CN115626916B - Pomalidomide derivative as well as preparation method and application thereof - Google Patents
Pomalidomide derivative as well as preparation method and application thereof Download PDFInfo
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- CN115626916B CN115626916B CN202211428204.6A CN202211428204A CN115626916B CN 115626916 B CN115626916 B CN 115626916B CN 202211428204 A CN202211428204 A CN 202211428204A CN 115626916 B CN115626916 B CN 115626916B
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- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical class O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 75
- -1 aryl compound Chemical class 0.000 claims abstract description 23
- 239000002994 raw material Substances 0.000 claims abstract description 15
- CRAUTELYXAAAPW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione Chemical compound O=C1C=2C(F)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O CRAUTELYXAAAPW-UHFFFAOYSA-N 0.000 claims abstract description 13
- 108091005625 BRD4 Proteins 0.000 claims abstract description 11
- 102100029895 Bromodomain-containing protein 4 Human genes 0.000 claims abstract description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 71
- 238000003756 stirring Methods 0.000 claims description 71
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 63
- 150000001875 compounds Chemical class 0.000 claims description 26
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 238000010898 silica gel chromatography Methods 0.000 claims description 23
- 239000012074 organic phase Substances 0.000 claims description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 21
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 20
- 238000010438 heat treatment Methods 0.000 claims description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000004809 thin layer chromatography Methods 0.000 claims description 11
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 10
- 239000000047 product Substances 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- GQBONCZDJQXPLV-UHFFFAOYSA-N 4-aminoisoindole-1,3-dione Chemical compound NC1=CC=CC2=C1C(=O)NC2=O GQBONCZDJQXPLV-UHFFFAOYSA-N 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 6
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000011630 iodine Substances 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 4
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 4
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 4
- 229960005055 sodium ascorbate Drugs 0.000 claims description 4
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- NNKQLUVBPJEUOR-UHFFFAOYSA-N 3-ethynylaniline Chemical group NC1=CC=CC(C#C)=C1 NNKQLUVBPJEUOR-UHFFFAOYSA-N 0.000 claims description 3
- JXYITCJMBRETQX-UHFFFAOYSA-N 4-ethynylaniline Chemical group NC1=CC=C(C#C)C=C1 JXYITCJMBRETQX-UHFFFAOYSA-N 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- ZHWGWSYNZIZTFL-UHFFFAOYSA-N 2-[2-(2-azidoethoxy)ethoxy]ethanamine Chemical compound NCCOCCOCCN=[N+]=[N-] ZHWGWSYNZIZTFL-UHFFFAOYSA-N 0.000 claims 1
- GNHSTLTWEOPKCR-UHFFFAOYSA-N 2-[2-(2-chloroethoxy)ethoxy]ethanamine Chemical compound NCCOCCOCCCl GNHSTLTWEOPKCR-UHFFFAOYSA-N 0.000 claims 1
- 241001139947 Mida Species 0.000 claims 1
- 239000003054 catalyst Substances 0.000 claims 1
- 229910001873 dinitrogen Inorganic materials 0.000 claims 1
- 238000007599 discharging Methods 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical class O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- 210000004881 tumor cell Anatomy 0.000 abstract description 3
- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000012650 click reaction Methods 0.000 abstract 1
- 150000002391 heterocyclic compounds Chemical group 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 28
- 229940125782 compound 2 Drugs 0.000 description 11
- 229960000688 pomalidomide Drugs 0.000 description 11
- 238000003032 molecular docking Methods 0.000 description 9
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical class O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 201000005202 lung cancer Diseases 0.000 description 7
- 208000020816 lung neoplasm Diseases 0.000 description 7
- 229960003433 thalidomide Drugs 0.000 description 7
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 6
- 208000034578 Multiple myelomas Diseases 0.000 description 6
- 206010035226 Plasma cell myeloma Diseases 0.000 description 6
- 201000004101 esophageal cancer Diseases 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 208000007766 Kaposi sarcoma Diseases 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- YDPZWUMQKMLLHC-UHFFFAOYSA-N 1,5-dibromo-3-methylpentane Chemical compound BrCCC(C)CCBr YDPZWUMQKMLLHC-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 206010029350 Neurotoxicity Diseases 0.000 description 2
- 102100032783 Protein cereblon Human genes 0.000 description 2
- 206010044221 Toxic encephalopathy Diseases 0.000 description 2
- 102000044159 Ubiquitin Human genes 0.000 description 2
- 108090000848 Ubiquitin Proteins 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 230000001772 anti-angiogenic effect Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 2
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000007135 neurotoxicity Effects 0.000 description 2
- 231100000228 neurotoxicity Toxicity 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 206010061159 Foot deformity Diseases 0.000 description 1
- 230000010190 G1 phase Effects 0.000 description 1
- 230000004668 G2/M phase Effects 0.000 description 1
- 208000006358 Hand Deformities Diseases 0.000 description 1
- 101000941994 Homo sapiens Protein cereblon Proteins 0.000 description 1
