CN107698562A - 一种喹啉衍生物及其用途 - Google Patents
一种喹啉衍生物及其用途 Download PDFInfo
- Publication number
- CN107698562A CN107698562A CN201710674273.8A CN201710674273A CN107698562A CN 107698562 A CN107698562 A CN 107698562A CN 201710674273 A CN201710674273 A CN 201710674273A CN 107698562 A CN107698562 A CN 107698562A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutically acceptable
- metabolism
- acceptable salt
- quinoline derivative
- hydrate
- 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
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title 2
- 238000002360 preparation method Methods 0.000 claims abstract description 22
- 230000033115 angiogenesis Effects 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 230000004060 metabolic process Effects 0.000 claims abstract description 18
- 239000002207 metabolite Substances 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 12
- 229940079593 drug Drugs 0.000 claims abstract description 10
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 claims abstract description 8
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 claims abstract 14
- 150000001875 compounds Chemical class 0.000 claims description 48
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 150000004677 hydrates Chemical class 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 229910052805 deuterium Inorganic materials 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 abstract description 7
- 108091008605 VEGF receptors Proteins 0.000 abstract description 5
- 208000037824 growth disorder Diseases 0.000 abstract description 5
- 230000006510 metastatic growth Effects 0.000 abstract description 5
- 230000004614 tumor growth Effects 0.000 abstract description 2
- 239000003112 inhibitor Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 25
- 150000003248 quinolines Chemical class 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 208000037803 restenosis Diseases 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 101001034652 Homo sapiens Insulin-like growth factor 1 receptor Proteins 0.000 description 3
- 101000851030 Homo sapiens Vascular endothelial growth factor receptor 3 Proteins 0.000 description 3
- 102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 3
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 3
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 3
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 3
