CN107935995A - A kind of new 2 anilino-pyrimidine derivative and its application in antitumor drug is prepared - Google Patents
A kind of new 2 anilino-pyrimidine derivative and its application in antitumor drug is prepared Download PDFInfo
- Publication number
- CN107935995A CN107935995A CN201711213902.3A CN201711213902A CN107935995A CN 107935995 A CN107935995 A CN 107935995A CN 201711213902 A CN201711213902 A CN 201711213902A CN 107935995 A CN107935995 A CN 107935995A
- Authority
- CN
- China
- Prior art keywords
- anilino
- new
- alkyl
- pyrimidines derivative
- pyrimidines
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- XGXNTJHZPBRBHJ-UHFFFAOYSA-N n-phenylpyrimidin-2-amine Chemical class N=1C=CC=NC=1NC1=CC=CC=C1 XGXNTJHZPBRBHJ-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 239000002246 antineoplastic agent Substances 0.000 title claims description 8
- 229940041181 antineoplastic drug Drugs 0.000 title claims description 8
- 150000003462 sulfoxides Chemical class 0.000 claims abstract description 20
- 150000003457 sulfones Chemical class 0.000 claims abstract description 16
- -1 methyl mercapto functional group Chemical group 0.000 claims abstract description 13
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 150000002367 halogens Chemical class 0.000 claims abstract description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 12
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 150000001450 anions Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 230000003287 optical effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 15
- 230000000259 anti-tumor effect Effects 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 9
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 description 31
- 239000000047 product Substances 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 11
- 201000011510 cancer Diseases 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 230000035772 mutation Effects 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 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
- 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
- 238000005406 washing Methods 0.000 description 7
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 6
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 4
- 229960003278 osimertinib Drugs 0.000 description 4
- DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical compound 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 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 102200048955 rs121434569 Human genes 0.000 description 4
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 101150039808 Egfr gene Proteins 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229940121647 egfr inhibitor Drugs 0.000 description 3
- 108700021358 erbB-1 Genes Proteins 0.000 description 3
- UEXQBEVWFZKHNB-UHFFFAOYSA-N intermediate 29 Natural products C1=CC(N)=CC=C1NC1=NC=CC=N1 UEXQBEVWFZKHNB-UHFFFAOYSA-N 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 150000003568 thioethers Chemical class 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 0 C*c(cc(c(N)c1)N(C)CCSC)c1NC(N)=NC=CC(c1c[n](C)c2c1cccc2)=C Chemical compound C*c(cc(c(N)c1)N(C)CCSC)c1NC(N)=NC=CC(c1c[n](C)c2c1cccc2)=C 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 102000001301 EGF receptor Human genes 0.000 description 2
- 108060006698 EGF receptor Proteins 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
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 229960001686 afatinib Drugs 0.000 description 2
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229940121645 first-generation egfr tyrosine kinase inhibitor Drugs 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 2
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 239000007848 Bronsted acid Substances 0.000 description 1
- XTWDAHXWNVGQHW-UHFFFAOYSA-N C[n]1c(cccc2)c2c(-c2ccnc(Nc(cc(c(N(CC3)CCC3=C)c3)N)c3OC)n2)c1 Chemical compound C[n]1c(cccc2)c2c(-c2ccnc(Nc(cc(c(N(CC3)CCC3=C)c3)N)c3OC)n2)c1 XTWDAHXWNVGQHW-UHFFFAOYSA-N 0.000 description 1
- 101000878540 Homo sapiens Protein-tyrosine kinase 2-beta Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 102100037787 Protein-tyrosine kinase 2-beta Human genes 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000000370 acceptor Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 229960002584 gefitinib Drugs 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
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000011968 lewis acid catalyst Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000003462 vein Anatomy 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of new 2 anilino-pyrimidine derivative, its side chain contains sulfoxide SO, sulfone SO2, hydroxyl, halogen or methyl mercapto functional group, be that NCH in Buddhist nun is replaced using above-mentioned functional group substitution west difficult to understand3With N (CH3)2Group.The present invention introduces sulfoxide SO, sulfone SO in the side chain2, hydroxyl, halogen or methyl mercapto, have good activity for solubility, bioavilability and the antitumor activity for improving medicine.
Description
Technical field
The present invention relates to drug field, more particularly to a kind of new 2- anilino-pyrimidines derivative and its anti-swollen preparing
Application in tumor medicine, its side chain contain sulfoxide SO, sulfone SO2, hydroxyl, halogen or methyl mercapto functional group.
