CN112174940A - 3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基-1h-三氮唑衍生物 - Google Patents
3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基-1h-三氮唑衍生物 Download PDFInfo
- Publication number
- CN112174940A CN112174940A CN201910605992.3A CN201910605992A CN112174940A CN 112174940 A CN112174940 A CN 112174940A CN 201910605992 A CN201910605992 A CN 201910605992A CN 112174940 A CN112174940 A CN 112174940A
- Authority
- CN
- China
- Prior art keywords
- group
- compound
- alkyl
- pharmaceutically acceptable
- reaction
- 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
- -1 3- (6, 7-bis (2-methoxyethoxy) -quinazoline-4-amido) phenyl-1H-triazole derivative Chemical class 0.000 title claims abstract description 49
- 150000001875 compounds Chemical class 0.000 claims abstract description 93
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 201000010099 disease Diseases 0.000 claims abstract description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
- 230000002159 abnormal effect Effects 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 230000000694 effects Effects 0.000 claims description 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 11
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 102000001301 EGF receptor Human genes 0.000 claims description 10
- 108060006698 EGF receptor Proteins 0.000 claims description 10
- 239000012453 solvate Substances 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 230000005764 inhibitory process Effects 0.000 claims description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 230000003287 optical effect Effects 0.000 claims description 7
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- 238000000338 in vitro Methods 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- 230000004614 tumor growth Effects 0.000 claims description 4
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 3
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 3
- 206010020651 Hyperkinesia Diseases 0.000 claims description 3
- 208000000269 Hyperkinesis Diseases 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 230000004663 cell proliferation Effects 0.000 claims description 3
- 229940121647 egfr inhibitor Drugs 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 230000004660 morphological change Effects 0.000 claims description 3
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 230000004565 tumor cell growth Effects 0.000 claims description 3
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 claims description 3
- 239000005483 tyrosine kinase inhibitor Substances 0.000 claims description 3
- 230000002491 angiogenic effect Effects 0.000 claims description 2
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 2
- 230000002018 overexpression Effects 0.000 claims description 2
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 claims description 2
- 208000013403 hyperactivity Diseases 0.000 claims 1
- 239000003981 vehicle Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 24
- 239000003112 inhibitor Substances 0.000 abstract description 5
- 210000004881 tumor cell Anatomy 0.000 abstract description 4
- 230000035755 proliferation Effects 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 59
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000007864 aqueous solution Substances 0.000 description 32
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 32
- 210000004027 cell Anatomy 0.000 description 28
- 235000010378 sodium ascorbate Nutrition 0.000 description 23
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 23
- 229960005055 sodium ascorbate Drugs 0.000 description 23
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 23
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 21
- 239000007787 solid Substances 0.000 description 21
- 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 20
- 229960001433 erlotinib Drugs 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 20
- 239000000243 solution Substances 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000003814 drug Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 11
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 11
- 229910005143 FSO2 Inorganic materials 0.000 description 10
- 206010028980 Neoplasm Diseases 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 10
- GTTBEUCJPZQMDZ-UHFFFAOYSA-N erlotinib hydrochloride Chemical compound [H+].[Cl-].C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 GTTBEUCJPZQMDZ-UHFFFAOYSA-N 0.000 description 10
- 238000010791 quenching Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000012295 chemical reaction liquid Substances 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
- 235000015497 potassium bicarbonate Nutrition 0.000 description 7
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 7
- 239000011736 potassium bicarbonate Substances 0.000 description 7
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 7
- 230000004083 survival effect Effects 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 125000004185 ester group Chemical group 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 150000004923 Erlotinib derivatives Chemical class 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- 201000001320 Atherosclerosis Diseases 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- 206010027476 Metastases Diseases 0.000 description 3
