CN106397407B - The preparation method of antitumor drug AZD9291 derivatives - Google Patents
The preparation method of antitumor drug AZD9291 derivatives Download PDFInfo
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- CN106397407B CN106397407B CN201610799718.0A CN201610799718A CN106397407B CN 106397407 B CN106397407 B CN 106397407B CN 201610799718 A CN201610799718 A CN 201610799718A CN 106397407 B CN106397407 B CN 106397407B
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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 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 12
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 46
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- 239000012043 crude product Substances 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 10
- 238000001514 detection method Methods 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- 230000006837 decompression Effects 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 4
- 235000004237 Crocus Nutrition 0.000 claims description 2
- 241000596148 Crocus Species 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- 229960003278 osimertinib Drugs 0.000 abstract description 11
- 239000003814 drug Substances 0.000 abstract description 10
- 230000004224 protection Effects 0.000 abstract description 7
- 239000002253 acid Substances 0.000 abstract description 5
- 150000003567 thiocyanates Chemical class 0.000 abstract description 5
- 150000001412 amines Chemical class 0.000 abstract description 4
- 230000000259 anti-tumor effect Effects 0.000 abstract description 4
- 239000011230 binding agent Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 abstract description 3
- 150000002540 isothiocyanates Chemical class 0.000 abstract description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 abstract description 2
- 230000000118 anti-neoplastic effect Effects 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 abstract 1
- 150000001448 anilines Chemical class 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 12
- 150000002431 hydrogen Chemical class 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- -1 chloro, bromo, iodo, nitro, phenyl Chemical group 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 8
- 230000000694 effects Effects 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
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 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
- 238000002474 experimental method Methods 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- 208000037841 lung tumor Diseases 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 3
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- QKFJKGMPGYROCL-UHFFFAOYSA-N phenyl isothiocyanate Chemical class S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 206010059866 Drug resistance Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-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
- 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
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-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
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 2
- 230000005764 inhibitory process Effects 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
- 150000007522 mineralic acids Chemical class 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
- 230000002062 proliferating effect 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
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 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
- 201000011510 cancer Diseases 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
- 238000001816 cooling Methods 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 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
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 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
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 230000007773 growth pattern Effects 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940084651 iressa Drugs 0.000 description 1
- 230000002427 irreversible effect Effects 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
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 239000001301 oxygen Chemical group 0.000 description 1
- 229910052760 oxygen Chemical group 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
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 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
Abstract
The present invention relates to a kind of new type antineoplastic medicine AZD9291 derivatives and preparation method thereof and its application in preparations of anti-tumor drugs.The present invention is in certain solution; 2 base containing (3 base of 1H indoles) pyrimidine is added] polysubstituted Aniline intermediates, the thiocyanates of R4 substitutions or the fatty amine or osamine of isothiocyanates, R protections, be added after suitable acid binding agent at a temperature of 30 DEG C~80 DEG C stirring extremely the reaction was complete AZD9291 derivatives are prepared.The present invention carries out derivative synthesis to AZD9291, helps to improve its antitumor activity, can be applied to prepare in antitumor drug, is of great significance to the antitumor drug for finding new.
Description
Technical field
The present invention relates to a kind of new type antineoplastic medicine AZD9291 derivatives and preparation method thereof and its prepare it is anti-
Application in tumour medicine.
