CN106397407A - Novel anti-tumor drug AZD9291 derivative and its preparation method and use - Google Patents
Novel anti-tumor drug AZD9291 derivative and its preparation method and use Download PDFInfo
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- CN106397407A CN106397407A CN201610799718.0A CN201610799718A CN106397407A CN 106397407 A CN106397407 A CN 106397407A CN 201610799718 A CN201610799718 A CN 201610799718A CN 106397407 A CN106397407 A CN 106397407A
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- DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical class COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 12
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 12
- 229960003278 osimertinib Drugs 0.000 claims abstract description 36
- -1 1H-indole-3-yl Chemical group 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 10
- 150000001412 amines Chemical class 0.000 claims abstract description 7
- 239000011230 binding agent Substances 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims abstract description 5
- 150000002540 isothiocyanates Chemical class 0.000 claims abstract description 4
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims abstract 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- 241001597008 Nomeidae Species 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 24
- 150000002431 hydrogen Chemical class 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 230000000118 anti-neoplastic effect Effects 0.000 claims description 12
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 7
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 6
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 238000001514 detection method Methods 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 6
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- 150000002118 epoxides Chemical class 0.000 claims description 5
- 239000000543 intermediate Substances 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000003147 glycosyl group Chemical group 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 229910052760 oxygen Chemical group 0.000 claims description 2
- 239000001301 oxygen Chemical group 0.000 claims description 2
- CWHFDTWZHFRTAB-UHFFFAOYSA-N phenyl cyanate Chemical compound N#COC1=CC=CC=C1 CWHFDTWZHFRTAB-UHFFFAOYSA-N 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 claims 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims 1
- NMOJAXCSURVGEY-UHFFFAOYSA-N N#CC#N.[S] Chemical compound N#CC#N.[S] NMOJAXCSURVGEY-UHFFFAOYSA-N 0.000 claims 1
- WQJONRMBVKFKOB-UHFFFAOYSA-N cyanatosulfanyl cyanate Chemical compound N#COSOC#N WQJONRMBVKFKOB-UHFFFAOYSA-N 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 abstract 2
- 229930182474 N-glycoside Natural products 0.000 abstract 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 abstract 1
- 150000001448 anilines Chemical class 0.000 abstract 1
- 150000002341 glycosylamines Chemical class 0.000 abstract 1
- 239000011259 mixed solution Substances 0.000 abstract 1
- 150000003567 thiocyanates Chemical class 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 210000004881 tumor cell Anatomy 0.000 description 8
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 7
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 7
- 230000035772 mutation Effects 0.000 description 7
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 7
- 238000012360 testing method Methods 0.000 description 6
- 102200048955 rs121434569 Human genes 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- 208000037841 lung tumor Diseases 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010059866 Drug resistance Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 3
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- QKFJKGMPGYROCL-UHFFFAOYSA-N phenyl isothiocyanate Chemical compound S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229940121647 egfr inhibitor Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- HVOYZOQVDYHUPF-UHFFFAOYSA-N n,n',n'-trimethylethane-1,2-diamine Chemical compound CNCCN(C)C HVOYZOQVDYHUPF-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical group 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- QZTWVDCKDWZCLV-UHFFFAOYSA-N 1-isocyanato-4-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=C(N=C=O)C=C1 QZTWVDCKDWZCLV-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 1
- 229940122531 Anaplastic lymphoma kinase inhibitor Drugs 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 235000004237 Crocus Nutrition 0.000 description 1
- 241000596148 Crocus Species 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 230000007773 growth pattern Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229940084651 iressa Drugs 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229940117953 phenylisothiocyanate Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a novel anti-tumor drug AZD9291 derivative and its preparation method and use in preparation of anti-tumor drugs. The preparation method comprises adding a multisubstituted aniline intermediate containing (1H-indole-3-yl)-pyrimidine-2-yl], R4-substituted thiocyanate or isothiocyanate, and R-protected fatty amine or glycosylamine into a certain amount of a solution, adding an appropriate acid-binding agent into the solution and then stirring the mixed solution at a temperature of 30-80 DEG C for a complete reaction to obtain an AZD 9291 derivative. The preparation method realizes derived synthesis of the AZD9291. The AZD9291 improves antitumor activity, can be used in preparation of anti-tumor drugs and has great significance to find novel antitumor drugs.