- 208000008589 Obesity Diseases 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000001464 adherent effect Effects 0.000 description 3
- 230000003698 anagen phase Effects 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 208000030159 metabolic disease Diseases 0.000 description 3
- 230000009401 metastasis Effects 0.000 description 3
- 235000020824 obesity Nutrition 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- KPRZOPQOBJRYSW-UHFFFAOYSA-N 2-(aminomethyl)phenol Chemical compound NCC1=CC=CC=C1O KPRZOPQOBJRYSW-UHFFFAOYSA-N 0.000 description 2
- JNZYADHPGVZMQK-UHFFFAOYSA-N 3-(aminomethyl)phenol Chemical compound NCC1=CC=CC(O)=C1 JNZYADHPGVZMQK-UHFFFAOYSA-N 0.000 description 2
- FITYFYMINUEMHW-UHFFFAOYSA-N 6,7-bis(2-methoxyethoxy)quinazolin-4-amine Chemical compound C1=NC(N)=C2C=C(OCCOC)C(OCCOC)=CC2=N1 FITYFYMINUEMHW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 241000662429 Fenerbahce Species 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 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
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 239000005935 Sulfuryl fluoride Substances 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-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
- 239000007983 Tris buffer Substances 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 2
- 150000008052 alkyl sulfonates Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- 229940077388 benzenesulfonate Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229910000365 copper sulfate Inorganic materials 0.000 description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- BDIBYQORZHGDIR-UHFFFAOYSA-N fluorosulfonyloxybenzene Chemical compound FS(=O)(=O)OC1=CC=CC=C1 BDIBYQORZHGDIR-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 230000000155 isotopic effect Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 125000004492 methyl ester group Chemical group 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- OBTWBSRJZRCYQV-UHFFFAOYSA-N sulfuryl difluoride Chemical compound FS(F)(=O)=O OBTWBSRJZRCYQV-UHFFFAOYSA-N 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- LOPKSXMQWBYUOI-IUCAKERBSA-N (1s,2s)-1-amino-2,3-dihydro-1h-inden-2-ol Chemical compound C1=CC=C2[C@H](N)[C@@H](O)CC2=C1 LOPKSXMQWBYUOI-IUCAKERBSA-N 0.000 description 1
- AUAKXRGQXZRTQC-MRVPVSSYSA-N (3r)-3-amino-1,3,4,5-tetrahydro-1-benzazepin-2-one Chemical compound N1C(=O)[C@H](N)CCC2=CC=CC=C21 AUAKXRGQXZRTQC-MRVPVSSYSA-N 0.000 description 1
- RPGDVPAENGWKAO-UHFFFAOYSA-N 2,4-difluoro-n-methylaniline Chemical compound CNC1=CC=C(F)C=C1F RPGDVPAENGWKAO-UHFFFAOYSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- SKMKJBYBPYBDMN-RYUDHWBXSA-N 3-(difluoromethoxy)-5-[2-(3,3-difluoropyrrolidin-1-yl)-6-[(1s,4s)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine Chemical compound C1=C(OC(F)F)C(N)=NC=C1C1=CC(N2[C@H]3C[C@H](OC3)C2)=NC(N2CC(F)(F)CC2)=N1 SKMKJBYBPYBDMN-RYUDHWBXSA-N 0.000 description 1
- AUAKXRGQXZRTQC-UHFFFAOYSA-N 3-amino-1,3,4,5-tetrahydro-1-benzazepin-2-one Chemical compound N1C(=O)C(N)CCC2=CC=CC=C21 AUAKXRGQXZRTQC-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 208000030808 Clear cell renal carcinoma Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 241000282412 Homo Species 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
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical group CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 229940100514 Syk tyrosine kinase inhibitor Drugs 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical group [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005256 alkoxyacyl group Chemical group 0.000 description 1
- 150000008055 alkyl aryl sulfonates Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 125000005228 aryl sulfonate group Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 125000004431 deuterium atom Chemical group 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229950007440 icotinib Drugs 0.000 description 1
- QQLKULDARVNMAL-UHFFFAOYSA-N icotinib Chemical compound C#CC1=CC=CC(NC=2C3=CC=4OCCOCCOCCOC=4C=C3N=CN=2)=C1 QQLKULDARVNMAL-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement 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
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 125000005254 oxyacyl group Chemical group 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940120982 tarceva Drugs 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- TVJWTRPGFVNAJI-UHFFFAOYSA-N tert-butyl 4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1N1N=CC(N)=C1 TVJWTRPGFVNAJI-UHFFFAOYSA-N 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Images
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
- C07D403/12—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 linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- C07D403/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/86—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with only atoms other than nitrogen atoms directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/865—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with only atoms other than nitrogen atoms directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/58—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3 with a nitrogen atom, which is a member of a hetero ring, attached in position 7