- 101000599042 Homo sapiens Zinc finger protein Aiolos Proteins 0.000 description 1
- 108010013958 Ikaros Transcription Factor Proteins 0.000 description 1
- 102000017182 Ikaros Transcription Factor Human genes 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 206010028817 Nausea and vomiting symptoms Diseases 0.000 description 1
- 208000031320 Teratogenesis Diseases 0.000 description 1
- 206010043275 Teratogenicity Diseases 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 229910021536 Zeolite Inorganic materials 0.000 description 1
- 102100037798 Zinc finger protein Aiolos Human genes 0.000 description 1
- SSSYTNQOUFVWCO-UHFFFAOYSA-N [Co](C#N)C#N.[Ti] Chemical class [Co](C#N)C#N.[Ti] SSSYTNQOUFVWCO-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 238000011225 antiretroviral therapy Methods 0.000 description 1
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000010219 correlation analysis Methods 0.000 description 1
- 229960002104 cyanocobalamin Drugs 0.000 description 1
- 235000000639 cyanocobalamin Nutrition 0.000 description 1
- 239000011666 cyanocobalamin Substances 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical group O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 229940100601 interleukin-6 Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- DCNUQRBLZWSGAV-UHFFFAOYSA-N n,n-diphenylformamide Chemical compound C=1C=CC=CC=1N(C=O)C1=CC=CC=C1 DCNUQRBLZWSGAV-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000011865 proteolysis targeting chimera technique Methods 0.000 description 1
- 229940124823 proteolysis targeting chimeric molecule Drugs 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 108010026668 snake venom protein C activator Proteins 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 231100000211 teratogenicity Toxicity 0.000 description 1
- 150000003608 titanium Chemical class 0.000 description 1
- 229940125725 tranquilizer Drugs 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a pomalidomide derivative, and a preparation method and application thereof, and belongs to the technical field of pharmaceutical chemistry synthesis. The technical scheme of the invention is as follows: the pomalidomide derivative molecule has a structureR is a heterocyclic compound or an aryl compound. The invention takes 2- (2, 6-dioxo-piperidine-3-yl) -4-fluoro-isoindole-1, 3-dione as an initial raw material, and the reaction is carried out firstly to obtainAnd aniline is introduced through click reaction, and finally the aniline is condensed with the phenyl isocyanate compound to obtain a target molecule with a novel structure, so that the target molecule has a certain inhibition effect on tumor cells, can form acting force with BRD4 targets, and can be used as a potential anti-tumor drug.
Description
Technical Field
The invention belongs to the technical field of synthesis of antitumor drugs, and particularly relates to a pomalidomide derivative, a preparation method and application thereof.
Background
Pomalidomide is an oral small molecule derivative with immunoregulatory, anti-angiogenic and antiproliferative activity. The stimulation of CD4+ and CD8+ T cells is enhanced mainly by targeting a ubiquitin E3 ligase Cereblon (CRBN), degrading the lymphotranscription factors ikaros (IKZF 1) and the lymphotranscription factors aiolos (IKZF 3), and simultaneously regulating tumor necrosis factor alpha, interleukin 6 and vascular endothelial growth factor. The U.S. food and drug administration approved pomalidomide for the treatment of Kaposi's Sarcoma (KS) patients associated with acquired immunodeficiency syndrome (AIDS) and resistant to highly effective antiretroviral therapy (HAART), as well as KS patients negative for Human Immunodeficiency Virus (HIV) on day 5, 15. Pomalidomide is the first new oral drug to treat KS in bulk for over 20 years. Is one of the very wide application of thalidomide derivatives. Thalidomide (shown in figure 2) is also known as reaction arrest, which is a tranquilizer for color change which is popular in Europe and America, africa and Japan, has a central inhibitory effect and is widely used for relieving nausea and vomiting symptoms in pregnancy reaction of women. However, it was later discovered that parturients who had taken thalidomide had different degrees of fetal hand and foot deformity, and that a large number of fetuses died from serious deformity before birth. However, due to the anti-inflammatory, immunomodulatory, anti-angiogenic, and anti-tumor effects of thalidomide itself, there are still a large number of students continuing to study thalidomide, and it is desired to obtain a drug having excellent properties of thalidomide without teratogenesis and neurotoxicity, and thus pomalidomide has developed. Compared with the latter, the amino group connected on the benzene ring of pomalidomide makes the chemical property of the pomalidomide more stable, and has stronger immunoregulation function than thalidomide. In clinical application, pomalidomide has higher safety than thalidomide, less adverse reaction, almost no teratogenicity and neurotoxicity, and has effects on various hematopathy and solid malignant tumors. In particular pomalidomide can be used as an important E3 ubiquitin ligand in PROTAC molecules, and plays a very important role in the development of new drugs at present, so that the new compounds with better antitumor activity are expected to be obtained by modifying the compounds again. The Henan university laboratory cooperates with Henan gulf stream biotechnology Co-Ltd to develop a pomalidomide derivative, and Henan gulf stream mainly synthesizes compounds, and Henan university laboratory performs small molecule design and biological activity test.