Description
Technical field
The present invention relates to a kind of new type antineoplastic medicine AZD9291 derivant and preparation method thereof, and it is anti-in preparation
Application in tumour medicine.
Background technology
AZD9291 (Osimertinib), EGFR T790M specific inhibitor.AZD9291 is that a kind of potent being administered orally can not
Inverse EGFR inhibitor, is specific to EGFR Positive mutants and T790M medicament-resistant mutation, and it is under the jurisdiction of third generation EGFR Lip river propylhomoserin and swashs
Enzyme inhibitor family, one very big feature of this medicine is that it has preferable effect to T790M mutation, simultaneously to EGFR wild type
Almost do not act on, therefore, the erythra incidence rate ratio of this medicine is relatively low, and side effect is less, clinical experiment confirms using AZD9291's
((46%) local tumor reduces, and 12 patients all have T790M to be mutated, and treatment is to wherein 7 (58%) 12 in 26 patients
Effectively, other patient experiences stable disease, the test currently for AZD9291 Dosage regimens is actively carried out, and expects the phase in future
The result of experiment.For Advanced Non-Small Cell adenocarcinoma of lung (NSCLC) patient, the targeted therapy of EGFR and ALK mutation is existing
Modern standard regimens.However, the curative effect of these medicines is typically very of short duration, drug resistance will be produced within 9-11 month, why go out
Existing this situation is because that cancerous cell can be by being mutated and changing the treatment work that growth pattern escapes EGFR or ALK inhibitor
Property.As the third generation be administered orally, irreversible selectivity EGFR inhibition from mutation agent, can be used for activate and resistant mutation EGFR,
That is, for patients with advanced NSCLC, 50% anti-EGFR treatment acquired drug-resistance (such as IRESSA, special sieve
Triumphant, Kai Meina drug resistance) caused by T790M mutation, AZD9291 can make this challenging mutation invalid.
AZD9291, due to its excellent antitumor performance, is ground with the preparation of reactive compound and activity derived from its structure
Study carefully and also will receive great concern, therefore synthesize AZD9291 derivant, research and develop its " Me-too " or " Me-better " medicine
Thing has significant application value.This patent is based on early stage document and itself Research foundation, and thiourea or urea functional group, osamine are drawn
Enter in AZD9291 precursor structure it is desirable to be able to increase the dissolubility of compound, increase drug molecule and tyrosine kinase catalytic domain
The specific spatial binding site in domain, thus competitively stoping tyrosine kinase from being combined with ATP, reduces tyrosine-kinase enzyme activity
Property, significant to the antitumor drug finding new.
Content of the invention
It is an object of the invention to provide a kind of new AZD9291 derivant and its preparation side with active anticancer feature
Method, and its application in preparing antitumor drug.
The invention provides a kind of AZD9291 derivant as shown in (I) for structural formula：
Wherein, R1For hydrogen, methyl, fluorine-based, one of chloro, bromo, iodo, nitro, phenyl；R2For hydrogen, methyl, first
One of epoxide, ethyoxyl；R is one of hydrogen-based, 2- dimethylaminoethyl, glycosyl；R3One kind for hydrogen, methyl；R4For
Aryl, one kind of heteroaryl；X is sulfur or oxygen.
Preferably, R1For hydrogen, R2The glucosyl group protected for pivaloyl group for methoxyl group, R, R3For hydrogen, R4For phenyl.
Preferably, R1For hydrogen, R2For methoxyl group, R is glucosyl group, R3For hydrogen, R4For phenyl.
Preferably, R1For hydrogen, R2For methoxyl group, R is 2- dimethylaminoethyl, R3For hydrogen, R4For phenyl.
Preferably, R1For hydrogen, R2For methoxyl group, R is 2- dimethylaminoethyl, R3For hydrogen, R4For trifluoromethyl.
In addition the pharmaceutically acceptable salt of suitable formula (I) compound is such as acid-addition salts.For example, it is possible to inorganic
Acid or organic acid form acid-addition salts.Can be with forming acid-addition salts selected from mineral acids such as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid.
Can be using selected from methanesulfonic acid, acetic acid, formic acid, benzoic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, fumaric acid, winestone
The organic acid of acid, lactic acid, benzenesulfonic acid and p-methyl benzenesulfonic acid forms acid-addition salts.