Background technology
Malignant tumour, is commonly called as cancer, is a kind of serious threat human health and the major disease of life, it has also become the whole world
Primary " life killer ".Cancer in China registration center (National Central Cancer Registry of China,
NCCRC) report, wherein newly-increased 4300,000 people of cases of cancer in 2015, death toll 2800,000 people.According to world health group
Knit expert to predict in the correlation meeting of Geneva, 2020, whole world number dead because of cancer every year may increase by one
Times, 84,000,000 people are about had in coming 10 years and die of cancer.To the year two thousand twenty, will also there be 5,500,000 new cancer cases in China,
Cancer will be died of by being wherein up to 4,000,000 people.In all cancers occurred frequently, lung cancer is the highest malignant tumour of the death rate, lung
Cancer and breast cancer occupy man, the first place of female malignant morbidity respectively.
Protein tyrosine kinase (protein tyrosine kinase, PTKs) is by controlling the signal transduction of cell to lead to
Road adjusts a series of physiological and biochemical procedures such as the growth, differentiation, apoptosis of cell.Receptor type tyrosine kinase has ligand binding
Extracellular domain, transmembrane domain and rise zymogenesis specific phosphorylated tyrosine residues and thus influence cell increase
The intracellular domain grown.As described in being had found in general human cancer (such as lung cancer, breast cancer, stomach cancer, oophoroma, lymthoma)
The unconventionality expression of kinases, protein tyrosine kinase have become one of important target spot of antitumor drug research and development.
Epidermal growth factor receptor (epidermal growth factor receptor, EGFR) tyrosine-kinase
Enzyme is exactly one kind in receptor tyrosine kinase.EGFR is distributed widely in the epithelial cell membrane in addition to vascular tissue.Normally
In cell, EGFR tyrosine kinase is adjusted by its ligand, plays the functions such as growth, the propagation of normal cell.When this is logical
When the controlling gene on road occurs being mutated or expands, the downstream passages abnormal activation of its mediation is may be such that, so as to induce a variety of cancers
Disease.
It is sensitive to EGFR gene by the first generation EGFR tyrosine kinase inhibitors (EGFR-TKI) of representative of Gefitinib
The Patients with Non-small-cell Lung tool of mutation has a better effect.However, usually after the treatment of 1~2 year, patient occurs not
With the acquired resistance of degree.
Afatinib be it is a kind of with the HER2 acceptors Irreversible binding of EGFR to suppress the second generation of EGFR-TK activation
The cell line expresses of EGFR sensitizing mutations including T790M Positive mutants have been gone out good activity by EGFR-TKI medicines, but
It is that Afatinib is selectively poor, while serious dosage correlation toxicity can be caused.
West difficult to understand is U.S. Food and Drug Administration (FDA) for Buddhist nun (Osimertinib, AZD9291, structural formula A)
Accelerate the antitumor drug for being used to treat advanced Non-small cell lung of approval in November, 2015, belong to third generation EGFR junket ammonia
Acid kinase inhibitor.West difficult to understand for Buddhist nun be mainly characterized by have preferable effect to T790M mutation, the wild type of EGFR is acted on
It is smaller.There is the patient that nearly half produces the first generation EGFR tyrosine kinase inhibitors drug resistance in clinical research, use west difficult to understand
Reduced for tumor by local after Buddhist nun, show excellent antitumous effect.Although west difficult to understand is for Buddhist nun to EGFR-T790M mutation patients'
Curative effect is encouraging, but tumour cell has extremely strong screening capacity, in this case it is still possible to makes tumour cell to the third generation
After EGFR-TKI is adapted to, drug resistance is produced.Therefore, antitumor activity is found or other if security is preferably similar to candidate's medicine
The research of thing has developed quickly.Replaced for example, PCT Patent WO2016070816 and WO2016094821 report west difficult to understand respectively
NCH in Buddhist nun's substituted-amino side chain3Group by the synthesis of oxygen atom substituted compound (structural formula B) and activity research,
WO2016094821 also reported NCH3The situation (structural formula C) that group is substituted by sulphur atom.
The content of the invention
It is an object of the invention to overcome shortcoming existing in the prior art, there is provided a kind of new 2- anilino-pyrimidines spread out
Biology, side chain contain sulfoxide SO, sulfone SO2, hydroxyl, halogen or methyl mercapto functional group, be to substitute west difficult to understand to replace using above-mentioned functional group
NCH in Buddhist nun3With N (CH3)2Group.
Another object of the present invention is to provide above-mentioned new 2- anilino-pyrimidines derivative in antitumor drug is prepared
Application.
The purpose of the present invention is achieved through the following technical solutions：
A kind of new 2- anilino-pyrimidines derivative, its side chain contain sulfoxide SO, sulfone SO2, hydroxyl, halogen or methyl mercapto
Functional group, its structural formula is shown in Formulas I or Formula II：
Wherein, R is the amino for having chain or cyclic alkyl substitution on hydrogen atom or nitrogen-atoms；There is chain on the nitrogen-atoms
Shape or the amino of cyclic alkyl substitution preferably-CH2N(CH3)2Or-CH2N(CH2CH3)2；Z is methyl or alkoxy；The alcoxyl
The preferred OCH of base3Or OCD3；
X and Y is sulfoxide structure SO or SOR independent of each other1, sulfone structure SO2Or SO2R1, the nitrogen-atoms, the hydroxyl that are connected with alkyl
Base, halogen or methyl mercapto；The R1It is the alkyl below methyl or four carbon, preferably methyl with alkyl.