Disclosure of Invention
The invention solves the technical problem of providing a preparation method and application of pomalidomide derivative.
The invention adopts the following technical scheme to solve the technical problems, and is characterized by comprising the following specific steps:
(1) Further preferably, the specific process of step (1) is: adding a certain amount of 2- (2, 6-dioxo-piperidin-3-yl) -4-fluoro-isoindole-1, 3-dione and 2- (2- (2- (2-azidoethoxy) ethoxy) ethyl-1-amine into N, N-dimethylformamide, stirring to dissolve, adding a certain amount of N, N-diisopropylethylamine, stirring at room temperature until the raw materials react completely, pouring the reaction solution into water, extracting with dichloromethane for multiple times, mixing organic phases, concentrating, and separating by silica gel column chromatography
Further preferably, the specific process of step (2) is as follows: adding a certain amount of 2- (2, 6-dioxo-piperidin-3-yl) -4-fluoro-isoindole-1, 3-dione and 2- (2- (2- (2-chloroethoxy) ethoxy) ethyl-1-amine into a mixed solution of N, N-dimethylformamide and diethyl ether, stirring at 0 ℃ for a period of time, adding N, N-diisopropylethylamine, continuing stirring at 0 ℃ for a period of time, adding diethyl ether and sodium azide, stirring at room temperature for a period of time, pouring the reaction solution into water, extracting with dichloromethane for a plurality of times, combining organic phases, concentrating, and separating by silica gel column chromatography
Further preferably, the specific process of step (2) is as follows: adding a certain amount of 4-bromoaniline, 1, 5-dibromo-3-methylpentane and potassium carbonate into N, N-dimethylformamide, heating to 100 ℃, stirring and reacting for a period of time, adding cuprous cyanide and sulfonated titanium cyanocobalamin, heating to 100 ℃ under the protection of nitrogen, reacting for a period of time, cooling to room temperature, adding diatomite, stirring and filtering, concentrating the filtrate, and separating by silica gel column chromatography to obtain N- (4-benzonitrile) -4-methylpiperidine; the feeding amount mole ratio of the 4-bromoaniline to the 1, 5-dibromo-3-methylpentane to the potassium carbonate to the cuprous cyanide is 1:1:1:1.5; the mass ratio of the 4-bromoaniline to the sulfonated titanium cobalt cyanide is 10:1.
further preferably, the specific process of step (3) is as follows: adding a certain amount of 4-aminoisoindoline-1, 3-dione and 2-bromo-1, 5-methyl dipentamate into N, N-dimethylformamide, stirring to dissolve, adding potassium carbonate, stirring at room temperature for a period of time, heating to 70 ℃, pouring the reaction solution into water after the reaction is complete, extracting with dichloromethane for multiple times, combining organic phases, concentrating, and separating by silica gel column chromatography
Further preferably, the specific process of step (4) is as follows: a certain amount of 2- (2- (2- (2- (2-azidoethoxy) ethoxy) ethyl-1-iodo andadding into N, N-dimethylformamide, stirring to dissolve, adding barium hydroxide, potassium iodide and potassium hydroxide, stirring at room temperature for a period of time, heating the reaction system to 100deg.C, vacuum removing air in the reaction kettle, introducing ammonia gas into the reaction kettle to make the pressure of the reaction kettle reach 0.5MPa, heating to 50deg.C, stirring to react until the raw materials are completely reacted, pouring the reaction solution into water, extracting with dichloromethane for multiple times, mixing organic phases, concentrating, and separating by silica gel column chromatography to obtain the final product>
Further preferably, the specific process of step (5) is as follows: will beAnd m-aminophenylacetylene or p-aminophenylacetylene to water, tetrahydrofuran and t-butanol in a volume ratio of 1:1:1, adding copper sulfate, sodium ascorbate and nitrogen protection, heating to 80 ℃, and carrying out reflux reactionAfter the reaction of the raw materials is completed, adding m-fluoroisocyanate, stopping the reaction after a period of reaction, filtering with diatomite, concentrating the filtrate in vacuum, and carrying out thin layer chromatography with dichloromethane and methanol (V/V=15:1) to obtain the target compound.
The invention has the technical advantages that: according to the invention, the 4-chloroaniline has oriented active positions with a certain distance, alkylation into a ring is carried out by a one-pot method, then aldehyde group is introduced, and the ring is further converted into amide to obtain N- (4-benzamide) -4-methylpiperidine, so that the yield of the product is effectively improved by a one-pot reaction.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of the target compound prepared in example 13.
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of the target compound prepared in example 14.
FIG. 3 shows the results of the molecular docking of the compound of example 13 with BRD4
Detailed Description
The above-described matters of the present invention will be described in further detail by way of examples, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples, and all techniques realized based on the above-described matters of the present invention are within the scope of the present invention.