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 150000001793 charged compounds Chemical class 0.000 description 3
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 3
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 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 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 3
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 208000003120 Angiofibroma Diseases 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 2
- 206010012689 Diabetic retinopathy Diseases 0.000 description 2
- 201000009273 Endometriosis Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 2
- 101710182386 Fibroblast growth factor receptor 1 Proteins 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
- 208000010412 Glaucoma Diseases 0.000 description 2
- 206010018364 Glomerulonephritis Diseases 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 2
- 101000579425 Homo sapiens Proto-oncogene tyrosine-protein kinase receptor Ret Proteins 0.000 description 2
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 2
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010020649 Hyperkeratosis Diseases 0.000 description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 description 2
- 208000001126 Keratosis Diseases 0.000 description 2
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 2
- 102100028286 Proto-oncogene tyrosine-protein kinase receptor Ret Human genes 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 2
- 208000034841 Thrombotic Microangiopathies Diseases 0.000 description 2
- 206010052779 Transplant rejections Diseases 0.000 description 2
- 229940124674 VEGF-R inhibitor Drugs 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 208000033679 diabetic kidney disease Diseases 0.000 description 2
- 208000030533 eye disease Diseases 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 201000011066 hemangioma Diseases 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 208000017169 kidney disease Diseases 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 210000003584 mesangial cell Anatomy 0.000 description 2
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 2
- 201000003142 neovascular glaucoma Diseases 0.000 description 2
- 201000009925 nephrosclerosis Diseases 0.000 description 2
- 210000000944 nerve tissue Anatomy 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- -1 quinoline derivative compound Chemical class 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000000451 tissue damage Effects 0.000 description 2