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/056—Triazole or tetrazole radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了3‑(6,7‑双(2‑甲氧乙氧基)‑喹唑啉‑4‑胺基)苯基‑1H‑三氮唑衍生物,及其制备和用途,具体地,本发明提供了一种如式I所示的化合物。本发明化合物可以作为肿瘤细胞抑制剂,用于制备治疗与肿瘤细胞异常增殖相关的疾病的药物组合物。
Description
技术领域
本发明涉及医药化合物领域,具体地,本申请涉及一种3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基-1H-1,2,3-三氮唑衍生物,其制备方法,以及其治疗用途。
背景技术
癌症是严重危害人类健康的常见病、多发病。一直以来,临床上常用的癌症化疗药物主要是细胞毒性药物,这类抗癌药具有选择性差、毒副作用强、易产生耐药性等缺点。近年来,随着对肿瘤生物学特性的进一步认识,发现了几种新的抗肿瘤靶点,其中酪氨酸激酶已经成为目前开发新一代抗肿瘤药物的重要靶点。酪氨酸激酶是细胞信号传导通路的关键蛋白质,蛋白酪氨酸激酶可分为受体型和非受体型。受体酪氨酸激酶都是由含有配体结合位点的细胞外结合域、单次跨膜的疏水α螺旋区、含有酪氨酸蛋白激酶活性的细胞内结构域这三部分组成。当配体与细胞外结合域结合后,将生长因子信号从细胞外传入细胞内,这一过程控制着细胞的许多生理功能如细胞生长、血管生成以及凋亡抑制等。在恶性肿瘤中,该信号通路与肿瘤的生长及转移关系密切。
抗肿瘤靶向药物厄洛替尼(Erlotinib,TarcevaTM,特罗凯,埃罗替尼)通过抑制EGFR-1的酪氨酸激酶活性而阻止该受体介导的细胞内信号传导途径,由此阻止肿瘤细胞生长并最终呈现抗肿瘤作用。然而,现有化合物的性能仍存在进一步提高的空间。
发明内容
本发明的目的是提供一种活性改善的厄洛替尼类似物,及其制备方法和用途。
本发明的第一方面,提供了一种如下式I所示的化合物,或其药学上可接受的盐、水合物或光学异构体,
其中,R选自下组:-(L)n-C1-C6烷基、-(L)n-C6-C10芳基、-(L)n-C3-C8硅烷基、-(CR'2)n-(具有1-3个选自N、S和O的杂原子的5-12元杂芳基)、-(CR'2)n-(5-12元碳环基)、-(CR'2)n-(具有1-3个选自N、S和O的杂原子的5-12元杂环基);上述的烷基、芳基、杂芳基、杂环基可为取代或未取代的;且R不为选自下组的基团:取代或未取代的苯基;
R1、R2各自独立地为选自下组的基团:C1-C6的烷基,或R1与R2共同构成-CH2-CH2-;
各个L各自独立地选自下组:(CR'2)m、取代或未取代的5-8元杂环、-C(O)-O-、-NH-C(O)-O-、-NH-C(O)-、-O-、-S-;
各个R'各自独立地选自下组:H、卤素、C1-C6烷基、C1-C6烷氧基、氧代(=O)、-NO2、-CN、-OH、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基;
n选自下组:0、1、2、3、4或5;
m选自下组:1、2、3、4或5;
所述的取代基选自下组:卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷基-OH、C1-C6烷氧基、C1-C6卤代烷氧基、C1-C6烷胺基、-C(O)NH2、氧代(=O)、-NO2、-CN、-OH、C6-C10芳基、-S(O)2-CH3、-COOH、C2-C10酰基(即C1-C9烷基-C(O)-)、C2-C10酯基(即C1-C9烷基-O-C(O)-)、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、
在另一优选例中,R1、R2各自独立地为甲基。
在另一优选例中,所述的R不为苄基。
在另一优选例中,所述的R不为未取代的苄基。
在另一优选例中,所述的各个L各自独立地选自下组:(CR'2)m。
在另一优选例中,所述的R为取代的-((CR'2)m)n-苯基。
在另一优选例中,所述的R选自下组:
在另一优选例中,所述的R为化合物1-288中的对应基团。
在另一优选例中,所述的m选自下组:1或2。
在另一优选例中,所述的化合物选自实施例化合物1-288。
在另一优选例中,所述的化合物选自下表:
本发明的第二方面,提供了一种药物组合物,所述的药物组合物包括:治疗有效量的如本发明第一方面所述的式(I)化合物,或其药学上可接受的盐、水合物、光学异构体中的一种或多种,以及任选的药学上可接受的载体。
在另一优选例中,所述的药物组合物用于治疗与酪氨酸激酶过表达和/或酪氨酸激酶活性过高相关的疾病。
本发明的第三方面,提供了一种EGFR抑制剂,所述的抑制剂含有抑制有效量的如本发明第一方面中所述的式I化合物,或其药学上可接受的盐、互变异构体、光学异构体、药学上可接受的溶剂合物中的一种或多种,以及任选的药学上可接受的载体、赋形剂、佐剂、辅料和/或稀释剂。
在另一优选例中,所述药学上可接受的盐是式I化合物的选自下组的盐:无机酸盐、有机酸盐、烷基磺酸盐、芳基磺酸盐,或其组合;较佳地,所述的盐选自下组:盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、磷酸盐、甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、甲基磺酸盐、乙基磺酸盐、苯磺酸盐、对甲苯磺酸盐,或其组合。
本发明的第四方面,提供了如本发明第一方面所述的式(I)化合物的用途,其用于选自下组的一个或多个用途:
(a)制备酪氨酸激酶抑制剂;
(b)用于体外非治疗性地抑制酪氨酸激酶的活性;
(c)用于体外非治疗性地抑制肿瘤细胞生长。
在另一优选例中,所述的表皮生长因子受体活性相关的疾病选自下组:细胞异常增殖、形态变化、运动功能亢进、血管新生疾病、肿瘤生长、肿瘤转移疾病,或其组合。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1为实施例3中MTT法测量19个化合物对A549细胞抑制率和IC50结果。
具体实施方式
本发明人经过长期而深入的研究,意外地发现,对于现有的肿瘤靶向治疗药物厄洛替尼进行三氮唑修饰后,化合物活性有明显提高。基于上述发现,发明人完成了本发明。
术语
在本发明中,所述的烷基包括直链或支链的烷基,所述的卤素为F、Cl、Br或I,优选为F或Br。
特别地,在本文中,除非特别说明,所提到的原子包括其所有同位素的形式,例如,当提到“氢原子”时,指氢原子、氘原子、氚原子或其组合。在本发明中,某元素各种同位素原子的丰度可以是该元素在自然界中天然存在的状态,也可以是某种同位素富集的状态。
术语“C1~C6烷基”指具有1~6个碳原子的直链或支链烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
特别地,除非特别说明,在本发明中,当未限定基团的碳原子个数时,指具有1-10个碳原子,优选1-4个碳原子的基团。
术语“5~7元杂环”指具有5~7个碳原子或杂原子(选自N、O、S)的杂环基,可以是饱和或部分未饱和的环状基团,例如四氢吡咯基、六氢吡啶基,或类似基团。
术语“C1~C6烷氧基”指具有1-4个碳原子的直链或支链烷氧基,例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、或类似基团。
术语“烷基酰基”指具有“-CO-烷基”结构的基团,例如甲基酰基、乙基酰基、丙基酰基、异丙基酰基、丁基酰基、异丁基酰基、仲丁基酰基、叔丁基酰基、或类似基团。
术语“酯基”或“氧基-酰基”可以互换使用,指具有“-O-CO-烷基”结构的基团,例如甲酯基、乙酯基、丙酯基、异丙酯基、丁酯基、异丁酯基、仲丁酯基、叔丁酯基、或类似基团。
术语“烷基酯基”或“烷氧基酰基”可以互换使用,均指具有“烷基-O-CO-烷基”结构的基团,例如甲基甲酯基、乙基甲酯基、丙基乙酯基、异丙基甲酯基、或类似基团。
术语“药学上可接受的溶剂合物”指相应的化合物与水、乙醇、异丙醇、乙醚、丙酮的溶剂合物。
在本发明中,“治疗有效量”是指能够在所需的对象中达到所需的治疗效果,但不会造成过度的负面影响的剂量。在本发明的化合物结构被公开后,上述剂量通常可以由本领域技术人员根据实际需要确定。
式I化合物
本发明提供了一类如下式I所示的化合物:
其中,R选自下组:-(L)n-C1-C6烷基、-(L)n-C6-C10芳基、-(L)n-C3-C8硅烷基、-(CR'2)n-(具有1-3个选自N、S和O的杂原子的5-12元杂芳基)、-(CR'2)n-(5-12元碳环基)、-(CR'2)n-(具有1-3个选自N、S和O的杂原子的5-12元杂环基);上述的烷基、芳基、杂芳基、杂环基可为取代或未取代的;且R不为选自下组的基团:取代或未取代的苯基;
R1、R2各自独立地为选自下组的基团:C1-C6的烷基,或R1与R2共同构成-CH2-CH2-;
各个L各自独立地选自下组:(CR'2)m、取代或未取代的5-8元杂环、-C(O)-O-、-NH-C(O)-O-、-NH-C(O)-、-O-、-S-;
各个R'各自独立地选自下组:H、卤素、C1-C6烷基、C1-C6烷氧基、氧代(=O)、-NO2、-CN、-OH、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基;
n选自下组:0、1、2、3、4或5;
m选自下组:1、2、3、4或5;
所述的取代基选自下组:卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷基-OH、C1-C6烷氧基、C1-C6卤代烷氧基、C1-C6烷胺基、-C(O)NH2、氧代(=O)、-NO2、-CN、-OH、C6-C10芳基、-S(O)2-CH3、-COOH、C2-C10酰基(即C1-C9烷基-C(O)-)、C2-C10酯基(即C1-C9烷基-O-C(O)-)、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、
在另一优选例中,所述的R为实施例中各个化合物所对应的基团。
式I化合物的合成方法
式I化合物可以通过本领域常规的方法,例如,通过反合成分析法进行制备,在本发明公开了式I化合物的结构后,上述制备方法是在本领域技术人员的能力范围之内的。
一种示例性的制备方法如下式所示,采用厄洛替尼与对应的叠氮化合物R-N3作为原料:
优选地,该反应在硫酸铜,三[(1-(3-羟丙基)-1H-1,2,3-三唑-4-基)]甲基]胺与抗坏血酸钠存在下(优选地在室温下)进行。
药学上可接受的盐和溶剂合物
本发明化合物的药用形式可包括化合物本身,以及药学上可接受的其他变化形式,如光学异构体,顺反异构体等,或者药学上可接受的盐或溶剂合物。
优选地,所述的药学上可接受的盐包括(但并不限于):无机酸盐,如盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、磷酸盐等;有机酸盐,如甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐等;烷基磺酸盐,如甲基磺酸盐、乙基磺酸盐等;芳基磺酸盐,如苯磺酸盐、对甲苯磺酸盐等。
优选地,所述的药学上可接受的溶剂合物包括(但并不限于):所述的化合物与水、乙醇、异丙醇、乙醚、丙酮等的溶剂合物。
式I化合物的用途
经研究,本发明所述的式I化合物具有表皮生长因子受体(EGFR)的抑制活性,因此,本发明所述的式I化合物或所述衍生物的互变异构体、外消旋体、对映异构体、非对映异构体、药学上可接受的盐、药学上可接受的溶剂合物中的任意一种或几种的混合物,可应用于制备酪氨酸激酶抑制剂,尤其可应用于制备EGFR抑制剂。
同时,所述的抑制剂可应用于制备预防或治疗与EGFR相关疾病的药物。具体说,可应用于制备预防或治疗与EGFR相关的细胞异常增殖、形态变化、运动功能亢进、血管新生及肿瘤转移疾病的药物。
另外,所述的抑制剂可应用于制备治疗或预防与表皮生长因子受体EGFR相关的肿瘤生长和转移的药物。
本申请所述抑制剂的活性成分优选为本发明中所示的具体化合物,或所示化合物的互变异构体、外消旋体、对映异构体、非对映异构体、药学上可接受的盐、药学上可接受的溶剂合物中的任意一种或几种的混合物。
药物组合物及其用途
本发明的另一方面提供了一种药物组合物,其含有治疗有效量的选自上述通式(Ⅰ)的化合物、其可药用的盐、对映异构体、非对映异构体或外消旋体中的一种或多种,以及任选地,一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。所述辅料例如为气味剂、香味剂、甜味剂等。