Example 1
In a reaction flask with a stirring device, 28g of 2- (2, 6-dioxo-piperidin-3-yl) -4-fluoro-isoindole-1, 3-dione and 22g of 2- (2- (2- (2-azidoethoxy) ethoxy) ethyl-1-amine are added into 1000mL of N, N-dimethylformamide, 13g of N, N-diisopropylethylamine is added after stirring and dissolution, after stirring for 120min at room temperature, the reaction solution is poured into 1000mL of water, after stirring for 30min, 500mL of dichloromethane are used for extraction for a plurality of times, the organic phases are combined, and after concentration, the compound 2 (19.5 g) is obtained by silica gel column chromatography, MS (ESI) + )m/z：475[M+H] + 。
Example 2
In a reaction flask with a stirring device, 28g of 2- (2, 6-dioxo-piperidin-3-yl) -4-fluoro-isoindole-1, 3-dione and 22g of 2- (2- (2- (2-azidoethoxy) ethoxy) ethyl-1-amine are added into 1000mL of N, N-dimethylformamide, 10g of N, N-diisopropylethylamine and 2g of N, N-diphenylformamide are added after stirring and dissolution, after stirring for 75min at room temperature, the reaction solution is poured into 1000mL of water, after stirring for 30min, 500mL of dichloromethane is used for extraction for a plurality of times, the organic phases are combined, the organic phases are adjusted to be neutral by dissolution with weak acid, the organic phases are separated, concentrated and then separated by silica gel column chromatography to obtain the compound 2 (34.7 g), MS (ESI) + )m/z：475[M+H] + 。
Example 3
In a reaction flask with a stirring device, 28g of 2- (2, 6-dioxo-piperidin-3-yl) -4-fluoro-isoindole-1, 3-dione and 22g of 2- (2- (2- (2-azidoethoxy) ethoxy) ethyl-1-amine are added into 1000mL of N, N-dimethylformamide, 20g of N, N-diisopropylethylamine is added after stirring and dissolution, after stirring for 120min at room temperature, the reaction solution is poured into 1000mL of water, after stirring for 30min, 500mL of dichloromethane are used for extraction for a plurality of times, the organic phases are combined, and after concentration, the compound 2 (22.9 g) is obtained by silica gel column chromatography, MS (ESI) + )m/z：475[M+H] + 。
Example 4
In a reaction flask with stirring device, 28g of 2- (2, 6-dioxo-piperidin-3-yl) -4-fluoro-isoindole-1, 3-dione and 22g of 2- (2- (2- (2-azidoethoxy) ethoxy) ethyl-1-amine were added to N, N-dimethylformamide1000mL, stirring for dissolving, adding 26g of N, N-diisopropylethylamine, stirring at room temperature for 120min, pouring the reaction solution into 1000mL of water, stirring for 30min, extracting with 500mL of dichloromethane for multiple times, mixing the organic phases, concentrating, separating by silica gel column chromatography to obtain compound 2 (28.17 g), and separating by MS (ESI) + )m/z：475[M+H] + 。
Example 5
In a reaction flask with a stirring device, 28g of 2- (2, 6-dioxo-piperidin-3-yl) -4-fluoro-isoindole-1, 3-dione and 21.5g of 2- (2- (2-chloroethoxy) ethoxy) ethyl-1-amine were added to a mixture of 800mL of N, N-dimethylformamide and 200mL of diethyl ether, the reaction temperature was stirred at 0℃for 10min, 26g of N, N-diisopropylethylamine was then added in the stirred state, stirring was continued at 0℃for 30min, 200mL of diethyl ether and 20g of sodium azide were then added, the mixture was stirred at room temperature for 2h, the reaction solution was poured into 1000mL of water, then extracted with 500mL of methylene chloride for a plurality of times, the organic phase was combined, and after concentration, the compound 2 (32.91 g) was separated by silica gel column chromatography, MS (ESI) + )m/z：475[M+H] + 。
Example 6
In a reaction flask with a stirring device, 2.4g of 2-bromo-1, 5-glutarate methyl ester and 1.7g of 4-aminoisoindoline-1, 3-dione (compound 3) are added into 150mL of N, N-dimethylformamide, 1.4g of potassium carbonate is added after stirring and dissolving, stirring is carried out for 30min at room temperature, the temperature is raised to 70 ℃, TLC monitors that the raw materials are completely reacted, then the reaction solution is poured into 200mL of water, then 50mL of dichloromethane is used for extraction for a plurality of times, the organic phases are combined, and after concentration, the compound 4 (2.11 g) is obtained through silica gel column chromatography separation, MS (ESI) + )m/z：321[M+H] + 。
Example 7