- 231100000827 tissue damage Toxicity 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 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 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 206010005003 Bladder cancer Diseases 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
- 206010063209 Chronic allograft nephropathy Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 208000022461 Glomerular disease Diseases 0.000 description 1
- 102100031000 Hepatoma-derived growth factor Human genes 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 101001083798 Homo sapiens Hepatoma-derived growth factor Proteins 0.000 description 1
- 239000002138 L01XE21 - Regorafenib Substances 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102000001393 Platelet-Derived Growth Factor alpha Receptor Human genes 0.000 description 1
- 108010068588 Platelet-Derived Growth Factor alpha Receptor Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 229940091171 VEGFR-2 tyrosine kinase inhibitor Drugs 0.000 description 1
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 1
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000000437 effect on angiogenesis Effects 0.000 description 1
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000003100 immobilizing effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 210000004088 microvessel Anatomy 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 description 1
- 229960004836 regorafenib Drugs 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 1
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 210000000264 venule Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—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 two hetero rings
- C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种新型的喹啉衍生物、其可药用盐、水合物或以任何形式代谢形成的代谢产物，及在制备预防和/或治疗与血管生成有关的适应症的药物中的用途。本发明的喹啉衍生物是理想的高效VEGFR抑制剂，可用于治疗或预防肿瘤生长，以及其他与血管生成相关的转移生长疾病。
Description
技术领域
本发明涉及一种喹啉衍生物及其在制备预防和/或治疗与血管生成有关的适应症的药物中的用途。
背景技术
血管生成是在已有毛细血管及毛细血管后微静脉的新的毛细血管性血管生长，是一个涉及多种细胞的多种分子的复杂过程。
血管内皮生长因子(vascular endothelial growth factor，VEGF)是血管内皮细胞特异性的肝素结合生长因子，可在体内诱导血管新生。VEGF的表达与组织中微血管的密度及新生血管的数量密切相关。VEGF受体(VEGFR)家族包括VEGFR-1，VEGFR-2和VEGFR3。
血管生成在肿瘤的发展转移过程中起到重要作用，抑制这一过程能明显阻止肿瘤组织的发展和扩散转移。抑制VEGFR能够治疗肿瘤生长，以及其他与血管生成相关的转移生长疾病，如银屑病、卡波西肉瘤、再狭窄如支架诱导的再狭窄、子宫内膜异位症、克隆病、霍奇金病、白血病；关节炎、血管瘤、血管纤维瘤、眼病如糖尿病性视网膜病变和新生血管性青光眼、肾病如肾小球肾炎、糖尿病肾病、恶性肾硬化、血栓性微血管病综合征、移植排斥和肾小球病，纤维化病如肝硬化、肾小球膜细胞增生性疾病、动脉硬化、神经组织损伤和老年性角化症等。