Further, when X is sulfoxide structure SO or sulfone structure SO2When, Y is preferably the nitrogen-atoms, hydroxyl, halogen for being connected with alkyl
Element or methyl mercapto；When Y is sulfoxide structure SO or sulfone structure SO2When, X is preferably the nitrogen-atoms for being connected with alkyl.
Further, when X or Y are the nitrogen-atoms for being connected with alkyl, the hydrogen on its alkyl can be its isotope, excellent
Select deuterated methyl CD3。
Further, when X or Y are sulfoxide structure SO, since the both ends of SO are connected with different groups, optics can be produced
Isomers, includes the derivative of chiral isomer, R configurations and S configurations.
The preparation method of above-mentioned new 2- anilino-pyrimidines derivative, comprises the following steps：
(1) intermediate 11 and 12 of commercialization is coupled to obtain intermediate 13 under the effect of lewis acid catalyst alchlor；
(2) under bronsted acid catalyst HCl catalysis, intermediate 13 and the fluoro- 5- nitros of commercialized raw materials 2- methoxyl groups -4-
Aniline reaction obtains intermediate 14；
(3) compound N-methy monoethanolamine substitutes the fluorine atom generation compound in intermediate 14 in the presence of DIPEA
15；
(4) compound 15 and thionyl chloride reaction generation chlorohydrocarbon intermediate 16；
(5) chlorohydrocarbon intermediate 16 reacts to obtain thioether 17 with sodium methyl mercaptide；
(6) under metachloroperbenzoic acid (m-CPBA) effect, thioether 17 is oxidized to sulfoxide 18；
(7) under reducing agent effect, the nitro in sulfoxide 18 is reduced to amino, obtains intermediate 19；
(8) intermediate 19 is reacted with acryloyl chloride, obtains new 2- anilino-pyrimidines derivative, its side chain contains sulfoxide
SO, sulfone SO2, hydroxyl, halogen or methyl mercapto functional group.
The synthetic route of above-mentioned new 2- anilino-pyrimidines derivative, it is as follows by taking the derivative of structural formula 1 as an example：
The new 2- anilino-pyrimidines derivative, it is to tumour cell, particularly to EGFR gene T7900M mutation
Non-small cell lung cancer cell has excellent Inhibit proliferaton effect, and inhibitory activity reaches nanomole level, is significantly better than
The NCH of WO2016070816 and WO2016094821 reports3The derivative that group is substituted by oxygen atom or sulphur atom.It is preferred that side
Chain is sulfoxide structure SO or sulfone structure SO2The 2- anilino-pyrimidine derivatives of functional group.
The present invention also provides the pharmaceutically acceptable salt of above-mentioned new 2- anilino-pyrimidines derivative, i.e., new 2- benzene
Amine pyrimidine derivates and pharmaceutically acceptable anion form corresponding salt, are prepared into using known salifying method
Arrive.
Application of the above-mentioned new 2- anilino-pyrimidines derivative in antitumor drug is prepared, be using this kind of compound as
Active ingredient, effectively treats tumour.
Above-mentioned new 2- anilino-pyrimidines derivative is used in the form of medicinal solvate, and the solvate is excellent
Select hydrate.
The present invention also provides a kind of pharmaceutical composition for being used to treat tumour, wherein above-mentioned new containing therapeutically effective amount
Type 2- anilino-pyrimidines derivative and pharmaceutically acceptable adjuvant.Injection, piece can be made in described pharmaceutical composition
Agent, capsule, pill, the form of suspending agent or emulsion use；Its method of administration can be oral, percutaneous, vein or muscle note
Penetrate.
The present invention has the following advantages that compared with prior art and effect：
(1) present invention introduces sulfoxide SO, sulfone SO in the side chain2, hydroxyl, halogen or methyl mercapto, for improving medicine
Solubility, bioavilability and antitumor activity play the role of good.
(2) present invention tests (the non-small cell lung cancer H1975 of T790M mutation by the antitumor activity on cellular level
Tumour cell) prove, compared with control compound (WO2016094821), antitumor activity has larger compound of the invention
The raising of amplitude.
Embodiment
Further detailed description is done to the present invention with reference to embodiment, but the implementation of the present invention is not limited to this.
Embodiment 1：The synthesis of target product 1 (structural formula 1).
Method in the synthesis reference literature (J.Med.Chem.2014,57,8249-8267) of intermediate 13-16 carries out.