本发明所提供的药物组合物优选含有重量比为1-99%的活性成份,其优选的比例是,通式I化合物作为活性成分占总重量的65wt%~99wt%,其余部分为药学可接受的载体、稀释液或溶液或盐溶液。
本发明所提供的化合物和药物组合物可以是多种形式,如片剂、胶囊、粉剂、糖浆、溶液状、悬浮液和气雾剂等,并可以存在于适宜的固体或液体的载体或稀释液中和适宜的用于注射或滴注的消毒器具中。
本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。其制剂配方的单位计量中包含0.05-200mg通式I化合物,优选地,制剂配方的单位计量中包含0.1mg-100mg通式I化合物。
本发明的化合物和药物组合物可对哺乳动物临床使用,包括人和动物,可以通过口、鼻、皮肤、肺或者胃肠道等的给药途径。最优选为口服。最优选日剂量为0.01-200mg/kg体重,一次性服用,或0.01-100mg/kg体重分次服用。不管用何种服用方法,个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始,逐渐增加剂量一直到找到最适合的剂量。
本发明的又一方面提供了一种肿瘤靶向抑制剂,其包含选自上述通式I所示的化合物、其可药用的盐、异构体或它们的混合物中的一种或多种,以及任选地一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。
在一些实施例,本发明的化合物和组合物用于治疗和预防与EGFR相关的代谢系统疾病,所述疾病包括,但不限于糖尿病、动脉粥样硬化、肥胖症等疾病。
因此,本发明的又一方面提供了上述通式I所示的化合物、其可药用的盐、异构体或它们的混合物在制备用于治疗与EGFR活性相关的代谢系统疾病,例如:糖尿病、动脉粥样硬化、肥胖症等疾病中的药物用途。
本发明的又一个方面提供了一种治疗与EGFR活性或表达量相关的代谢系统疾病,例如:糖尿病、动脉粥样硬化、肥胖症等疾病的方法,其包括向需要该治疗的患者给药选自上述通式I所示的化合物、其可药用的盐、异构体或它们的混合物中的一种或多种。
与现有技术相比,本发明的主要优点包括:
(1)提供了一类结构新颖的肿瘤靶向抑制活性化合物,与现有的近似化合物相比,本发明的化合物具有更低的肿瘤细胞抑制浓度。
(2)与现有化合物相比,本发明的部分化合物对于一些肿瘤株系的选择性提高。
(3)本发明的化合物具有与现有化合物不同的物理性质(如水溶性等),因此能够制备得到与现有化合物不同的剂型。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
实验仪器:
1H NMR谱用Agilent-400(400MHz)型核磁共振仪测定,1H NMR的内标为TMS(δ0.00)或CDCl3(δ7.26)。
LC-MS(ESI)谱用Waters ACQUITY UPLC H-Class系统和ACQUITY QDa质谱检测器测定(洗脱剂:0.1%的三氟乙酸水溶液和乙腈)。[方法:7000psi,flow rate=0.6ml/min.t=0min,95%H2O;t=0.10min,95%H2O;t=1.20min,5%H2O;t=2.00min,5%H2O;t=2.50min,95%H2O.Total aquisition time=2.50min.]实施例中所示谱图为紫外吸收色谱,其对应质谱未展示。色谱的横轴为时间(单位min),纵轴为吸收强度。色谱右上角三位数数字为所选取的紫外波长(单位nm)。
柱层析使用烟台江友硅胶开发有限公司生产的硅胶(300-400目或100-200目),薄层层析板用烟台江友硅胶开发有限公司生产的薄层层析板,显色工具有ZF-7A手提紫外检测仪、碘缸、碱性高锰酸钾溶液。
所用试剂购自武汉药明览博化学科技有限公司,上海阿拉丁生化科技股份有限公司(Aladdin),梯希爱(上海)化成工业发展有限公司(TCI),上海麦克林生化科技有限公司(Macklin),萨恩化学技术(上海)有限公司(Energy Chemical),阿法埃莎(中国)化学有限公司(Alfa Aesar),上海泰坦科技股份有限公司(adamas),上海书亚医药科技有限公司,上海毕得医药科技有限公司,上海天莲化工科技有限公司,上海贤鼎生物科技有限公司,上海凌峰化学试剂有限公司和上海试剂三厂。
溶剂从上海麦克林生化科技有限公司(Macklin),上海泰坦科技股份有限公司(adamas),上海天莲化工科技有限公司,上海大合化学品有限公司,上海合邦医药技术有限公司采购,未经额外处理,采购后直接使用。
实施例1
厄洛替尼(Erlotinib)衍生物库的建立
操作步骤:
(1)向96孔板中每孔加入37μL DMSO,13μL H2O,10μL叠氮砌块的DMSO溶液(50mM)与20μL厄洛替尼的DMSO溶液(25mM),混合均匀。
(2)向96孔板中每孔加入5μL硫酸铜水溶液(5mM),5μL三[(1-(3-羟丙基)-1H-1,2,3-三唑-4-基)]甲基]胺水溶液(5mM)与10μL抗坏血酸钠水溶液(250mM),室温下摇床震荡反应12小时
LC/MS随机跟踪部分样品显示,大部分样品转化率在70%以上,直接用于实施例2中的MTT法筛选。
实施例2
MTT法筛选265个Erlotinib衍生物
操作步骤:
(1)A549(肺癌)细胞贴壁过夜:取对数生长期的细胞,消化处理后计数,以每孔5000个细胞铺96孔板过夜。
(2)加药:用完全培养液稀释化合物浓度至10μM,吸弃上清液,以每孔100μL体积给药处理24小时。
(3)加MTT:每孔加入20μL MTT(5mg/mL),培养4小时。
(4)测吸光度值:吸弃上清,每孔加DMSO 150μL,摇床阵摇10分钟,使结晶充分溶解。酶标仪测溶液570nm处吸光度。
实验结果:
结果如下表所述,其中,相对存活率指Erlotinib衍生物处理细胞的存活率与阳性化合物(Erlotinib)处理细胞的存活率之比。结果显示,在A549细胞上,本申请的化合物体现出高于Erlotinib的活性(相对存活率<1),其中活性最好的化合物(相对存活率<0.5)共19个,列于下表。
(1)相对存活率<0.5
(2)相对存活率=0.5~1
实施例3
MTT法测量19个化合物对A549细胞抑制率和IC50
操作步骤:
(1)A549(肺癌)细胞贴壁过夜:取对数生长期的细胞,消化处理后计数,以每孔5000个细胞铺96孔板过夜。
(2)加药:用完全培养液稀释化合物浓度至10μM,吸弃上清液,以每孔100μL体积给药处理24小时。
(3)加MTT:每孔加入20μL MTT(5mg/mL),培养4小时。
(4)测吸光度值:吸弃上清,每孔加DMSO 150μL,摇床阵摇10分钟,使结晶充分溶解。酶标仪测溶液570nm处吸光度。
实验结果如图1和下表所示:
实施例4
2-((4-(3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基)-1H-1,2,3-三氮唑-1-基)甲基)苯酚的制备
室温下向2-羟基苄胺[化合物271](98.5mg,0.8mmol)的DMF(10ml)溶液中加入碳酸氢钾水溶液(3mol/L,1.06ml,3.2mmol)与FSO2N3的甲基叔丁基醚溶液(0.4mol/L,4.4ml,0.88mmol),室温下搅拌反应1小时。LC/MS检测反应完毕,加入0.5ml抗坏血酸钠水溶液(0.5mol/L,0.25mmol)淬灭反应。向上述反应液中加入N-(3-乙炔基苯基)-6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺盐酸盐[Erlotinib](172.0mg,0.4mmol),0.4ml CuSO4水溶液(0.1mol/L,0.04mmol),0.4ml抗坏血酸钠水溶液(2mol/L,0.8mmol),50℃下搅拌反应3小时。LC/MS检测反应完毕,向反应液中加入100ml乙酸乙酯,饱和食盐水(100ml X 3)洗涤,无水硫酸钠干燥。柱层析分离,得到浅黄色固体2-((4-(3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基)-1H-1,2,3-三氮唑-1-基)甲基)苯酚[化合物1](140.9mg,产率64%)。
1H NMR(400MHz,d6-DMSO)9.90(s,1H),9.53(s,1H),8.42-8.42(m,2H),8.19(t,J=2.0Hz,1H),7.92-7.83(m,2H),7.56-7.48(m,1H),7.46-7.36(m,1H),7.22-7.05(m,3H),6.88-6.73(m,2H),5.52(s,2H),4.31-4.21(m,4H),3.79-3.68(m,4H),3.34(s,3H),3.32(s,3H).
LC-MS(tR):1.34min;ESI-MS(m/z):543.39[M+H]+.
实施例5
2-((4-(3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基)-1H-1,2,3-三氮唑-1-基)甲基)苯基氟磺酸酯的制备
室温下向2-((4-(3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基)-1H-1,2,3-三氮唑-1-基)甲基)苯酚[化合物1](79.2mg,0.145mmol)的乙腈悬浊液中加入三乙胺(22.3mg,0.22mmol),插上一个硫酰氟气体的气球(SO2F2,50ml,2mmol),室温下搅拌反应4小时。LC/MS检测反应完毕,旋转蒸发仪除去乙腈,加入50ml乙酸乙酯,水(100ml X2)与饱和食盐水(100ml X 3)洗涤,无水硫酸钠干燥,旋干得到黄色固体3-((4-(3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基)-1H-1,2,3-三氮唑-1-基)甲基)苯基氟磺酸酯[化合物272](81.2mg,90%yield)。
1H NMR(400MHz,d6-DMSO)10.50(s,1H),8.64(s,1H),8.59(s,1H),8.24-8.12(m,2H),7.82-7.76(m,1H),7.67-7.40(m,6H),7.32-7.26(m,1H),5.80(s,2H),4.36-4.23(m,4H),3.79-3.30(m,4H),3.34-3.31(m,6H).
LC-MS(tR):1.43min;ESI-MS(m/z):625.30[M+H]+.
实施例6
4-((4-(3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基)-1H-1,2,3-三氮唑-1-基)甲基)-2-氟苯乙腈的制备
室温下向4-溴甲基-2氟苯乙腈[化合物273](171.2mg,0.8mmol)的DMF(5ml)溶液中加入叠氮化钠(62.4mg,0.96mmol),60℃下搅拌反应1小时。向上述反应液中加入1ml水,N-(3-乙炔基苯基)-6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺盐酸盐[Erlotinib](172.0mg,0.4mmol),0.4ml CuSO4水溶液(0.1mol/L,0.04mmol),0.4ml抗坏血酸钠水溶液(2mol/L,0.8mmol),60℃下搅拌反应8小时。LC/MS检测反应完毕,向反应液中加入50ml乙酸乙酯,饱和食盐水(50ml X 3)洗涤,无水硫酸钠干燥。柱层析分离,得到浅黄色固体4-((4-(3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基)-1H-1,2,3-三氮唑-1-基)甲基)-2-氟苯乙腈[化合物2](188.9mg,产率83%)。
1H NMR(400MHz,d6-DMSO)9.53(s,1H),8.67(s,1H),8.44(s,1H),8.24(t,J=2.0Hz,1H),7.98-7.83(m,3H),7.55-7.48(m,2H),7.46-7.39(m,1H),7.30(dd,J=8.0Hz,J=2.0Hz,1H),7.19(s,1H),5.78(s,2H),4.30-4.22(m,4H),3.78-3.68(m,4H),3.34(s,3H),3.32(s,3H).