发明内容
本发明所要解决的技术问题是提供一种新型的喹啉衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物，其是理想的VEGFR抑制剂。
本发明同时还提供喹啉衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物在制备预防和/或治疗与血管生成功能有关的适应症的药物中的用途。
为解决以上技术问题，本发明采取如下技术方案：
具有通式(I)所示结构的喹啉衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物，
其中：
R1选自R5或NHR5，其中R5为环烷基、杂环或取代杂环；
R2选自氢、卤素、羟基、烷氧基或氰基；
R3和R4独立地选自OR6、C(O)NH2、C(O)NHR6，其中R6为C1-C6烷基或卤代烷基；
X选自NH或O；
所述具有通式(I)所示结构的喹啉衍生物，其可药用盐、水合物或以任何形式代谢形成的代谢产物中，非交换性的氢未被取代，或部分或全部被氘取代。
本发明中，R2优选为Cl或F。
本发明中，R5优选为环烷基或卤代环烷基；含N或O的杂环，其未被取代或为卤素、C1-C6烷基中的一个或多个取代基取代，其中所述环烷基碳数优选为3～6个。
更优选地，R5为碳数为3的环烷基；含1或2或3个N的不饱和五元或六元杂环，其未被取代或被一个或二个选自甲基、乙基取代。
进一步更优选地，R5为碳数为3的环烷基；含2个N的不饱和五元杂环，其未被取代或被一个甲基取代。
根据本发明的一些优选实施方式，R5为
本发明中，R6优选为甲基或乙基。
本发明中，所述的喹啉衍生物的代表性化合物为如下结构式表示的化合物中的一种：
根据本发明，所述的喹啉衍生物的化合物，其不仅包括单一的某种化合物形式，还包括多种结构满足通式(Ⅰ)要求的化合物的混合物形式，以及同一化合物的不同异构体形式例如外消旋体、对映异构体、非对映异构体等。所述的可药用盐包括但不限于盐酸盐、磷酸盐、硫酸盐、醋酸盐、马来酸盐、甲磺酸盐、苯磺酸盐、苯酸盐、甲基苯磺酸盐、琥珀酸盐、延胡索酸盐、富马酸盐、酒石酸盐、没食子酸盐、柠檬酸盐等。“具有通式(Ⅰ)的化合物的前药”指一种物质，当采用适当的方法施用后，可在受试者体内进行代谢或化学反应而转变成通式(Ⅰ)的至少一种化合物或其盐。
本发明喹啉衍生物的制备可以通过化学领域众所周知的那些类似的方法的合成途径，特别是根据本文包含的描述合成本发明的化合物。试剂一般从商业来源获得或易于使用本领域技术人员众所周知的方法制备。
本发明的又一技术方案：一种喹啉衍生物中间体，所述中间体为如下结构式表示的化合物中的一种：
本发明采用的另一技术方案：上述喹啉衍生物，其可药用盐、水合物或以任何形式代谢形成的代谢产物在制备预防和/或治疗与血管生成有关的适应症的药物中的用途。
所述与血管生成有关的适应症包括恶性肿瘤疾病。
所述恶性肿瘤疾病包括肺癌、间皮瘤、胃肠癌、乳腺癌、胰腺癌、膀胱癌、卵巢癌、食管癌、头颈癌、结肠癌、皮肤癌、前列腺癌、子宫颈癌、淋巴瘤、白血病、黑素瘤、神经胶质瘤和鼻咽癌等多种恶性肿瘤疾病。
所述与适应症还包括其他与血管生成相关的转移生长疾病，如银屑病，卡波西肉瘤，再狭窄如支架诱导的再狭窄，子宫内膜异位症，克隆病，霍奇金病，白血病，关节炎，血管瘤，血管纤维瘤，眼病如糖尿病性视网膜病变和新生血管性青光眼，肾病如肾小球肾炎、糖尿病肾病、恶性肾硬化、血栓性微血管病综合征、移植排斥和肾小球病，纤维化病如肝硬化、肾小球膜细胞增生性疾病、动脉硬化、神经组织损伤和老年性角化症等。
本发明采用的又一技术方案：一种预防和/或治疗与血管生成有关的适应症的药物，含有上述的具有通式(I)的喹啉衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物。
由于以上技术方案的实施，本发明与现有技术相比具有如下优点：
本发明提供的化合物是新型的喹啉衍生物，其是理想的高效理想的VEGFR抑制剂，通过作用于VEGFR，可以抑制血管生成，在血管生成有关的疾病方面具有一定的药物治疗作用。因此本发明化合物可用于制备治疗或预防各种与血管生成有关的适应症的药物，而且通过对血管生成的抑制也能够增强其他药物的抗肿瘤作用。
具体实施方式
下面结合具体实施例对本发明做进一步详细的说明，但本发明并不限于以下实施例。
实施例1
本实施例提供式Ⅰa化合物，其化学结构如下：
式Ia化合物可通过如下合成路线获得：
式Ia化合物的制备方法具体包括如下步骤：
(1)、制备中间体2：在50mL反应瓶中，依次加入化合物1(500mg，2mmol)、NMP(20mL)、化合物1a(471mg，3mmol)和DIPEA(774mg，6mmol)。将混合物加热到160℃搅拌反应2小时。冷却后浓缩，硅胶柱层析分离得到中间体2(0.4g,1.08mmol,收率56％)，为灰色固体。
(2)、制备中间体3：在250mL反应瓶中，依次加入中间体2(400mg，1.08mmol)、MeOH(80mL)和钯潭(5％，100mg)。反应液在氢气中常温搅拌3小时。过滤反应液，滤液浓缩后得到中间体3(0.3g，0.88mmol，收率80％)，为白色固体。LCMS显示分子离子峰m/z[MH]+：342.2。