The preparation of intermediate 17：Intermediate 16 (1.0mmol) is dissolved in n,N-Dimethylformamide (DMF) (10mL),
Sodium methyl mercaptide (1.5mmol) and triethylamine (1.5mmol), 50 DEG C of reactions are added dropwise to successively；TLC is monitored after completion of the reaction, will be anti-
Answer system to pour into frozen water, produce a large amount of precipitations.Gained precipitation is filtered out, three times, vacuum drying, obtains intermediate 17 to water washing.
Yield：65%.
The preparation of intermediate 18：Intermediate 17 (1.0mmol) is dissolved in CH2Cl2(10mL), reaction system are down to 0 DEG C, point
Criticize and add m-CPBA (1.0mmol)；TLC is monitored after completion of the reaction, adds saturated sodium bicarbonate solution extraction three times, saturation food
Salt water washing, anhydrous sodium sulfate drying, is removed under reduced pressure solvent and obtains crude product, column chromatography for separation (dichloromethane：Methanol is 10：
1) intermediate 18, is obtained.Yield：67%.
The preparation of intermediate 19：Sodium dithionite (abbreviation sodium hydrosulfite) (5.0mmol) is added to intermediate at room temperature
In the acetone (10mL) and water (6mL) mixed solution of 18 (1.0mmol), 50 DEG C of reactions are warming up to.TLC is monitored after completion of the reaction,
Saturated sodium bicarbonate solution (10mL) is added, ethyl acetate extracts three times.Merge organic phase, saturated common salt water washing, anhydrous sulphur
Sour sodium drying, is removed under reduced pressure solvent and obtains crude product, column chromatography for separation (dichloromethane：Methanol, 10：1) intermediate 19, is obtained.Production
Rate：64%.
The preparation of target product 1：Intermediate 19 (1mmol) is dissolved in CH2Cl2(10mL), reaction system are cooled to 0 DEG C,
Triethylamine (2mmol), acryloyl chloride (1.1mmol) are added dropwise to successively.TLC is monitored after completion of the reaction, adds saturated sodium bicarbonate
Solution extracts three times, saturated common salt water washing, and anhydrous sodium sulfate drying, is removed under reduced pressure solvent and obtains crude product, column chromatography for separation
(dichloromethane：Methanol is 10：1) target product 1, is obtained.Yield：84%.1H NMR(400MHz,Chloroform-d)δ
9.88 (s, 1H), 9.05 (d, J=14.9Hz, 2H), 8.39 (d, J=5.3Hz, 1H), 8.11-8.01 (m, 1H), 7.73 (s,
1H), 7.40 (dd, J=6.9,2.3Hz, 1H), 7.22 (d, J=5.3Hz, 1H), 6.79 (s, 2H), 6.75-6.40 (m, 3H),
5.75 (dd, J=9.8,2.2Hz, 1H), 3.98 (s, 3H), 3.90 (s, 3H), 3.50 (ddd, J=13.7,9.4,4.6Hz,
1H), 3.33 (dt, J=13.4,5.1Hz, 1H), 2.79 (dt, J=13.3,4.9Hz, 1H), 2.72 (s, 3H), 2.57 (s,
3H).MS：[M+H]+=519.2.
Embodiment 2：The synthesis of target product 2 (structural formula 2)
The preparation method of intermediate 20 is the same as intermediate 19, yield：63%.
The preparation of target product 2 is the same as target product 1.Yield：72%.1H NMR(400MHz, Chloroform-d)δ
9.79 (s, 1H), 9.28 (s, 1H), 9.00 (s, 1H), 8.36 (d, J=5.3Hz, 1H), 8.12-7.97 (m, 1H), 7.68 (s,
1H),7.43–7.34(m,1H),7.23–7.15(m,1H), 6.72(s,1H),6.47–6.36(m,2H),5.72–5.60(m,
1H), 3.95 (s, 3H), 3.86 (s, 3H), 3.65 (t, J=5.0Hz, 2H), 2.93 (t, J=5.0Hz, 2H), 2.69 (s,
3H).MS： [M+H]+=473.2.
Embodiment 3：The synthesis of target product 3 (structural formula 3).
The preparation method of intermediate 21 is the same as intermediate 19, yield：65%.
The preparation method of target product 3 is the same as target product 1.Yield：82%.1H NMR(400MHz, Chloroform-d)
δ 9.89 (d, J=3.4Hz, 1H), 9.10 (d, J=22.6Hz, 2H), 8.38 (s, 1H), 8.06 (t, J=5.2Hz, 1H),
7.76 (s, 1H), 7.40 (d, J=8.1Hz, 1H), 7.22 (d, J=4.6 Hz, 1H), 6.76 (d, J=3.5Hz, 1H), 6.52-
6.31 (m, 2H), 5.74 (d, J=9.6Hz, 1H), 3.99 (d, J=3.5Hz, 3H), 3.89 (d, J=3.3Hz, 3H), 3.58
(q, J=4.9Hz, 2H), 3.18 (q, J=5.0Hz, 2H), 2.71 (d, J=3.5Hz, 3H) .MS：[M+H]+=491.2.