LC-MS(tR):1.41min;ESI-MS(m/z):570.35[M+H]+.
实施例7
N-(3-(1-(2-(6-氟-1H-吲哚-3-基)乙基)-1H-1,2,3-三氮唑-4-基)苯基)-6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺
室温下向2-(6-氟-1H-吲哚-3-基)乙基-1-胺[化合物274](89.1mg,0.5mmol)的DMF(5ml)溶液中加入碳酸氢钠水溶液(2mol/L,0.75ml,1.5mmol)与FSO2N3的甲基叔丁基醚溶液(0.3mol/L,2ml,0.6mmol),室温下搅拌反应1小时。LC/MS检测反应完毕,加入0.5ml抗坏血酸钠水溶液(0.5mol/L,0.25mmol)淬灭反应。向上述反应液中加入N-(3-乙炔基苯基)-6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺盐酸盐[Erlotinib](214.9mg,0.5mmol),0.5mlCuSO4水溶液(0.1mol/L,0.05mmol),0.5ml抗坏血酸钠水溶液(2mol/L,1mmol),室温下搅拌反应过夜。LC/MS检测反应完毕,向反应液中加入50ml乙酸乙酯,饱和食盐水(50ml X 3)洗涤,无水硫酸钠干燥。柱层析分离,得到白色固体N-(3-(1-(2-(6-氟-1H-吲哚-3-基)乙基)-1H-1,2,3-三氮唑-4-基)苯基)-6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺[化合物3](193.0mg,产率65%)。
1H NMR(400MHz,d6-DMSO)10.91(s,1H),9.53(s,1H),8.55(s,1H),8.44(s,1H),8.20(t,J=2.0Hz,1H),7.91-7.82(m,2H),7.56-7.38(m,3H),7.19(s,1H),7.11-7.05(m,2H),6.85-6.71(m,1H),4.65(t,J=8.0Hz,1H),4.32-4.21(m,4H),3.81-3.67(m,4H),3.35-3.10(m,8H).
LC-MS(tR):1.45min;ESI-MS(m/z):598.40[M+H]+.
实施例8
(1S,2S)-1-(4-(3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺)苯基)-1H-1,2,3-三氮唑-1-基)-2,3-二氢-1H-茚基-2醇的制备
Scheme 8(1S,2S)-1-(4-(3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺)苯基)-1H-1,2,3-三氮唑-1-基)-2,3-二氢-1H-茚基-2醇的制备
室温下向(1S,2S)-1-氨基-2,3-二氢-1H-茚-2-醇[化合物275](53.3mg,0.2mmol)的DMF(5ml)溶液中加入碳酸氢钾水溶液(3mol/L,0.53ml,1.6mmol)与FSO2N3的甲基叔丁基醚溶液(0.4mol/L,2.2ml,0.44mmol),室温下搅拌反应1小时。LC/MS检测反应完毕,加入0.25ml抗坏血酸钠水溶液(0.5mol/L,0.125mmol)淬灭反应。向上述反应液中加入N-(3-乙炔基苯基)-6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺盐酸盐[Erlotinib](77.4mg,0.18mmol),0.2ml CuSO4水溶液(0.1mol/L,0.02mmol),0.2ml抗坏血酸钠水溶液(2mol/L,0.4mmol),50℃下搅拌反应3小时。LC/MS检测反应完毕,向反应液中加入20ml乙酸乙酯,饱和食盐水(50ml X 3)洗涤,无水硫酸钠干燥。柱层析分离,得到白色固体N-(3-(1-(2,3-二氢-1H-1-茚基)-1H-1,2,3-三氮唑-4-基)苯基)-6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺[化合物6](99.6mg,产率92%)。
1H NMR(400MHz,d6-DMSO)9.54(s,1H),8.63(s,1H),8.44(s,1H),8.24(t,J=2.0Hz,1H),7.92-7.83(m,2H),7.56-7.52(m,1H),7.42(t,J=8.0Hz,1H),7.34-7.26(m,2H),7.22-7.16(m,2H),6.91(d,J=8.0Hz,1H),5.90(d,J=4.0Hz,1H),5.81(d,J=8.0Hz,1H),4.86-4.76(m,1H),4.31-4.22(m,4H),3.79-3.68(m,4H),3.34(s,3H),3.32(s,3H),2.93-2.85(m,1H).
LC-MS(tR):1.31min;ESI-MS(m/z):585.35[M+H]+.
实施例9
(3-(4-(3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基)-1H-1,2,3-三氮唑-1-基)-1,3,4,5-四氢-2H-苯并氮杂卓-2-酮的制备
室温下向(3-氨基-1,3,4,5-四氢-2H-苯并氮杂卓-2-酮[化合物276](88.1mg,0.5mmol)的DMF(5ml)溶液中加入碳酸氢钠水溶液(2mol/L,0.75ml,1.5mmol)与FSO2N3的甲基叔丁基醚溶液(0.3mol/L,2ml,0.6mmol),室温下搅拌反应1小时。LC/MS检测反应完毕,加入0.5ml抗坏血酸钠水溶液(0.5mol/L,0.25mmol)淬灭反应。向上述反应液中加入N-(3-乙炔基苯基)-6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺盐酸盐[Erlotinib](214.9mg,0.5mmol),0.5ml CuSO4水溶液(0.1mol/L,0.05mmol),0.5ml抗坏血酸钠水溶液(2mol/L,1mmol),室温下搅拌反应过夜。LC/MS检测反应完毕,向反应液中加入50ml乙酸乙酯,饱和食盐水(50ml X3)洗涤,无水硫酸钠干燥。柱层析分离,得到浅黄色固体N-(3-(1-(2,3-二氢-1H-1-茚基)-1H-1,2,3-三氮唑-4-基)苯基)-6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺[化合物10](288.0mg,产率97%)。
1H NMR(400MHz,d6-DMSO)10.24(s,1H),9.56(s,1H),8.74(s,1H),8.46(s,1H),8.25(t,J=2.0Hz,1H),7.92-7.81(m,2H),7.55-7.51(m,1H),7.47-7.41(m,1H),7.38-7.28(m,1H),7.19(s,1H),7.22-7.14(m,2H),7.11-7.05(m,1H),5.33-5.23(m,1H),4.32-4.21(m,4H),3.80-3.68(m,4H),3.37-3.30(m,6H),3.04-2.82(m,3H),2.72-2.59(m,1H).
LC-MS(tR):1.37min;ESI-MS(m/z):596.40[M+H]+.
实施例10
N-(3-(1-(2,4-二氟苄基)-1H-1,2,3-三氮唑-4-基)苯基)-6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺的制备
室温下向(2,4-二氟苯基)甲胺[化合物277](71.5mg,0.5mmol)的DMF(5ml)溶液中加入碳酸氢钠水溶液(2mol/L,0.75ml,1.5mmol)与FSO2N3的甲基叔丁基醚溶液(0.3mol/L,2ml,0.6mmol),室温下搅拌反应1小时。LC/MS检测反应完毕,加入0.5ml抗坏血酸钠水溶液(0.5mol/L,0.25mmol)淬灭反应。向上述反应液中加入N-(3-乙炔基苯基)-6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺盐酸盐[Erlotinib](214.9mg,0.5mmol),0.5ml CuSO4水溶液(0.1mol/L,0.05mmol),0.5ml抗坏血酸钠水溶液(2mol/L,1mmol),室温下搅拌反应过夜。LC/MS检测反应完毕,向反应液中加入50ml乙酸乙酯,饱和食盐水(50ml X 3)洗涤,无水硫酸钠干燥。柱层析分离,得到浅黄色固体N-(3-(1-(2,4-二氟苄基)-1H-1,2,3-三氮唑-4-基)苯基)-6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺[化合物17](142.0mg,产率51%)。
1H NMR(400MHz,d6-DMSO)9.56(s,1H),8.63(s,1H),8.47(s,1H),8.24(t,J=2.0Hz,1H),7.96-7.85(m,2H),7.60-7.30(m,4H),7.26-7.12(m,2H),5.70(s,2H),4.35-4.25(m,4H),3.83-3.72(m,4H),3.38(m,3H),3.36(s,3H).
