing agent is DMAP and EDC & HCl; the molar ratio of the intermediate 6, the amino compound, the DMAP and the EDC & HCl is 1:2-2.5:1.2:1.2, and the temperature of the second amide condensation reaction is room temperature.
8. The method for producing pterostilbene piperidine amide derivatives according to any one of claims 3 to 7, wherein the amine-based compound is aniline, 4-methylaniline, 4-trifluoromethylaniline, 4-methoxyaniline, 3, 4-dimethoxyaniline, 2-fluoro-4-methoxyaniline, 2-fluoroaniline, 3-fluoroaniline, 4-fluoroaniline, cyclohexylamine.
9. A pharmaceutical composition characterized by: the pterostilbene piperidine amide derivatives prepared by the preparation method of any one of claims 3-8 are used as active ingredients or main active ingredients, and are prepared into pharmaceutically acceptable dosage forms with pharmaceutically acceptable carriers.
10. The pharmaceutical composition according to claim 9, wherein: the preparation is any one of tablets, dripping pills, capsules, powder, syrup, liquid, suspending agents, freeze-dried powder injection or injection and nano preparation.
11. Use of a pterostilbene piperidine amide derivative according to any one of claims 1, 2 or a pharmaceutical composition according to claim 9 for the preparation of an antitumor drug.
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