Background technology
AZD9291 (Osimertinib), EGFR T790M specific inhibitors.AZD9291 is that potent take orally of one kind can not
Inverse EGFR inhibitor, is specific to EGFR Positive mutants and T790M medicament-resistant mutations, it is under the jurisdiction of the Lip rivers third generation EGFR propylhomoserin and swashs
Enzyme inhibitor family, one very big feature of the medicine is it has preferable effect to T790M mutation, while to EGFR wild types
Almost without effect, therefore, the fash incidence of the medicine is relatively low, and side effect is smaller, and clinical trial is confirmed using AZD9291's
Having 12 in 26 patients, ((46%) local tumor reduces, and 12 patients have T790M mutation, treats to wherein 7
(58%) effectively, other patient experiences stable diseases in being actively being implemented at present for the experiment of AZD9291 Dosage regimens, expect
The result of phase in future experiment.For Advanced Non-Small Cell adenocarcinoma of lung (NSCLC) patient, the targeting of EGFR and ALK mutation is controlled
Treatment is standard regimens now.However, the effect of these drugs is generally very of short duration, drug resistance will be generated within 9-11 months, it
So EGFR or ALK inhibitor can be escaped because of cancer cell by being mutated and changing growth pattern by such case occur
Therapeutic activity.As the third generation, oral, irreversible selectivity EGFR inhibition from mutation agent, can be used for activating and resistant mutation
EGFR, that is to say, that for patients with advanced NSCLC, 50% anti-EGFR treatment acquired resistance (such as Iressa,
The drug resistance of Erlotinib, Kai Meina) it is caused by being mutated by T790M, AZD9291 can make the mutation of this challenge invalid.
AZD9291 is ground due to its excellent antitumor activity energy with the preparation of reactive compound and activity derived from its structure
Great concern will also be received by studying carefully, therefore synthesize AZD9291 derivatives, research and develop its " Me-too " or " Me-better " medicine
Object has significant application value.This patent is based on document early period and itself Research foundation, and thiocarbamide or urea functional group, osamine are drawn
Enter in AZD9291 precursor structures, 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 reduces tyrosine-kinase enzyme activity to competitively tyrosine kinase be prevented to be combined with ATP
Property, it is of great significance to the antitumor drug for finding new.
Invention content
The purpose of the present invention is to provide a kind of new AZD9291 derivatives and its preparation side with active anticancer feature
Method and its application in preparation of anti-tumor drugs.
A kind of the present invention provides structural formulas AZD9291 derivatives as shown in (I)：
Wherein, R1For one kind in hydrogen, methyl, fluorine-based, chloro, bromo, iodo, nitro, phenyl； R2For hydrogen, methyl, first
One kind in oxygroup, ethyoxyl；R is one kind in hydrogen-based, 2- dimethylaminoethyls, glycosyl；R3For one kind of hydrogen, methyl；R4For
One kind of aryl, heteroaryl；X is sulphur or oxygen.
Preferably, R1For hydrogen, R2For methoxyl group, R is the glucosyl group of pivaloyl group protection, 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- dimethylaminoethyls, R3For hydrogen, R4For phenyl.
Preferably, R1For hydrogen, R2For methoxyl group, R is 2- dimethylaminoethyls, R3For hydrogen, R4For trifluoromethyl.
In addition the pharmaceutically acceptable salt of suitable formula (I) compound is such as acid-addition salts.For example, can be with inorganic
Acid or organic acid form acid-addition salts.It can use and form acid-addition salts selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid.
It can use selected from methanesulfonic acid, acetic acid, formic acid, benzoic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, fumaric acid, winestone
The organic acid formation acid-addition salts of acid, lactic acid, benzene sulfonic acid and p-methyl benzenesulfonic acid.
The present invention also provides a kind of preparation methods of structural formula AZD9291 derivatives as shown in (I), in certain solution
In, structural formula is added such as (II) shown in containing (1H- indol-3-yls) pyrimidine -2-base]-polysubstituted Aniline intermediates, structural formula
The R as shown in (III)4Fatty amine that substituted thiocyanates or isothiocyanates, the structural formula R as shown in (IV) are protected or
Osamine, stirring at a temperature of 30 DEG C~80 DEG C is added after suitable acid binding agent, and extremely the reaction was complete.
Preferably, the solution is one of following：Acetonitrile, tetrahydrofuran or dichloromethane；Acid binding agent is one of following：
Triethylamine, tri-n-butylamine or diisopropylethylamine；It is described contain (1H- indol-3-yls) pyrimidine -2-base]-polysubstituted aniline among
Body, R4Substituted thiocyanates or isothiocyanates, the fatty amine of R protections or osamine, acid binding agent the amount ratio of substance be 1.0：
0.95~1.05：0.95~1.05：1.95~2.05.