Present invention also offers a kind of preparation method of AZD9291 derivant as shown in (I) for structural formula, in certain solution
In, add structural formula as shown in (II) containing (1H- indol-3-yl) pyrimidine -2-base]-polysubstituted Aniline intermediates, structural formula
R as shown in (III)4Fatty amine or sugar that R as shown in (IV) for the sulfocyanic ester or isothiocyanate, structural formula replacing protects
Amine, stirs after adding suitable acid binding agent to reaction completely at a temperature of 30 DEG C～80 DEG C.
Preferably, described solution is one of following：Acetonitrile, oxolane or dichloromethane；Acid binding agent is one of following：
Triethylamine, tri-n-butylamine or diisopropylethylamine；Described containing (1H- indol-3-yl) pyrimidine -2-base]-polysubstituted aniline in the middle of
Body, R4The sulfocyanic ester replacing or isothiocyanate, the fatty amine of R protection or osamine, the amount ratio of the material of acid binding agent are for 1.0：
0.95～1.05：0.95～1.05：1.95～2.05.
Its syntheti c route is as follows：
Preferably, reaction temperature is 55 DEG C, reaction adopts HPLC tracing detection, reacts after terminating through cooling down, filtering, dry
Dry, recrystallization obtains product after purification.
Preferably, the preparation method of AZD9291 derivant comprises the steps：
(1) prepare：In oxolane, add (1H- indol-3-yl) pyrimidine -2-base]-polysubstituted aniline and phenyl
Isothiocyanate, generates intermediate state at a temperature of 35 DEG C, then adds fatty amine or osamine, under triethylamine effect, is warming up to
55 DEG C of stirring reactions are to complete；Wherein (1H- indol-3-yl) pyrimidine -2-base]-polysubstituted aniline, PITC,
The glucamine of pivaloyl group protection, the ratio of the amount of the material of triethylamine are 1.0：1.05：1.05：2.0；
(2) purification：It is cooled to 10 DEG C, filter, washed with cold oxolane, after drying, obtain target with ethyl alcohol recrystallization again
Product.
Application in preparing antitumor drug for the AZD9291 derivant as shown in (I) for the structural formula.
The purity grade of the oxolane that the present invention relates to is more than chemical pure (CP), and (1H- indol-3-yl) is phonetic
Pyridine -2- base]-polysubstituted aniline be purchased from Hangzhou Lu Pu bio tech ltd, triethylamine is purchased from Jiangsu prosperous and powerful chemistry share
Company limited, the glucamine of pivaloyl group protection is purchased from Aladdin reagent (Shanghai) Co., Ltd..
The AZD9291 derivant of preparation is applied to H1975 cell (lung tumor cell), carries out active anticancer test, use
Mtt assay measure above-mentioned tumor cell proliferative conditions, test result indicate that its H1975 cell (lung tumor cell) is had certain
Inhibitory action.
AZD9291 derivant of the present invention can be applicable to prepare in antitumor drug.
The present invention provides a kind of new AZD9291 derivant with active anticancer, by molecular modification, is favorably improved
Its anti-tumor activity, can be applicable to prepare in antitumor drug, significant to the antitumor drug finding new.
Specific embodiment
With reference to specific embodiment, the invention will be further described, but protection scope of the present invention is not limited to this.
Embodiment 1
The preparation of AZD9291 derivant (I)
Add compound II-a.63g (0.1mol) in 250mL flask, be dissolved in 80mL THF, add the different sulfur of phenyl
Cyanate III-a1.27g (0.101mol), reacts 3h in 35 DEG C, and decompression boils off oxolane, obtains crude product.Crude product without point
From direct and Piv protection glucamine IV-a (5.20g, 0.101mol), 5.6mL triethylamine and 20mL THF, anti-in 55 DEG C
Answer 24h, separate out a large amount of bright yellow solid, reaction adopts HPLC tracing detection.It is cooled to 10 DEG C, filter, washed with cold oxolane
Wash, crude product obtains yellow solid I-a, yield 98%, fusing point with ethyl alcohol recrystallization after drying：152～154 DEG C.