In a reaction flask with a stirring device, 2.4g of 2-bromo-1, 5-glutarate methyl ester and 1.7g of 4-aminoisoindoline-1, 3-dione (compound 3) are added into 150mL of N, N-dimethylformamide, after stirring and dissolving, 2.1g of potassium carbonate is added, stirring is carried out at room temperature for 30min, heating is carried out to 100 ℃, TLC monitors that the raw materials are completely reacted, then the reaction solution is poured into 200mL of water, then 50mL of dichloromethane is used for extraction for a plurality of times, organic phases are combined, and after concentration, silica gel column chromatography is carried out to obtain compound 4 (2.35 g), MS (ESI) + )m/z：321[M+H] + 。
Example 8
In a reaction flask with a stirring device, 2.4g of 2-bromo-1, 5-glutarate methyl ester and 1.7g of 4-aminoisoindoline-1, 3-dione (compound 3) are added into 150mL of N, N-dimethylformamide, after stirring and dissolving, 2.8g of potassium carbonate is added, stirring is carried out at room temperature for 30min, heating is carried out to 100 ℃, TLC monitors that the raw materials are completely reacted, then the reaction solution is poured into 200mL of water, then 50mL of dichloromethane is used for extraction for a plurality of times, the organic phases are combined, and after concentration, the compound 4 (2.67 g) is obtained through silica gel column chromatography separation, MS (ESI) + )m/z：321[M+H] + 。
Example 9
In a high-pressure reaction kettle with a stirring device, 3.3g of 2- (2- (2- (2-azidoethoxy) ethoxy) ethyl-1-iodine and 3.2g of compound 4 (3.2 g) are added into 200mL of N, N-dimethylformamide, 3.5g of barium hydroxide, 1.7g of potassium iodide and 0.56g of potassium hydroxide are added after stirring and dissolution, stirring is carried out for 30min at room temperature, then the reaction system is heated to 100 ℃, air in the reaction kettle is removed in vacuum, and the reaction is carried outIntroducing ammonia gas into the reactor to make the pressure of the reactor reach 0.5MPa, heating to 50deg.C, stirring for 3h, monitoring the reaction of the raw materials by TLC, pouring the reaction liquid into 200mL of water, extracting with 80mL of dichloromethane for multiple times, mixing the organic phases, concentrating, separating by silica gel column chromatography to obtain compound 2 (3.17 g), and separating by MS (ESI) + )m/z：475[M+H] + 。
Example 10
Adding 3.3g of 2- (2- (2- (2-azidoethoxy) ethoxy) ethyl-1-iodine and 200mL of N, N-dimethylformamide of a compound 4 (3.2 g) into a high-pressure reaction kettle with a stirring device, stirring and dissolving, adding 3.5g of barium hydroxide, 1.7g of potassium iodide and 0.56g of potassium hydroxide, stirring at room temperature for 30min, heating the reaction system to 100 ℃, evacuating air in the reaction kettle in vacuum, introducing ammonia gas into the reaction kettle, enabling the pressure of the reaction kettle to reach 0.3MPa, heating to 50 ℃, stirring and reacting for 3h, TLC monitoring raw materials, completely reacting, pouring the reaction liquid into 200mL of water, extracting for multiple times by using dichloromethane, combining organic phases, concentrating, separating by silica gel column chromatography to obtain the compound 2 (2.51 g), and obtaining MS (ESI) + )m/z：475[M+H] + 。
Example 11
Adding 3.3g of 2- (2- (2- (2-azidoethoxy) ethoxy) ethyl-1-iodine and 3.2g of compound 4 (3.2 g) into 200mL of N, N-dimethylformamide in a high-pressure reaction kettle with a stirring device, stirring and dissolving, adding 3.5g of barium hydroxide, 1.7g of potassium iodide, 0.56g of potassium hydroxide and 1g of porous zeolite, stirring at room temperature for 30min, heating the reaction system to 100 ℃, evacuating air in the reaction kettle in vacuum, introducing ammonia gas into the reaction kettle, enabling the pressure of the reaction kettle to reach 0.3MPa, heating to 50 ℃, keeping the pressure unchanged, stirring and reacting for 3h, and performing TLC monitoring on the raw materialsThe reaction was completed, then the reaction solution was poured into 200mL of water, stirred and filtered, extracted with 80mL of methylene chloride multiple times, the organic phases were combined, concentrated and separated by silica gel column chromatography to give Compound 2 (3.44 g), MS (ESI) + )m/z：475[M+H] + 。
Example 12