(3)、制备式Ia化合物：在50mL三口瓶中依次加入中间体3(0.3g，0.88mmol)和干燥THF(20mL)。在氮气保护下将反应液冷却到0℃，缓慢滴加DIPEA(0.227g，1.76mmol)。反应液0℃搅拌反应1小时。向反应液中加入三光气(90mg，0.3mmol)。反应液0℃搅拌反应3小时。然后向反应液中快速加入化合物3a(94mg，0.97mmol)。反应液在室温搅拌过夜，浓缩，HPLC分离得到式Ia化合物(0.12g，0.26mmol，收率29％)，为白色固体。
对得到的目标产品式Ia化合物进行了氢核磁共振1H-NMR(400MHz，d-DMSO)和质谱测试，结果如下：
1H-NMR谱图中吸收峰：δ＝8.99(s,1H,ArH),8.65(d,J＝5.2Hz,1H,ArH),8.59(s,1H,ArH),8.51(s,1H,ArH),8.37-8.36(m,1H,CONHCH3),7.74-7.71(m,2H,一个CONH，一个ArH),7.50(s,1H,ArH),7.39-7.34(m,2H,一个CONH，一个ArH),7.23(d,J＝8.8Hz,1H,ArH),6.48(d,J＝4.8Hz,1H,ArH),4.00(s,3H,NCH3),3.77(s,3H,OCH3)，2.82(d,J＝4.8Hz,3H,CONHCH3)。
m/z[MH]+：465.2。计算得出产品具有分子式C23H21FN6O4，精确分子质量(exactmass)为464.16。
实施例2
本实施例提供式Ib化合物，其化学结构如下：
式Ib化合物可通过如下合成路线获得：
式Ib化合物的制备方法具体包括如下步骤：
(1)、制备中间体5：在150mL三口瓶中依次加入化合物4(1.8g，7.63mmol)、NMP(40mL)、化合物1a(1.797g，11.45mmol)和DIPEA(5.9g，45.78mmol)。将混合物加热到160℃反应2小时。冷却到室温后，将反应液加入到水中，析出固体。过滤混合物，滤饼用水洗涤，干燥得到中间体5(2.2g，收率80％)，为灰色固体。LCMS显示分子离子峰m/z[MH]+：358.1。
(2)、制备中间体6：在500mL三口瓶中依次加入中间体5(700mg，1.96mmol)、MeOH(200mL)和雷尼镍(700mg)。反应液在氢气中常温搅拌反应3小时。过滤反应液，滤液浓缩干燥后得到中间体6(620mg，收率96.7％)，为浅棕色固体。LCMS显示分子离子峰m/z[MH]+：328.1。
(3)、制备式Ib化合物：在10mL三口瓶中依次加入中间体6(163mg，0.5mmol)、三光气(49mg，0.165mmol)和干燥THF(5mL)。在氮气保护下将反应液冷却到0℃，缓慢滴加DIPEA(194mg，1.5mmol)。反应液搅拌反应10分钟。然后向反应液中快速加入化合物3a(62mg，0.5mmol)。反应液在室温搅拌过夜，浓缩，用反相柱层析和HPLC纯化得到式Ib化合物(38mg，收率16.9％)，为白色固体。
对得到的目标产品式Ib化合物进行了氢核磁共振1H-NMR(400MHz，d-DMSO)和质谱测试，结果如下：
1H-NMR谱图中吸收峰：δ＝9.16(s,1H,ArH),8.85(d,J＝6Hz,1H,ArH),8.72(s,1H,ArH),8.67(s,1H,ArH),7.95(b,1H,CONH2),7.86(b,1H,CONH2),7.80(dd,1H,J1＝2.4Hz,J2＝13.2Hz,ArH),7.76(s,1H,ArH),7.59(s,1H,CONH),7.45(t,J＝8.8Hz,1H,ArH),7.40(s,1H,CONH),7.30-7.28(m,1H,ArH),6.76(d,J＝6Hz,1H,ArH),4.07(s,3H,NCH3),3.79(s,3H,OCH3)。
m/z[MH]+：451.2。计算得出产品具有分子式C22H19FN6O4，精确分子质量(exactmass)为450.15。
实施例3
本实施例提供式Ic化合物，其化学结构如下：
式Ic化合物可通过如下合成路线获得：
式Ic化合物的制备方法具体包括如下步骤：
(1)、制备中间体8：在500mL三口瓶中依次加入化合物7(11.3g，100mmol)、DMAP(2.44g，20mmol)和DCM(140mL)。将(Boc)2O(26g，120mmol)溶解在DCM(40mL)中，缓慢加入到三口瓶中。反应液在室温搅拌反应1小时。反应液用0.5N HCl(150mL)洗涤两次，饱和食盐水洗涤，Na2SO4干燥浓缩后得到中间体8(20g，收率93.8％)，为白色固体。
(2)、制备中间体9：在250mL三口瓶中依次加入中间体8(10g，46.9mmol)、MeOH(200mL)、EtOH(100mL)和10％Pd/C(2g)。反应液在氢气中室温搅拌反应14小时。反应液过滤浓缩，滤饼干燥后得到中间体9(8.0g，收率93.2％)，为浅紫色固体。
(3)、制备式Ic化合物：在10mL三口瓶中依次加入中间体6(220mg，0.67mmol)、三光气(66mg，0.22mmol)和干燥THF(5mL)。在氮气保护下将反应液冷却到0℃，缓慢滴加DIPEA(173mg，1.34mmol)。反应液搅拌反应10分钟。然后向反应液中快速加入中间体9(240mg，1.34mmol)。反应液在室温搅拌过夜，浓缩，反相柱层析分离得到中间体10(95mg，收率32.4％)，为白色固体。因为在溶液中有TFA，冻干的过程中中间体10转变为式Ic化合物。
对得到的目标产品式Ic化合物进行了氢核磁共振1H-NMR(400MHz，d-DMSO)和质谱测试，结果如下：