1H NMR(400MHz,DMSO)δ:δ 10.08 (s, 1H), 9.19 (s, 1H), 8.59 (s, 1H), 8.29 (d, J=
4.9Hz, 1H), 8.15 (d, J=46.8Hz, 2H), 7.68 (s, 1H), 7.46 (d, J=7.5Hz, 2H), 7.33 7.28 (m,
3H), 7.22 (d, J=7.0Hz, 2H), 7.11 (d, J=5.4Hz, 2H), 6.75 (s, 1H), 6.82-6.86 (m, 1H), 5.33
(d, J=9.2Hz, 1H, G3), H 5.16 (t, J=9.6Hz, 1H, G4), H 5.09 (t, J=9.2Hz, 1H, G2), H 5.51 (t, J=
9.2Hz,1H,G1H),4.22-4.11(m,2H,G6H),3.96(m,1H,G5H),3.90(s,3H),2.18(s,6H).1.17-
1.09(m,36H),13C NMR(126MHz,CDCl3)δ178.75,162.21,159.69,157.48,146.24,138.74,
138.03,132.52,128.70,126.96,125.81,125.54,124.49,122.36,121.24,120.81,114.25,
113.66,110.08,108.46,104.62,56.94,56.06,55.01,45.01,43.45,33.34.
Embodiment 2
Add compound II-a (3.63g, 0.1mol) to be dissolved in 80mL THF in 250mL flask, add phenyl different
Sulfocyanic ester III-a (1.27g, 0.101mol), reacts 3h in 35 DEG C, and decompression boils off oxolane, obtains crude product.Crude product without
Separate direct and glucamine IV-b (1.80g, 0.101mol), 5.6mL triethylamine and 20mL THF, react 24h, analysis in 55 DEG C
Go out a large amount of bright yellow solid, reaction adopts HPLC tracing detection.It is cooled to 10 DEG C, filters, washed with cold oxolane, crude product dries
Yellow solid I-b, yield 95%, fusing point is obtained with ethyl alcohol recrystallization after dry：132～134 DEG C.
1H NMR(400MHz,DMSO)δ:δ 10.07 (s, 1H), 9.19 (s, 1H), 8.57 (s, 1H), 8.29 (d, J=
4.9Hz, 1H), 8.13 (d, J=42.8Hz, 2H), 7.65 (s, 1H), 7.45 (d, J=7.5Hz, 2H), 7.33 7.28 (m,
3H), 7.22 (d, J=7.0Hz, 2H), 7.11 (d, J=5.4Hz, 2H), 6.75 (s, 1H), 6.82-6.86 (m, 1H), 5.33
(d, J=9.2Hz, 1H, G3), H 5.16 (t, J=9.6Hz, 1H, G4), H 5.09 (t, J=9.2Hz, 1H, G2), H 5.51 (t, J=
9.2Hz,1H,G1H),4.22-4.11(m,2H,G6H),3.96(m,1H,G5H),3.90(s,3H),2.18(s,6H).13C NMR
(126MHz,CDCl3)δ178.75,162.21,159.69,157.48,146.24,138.74,138.03,132.52,
128.70,126.96,125.81,125.54,124.49,122.36,121.24,120.81,114.25,113.66,110.08,
108.46,104.62,56.94,56.06,55.01,45.01,33.34.
Embodiment 3
Add compound II-a (3.63g, 0.1mol) to be dissolved in 80mL THF in 250mL flask, add phenyl different
Sulfocyanic ester III-a (1.27g, 0.101mol), reacts 3h in 35 DEG C, and decompression boils off oxolane, obtains crude product.Crude product without
Separate direct and N, N, N'- trimethyl ethylenediamine IV-c (1.03g, 0.101mol), 5.6mL triethylamine and 20mL THF, in 55
DEG C reaction 24h, separate out a large amount of bright yellow solid, reaction adopt HPLC tracing detection.It is cooled to 10 DEG C, filter, with cold tetrahydrochysene furan
Mutter washing, crude product obtains bright yellow solid, yield 95%, fusing point with ethyl alcohol recrystallization after drying：166～168 DEG C.
1H NMR(400MHz,DMSO)δ:δ 10.08 (s, 1H), 9.19 (s, 1H), 8.59 (s, 1H), 8.29 (d, J=
4.9Hz, 1H), 8.15 (d, J=46.8Hz, 2H), 7.68 (s, 1H), 7.46 (d, J=7.5Hz, 2H), 7.33 7.28 (m,
3H), 7.22 (d, J=7.0Hz, 2H), 7.11 (d, J=5.4Hz, 2H), 6.75 (s, 1H), 3.90 (s, 3H), 3.79 (s, 3H),
2.98(s,2H),2.73(s,3H),2.26(s,2H),2.18(s,6H).13C NMR(126MHz,CDCl3)δ178.75,
162.21,159.69,157.48,146.24,138.74,138.03,132.52,128.70,126.96,125.81,125.54,
124.49,122.36,121.24,120.81,114.25,113.66,110.08,108.46,104.62,56.94,56.06,
55.01,45.01,43.45,33.34.