LC-MS(tR):1.50min;ESI-MS(m/z):553.34[M+H]+.
实施例11
(S)-2-(3-(4-(3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基)-1H-1,2,3-三氮唑-4-基)-2-氧-2,3,4,5-四氢-1H-苯并氮杂卓-1-基)乙酸叔丁酯的制备
室温下向4-(4-氨基-1H-吡唑-1-基)-1-叔丁氧羰基-哌啶[化合物278](609.7mg,2.1mmol)的DMF(10ml)溶液中加入碳酸氢钾水溶液(3mol/L,2.8ml,8.4mmol)与FSO2N3的甲基叔丁基醚溶液(0.4mol/L,5.75ml,2.3mmol),室温下搅拌反应1小时。LC/MS检测反应完毕,加入0.25ml抗坏血酸钠水溶液(0.5mol/L,0.125mmol)淬灭反应。向上述反应液中加入N-(3-乙炔基苯基)-6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺盐酸盐[Erlotinib](859.8mg,2mmol),0.4ml CuSO4水溶液(0.5mol/L,0.2mmol),2ml抗坏血酸钠水溶液(2mol/L,4mmol),50℃下搅拌反应6小时。LC/MS检测反应完毕,将反应液分批加入饱和食盐水(200ml)中,大量白色固体析出。抽滤得到白色固体,蒸馏水(50ml X 3)洗涤,50℃下真空干燥,得到白色固体4-(4-(4-(3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基)-1H-1,2,3-三氮唑-1-基)-1H-吡唑-1-基)-1-叔丁氧羰基-哌啶[化合物279](1.3g,产率91%)。
1H NMR(400MHz,d6-DMSO)9.53(s,1H),8.80(s,1H),8.24(s,1H),8.00-7.90(m,2H),7.56-7.21(m,7H),5.37-5.24(m,1H),4.61-4.54(m,1H),4.46-4.37(m,1H),4.34-4.18(m,4H),3.82-3.65(m,4H),3.36-3.31(m,6H),3.09-2.75(m,3H),2.66-2.55(m,1H),1.32(s,9H).
LC-MS(tR):1.57min;ESI-MS(m/z):710.4[M+H]+.
实施例12
3-((4-(3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基)-1H-1,2,3-三氮唑-1-基)甲基)苯基氟磺酸酯的制备
室温下向3-羟基苄胺[化合物280](98.5mg,0.8mmol)的DMF(10ml)溶液中加入碳酸氢钾水溶液(3mol/L,1.06ml,3.2mmol)与FSO2N3的甲基叔丁基醚溶液(0.4mol/L,4.4ml,0.88mmol),室温下搅拌反应1小时。LC/MS检测反应完毕,加入0.5ml抗坏血酸钠水溶液(0.5mol/L,0.25mmol)淬灭反应。向上述反应液中加入N-(3-乙炔基苯基)-6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺盐酸盐[Erlotinib](172.0mg,0.4mmol),0.4ml CuSO4水溶液(0.1mol/L,0.04mmol),0.4ml抗坏血酸钠水溶液(2mol/L,0.8mmol),50℃下搅拌反应3小时。LC/MS检测反应完毕,向反应液中加入100ml乙酸乙酯,饱和食盐水(100ml X 3)洗涤,无水硫酸钠干燥,柱层析分离得到3-((4-(3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基)-1H-1,2,3-三氮唑-1-基)甲基)苯酚[化合物281]。
室温下向[化合物18]的乙腈悬浊液中加入三乙胺(60.7mg,0.6mmol),插上一个硫酰氟气体的气球(SO2F2,100ml,4mmol),室温下搅拌反应4小时。LC/MS检测反应完毕,旋转蒸发仪除去乙腈,加入50ml乙酸乙酯,水(100ml X 2)与饱和食盐水(100ml X 3)洗涤,无水硫酸钠干燥,旋干得到浅黄色固体3-((4-(3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基)-1H-1,2,3-三氮唑-1-基)甲基)苯基氟磺酸酯[化合物282](154.9mg,产率62%)。
1H NMR(400MHz,d6-DMSO)10.20(s,1H),8.70(s,1H),8.75(s,1H),8.21(s,1H),8.03(s,1H),7.84-7.75(m,1H),7.68-7.38(m,6H),7.4(s,1H),5.75(s,2H),4.35-4.22(m,4H),3.84-3.64(m,4H),3.36-3.29(m,6H).
LC-MS(tR):1.41min;ESI-MS(m/z):625.30[M+H]+.
实施例13
(R)-(3-(4-(3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基)-1H-1,2,3-三氮唑-1-基)-1,3,4,5-四氢-2H-苯并氮杂卓-2-酮的制备
室温下向(R)-3-氨基-1,3,4,5-四氢-2H-苯并氮杂卓-2-酮[化合物283](609.7mg,2.1mmol)的DMF(10ml)溶液中加入碳酸氢钾水溶液(3mol/L,2.8ml,8.4mmol)与FSO2N3的甲基叔丁基醚溶液(0.4mol/L,5.75ml,2.3mmol),室温下搅拌反应1小时。LC/MS检测反应完毕,加入0.25ml抗坏血酸钠水溶液(0.5mol/L,0.125mmol)淬灭反应。向上述反应液中加入N-(3-乙炔基苯基)-6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺盐酸盐[Erlotinib](859.8mg,2mmol),0.4ml CuSO4水溶液(0.5mol/L,0.2mmol),2ml抗坏血酸钠水溶液(2mol/L,4mmol),50℃下搅拌反应6小时。LC/MS检测反应完毕,旋蒸除去DMF,柱层析分离,得到浅黄色固体(R)-(3-(4-(3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基)-1H-1,2,3-三氮唑-1-基)-1,3,4,5-四氢-2H-苯并氮杂卓-2-酮的制备[化合物284](1.3g,产率91%)。
1H NMR(400MHz,d6-DMSO)10.24(s,1H),9.56(s,1H),8.74(s,1H),8.46(s,1H),8.25(t,J=2.0Hz,1H),7.92-7.81(m,2H),7.55-7.51(m,1H),7.47-7.41(m,1H),7.38-7.28(m,1H),7.19(s,1H),7.22-7.14(m,2H),7.11-7.05(m,1H),5.33-5.23(m,1H),4.32-4.21(m,4H),3.80-3.68(m,4H),3.37-3.30(m,6H),3.04-2.82(m,3H),2.72-2.59(m,1H).
LC-MS(tR):1.37min;ESI-MS(m/z):596.40[M+H]+.
实施例14
(S)-(3-(4-(7,8,10,11,13,14-六氢-[1,4,7,10]四氧环癸基[2,3-并]-喹唑啉-4-胺基)苯基)-1H-1,2,3-三氮唑-1-基)-1,3,4,5-四氢-2H-苯并氮杂卓-2-酮盐酸盐的制备
室温下向(S)-3-氨基-1,3,4,5-四氢-2H-苯并氮杂卓-2-酮-双-(2R,3R)-2,3-二羟基丁二酸盐[化合物285](24.0mg,0.05mmol)的DMF(1ml)溶液中加入碳酸氢钾(30.3mg,0.3mmol)、碳酸钾(13.8mg,0.1mmol)与FSO2N3的甲基叔丁基醚溶液(0.4mol/L,0.125ml,0.05mmol),室温下搅拌反应1小时。LC/MS检测反应完毕,加入0.1ml抗坏血酸钠水溶液(0.5mol/L,0.05mmol)淬灭反应。向上述反应液中加入N-(3-乙炔基苯基)-7,8,10,11,13,14-六氢-[1,4,7,10]四氧环癸基[2,3-并]-喹唑啉-4-胺[Icotinib](10.0mg,0.025mmol),0.05ml CuSO4水溶液(0.1mol/L,0.005mmol),0.4ml抗坏血酸钠水溶液(2mol/L,0.8mmol),50℃下搅拌反应3小时。LC/MS检测反应完毕,向反应液中加入100ml乙酸乙酯,饱和食盐水(100ml X 3)洗涤,无水硫酸钠干燥。柱层析分离,得到白色固体(S)-(3-(4-(7,8,10,11,13,14-六氢-[1,4,7,10]四氧环癸基[2,3-并]-喹唑啉-4-胺基)苯基)-1H-1,2,3-三氮唑-1-基)-1,3,4,5-四氢-2H-苯并氮杂卓-2-酮[化合物286](14.9mg,产率98%)。
1H NMR(400MHz,CD3CN)8.53(s,1H),8.38-8.30(m,2H),8.25(s,1H),8.17(s,1H),7.86-7.81(m,1H),7.73(s,1H),7.60-7.54(m,1H),7.49-7.42(m,1H),7.40-7.32(m,2H),7.31-7.22(m,2H),7.17-7.11(m,1H),5.40-5.32(m,1H),4.37-4.25(m,4H),3.87-3.76(m,2H),3.68(s,4H).