Embodiment 4：The synthesis of target product 4 (structural formula 4).
The preparation method of intermediate 22 is the same as intermediate 19.Yield：64%.
The preparation method of target product 4 is the same as target product 1.Yield：80%.1H NMR(400MHz, Chloroform-d)
δ 9.89 (s, 1H), 9.31 (s, 1H), 9.08 (s, 1H), 8.38 (d, J=5.3Hz, 1H), 8.06 (dd, J=6.4,2.5Hz,
1H), 7.74 (s, 1H), 7.46-7.35 (m, 1H), 7.21 (d, J=5.3Hz, 1H), 6.77 (s, 1H), 6.54-6.42 (m,
2H), 5.73 (dd, J=8.4,3.4Hz, 1H), 3.99 (s, 3H), 3.89 (s, 3H), 3.03 (t, J=6.2Hz, 2H), 2.67
(s, 3H), 2.62 (t, J=6.2 Hz, 2H), 2.09 (s, 3H) .MS：[M+H]+=503.2.
Embodiment 5：The synthesis of target product 5 (structural formula 5).
The preparation method of intermediate 23 is the same as intermediate 15, yield：81%；The preparation method of intermediate 24 with intermediate 18,
Yield：62%.The preparation method of intermediate 25 is the same as intermediate 19, yield：67%.
The preparation method of target product 5 is the same as target product 1.Yield：86%.1H NMR(400MHz, Chloroform-d)
δ 9.80 (s, 1H), 8.95 (s, 1H), 8.48 (s, 1H), 8.39 (d, J=5.3Hz, 1H), 8.08 (d, J=7.4Hz, 1H),
7.73 (s, 1H), 7.40 (d, J=7.6Hz, 1H), 7.22 (d, J=5.3Hz, 1H), 6.85 (s, 1H), 6.47-6.27 (m,
2H), 5.79 (d, J=10.0Hz, 1H), 3.98 (s, 3H), 3.90 (s, 3H), 3.69 (t, J=12.3Hz, 2H), 3.09 (d, J
=12.6Hz, 2H), 2.96 (dd, J=11.9,5.9Hz, 4H) .MS：[M+H]+=517.2.
Embodiment 6：The synthesis of target product 6 (structural formula 6).
The preparation method of intermediate 23 is the same as intermediate 15, yield：81%.
The preparation of intermediate 26：Intermediate 23 (1mmol) is dissolved in CH2Cl2(10mL), reaction system are cooled to 0 DEG C, delay
It is slow to add m-CPBA (2mmol).TLC is monitored after completion of the reaction, adds saturated sodium bicarbonate solution extraction three times, saturated common salt
Water washing, anhydrous sodium sulfate drying, is removed under reduced pressure solvent and obtains crude product, column chromatography for separation (dichloromethane：Methanol, 10：1), obtain
To intermediate 26.Yield：67%.
The preparation method of intermediate 27 is the same as intermediate 19, yield：61%.
The preparation method of target product 6 is the same as target product 1, yield：84%.1H NMR(400MHz, Chloroform-d)
δ 9.99 (s, 1H), 8.91 (s, 1H), 8.40 (d, J=5.3Hz, 1H), 8.12-7.97 (m, 1H), 7.80 (s, 1H), 7.42-
7.34 (m, 1H), 7.25 (t, J=4.2Hz, 2H), 6.95 (s, 1H), 6.42-6.28 (m, 2H), 5.73 (dd, J=9.3,
2.3Hz, 1H), 4.57 (t, J=12.1Hz, 2H), 3.97-3.83 (m, 8H), 3.67 (d, J=12.0Hz, 2H), 2.96 (d, J
=14.1Hz, 2H) .MS： [M+H]+=533.1.
Embodiment 7：The synthesis of target product 7 (structural formula 7).
The preparation method of intermediate 28 is the same as intermediate 19, yield：64%.
The preparation method of target product 7 is the same as target product 1.Yield：83%.1H NMR(400MHz, Chloroform-d)
δ 9.81 (s, 1H), 9.00 (s, 1H), 8.65 (s, 1H), 8.38 (d, J=5.3Hz, 1H), 8.11-8.01 (m, 1H), 7.71
(s, 1H), 7.46-7.36 (m, 1H), 7.21 (d, J=5.3Hz, 1H), 6.75 (s, 1H), 6.46-6.29 (m, 2H), 5.78
(dd, J=9.8,1.8Hz, 1H), 3.99 (s, 3H), 3.90 (s, 3H), 3.20-3.02 (m, 4H), 2.85 (s, 4H) .MS：[M+
H]+=501.2.