Embodiment 4
Add compound II-a (3.63g, 0.1mol) to be dissolved in 80mL THF in 250mL flask, add trifluoro
Methylphenyl isocyanate III-b (1.88g, 0.101mol), reacts 3h in 35 DEG C, and decompression boils off oxolane, obtains crude product.
Crude product without isolation directly and N, N, N'- trimethyl ethylenediamine IV-c (1.03g, 0.101mol), 5.6mL triethylamine and 20mL
THF, reacts 24h in 55 DEG C, separates out a large amount of bright yellow solid, and reaction adopts HPLC tracing detection.It is cooled to 10 DEG C, filters, use
Cold oxolane washing, crude product obtains crocus solid, yield 90%, fusing point with ethyl alcohol recrystallization after drying：182～183 DEG C.
1H NMR(500MHz,CDCl3) δ 10.82 (s, 1H), 9.05 (s, 1H), 8.87 (s, 1H), 8.26 (d, J=
5.3Hz, 1H), 8.23 8.20 (m, 1H), 7.92 (s, 1H), 7.68 (s, 1H), 7.65 (d, J=8.4Hz, 2H), 7.38 (d, J
=8.3Hz, 2H), 7.29 (dd, J=5.9,3.8Hz, 3H), 7.10 (d, J=5.3Hz, 1H), 6.80 (s, 1H), 3.91 (s,
3H), 3.75 (s, 3H), 3.01 (t, J=6.0Hz, 2H), 2.78 (s, 3H), 2.31 (t, J=5.9Hz, 2H), 2.26 (s, 6H)
.13C NMR(126MHz,CDCl3)δ178.30,162.25,159.65,157.32,146.40,142.31,137.93,
131.87,127.38,126.37,126.11,125.73,125.41,125.17,123.08,122.59,121.38,120.81,
113.89,113.69,110.05,108.65,105.22,56.66,56.01,55.38,44.70,43.56,33.30.
Biological activity test：
For the biologic activity of this compound, with H1975 (lung tumor cell) as object of study, derive in AZD9291
The growing state of observation of cell in the presence of thing, and the proliferative conditions of tumor cell are measured with mtt assay.Concrete operations are as follows：Will
H1975 tumor cell is inoculated in 96 well culture plates by certain cell concentration, and cell density is 2 × 104/ml；37 DEG C, CO2
In the incubator of concentration 5% overnight after, (sample concentration reference table 1, dosing group adds 10 μ l/ hole respective concentration to add sieved sample
Medicine, matched group adds 10 μ l/ hole PBS), after culture 44h, add 10 μ l/ hole MTT to continue culture 6h, with DMSO dissolving, shake,
Detected under 570nm microplate reader.
The AZD9291 derivant that embodiment 1～4 is obtained presses down to the half of H1975 cell (lung tumor cell) test experiments
Concentration IC processed50, test result is as shown in table 1：
Table 1
We have found that the AZD9291 derivant of synthesis has the function of suppression H1975 tumor cell by experiment, can be with
This optimizes further for mother nucleus structure and obtains activity preferably molecular structure, and the AZD9291 that can reflect our designs derives
There is suppression function in thing in terms of antitumor cell, have certain application prospect.
Claims (10)
1. a kind of new type antineoplastic medicine AZD9291 derivant is it is characterised in that structural formula is as shown in (I)：
Wherein, R1For hydrogen, methyl, fluorine-based, one of chloro, bromo, iodo, nitro, phenyl；R2For hydrogen, methyl, methoxyl group,
One of ethyoxyl；R is one of hydrogen-based, 2- dimethylaminoethyl, glycosyl；R3One kind for hydrogen, methyl；R4For aryl,
One kind of heteroaryl；X is sulfur or oxygen.
2. new type antineoplastic medicine AZD9291 derivant according to claim 1 it is characterised in that：R1For hydrogen, R2For first
Epoxide, the glucosyl group that R protects for pivaloyl group, R3For hydrogen, R4For phenyl.