Its preparation route is as follows：
Preferably, reaction temperature is 55 DEG C, reaction uses HPLC tracing detections, after reaction through cooling, filtering, baking
The product done, recrystallize after purification.
Preferably, the preparation method of AZD9291 derivatives includes the following steps：
(1) it prepares：In tetrahydrofuran, be added (1H- indol-3-yls) pyrimidine -2-base]-polysubstituted aniline and phenyl
Isothiocyanates 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 are stirred to react to complete；Wherein (1H- indol-3-yls) pyrimidine -2-base]-polysubstituted aniline, phenyl isothiocyanate,
The ratio between the gucosamine of pivaloyl group protection, amount of substance of triethylamine are 1.0：1.05：1.05：2.0；
(2) it purifies：10 DEG C are cooled to, filtering is washed with cold tetrahydrofuran, target is obtained with ethyl alcohol recrystallization again after drying
Product.
Structural formula AZD9291 derivatives application in preparation of anti-tumor drugs as shown in (I).
The purity grade of the tetrahydrofuran involved in the present invention arrived is chemical pure (CP) or more, and (1H- indoles -3- bases) is phonetic
Pyridine -2- bases]-polysubstituted aniline be purchased from the Hangzhou bio tech ltd Lu Pu, triethylamine is purchased from the prosperous and powerful chemical share in Jiangsu
The gucosamine of Co., Ltd, pivaloyl group protection is purchased from Aladdin reagent (Shanghai) Co., Ltd..
The AZD9291 derivatives of preparation are applied to H1975 cells (lung tumor cell), carry out active anticancer test, are used
Mtt assay measures the proliferative conditions of above-mentioned tumour cell, the experimental results showed that its have to H1975 cells (lung tumor cell) it is certain
Inhibiting effect.
AZD9291 derivatives of the present invention can be applied to prepare in antitumor drug.
The present invention provides a kind of AZD9291 derivatives with active anticancer newly and is helped to improve by molecular modification
Its antitumor activity can be applied to prepare in antitumor drug, be of great significance to the antitumor drug for finding new.
Specific implementation mode
The present invention is further explained in the light of specific embodiments, but protection scope of the present invention is not limited to this.
Embodiment 1
The preparation of AZD9291 derivatives (I)
Compound II-a.63g (0.1mol) is added in 250mL flasks, is dissolved in 80mL THF, the different sulphur of phenyl is added
Cyanate III-a1.27g (0.101mol), 3h is reacted in 35 DEG C, and decompression boils off tetrahydrofuran, obtains crude product.Crude product without point
Gucosamine IV-a (5.20g, 0.101mol) from direct and Piv protections, 5.6mL triethylamines and 20mL THF are anti-in 55 DEG C
Should a large amount of bright yellow solids be precipitated for 24 hours, reaction uses HPLC tracing detections.10 DEG C are cooled to, filtering is washed with cold tetrahydrofuran
It washs, yellow solid I-a, yield 98%, fusing point is obtained with ethyl alcohol recrystallization after crude product 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, G2H),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(126 MHz,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
Compound II-a (3.63g, 0.1mol) is added in 250mL flasks to be dissolved in 80mL THF, it is different that phenyl is added
Thiocyanates III-a (1.27g, 0.101mol), 3h is reacted in 35 DEG C, and decompression boils off tetrahydrofuran, obtains crude product.Crude product without
Direct and gucosamine IV-b (1.80g, 0.101mol), 5.6 mL triethylamines and 20mL THF are detached, for 24 hours in 55 DEG C of reactions,
A large amount of bright yellow solids are precipitated, reaction uses HPLC tracing detections.10 DEG C are cooled to, filtering is washed, slightly with cold tetrahydrofuran
After product drying yellow solid I-b, yield 95%, fusing point are obtained with ethyl alcohol recrystallization：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, G2H),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