Embodiment 8：The synthesis of target product 8 (structural formula 8).
The preparation of intermediate 29：Intermediate 14 (1mmol) is dissolved in DMF (10mL) at room temperature, sequentially adds sodium hydride
(2mmol), 2- methylaminos ethyl mercaptan (1.2mmol), rises to 60 DEG C of reactions.TLC is monitored after completion of the reaction, and reaction system is fallen
Enter in frozen water, separate out a large amount of precipitations.Gained precipitation is filtered out, three times, vacuum drying, obtains intermediate 29 to water washing.Yield：
78%.
The preparation of intermediate 30：Intermediate 29 (1mmol) is dissolved in AcOH (10mL), H is slowly added dropwise2O2(3mmol), room
Temperature reaction.TLC is monitored after completion of the reaction, adds water, and dichloromethane extracts three times, and saturated common salt water washing, anhydrous sodium sulfate is done
It is dry, solvent is removed under reduced pressure and obtains crude product, column chromatography for separation (dichloromethane：Methanol, 10：1) intermediate 30, is obtained.Yield：
67%.
The preparation of intermediate 31：Preparation method is the same as intermediate 19, yield：84%.
The preparation of target product 8：Preparation method is the same as target product 1, yield：84%.1H NMR(400MHz,
Chloroform-d) δ 10.43 (s, 1H), 9.74 (s, 1H), 8.85 (s, 1H), 8.42 (d, J=5.3Hz, 1H), 8.15-
8.02 (m, 1H), 7.95 (s, 1H), 7.47-7.32 (m, 2H), 7.09 (s, 1H), 6.45 (dd, J=17.1,1.4Hz, 1H),
6.26 (dd, J=17.0,10.3Hz, 1H), 5.78 (dd, J=10.2,1.4Hz, 1H), 3.97 (s, 3H), 3.95 (d, J=
7.1Hz, 3H), 3.51 (ddd, J=13.0,9.1,5.7 Hz, 1H), 3.00 (dt, J=13.0,5.2Hz, 1H), 2.57 (dt, J
=12.9,5.3Hz, 1H), 2.44 (ddd, J=13.4,9.2,5.7Hz, 1H), 2.30 (s, 6H) .MS：[M+H] +=519.2.
Reference examples 1：Comparison 1 (structural formula 9) is synthesized according to patent WO2016094821
The preparation of intermediate 32：Preparation method is the same as intermediate 19, yield：64%.
The preparation of target product 9：Preparation method is the same as target product 1.Yield：84%.1H NMR(400MHz,
Chloroform-d) δ 10.22 (s, 1H), 9.77 (s, 1H), 8.99 (s, 1H), 8.41 (d, J=4.6Hz, 1H), 8.15-
8.01 (m, 1H), 7.86 (s, 1H), 7.40 (d, J=7.9Hz, 1H), 7.24 (d, J=3.7 Hz, 1H), 7.09 (d, J=
3.1Hz, 1H), 6.51-6.28 (m, 2H), 5.76 (d, J=10.1Hz, 1H), 4.00 (d, J=2.9Hz, 3H), 3.97-3.88
(m, 3H), 2.85 (dt, J=7.9,4.7Hz, 2H), 2.32 (q, J=5.3,4.9Hz, 2H), 2.27-2.15 (m, 6H) .MS：
[M+H]+=503.2.
Test case：The antitumor activity of new 2- anilino-pyrimidines derivative：
Tested for the Anti-tumor angiogenesis of the new 2- anilino-pyrimidines derivative of the present invention, we select non-
Small cell lung cancer cell H1975 and cell Pc9 has carried out the assessment of mtt assay anti-tumour cell proliferative activity.Concrete operation step
It is as follows：Tumour cell is seeded in 96 well culture plates by certain cell concentration, cell density 5*103-10*103A/hole,
After being stayed overnight in 37 DEG C, the incubator that gas concentration lwevel is 5%, test compound sample is added.Cultivate 72 it is small when after, add
Enter MTT continue 4 it is small when, add DMSO dissolving, shake, be then detected under microplate reader (570nm).Above-claimed cpd pair
The half-inhibition concentration IC of non-small cell lung cancer cell H1975 and cell Pc950Value is as shown in table 1.