LC-MS(tR):1.34min;ESI-MS(m/z):594.30[M+H]+.
实施例15
(S)-(3-(4-(3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基)-1H-1,2,3-三氮唑-1-基)-1,3,4,5-四氢-2H-苯并氮杂卓-2-酮盐酸盐的制备
室温下向(S)-3-氨基-1,3,4,5-四氢-2H-苯并氮杂卓-2-酮-双-(2R,3R)-2,3-二羟基丁二酸盐[化合物285](11.91g,25mmol)的DMF(65ml)溶液中加入碳酸氢钾(10.01g,100mmol)、碳酸钾(6.9g,50mmol)、水(35ml)与FSO2N3的甲基叔丁基醚溶液(0.4mol/L,62.5ml,25mmol),室温下搅拌反应1小时。LC/MS检测反应完毕,加入5ml抗坏血酸钠水溶液(0.5mol/L,2.5mmol)淬灭反应。向上述反应液中加入200ml乙酸乙酯,饱和食盐水(300ml X3)洗涤,无水硫酸钠干燥,浓缩得到浅黄色固体(S)-3-叠氮基-1,3,4,5-四氢-2H-苯并氮杂卓-2-酮。
向(S)-3-叠氮基-1,3,4,5-四氢-2H-苯并氮杂卓-2-酮的DMF溶液(70ml)中加入N-(3-乙炔基苯基)-6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺盐酸盐[Erlotinib](10.74g,25mmol),1.25ml CuSO4水溶液(1mol/L,1.25mmol),8ml抗坏血酸钠水溶液(2mol/L,16mmol),60℃下搅拌反应4小时。LC/MS检测反应完毕,将反应液分批加入1mol/L盐酸(1400ml)中,大量浅黄色固体析出,室温下搅拌1小时。抽滤出粗产品,将固体分批加入NH3/NH4Cl缓冲溶液(2mol/L,pH=9)中,固体颜色逐渐变为白色,室温下搅拌20分钟,再次抽滤得到白色固体(S)-(3-(4-(3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基)-1H-1,2,3-三氮唑-1-基)-1,3,4,5-四氢-2H-苯并氮杂卓-2-酮[化合物287]。
将[化合物27]分批加入1mol/L盐酸(1000ml)中,60℃水浴加热下搅拌反应1小时,抽滤得到浅黄色固体,60℃下真空干燥,得到浅黄色固体(S)-(3-(4-(3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基)-1H-1,2,3-三氮唑-1-基)-1,3,4,5-四氢-2H-苯并氮杂卓-2-酮盐酸盐[化合物288](15.0g,产率95%)
1H NMR(400MHz,d6-DMSO)11.52(s,1H),10.25(s,1H),8.83-8.75(m,2H),8.38(s,1H),8.18(t,J=2.0Hz,1H),7.75-7.67(m,2H),7.52(t,J=8.0Hz,1H),7.46-7.26(m,3H),7.21-7.05(m,2H),5.32-5.24(m,1H),4.41-4.25(m,4H),3.80-3.70(m,4H),3.33(s,6H),3.01-2.82(m,3H),2.72-2.61(m,1H).
LC-MS(tR):1.37min;ESI-MS(m/z):596.40[M+H]+.
实施例16
MTT法测量Erlotinib、化合物285、化合物288对不同肿瘤细胞株的抑制情况和IC50
操作步骤:
(1)A549(或其他癌细胞系)细胞贴壁过夜:取对数生长期的细胞,消化处理后计数,以每孔5000个细胞铺96孔板过夜。
(2)加药:用完全培养液稀释化合物浓度分别为40μM、20μM、10μM、5μM、2.5μM、1.25μM,吸弃上清液,以每孔100μL体积给药处理24小时。
(3)加MTT:每孔加入20μL MTT(5mg/mL),培养4小时
(4)测吸光度值:吸弃上清,每孔加入150μL DMSO,摇床阵摇10分钟,使结晶充分溶解。酶标仪测溶液570nm处吸光度。
实验结果IC50(μM):
U251:人胶质瘤癌细胞
HeLa:人宫颈癌细胞
PC-3:人前列腺癌细胞
786-O:人肾透明细胞腺癌细胞
MCF-7:人乳腺癌细胞
Panc-1:人胰腺癌细胞
A549/H1299:人肺癌细胞
AGS:人胃癌细胞
LOVO/HT-29/HCT116:人结肠癌细胞
THP-1:人单核巨噬细胞
HL-60人早幼粒急性白血病细胞
HepG2:人肝癌细胞
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种如下式I所示的化合物,或其药学上可接受的盐、水合物或光学异构体,
其中,R选自下组:-(L)n-C1-C6烷基、-(L)n-C6-C10芳基、-(L)n-C3-C8硅烷基、-(CR'2)n-(具有1-3个选自N、S和O的杂原子的5-12元杂芳基)、-(CR'2)n-(5-12元碳环基)、-(CR'2)n-(具有1-3个选自N、S和O的杂原子的5-12元杂环基);上述的烷基、芳基、杂芳基、杂环基可为取代或未取代的;且R不为选自下组的基团:取代或未取代的苯基;
R1、R2各自独立地为选自下组的基团:C1-C6的烷基,或R1与R2共同构成-CH2-CH2-;
各个L各自独立地选自下组:(CR'2)m、取代或未取代的5-8元杂环、-C(O)-O-、-NH-C(O)-O-、-NH-C(O)-、-O-、-S-;
各个R'各自独立地选自下组:H、卤素、C1-C6烷基、C1-C6烷氧基、氧代(=O)、-NO2、-CN、-OH、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基;
n选自下组:0、1、2、3、4或5;
m选自下组:1、2、3、4或5;
2.如权利要求1所述的化合物,其特征在于,所述的各个L各自独立地选自下组:(CR'2)m。
3.如权利要求1所述的化合物,其特征在于,所述的m选自下组:1或2。
6.一种药物组合物,其特征在于,所述的药物组合物包括:治疗有效量的如权利要求1所述的式(I)化合物,或其药学上可接受的盐、水合物、光学异构体中的一种或多种,以及任选的药学上可接受的载体。
7.如权利要求6所述的药物组合物,其特征在于,所述的药物组合物用于治疗与酪氨酸激酶过表达和/或酪氨酸激酶活性过高相关的疾病。
8.一种EGFR抑制剂,其特征在于,所述的抑制剂含有抑制有效量的如本发明第一方面中所述的式I化合物,或其药学上可接受的盐、互变异构体、光学异构体、药学上可接受的溶剂合物中的一种或多种,以及任选的药学上可接受的载体、赋形剂、佐剂、辅料和/或稀释剂。
9.如权利要求1所述的式(I)化合物的用途,其特征在于,用于选自下组的一个或多个用途:
(a)制备酪氨酸激酶抑制剂;
(b)用于体外非治疗性地抑制酪氨酸激酶的活性;
(c)用于体外非治疗性地抑制肿瘤细胞生长。
10.如权利要求9所述的用途,其特征在于,所述的表皮生长因子受体活性相关的疾病选自下组:细胞异常增殖、形态变化、运动功能亢进、血管新生疾病、肿瘤生长、肿瘤转移疾病,或其组合。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910605992.3A CN112174940A (zh) | 2019-07-05 | 2019-07-05 | 3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基-1h-三氮唑衍生物 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910605992.3A CN112174940A (zh) | 2019-07-05 | 2019-07-05 | 3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基-1h-三氮唑衍生物 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN112174940A true CN112174940A (zh) | 2021-01-05 |
Family
ID=73918743
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910605992.3A Pending CN112174940A (zh) | 2019-07-05 | 2019-07-05 | 3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基-1h-三氮唑衍生物 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN112174940A (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113149965A (zh) * | 2020-04-21 | 2021-07-23 | 南方医科大学 | 一种厄洛替尼衍生物及其在制备抑制ido1活性药物、抗肿瘤药物中的应用 |
CN113603676A (zh) * | 2021-04-28 | 2021-11-05 | 浙江工业大学 | 基于厄洛替尼靶向降解egfr蛋白小分子化合物及其制备方法和应用 |