Compound II-a (3.63g, 0.1mol) is added in 250mL flasks to be dissolved in 80mL THF, it is different that phenyl is added
Thiocyanates III-a (1.27g, 0.101mol), 3h is reacted in 35 DEG C, and decompression boils off tetrahydrofuran, obtains crude product.Crude product without
Detach direct and N, N, N'- trimethyl ethylenediamine IV-c (1.03g, 0.101 mol), 5.6mL triethylamines and 20mL THF, in 55
For 24 hours, a large amount of bright yellow solids are precipitated, reaction uses HPLC tracing detections in DEG C reaction.10 DEG C are cooled to, filtering, with cold tetrahydrochysene furan
It mutters washing, bright yellow solid, yield 95%, fusing point is obtained with ethyl alcohol recrystallization after crude product 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(126 MHz,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
Compound II-a (3.63g, 0.1mol) is added in 250mL flasks to be dissolved in 80mL THF, is added to trifluoro
Methylphenyl isocyanate III-b (1.88g, 0.101mol), 3h is reacted in 35 DEG C, and decompression boils off tetrahydrofuran, obtains crude product.
Crude product without isolation directly and N, N, N'- trimethyl ethylenediamine IV-c (1.03 g, 0.101mol), 5.6mL triethylamines and 20mL
For 24 hours in 55 DEG C of reactions a large amount of bright yellow solids are precipitated in THF, and reaction uses HPLC tracing detections.10 DEG C are cooled to, is filtered, is used
Cold tetrahydrofuran washing, crocus solid, yield 90%, fusing point are obtained after crude product drying with ethyl alcohol recrystallization：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 biological activity of the compound, with H1975 (lung tumor cell) for research object, derive in AZD9291
The growing state that cell is observed under the action of object, is used in combination mtt assay to measure the proliferative conditions of tumour cell.Concrete operations are as follows：It will
H1975 tumour cells are inoculated in by certain cell concentration in 96 well culture plates, and cell density is 2 × 104/ml；37 DEG C, CO2
After being stayed overnight in the incubator of concentration 5%, sieved sample is added, and (sample concentration adds 10 holes μ l/ respective concentrations with reference to table 1, dosing group
Drug, control group add 10 μ l/ hole PBS), after cultivating 44h, 10 μ l/ hole MTT are added and continue to cultivate 6h, is dissolved, is shaked with DMSO,
It is detected under 570nm microplate reader.
AZD9291 derivatives made from Examples 1 to 4 press down the half of H1975 cells (lung tumor cell) test experiments
Concentration IC processed50, test result is as shown in table 1：
Table 1
It, can be with by experiment we have found that the AZD9291 derivatives of synthesis have the function of inhibition H1975 tumour cells
This advanced optimizes to obtain the preferable molecular structure of activity for mother nucleus structure, and the AZD9291 that can reflect our designs derives
Object exists in terms of antitumor cell inhibits function, has certain application prospect.
Claims (1)
1. a kind of preparation method of antitumor drug AZD9291 derivatives, it is characterised in that structural formula is such as（I）It is shown：
Its preparation route is as follows：
Structural formula is added such as in 250 mL flasks（II）Compound represented a 3.63g are dissolved in 80 mL THF, are added
Structural formula is such as（III）Compound represented b 1.88g, 3h is reacted in 35 DEG C, and decompression boils off tetrahydrofuran, obtains crude product；Crude product
Without isolation directly and 1.03g structural formulas such as（IV）Compound represented c, 5.6mL triethylamine and 20mL THF are anti-in 55 DEG C
Should bright yellow solid be precipitated for 24 hours, reaction uses HPLC tracing detections；
10 DEG C are cooled to, filtering is washed with cold tetrahydrofuran, obtains the target of crocus solid after crude product drying with ethyl alcohol recrystallization
Product, yield 90%.
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