The experiment display of above-mentioned Anti-tumor angiogenesis, with prior art west difficult to understand for Buddhist nun (Osimertinib, AZD9291),
Patent WO2016094821 synthesis comparisons 1 (structural formula 9) are compared, the new 2- anilino-s for the structural formula 1-8 that the present invention designs
Pyrimidine derivatives have the cell proliferation of NSCLC effect of good suppression EGFR gene T7900M mutation.Wherein, tie
The activity of the anti-T7900M mutation of the compound of structure formula 8 is not only significantly better than thioether type in patent document WO2016094821
Austria west replace Buddhist nun's derivative (structural formula 9), for the H1975 of the T7900M mutation of the double mutation of T7900M, also show that than sun
Property medicine west difficult to understand for the slightly excellent effect of Buddhist nun, there is the prospect of further patent medicine Journal of Sex Research.
Claims (9)
- A kind of 1. new 2- anilino-pyrimidines derivative, it is characterised in that：Its side chain contains sulfoxide SO, sulfone SO2, hydroxyl, halogen or Methyl mercapto functional group, its structural formula is shown in Formulas I or Formula II：Wherein, R is the amino for having chain or cyclic alkyl substitution on hydrogen atom or nitrogen-atoms；Z is methyl or alkoxy；X and Y is sulfoxide structure SO or SOR independent of each other1, sulfone structure SO2Or SO2R1, the nitrogen-atoms, hydroxyl, the halogen that are connected with alkyl Element or methyl mercapto；The R1It is the alkyl below methyl or four carbon with alkyl.
- 2. new 2- anilino-pyrimidines derivative according to claim 1, it is characterised in that：When X be sulfoxide structure SO or Sulfone structure SO2When, Y is nitrogen-atoms, hydroxyl, halogen or the methyl mercapto for being connected with alkyl；When Y is sulfoxide structure SO or sulfone structure SO2 When, X is the nitrogen-atoms for being connected with alkyl.
- 3. new 2- anilino-pyrimidines derivative according to claim 1, it is characterised in that：When X or Y are connected with alkyl During nitrogen-atoms, the alkyl is deuterated methyl CD3。
- 4. new 2- anilino-pyrimidines derivative according to claim 1, it is characterised in that：When X or Y are sulfoxide structure SO When, since the both ends of SO are connected with different groups, optical isomer can be produced, including chiral isomer, R configurations and S configurations Derivative.
- 5. new 2- anilino-pyrimidines derivative according to claim 1, it is characterised in that：Its side chain contains sulfoxide structure SO or sulfone structure SO2Functional group.
- A kind of 6. pharmaceutically acceptable salt of the new 2- anilino-pyrimidines derivative described in claim 1, it is characterised in that： New 2- anilino-pyrimidines derivative and pharmaceutically acceptable anion form corresponding salt, using known salifying method It is prepared.
- 7. application of the new 2- anilino-pyrimidines derivative in antitumor drug is prepared described in a kind of claim 1, it is special Sign is：It is using new 2- anilino-pyrimidines derivative as active ingredient.
- 8. application of the new 2- anilino-pyrimidines derivative according to claim 7 in antitumor drug is prepared, it is special Sign is：New 2- anilino-pyrimidines derivative is used in the form of medicinal solvate.
- A kind of 9. pharmaceutical composition for being used to treat tumour, it is characterised in that：Wherein containing therapeutically effective amount claim 1 institute The new 2- anilino-pyrimidines derivative stated and pharmaceutically acceptable adjuvant.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711213902.3A CN107935995A (en) | 2017-11-28 | 2017-11-28 | A kind of new 2 anilino-pyrimidine derivative and its application in antitumor drug is prepared |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711213902.3A CN107935995A (en) | 2017-11-28 | 2017-11-28 | A kind of new 2 anilino-pyrimidine derivative and its application in antitumor drug is prepared |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107935995A true CN107935995A (en) | 2018-04-20 |
Family
ID=61950266
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711213902.3A Pending CN107935995A (en) | 2017-11-28 | 2017-11-28 | A kind of new 2 anilino-pyrimidine derivative and its application in antitumor drug is prepared |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107935995A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112592318A (en) * | 2020-12-12 | 2021-04-02 | 贵州医科大学 | 2- (4-methionyl) anilino-4-aminopyrimidine derivatives and application thereof |
| AU2020255100A8 (en) * | 2019-03-29 | 2021-12-02 | Shenzhen Forward Pharmaceuticals Co., Ltd. | N-heteroaromatic amide derivatives for treatment of cancer |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016070816A1 (en) * | 2014-11-05 | 2016-05-12 | 上海页岩科技有限公司 | Pyrimidine or pyridine compounds, preparation method therefor and pharmaceutical uses thereof |