In a high-pressure reaction kettle with a stirring device, 3.3g of 2- (2- (2-azidoethoxy) ethoxy) ethyl-1-iodine and 200mL of compound 4 (3.2 g) are added into 200mL of N, N-dimethylformamide, 3.5g of barium hydroxide, 1.7g of potassium iodide, 0.56g of potassium hydroxide and 1g of porous alumina are added after stirring and dissolving, stirring is carried out for 30min at room temperature, then the reaction system is heated to 100 ℃, air in the reaction kettle is removed in vacuum, ammonia gas is introduced into the reaction kettle, the pressure of the reaction kettle reaches 0.3MPa, the temperature is heated to 50 ℃, the pressure is kept unchanged, stirring is carried out for 3h, TLC is used for monitoring the raw materials to react completely, then the reaction liquid is poured into 200mL of water, 80mL of dichloromethane is used for extraction for multiple times after stirring and filtering, the organic phase is combined, compound 2 (3.29 g) is obtained after concentration and separation through silica gel column chromatography, MS (ESI) + )m/z：475[M+H] + 。
Example 13
In a reaction flask with stirring device, compound 2 (4.8 g) and m-aminophenylacetylene (1.2 g) are added to water, tetrahydrofuran and t-butanol in a volume ratio of 1:1:1, then adding copper sulfate (1.6 g), sodium ascorbate (4.0 g), heating to 80 ℃ under nitrogen protection, carrying out reflux reaction for 5h, monitoring the raw materials by TLC to react completely, then adding m-fluoroisocyanate (1.4 g), stirring and reacting for 2h, stopping the reaction, filtering by using kieselguhr, concentrating the filtrate in vacuum, and carrying out silica gel column chromatography by using dichloromethane and methanol (V/V=15:1), thus obtaining 6.82g of target compound; 1 H NMR(600MHz,DMSO-d 6 )δ11.09(s,1H),8.91(s,1H),8.85(s,1H),8.47(s,1H),8.03(s,1H),7.56-7.50(m,2H),7.43-7.41(m,1H),7.35-7.28(m,3H),7.13-7.07(m,2H),7.02(d,J＝12.0Hz,1H),6.80–6.77(m,1H),6.58–6.55(m,1H),5.05-5.02(m,1H),4.56–4.53(m,2H),3.86–3.84(m,2H),3.56–3.53(m,4H),3.50-3.48(m,6H),3.41-3.39(m,3H),2.90-2.84(m,1H),2.59-2.52(m,1H),2.03-2.00(m,1H).
example 14
In a reaction flask with stirring device, compound 2 (4.8 g) and p-aminophenylacetylene (1.2 g) are added to water, tetrahydrofuran and t-butanol in a volume ratio of 1:1:1, copper sulfate (1.6 g,0.01 mol), sodium ascorbate (4.0 g) and nitrogen are added into 150mL of mixed solvent, the mixture is heated to 80 ℃ for reflux reaction for 5 hours, TLC monitors the complete reaction of the raw materials, then m-fluoroisocyanate (1.4 g) is added into the mixture for stirring reaction for 2 hours, the reaction is stopped, diatomite is used for filtration, the filtrate is concentrated in vacuum, and the concentrate is subjected to silica gel column chromatography with methylene dichloride and methanol (V/V=15:1) to obtain 5.23g of target compound; 1 H NMR(600MHz,DMSO)δ11.09(s,1H),8.93(s,1H),8.84(s,1H),8.41(s,1H),7.74(d,J＝8.6Hz,2H),7.57–7.48(m,4H),7.30(dd,J＝15.1,8.2Hz,1H),7.14–7.08(m,2H),7.02(d,J＝7.0Hz,1H),6.81–6.76(m,1H),6.58–6.55(m,1H),5.04(dd,J＝12.8,5.5Hz,1H),4.56–4.51(m,2H),3.86–3.82(m,2H),3.58–3.55(m,2H),3.53(d,J＝5.6Hz,2H),3.50(d,J＝5.5Hz,5H),3.41(dd,J＝11.2,5.6Hz,2H),2.91–2.83(m,1H),2.61–2.51(m,4H),2.04–1.98(m,1H).
example 15
Activity test
(1) Cell proliferation inhibition assay
On the structure of the phenylamine, a linker is added to reconstruct the preliminary tumor inhibition experimental result. Through an anti-tumor activity experiment, the compounds have generally better effect of inhibiting the activity of tumor cells, and the IC of the product obtained in the example 10 on esophageal cancer cells, lung cancer cells and multiple myeloma cells is found 50 Are all below 10 mu M. Esophageal cancerIC of cell 50 The values are KYSE30 (8.83. Mu.M), KYSE150 (12.71. Mu.M), KYSE450 (4.45. Mu.M), respectively. IC of lung cancer cell 50 The values were H460 (22.66. Mu.M), A549 (19.51. Mu.M), respectively. IC of colon cancer cell 50 The values are HCT116 (10.64. Mu.M) and AOG (5.55. Mu.M), respectively. IC of multiple myeloma cells 50 The values were RPMI8226 (1.89. Mu.M) and MM-1R (0.75. Mu.M), respectively. IC of the product obtained in example 11 against esophageal cancer cells, lung cancer cells and multiple myeloma cells 50 Are all below 10 mu M. IC of esophagus cancer cell 50 The values were KYSE30 (8.49. Mu.M) and KYSE450 (7.31. Mu.M), respectively. IC of lung cancer cell 50 The values are H460 (10.59 mu M), A549 #, respectively>50 μm). IC of multiple myeloma cells 50 The values were RPMI8226 (6.01. Mu.M) and MM-1R (5.45. Mu.M), respectively. Modification by adding a linker to the phenylamine structure was therefore successful.