1H-NMR谱图中吸收峰：δ＝9.17-9.14(m,1H,ArH),8.90-8.89(m,1H,ArH),8.73(s,1H,ArH),8.65-8.62(m,1H,ArH),7.97(b,1H,CONH2),7.88(b,1H,CONH2),7.82(dd,1H,J1＝2.0Hz,J2＝13.6Hz,ArH),7.63(s,2H,NHCONH),7.59(m,1H,ArH),7.46(t,J＝8.8Hz,1H,ArH),7.32-7.29(m,1H,ArH),6.83-6.82(m,1H,ArH),4.07(s,3H,OCH3)。
m/z[MH]+：437.2。计算得出产品具有分子式C21H17FN6O4，精确分子质量(exactmass)为436.13。
实施例4
本实施例提供化合物酶活性测试试验。
1、试验方法
化合物的半抑制浓度IC50(把酶活性抑制至50％时所需的化合物的浓度)是以固定的酶混合特定底物及不同浓度的待测化合物来测定的。所用的测定方法是卡尺迁移变动分析(Caliper Mobility Shift Assay)，所测定的激酶为VEGFR1、VEGFR2、VEGFR3、FLT3、PDGFRα、PDGFRβ、FGFR1、RET、EGFR和IGF1R，所应用的标准参照化合物为星形孢菌素(staurosporine)。
2、试验结果
表1总结了目标化合物(Ia、Ib和Ic)对VEGFR1、VEGFR2、VEGFR3、FLT3、PDGFRα、PDGFRβ、FGFR1、RET、EGFR和IGF1R酶活性抑制实验结果，结果显示目标化合物对VEGFR2具有很强的抑制活性，对其他相关激酶，特别是EGFR和IGF1R具有很好的选择性抑制活性。这一对VEGFR2选择性的抑制作用对血管生成有关的适应症包括恶性肿瘤疾病及其他与血管生成相关的转移生长疾病的治疗具有重要的治疗意义。表1也总结了目前已经上市疗效较好的VEGFR2抑制剂瑞戈非尼的相关数据。
表1化合物酶活性抑制实验结果
实施例5
本实施例提供药物动力学属性评估试验。
1、实验方法
实验动物：CD-1小鼠、雄性和雌性；体重：20-25g；
供试品配制：将目标化合物配制成0.2mg/mL，待用。给药途径：静脉注射。给药容量及频率：2mL/kg，单次给药。剂量：3mg/kg。
样品采集：按照下列时间点采集血液，给药后5min、15min、30min、1hr、2hr、4hr、8hr和24hr取血。
2、样品分析及结果
样品分析：使用LC-MS/MS方法对采集样品进行检测。使用仪器型号为API4000。
药物动力学数据分析：使用WinNolin按照非房室模型法对所得血药浓度数据进行拟合和计算，部分结果总结在表2中。
表2按照非房室模型法计算出的目标化合物药物动力学参数
试验结果表明本发明化合物具有与治疗途径相当的药物动力学特征。
以上实施例仅是代表性的。通过上述实施例可见，本发明的化合物是理想的高效选择性VEGFR2激酶抑制剂，可期望用于治疗或预防血管生成有关的适应症包括恶性肿瘤疾病及其他与血管生成相关的转移生长疾病并取得非常好的效果，其还可以和不同类型的药用盐相结合制成口服制剂(片剂或胶囊等)。用本发明化合物制成的片剂或胶囊可被服用每日一次或多次。本发明化合物还可和其他它药物结合制成复方制剂或局部用药制剂。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。
Claims (10)
1.具有通式(I)所示结构的喹啉衍生物，其可药用盐、水合物或以任何形式代谢形成的代谢产物，
其中：
R1选自R5或NHR5，其中R5为环烷基、杂环或取代杂环；
R2选自氢、卤素、羟基、烷氧基或氰基；
R3和R4独立地选自OR6、C(O)NH2、C(O)NHR6，其中R6为C1-C6烷基或卤代烷基；
X选自NH或O；
所述具有通式(I)所示结构的喹啉衍生物，其可药用盐、水合物或以任何形式代谢形成的代谢产物中，非交换性的氢未被取代，或部分或全部被氘取代。
2.根据权利要求1所述的喹啉衍生物，其可药用盐、水合物或以任何形式代谢形成的代谢产物，其特征在于：R2为Cl或F。
3.根据权利要求1所述的喹啉衍生物，其可药用盐、水合物或以任何形式代谢形成的代谢产物，其特征在于：R5为环烷基或卤代环烷基；含N或O的杂环，其未被取代或为卤素、C1-C6烷基中的一个或多个取代基取代，其中所述环烷基碳数优选为3～6个。
4.根据权利要求3所述的喹啉衍生物，其可药用盐、水合物或以任何形式代谢形成的代谢产物，其特征在于：R5为碳数为3的环烷基；含1或2或3个N的不饱和五元或六元杂环，其未被取代或被一个或二个选自甲基、乙基取代。
5.根据权利要求4所述的喹啉衍生物，其可药用盐、水合物或以任何形式代谢形成的代谢产物，其特征在于：R5为碳数为3的环烷基；含2个N的不饱和五元杂环，其未被取代或被一个甲基取代。
6.根据权利要求1所述的喹啉衍生物，其可药用盐、水合物或以任何形式代谢形成的代谢产物，其特征在于：R6为甲基或乙基。
7.根据权利要求1所述的喹啉衍生物，其可药用盐、水合物或以任何形式代谢形成的代谢产物，其特征在于：所述的喹啉衍生物为如下结构式表示的化合物中的一种：
8.一种制备如权利要求1至7中任一项权利要求所述的喹啉衍生物，其可药用盐、水合物的间体，其特征在于：所述中间体为如下结构式表示的化合物中的一种：
9.如权利要求1至7中任一项权利要求所述的喹啉衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物在制备预防和/或治疗与血管生成有关的适应症的药物中的用途。
10.一种预防和/或治疗与血管生成有关的适应症的药物，其特征在于：含有如权利要求1～7中任一项权利要求所述的喹啉衍生物，其可药用盐、水合物，或以任何形式代谢形成的代谢产物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2016106497322 | 2016-08-09 | ||