| WO2016094821A2 (en) * | 2014-12-11 | 2016-06-16 | Beta Pharma, Inc. | Substituted 2-anilinopyrimidine derivatives as egfr modulators |
| CN107793413A (en) * | 2016-09-05 | 2018-03-13 | 天津滨江药物研发有限公司 | Pyrimidine heterocyclic compound and its preparation method and application |
-
2017
- 2017-11-28 CN CN201711213902.3A patent/CN107935995A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016070816A1 (en) * | 2014-11-05 | 2016-05-12 | 上海页岩科技有限公司 | Pyrimidine or pyridine compounds, preparation method therefor and pharmaceutical uses thereof |
| WO2016094821A2 (en) * | 2014-12-11 | 2016-06-16 | Beta Pharma, Inc. | Substituted 2-anilinopyrimidine derivatives as egfr modulators |
| CN107793413A (en) * | 2016-09-05 | 2018-03-13 | 天津滨江药物研发有限公司 | Pyrimidine heterocyclic compound and its preparation method and application |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2020255100A8 (en) * | 2019-03-29 | 2021-12-02 | Shenzhen Forward Pharmaceuticals Co., Ltd. | N-heteroaromatic amide derivatives for treatment of cancer |
| AU2020255100B2 (en) * | 2019-03-29 | 2022-11-24 | Shenzhen Forward Pharmaceuticals Co., Ltd. | N-heteroaromatic amide derivatives for treatment of cancer |
| AU2020255100C1 (en) * | 2019-03-29 | 2023-02-23 | Shenzhen Forward Pharmaceuticals Co., Ltd. | N-heteroaromatic amide derivatives for treatment of cancer |
| CN112592318A (en) * | 2020-12-12 | 2021-04-02 | 贵州医科大学 | 2- (4-methionyl) anilino-4-aminopyrimidine derivatives and application thereof |
| CN112592318B (en) * | 2020-12-12 | 2022-05-03 | 贵州医科大学 | 2- (4-methionyl) anilino-4-aminopyrimidine derivatives and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3216786B1 (en) | Pyrimidine compounds, preparation method therefor and pharmaceutical uses thereof | |
| US8822482B2 (en) | Icotinib hydrochloride, synthesis, crystalline forms, pharmaceutical compositions, and uses thereof | |
| CN105985342B (en) | As the pyrimido-pyrimidine derovatives of EGFR inhibitor and its application | |
| CN107245075B (en) | 2,4, 6-trisubstituted pyrido [3,4-d ] pyrimidine compound and salt and application thereof | |
| CN107922348A (en) | Bicyclic heterocycle amide derivatives | |
| JP7036939B2 (en) | A novel pyrimidine derivative showing a growth inhibitory effect on cancer cells and a pharmaceutical composition containing the same. | |
| CN110483485A (en) | Pyrimidines, preparation method and medical usage | |
| CN105705493A (en) | Quinazoline derivative, preparation method therefor, and pharmaceutical composition and application thereof | |
| CN113825754A (en) | Selective BCL-2 inhibitors of disubstituted sulfonamides including methyl and trifluoromethyl | |
| CN105153026B (en) | Sorafenib derivative of the amide structure containing biaryl and its preparation method and application | |
| CN107935995A (en) | A kind of new 2 anilino-pyrimidine derivative and its application in antitumor drug is prepared | |
| CN108558865B (en) | Derivative taking pyrido [2,3-d ] pyrimidine structure as mother nucleus, and preparation method and application thereof | |
| CN107129506B (en) | As pyrimido [4,5-d] [1,3] oxazines -2- ketone derivatives of EGFR inhibitor and its application | |
| CN106243044A (en) | Pyridine derivatives containing halo acrylamide side chain and preparation and application | |
| CN106892922B (en) | As the 5,8- dihydropteridine -6,7- derovatives of EGFR inhibitor and its application | |
| CN110283162B (en) | Epidermal growth factor receptor inhibitor and application thereof | |
| CN105017162B (en) | 4 pairs of propenylbenzene amido quinazoline derivatives and its application in antineoplastic is prepared | |
| CN109988110A (en) | 4- phenoxyquinolines and sulfonyl urea compound, the intermediate for synthesizing the compound and its preparation method and application | |
| CN111718325A (en) | 2,4, 5-substituted pyrimidine compound and preparation method and application thereof | |
| TWI535724B (en) | New polymorphic forms of icotinib phosphate and uses thereof | |
| CN107513040A (en) | Substitute the preparation of benzo pyridine compound and the application of molecular targeted anti-tumor medicine | |
| CN107235994B (en) | Simultaneously [3,2-a] pyrimidine -3- acetamide derivative and the application of 5,7- diphenyl -5H- thiazole | |
| CN104402875A (en) | Synthesis method and application N-(2-aminoethyl)-N'-(6-substituted-2-benzothiazolyl)urea and salt compounds thereof | |
| CN107501283B (en) | Preparation of substituted arylmethyl hetero-substituted anilino ethylene glycol ether cycloquinazoline and application of tumor treatment drug | |
| CN105001167A (en) | 1-substituted phenyl-3-(4-substituted phenyl amino-6-quinazolinyl)urea compounds and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180420 |
|
| WD01 | Invention patent application deemed withdrawn after publication |