(2) Cell clone formation assay
The plate cloning experiment shows that the product obtained in the example 10 can obviously inhibit the proliferation of esophageal cancer cells KYSE450 and lung cancer cells H460 and A549. The proliferation inhibition effect of pomalidomide is not obvious, and the result is consistent with the MTT result.
(3) Soft-agar clone formation experiments
Soft-agar clone formation experiments show that the product obtained in example 10 can obviously inhibit independent proliferation of multiple myeloma cells RPMI8226, esophageal cancer cells KYSE450 and lung cancer cells H460. The pomalidomide inhibition effect was not obvious, and the result was consistent with MTT result and plate cloning result.
(4) Cell cycle detection
The product obtained in example 10 was able to block multiple myeloma cells RPMI8226 in G2/M phase, esophageal cancer cells KYSE450 and lung cancer cells H460 in G1 phase, whereas pomalidomide had no significant blocking effect on tumor cell cycle.
(5) Protein expression changes in BRD4 and downstream genes
Protein levels of BRD4 tended to decrease in cancer cells with increasing duration and concentration, with KYSE450 and H460 cells acting most significantly at a concentration of 12 μm at 24H. RPMI8226 cells worked most significantly at a concentration of 12. Mu.M at 6 h. The change of C-MYC before and after the action of P4 is detected at the protein level. KYSE450 cells and H460 cells worked most significantly at a concentration of 12. Mu.M at 24H. RPMI8226 cells worked most significantly at a concentration of 12. Mu.M at 6 h. Consistent with the trend of BRD 4. Correlation analysis results showed that BRD4 and C-MYC expression were significantly positively correlated (r=0.94, p=0.015).
(6) Kinetic affinity assay
The product obtained in example 10 was tested for binding to wild-type BRD4 protein using SPR. The results suggest that the product obtained in example 10 binds to the BRD4 wild-type protein with a KD (M) value of 3.612E-5. Illustrating that the product from example 10 was able to bind to wild-type BRD4 protein.
Example 16
Molecular docking: example 10 results of molecular docking of compounds with BRD 4. a-C of fig. 3: example 10 interaction of compounds with BD1 domain of BRD4 Autodock docking scores: -10.37; D-F of fig. 3: example 10 interaction of compounds with BD2 domain of BRD4 Autodock docking scores: -7.41. Docking of the compound of example 10 with BD1 domain of BRD 4: the compound of example 10 forms hydrogen bonds with PR082, LYS 91; forming pi-pi conjugated interactions with TRP 81; hydrophobic interactions with PHE83, VAL87, LEU92, ILE146 (FIG. 3, A-C). Autodock docking scoring: -10.37. Docking of the compound of example 10 with BD2 domain of BRD 4: the compound of example 10 forms hydrogen bonds with PRO375, HIS 437; forming pi-pi conjugated interactions with HIS 437; forming hydrophobic interactions with VAL380 and VAL439 (fig. 3, d-F). Autodock docking scoring: -7.41.
While the basic principles, principal features and advantages of the present invention have been described in the foregoing examples, it will be appreciated by those skilled in the art that the present invention is not limited by the foregoing examples, but is merely illustrative of the principles of the invention, and various changes and modifications can be made without departing from the scope of the invention, which is defined by the appended claims.
Claims (8)
1. A pomalidomide derivative, characterized in that the pomalidomide derivative has the structure:
r is->
2. The preparation method of the pomalidomide derivative according to claim 1, which is characterized by comprising the following specific processes:
(1.1), 2- (2, 6-dioxo-piperidin-3-yl) -4-fluoro-isoindole-1, 3-dione and 2- (2- (2- (2-azidoethoxy) ethoxy) ethan-1-amine to giveOr alternatively, the first and second heat exchangers may be,
(1.2), 2- (2, 6-dioxo-piperidin-3-yl) -4-fluoro-isoindole-1, 3-dione is reacted with 2- (2- (2- (2-chloroethoxy) ethoxy) ethan-1-amine, and then with sodium azide to giveOr alternatively, the first and second heat exchangers may be,
(1.3) reacting 4-aminoisoindoline-1, 3-dione with methyl 2-bromo-1, 5-dipentamate to obtain And 2- (2- (2- (2- (2-azidoethoxy) ethoxy) ethyl-1-iodo to give
(2)、Reacting with alkyne compounds and phenyl isocyanate compounds to obtain target compounds.
3. The method of claim 2, wherein the specific process of step (1.1) is as follows: adding a certain amount of 2- (2, 6-dioxo-piperidin-3-yl) -4-fluoro-isoindole-1, 3-dione and 2- (2- (2- (2-azidoethoxy) ethoxy) ethyl-1-amine into N, N-dimethylformamide, stirring to dissolve, adding a certain amount of N, N-diisopropylethylamine, stirring at room temperature until the raw materials react completely, pouring the reaction solution into water, extracting with dichloromethane for multiple times, mixing organic phases, concentrating, and separating by silica gel column chromatographyThe molar ratio of the 2- (2, 6-dioxo-piperidine-3-yl) -4-fluoro-isoindole-1, 3-dione to the 2- (2- (2- (2-azidoethoxy) ethoxy) ethyl-1-amine to the N, N-diisopropylethylamine is 1:1:1-2.