| CN201610649732 | 2016-08-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107698562A true CN107698562A (zh) | 2018-02-16 |
Family
ID=61161721
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710674273.8A Pending CN107698562A (zh) | 2016-08-09 | 2017-08-09 | 一种喹啉衍生物及其用途 |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US10689361B2 (zh) |
| CN (1) | CN107698562A (zh) |
| WO (1) | WO2018028591A1 (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113480479A (zh) * | 2021-08-12 | 2021-10-08 | 上海爱博医药科技有限公司 | 脲类多靶点酪氨酸激酶抑制剂及其医药应用 |
| CN115215799A (zh) * | 2022-08-12 | 2022-10-21 | 上海爱博医药科技有限公司 | 脲类多靶点酪氨酸激酶抑制剂及其多种医药应用 |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018145621A1 (zh) * | 2017-02-07 | 2018-08-16 | 恩瑞生物医药科技（上海）有限公司 | 喹啉类化合物、其制备方法及其医药用途 |
| CN113302175A (zh) | 2018-11-09 | 2021-08-24 | 维瓦斯治疗公司 | 双环化合物 |
| MX2021012638A (es) * | 2019-04-16 | 2022-01-04 | Vivace Therapeutics Inc | Compuestos biciclicos. |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1478078A (zh) * | 2000-10-20 | 2004-02-25 | ������������ʽ���� | 含氮芳环衍生物 |
| CN1543459A (zh) * | 2001-04-27 | 2004-11-03 | ������������ʽ���� | 具有唑基的喹啉衍生物和喹唑啉衍生物 |
| CN101998951A (zh) * | 2008-04-10 | 2011-03-30 | 大鹏药品工业株式会社 | 酰基硫脲化合物或其盐及其用途 |
| WO2012008564A1 (ja) * | 2010-07-16 | 2012-01-19 | 協和発酵キリン株式会社 | 含窒素芳香族複素環誘導体 |
| CN103003262A (zh) * | 2010-07-16 | 2013-03-27 | 协和发酵麒麟株式会社 | 含氮芳香族杂环衍生物 |
| CN103124729A (zh) * | 2010-08-28 | 2013-05-29 | 利德探索中心有限公司 | 作为Axl抑制剂的药物活性化合物 |
| CN103405429A (zh) * | 2013-08-22 | 2013-11-27 | 中国药科大学 | 一类vegfr-2抑制剂及其用途 |
| WO2013180949A1 (en) * | 2012-05-27 | 2013-12-05 | Ning Xi | Substituted quinoline compounds and methods of use |
-
2017
- 2017-08-09 WO PCT/CN2017/096569 patent/WO2018028591A1/zh not_active Ceased
- 2017-08-09 CN CN201710674273.8A patent/CN107698562A/zh active Pending
-
2019
- 2019-02-02 US US16/266,000 patent/US10689361B2/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1478078A (zh) * | 2000-10-20 | 2004-02-25 | ������������ʽ���� | 含氮芳环衍生物 |
| CN1543459A (zh) * | 2001-04-27 | 2004-11-03 | ������������ʽ���� | 具有唑基的喹啉衍生物和喹唑啉衍生物 |
| CN101998951A (zh) * | 2008-04-10 | 2011-03-30 | 大鹏药品工业株式会社 | 酰基硫脲化合物或其盐及其用途 |
| WO2012008564A1 (ja) * | 2010-07-16 | 2012-01-19 | 協和発酵キリン株式会社 | 含窒素芳香族複素環誘導体 |
| CN103003262A (zh) * | 2010-07-16 | 2013-03-27 | 协和发酵麒麟株式会社 | 含氮芳香族杂环衍生物 |