3. new type antineoplastic medicine AZD9291 derivant according to claim 1 it is characterised in that：R1For hydrogen, R2For first
Epoxide, R is glucosyl group, R3For hydrogen, R4For phenyl.
4. new type antineoplastic medicine AZD9291 derivant according to claim 1 it is characterised in that：R1For hydrogen, R2For first
Epoxide, R is 2- dimethylaminoethyl, R3For hydrogen, R4For phenyl.
5. new type antineoplastic medicine AZD9291 derivant according to claim 1 it is characterised in that：R1For hydrogen, R2For first
Epoxide, R is 2- dimethylaminoethyl, R3For hydrogen, R4For trifluoromethyl.
6. new type antineoplastic medicine AZD9291 derivant described in claim 1 preparation method it is characterised in that：Necessarily molten
In liquid, add contain (1H- indol-3-yl) pyrimidine -2-base]-polysubstituted Aniline intermediates, R4The sulfocyanic ester replacing or different sulfur
Cyanate, the fatty amine of R protection or osamine, stir after adding acid binding agent to reaction completely at a temperature of 30 DEG C～80 DEG C.
7. according to claim 6 new type antineoplastic medicine AZD9291 derivant preparation method it is characterised in that：Described
Solution is one of following：Acetonitrile, oxolane or dichloromethane；Acid binding agent is one of following：Triethylamine, tri-n-butylamine or diisopropyl
Base ethamine；Described containing (1H- indol-3-yl) pyrimidine -2-base]-polysubstituted Aniline intermediates, R4The substituted Hydrogen thiocyanate replacing
Ester or isothiocyanate, the fatty amine of R protection or osamine, the amount ratio of the material of acid binding agent are for 1.0：0.95～1.05：0.95～
1.05：1.95～2.05.
8. according to claim 6 new type antineoplastic medicine AZD9291 derivant preparation method it is characterised in that：Reaction
Temperature is 55 DEG C, and reaction adopts HPLC tracing detection, reaction terminate after through cooling, filter, dry, recrystallization obtains product after purification
Thing.
9. under the preparation method of new type antineoplastic medicine AZD9291 derivant is it is characterised in that include according to claim 6
State step：
(1) prepare：In oxolane, add (1H- indol-3-yl) pyrimidine -2-base]-polysubstituted aniline and the different sulfur of phenyl
Cyanate, generates intermediate state, then adds the glucamine of pivaloyl group protection at a temperature of 35 DEG C, under triethylamine effect,
It is warming up to 55 DEG C of stirring reactions to complete；Wherein (1H- indol-3-yl) pyrimidine -2-base]-polysubstituted aniline, phenyl different sulfur cyanogen
Acid esters, the glucamine of pivaloyl group protection, the ratio of the amount of the material of triethylamine are 1.0：1.05∶1.05∶2.0；
(2) purification：It is cooled to 10 DEG C, filters, washed with cold oxolane, obtain target with ethyl alcohol recrystallization again after drying and produce
Thing.
10. application in preparing antitumor drug for the new type antineoplastic medicine AZD9291 derivant described in claim 1.
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| US10513509B2 (en) | 2016-05-26 | 2019-12-24 | Recurium Ip Holdings, Llc | EGFR inhibitor compounds |
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| WO2001029009A1 (en) * | 1999-10-20 | 2001-04-26 | Celltech R&D Limited | 4,5-disubstituted-2-aminopyrimidines |
| CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
| CN105001208A (en) * | 2015-08-06 | 2015-10-28 | 南京雷科星生物技术有限公司 | EGFR inhibitor and preparing method and application thereof |
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| WO2001029009A1 (en) * | 1999-10-20 | 2001-04-26 | Celltech R&D Limited | 4,5-disubstituted-2-aminopyrimidines |
| CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
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| US10513509B2 (en) | 2016-05-26 | 2019-12-24 | Recurium Ip Holdings, Llc | EGFR inhibitor compounds |
| US11098030B2 (en) | 2016-05-26 | 2021-08-24 | Recurium Ip Holdings, Llc | EGFR inhibitor compounds |
| CN107596394A (en) * | 2017-08-23 | 2018-01-19 | 哈尔滨医科大学 | Using full-automatic, one-step synthesis method18The method of the pyrimidine acrylic amide EGFR positive electron tracers of F marks |
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