4. The method of claim 2, wherein the specific process of step (1.2) is as follows: adding a certain amount of 2- (2, 6-dioxo-piperidin-3-yl) -4-fluoro-isoindole-1, 3-dione and 2- (2- (2- (2-chloroethoxy) ethoxy) ethyl-1-amine into a mixed solution of N, N-dimethylformamide and diethyl ether, stirring for a period of time at a reaction temperature of 0 ℃, adding N, N-diisopropylethylamine under stirring, continuing stirring for a period of time at a temperature of 0 ℃, adding diethyl ether and sodium azide, stirring for a period of time at room temperature, pouring the reaction solution into water, extracting with dichloromethane for a plurality of times, combining organic phases, concentrating, and separating by silica gel column chromatography to obtain the productSaid 2- (2, 6-dioxo-piperidine-3)The molar ratio of the charged amount of the (E) -4-fluoro-isoindole-1, 3-dione to the charged amount of the 2- (2- (2- (2- (2-chloroethoxy) ethoxy) ethyl-1-aldehyde to the charged amount of the sodium azide is 1:1:3, a step of; the volume ratio of the N, N-dimethylformamide to the diethyl ether is 4:1.
5. the method for producing a pomalidomide derivative according to claim 2, wherein in the step (1.3)The specific preparation process of (2) is as follows: adding a certain amount of 4-aminoisoindoline-1, 3-dione and 2-bromo-1, 5-methyl dipentamate into N, N-dimethylformamide, stirring to dissolve, adding potassium carbonate, stirring at room temperature for a period of time, heating to 70 ℃, pouring the reaction solution into water after the reaction is complete, extracting with dichloromethane for multiple times, combining organic phases, concentrating, and separating by silica gel column chromatography to obtain the MIDA>The molar ratio of the 4-aminoisoindoline-1, 3-dione to the 2-bromo-1, 5-methyl dipentamate to the potassium carbonate is 1:1:1 to 2.
6. The method for producing a pomalidomide derivative according to claim 2, wherein in the step (1.3)The specific preparation process of (2) is as follows: an amount of 2- (2- (2- (2- (2-azidoethoxy) ethoxy) ethyl-1-iodo and +.>Adding into N, N-dimethylformamide, stirring to dissolve, adding barium hydroxide, potassium iodide and potassium hydroxide, stirring at room temperature for a period of time, heating the reaction system to 100deg.C, vacuum discharging air in the reaction kettle, introducing ammonia gas into the reaction kettle to make the pressure of the reaction kettle reach 0.5MPa, and heatingControlling the reaction pressure to be 0.3-0.5 MPa at 50 ℃, stirring and reacting until the raw materials are completely reacted, pouring the reaction liquid into water, extracting for a plurality of times by using dichloromethane, merging organic phases, concentrating and separating by using a silica gel column chromatography to obtain the catalystSaid->The molar ratio of the 2- (2- (2- (2- (2-azidoethoxy) ethoxy) ethyl-1-iodine to the potassium iodide to the potassium hydroxide is 1:2:1:1, and the molar ratio of the 2- (2- (2- (2-azidoethoxy) ethoxy) ethyl-1-iodine to the potassium hydroxide is 1:1.
7. The method for preparing pomalidomide derivative according to claim 2, wherein the specific process of step (2) is as follows: will beAnd m-aminophenylacetylene or p-aminophenylacetylene to water, tetrahydrofuran and t-butanol in a volume ratio of 1:1:1, then adding copper sulfate, sodium ascorbate and nitrogen gas into the mixed solvent, heating to 80 ℃, carrying out reflux reaction until the raw materials are reacted completely, then adding m-fluoroisocyanate phenyl ester, stopping the reaction after a period of reaction, filtering by diatomite, concentrating the filtrate in vacuum, and carrying out thin layer chromatography by using a mixed solution with the volume ratio of dichloromethane to methanol being 15:1 to obtain the target compound.
8. Use of a pomalidomide derivative according to claim 1 in the preparation of a BRD4 inhibitor.
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| CN113603676A (en) * | 2021-04-28 | 2021-11-05 | 浙江工业大学 | Erlotinib-based EGFR protein targeted degradation small molecule compound and preparation method and application thereof |
| CN114591252A (en) * | 2022-03-31 | 2022-06-07 | 河南湾流生物科技有限公司 | Triazole feed additive and preparation method and application thereof |
| CN114591253A (en) * | 2022-03-31 | 2022-06-07 | 河南湾流生物科技有限公司 | Urea feed additive and preparation method and application thereof |
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| CN115626916A (en) | 2023-01-20 |
| CN115636815A (en) | 2023-01-24 |
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