CN114634487A (zh) * | 2022-03-31 | 2022-06-17 | 河南湾流生物科技有限公司 | 具有提高免疫力功能的喹啉类饲料添加剂的制备方法 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030144308A1 (en) * | 2001-09-24 | 2003-07-31 | Bauer Paul H. | Fructose 1,6-bisphosphatase inhibitors |
WO2013013614A1 (zh) * | 2011-07-28 | 2013-01-31 | 南京英派药业有限公司 | 4-(3-杂芳基芳基氨基)喹唑啉和1-(3-杂芳基芳基氨基)异喹啉作为Hedgehog通路抑制剂及其应用 |
CN103288840A (zh) * | 2013-06-18 | 2013-09-11 | 福州大学 | 一种酞菁-埃罗替尼轭合物及其制备与应用 |
CN103694227A (zh) * | 2013-12-20 | 2014-04-02 | 浙江树人大学 | 埃罗替尼衍生物及其制备方法和应用 |
CN104817542A (zh) * | 2015-03-16 | 2015-08-05 | 南方医科大学南方医院 | 一种egfr正电子示踪剂及其制备方法和应用 |
CN106632271A (zh) * | 2016-11-18 | 2017-05-10 | 河南师范大学 | 具有抗肿瘤活性的厄洛替尼衍生物及其制备方法和应用 |
CN106946857A (zh) * | 2017-05-02 | 2017-07-14 | 河南师范大学 | 具有抗肿瘤活性的厄洛替尼‑1,2,3‑三氮唑化合物及其制备方法和应用 |
-
2019
- 2019-07-05 CN CN201910605992.3A patent/CN112174940A/zh active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030144308A1 (en) * | 2001-09-24 | 2003-07-31 | Bauer Paul H. | Fructose 1,6-bisphosphatase inhibitors |
WO2013013614A1 (zh) * | 2011-07-28 | 2013-01-31 | 南京英派药业有限公司 | 4-(3-杂芳基芳基氨基)喹唑啉和1-(3-杂芳基芳基氨基)异喹啉作为Hedgehog通路抑制剂及其应用 |
CN103288840A (zh) * | 2013-06-18 | 2013-09-11 | 福州大学 | 一种酞菁-埃罗替尼轭合物及其制备与应用 |
CN103694227A (zh) * | 2013-12-20 | 2014-04-02 | 浙江树人大学 | 埃罗替尼衍生物及其制备方法和应用 |
CN104817542A (zh) * | 2015-03-16 | 2015-08-05 | 南方医科大学南方医院 | 一种egfr正电子示踪剂及其制备方法和应用 |
CN106632271A (zh) * | 2016-11-18 | 2017-05-10 | 河南师范大学 | 具有抗肿瘤活性的厄洛替尼衍生物及其制备方法和应用 |
CN106946857A (zh) * | 2017-05-02 | 2017-07-14 | 河南师范大学 | 具有抗肿瘤活性的厄洛替尼‑1,2,3‑三氮唑化合物及其制备方法和应用 |
Non-Patent Citations (3)
Title |
---|
MARCOS COUTO等: ""Small-Molecule Kinase-Inhibitors-Loaded Boron Cluster as Hybrid Agents for Glioma-Cell-Targeting Therapy"", 《CHEMISTRY-A EUROPEAN JOURNAL》 * |
WENBO YU等: ""Synthesis and Biological Evaluation of Novel Carbohydrate-Derived Derivatives of Erlotinib"", 《DRUG DEVELOPMENT RESEARCH》 * |
ZHANG, FENG-LING等: ""Molecular-Target-Based Anticancer Photosensitizer: Synthesis and in vitro Photodynamic Activity of Erlotinib–Zinc(II) Phthalocyanine Conjugates"", 《CHEM MED CHEM》 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113149965A (zh) * | 2020-04-21 | 2021-07-23 | 南方医科大学 | 一种厄洛替尼衍生物及其在制备抑制ido1活性药物、抗肿瘤药物中的应用 |
CN113493443A (zh) * | 2020-04-21 | 2021-10-12 | 侯延生 | 对野生型肺癌肿瘤细胞具有杀伤性能的厄洛替尼衍生物及其制备方法 |
CN113493443B (zh) * | 2020-04-21 | 2023-06-27 | 侯延生 | 一种厄洛替尼衍生物在制备治疗食管癌的药物中的应用 |
CN113603676A (zh) * | 2021-04-28 | 2021-11-05 | 浙江工业大学 | 基于厄洛替尼靶向降解egfr蛋白小分子化合物及其制备方法和应用 |
CN113603676B (zh) * | 2021-04-28 | 2022-05-24 | 浙江工业大学 | 基于厄洛替尼靶向降解egfr蛋白小分子化合物及其制备方法和应用 |
CN114634487A (zh) * | 2022-03-31 | 2022-06-17 | 河南湾流生物科技有限公司 | 具有提高免疫力功能的喹啉类饲料添加剂的制备方法 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11046697B2 (en) | Compounds and compositions useful for treating disorders related to NTRK | |
CN111484477B (zh) | 一种苯并吡啶酮杂环化合物及其用途 | |
CN109311889B (zh) | 激活素受体样激酶抑制剂 | |
WO2021190467A1 (zh) | 含螺环的喹唑啉化合物 | |
CN111902417B (zh) | 一种二芳基巨环化合物、药物组合物以及其用途 | |
CN113527335A (zh) | 作为egfr抑制剂的大环类化合物及其应用 | |
CN110156786A (zh) | 嘧啶并环化合物及其制备方法和应用 | |
CN115175679A (zh) | 治疗雌激素受体相关疾病的方法 | |
WO2021213317A1 (zh) | Hpk1抑制剂及其制备方法和用途 | |
CN112174940A (zh) | 3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基-1h-三氮唑衍生物 | |
CN106687446A (zh) | 作为t790m/wt‑egfr的选择性和不可逆的激酶抑制剂的5‑氨基‑4‑氨甲酰基‑吡唑化合物及其用途 | |
CN107922417A (zh) | 蝶啶酮衍生物作为egfr抑制剂的应用 | |
CN114057692A (zh) | 一种杂环类化合物、其制备方法及用途 | |
CN113784963A (zh) | 用作ret激酶抑制剂的化合物及其应用 | |
JP6779318B2 (ja) | 抗転移性2H‐セレノフェノ[3,2‐h]クロメン、それらの合成、および同薬剤の使用方法 | |
TW202110848A (zh) | 取代的稠合雙環類衍生物、其製備方法及其在醫藥上的應用 | |
CN110577526A (zh) | 溴域结构蛋白抑制剂的盐及其制备方法和应用 | |
CN113045569B (zh) | 用作ret激酶抑制剂的化合物及其应用 | |
CN112243437A (zh) | 含丙烯酰基的核转运调节剂及其用途 | |
CN105367575B (zh) | 一种叶酸类化合物、其制备方法及医药用途 | |
CN110283162B (zh) | 一种表皮生长因子受体抑制剂及其应用 | |
CN111393368B (zh) | 一种茚并吡唑盐酸盐类衍生物及其制备方法与应用 | |
CN111484495B (zh) | 含二氢蝶啶二酮骨架衍生物的制备方法和用途 | |
WO2022007841A1 (zh) | 一种egfr抑制剂、其制备方法和在药学上的应用 | |
CN115667275A (zh) | 含硼化合物及其应用 |
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 |