| CN103124729A (zh) * | 2010-08-28 | 2013-05-29 | 利德探索中心有限公司 | 作为Axl抑制剂的药物活性化合物 |
| WO2013180949A1 (en) * | 2012-05-27 | 2013-12-05 | Ning Xi | Substituted quinoline compounds and methods of use |
| CN103405429A (zh) * | 2013-08-22 | 2013-11-27 | 中国药科大学 | 一类vegfr-2抑制剂及其用途 |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113480479A (zh) * | 2021-08-12 | 2021-10-08 | 上海爱博医药科技有限公司 | 脲类多靶点酪氨酸激酶抑制剂及其医药应用 |
| CN113480479B (zh) * | 2021-08-12 | 2022-08-02 | 上海爱博医药科技有限公司 | 脲类多靶点酪氨酸激酶抑制剂及其医药应用 |
| CN115215799A (zh) * | 2022-08-12 | 2022-10-21 | 上海爱博医药科技有限公司 | 脲类多靶点酪氨酸激酶抑制剂及其多种医药应用 |
| CN115215799B (zh) * | 2022-08-12 | 2024-05-31 | 上海爱博医药科技有限公司 | 脲类多靶点酪氨酸激酶抑制剂及其多种医药应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2018028591A1 (zh) | 2018-02-15 |
| US20190169163A1 (en) | 2019-06-06 |
| US10689361B2 (en) | 2020-06-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105254615B (zh) | 苯胺嘧啶衍生物及其在制备抗恶性肿瘤药物中的用途 | |
| CN113683616A (zh) | Kras g12c突变蛋白抑制剂 | |
| CN105669564B (zh) | 脲类化合物、其制备方法、药物组合物、中间体及其应用 | |
| CN107698562A (zh) | 一种喹啉衍生物及其用途 | |
| OA12735A (en) | Salts forms of E-2-methoxy-N-(3-(4-(3-methyl-pyridin-3-yloxy)-phenylamino)-quinazolin-6-YL)-allyl)-acetamide, its preparation ant its use against cancer. | |
| AU2017287553A1 (en) | Imidazopyrazinamine phenyl derivative and use thereof | |
| CN113454081A (zh) | 咪唑并吡啶基化合物及其用于治疗增生性疾病的用途 | |
| JP2021523168A (ja) | がん幹細胞を標的化するがん治療 | |
| JP2023536948A (ja) | Ｅｇｆｒ阻害剤およびその製造方法と応用 | |
| CN113831344A (zh) | 炔苯基苯酰胺类化合物及其应用 | |
| WO2021180238A1 (zh) | 一类用作激酶抑制剂的化合物及其应用 | |
| CN115551859B (zh) | 氮杂稠环酰胺类化合物及其用途 | |
| CN103833756B (zh) | 一类哒嗪酮类化合物及其制备方法和用途 | |
| WO2021164793A1 (zh) | 用作激酶抑制剂的化合物及其应用 | |
| CN110804059B (zh) | 氨基甲酸酯类化合物、药物组合物及其应用 | |
| CA3069602A1 (en) | Formylpyridine derivative having fgfr4 inhibitory activity, preparation method therefor and use thereof | |
| CN113248474A (zh) | 五元氮唑杂环衍生物及其制备方法和用途 | |
| WO2022002100A1 (zh) | 新型苯并咪唑化合物 | |
| CN110684016A (zh) | 一种含氟的azd9291衍生物及其制备方法和应用 | |
| CN105541810B (zh) | 一种香豆素类nedd8激活酶抑制剂及其制备方法与应用 | |
| WO2019029554A1 (zh) | 磺酰胺类衍生物、其制备方法及其在医药上的用途 | |
| CN103373971B (zh) | 作为蛋白激酶抑制剂的脲类化合物 | |
| CN116535423B (zh) | 抑制/诱导降解egfr激酶的化合物及其药物组合物和应用 | |
| CN115403568B (zh) | 一种喹唑啉类Aurora A共价抑制剂及其制备方法和应用 | |
| JP2020531592A (ja) | 重水素化インドールアミン２，３−ジオキシゲナーゼ阻害剤及びその使用 |
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 | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180216 |