CN116693452B - Quinoline derivative and preparation method and application thereof - Google Patents
Quinoline derivative and preparation method and application thereof Download PDFInfo
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- CN116693452B CN116693452B CN202310592678.2A CN202310592678A CN116693452B CN 116693452 B CN116693452 B CN 116693452B CN 202310592678 A CN202310592678 A CN 202310592678A CN 116693452 B CN116693452 B CN 116693452B
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- compound
- alkyl
- mmol
- group
- alkenyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 title claims abstract 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 69
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 14
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 claims abstract description 10
- 201000011510 cancer Diseases 0.000 claims abstract description 10
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 7
- 201000005202 lung cancer Diseases 0.000 claims abstract description 7
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 7
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 6
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims abstract description 6
- 208000032612 Glial tumor Diseases 0.000 claims abstract description 6
- 206010018338 Glioma Diseases 0.000 claims abstract description 6
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 6
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 6
- 201000007270 liver cancer Diseases 0.000 claims abstract description 6
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 6
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 2
- 230000036210 malignancy Effects 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- -1 hydroxy, amino Chemical group 0.000 abstract description 79
- 125000003342 alkenyl group Chemical group 0.000 abstract description 41
- 125000000217 alkyl group Chemical group 0.000 abstract description 41
- 125000000304 alkynyl group Chemical group 0.000 abstract description 31
- 150000002367 halogens Chemical class 0.000 abstract description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 11
- 230000000259 anti-tumor effect Effects 0.000 abstract description 10
- 201000010099 disease Diseases 0.000 abstract description 10
- 230000002062 proliferating effect Effects 0.000 abstract description 8
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 4
- 239000001257 hydrogen Substances 0.000 abstract description 4
- 125000002252 acyl group Chemical group 0.000 abstract description 3
- 150000004677 hydrates Chemical class 0.000 abstract 1
- 150000002431 hydrogen Chemical class 0.000 abstract 1
- 239000000651 prodrug Substances 0.000 abstract 1
- 229940002612 prodrug Drugs 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 239000012453 solvate Substances 0.000 abstract 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 110
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 29
- 238000005160 1H NMR spectroscopy Methods 0.000 description 29
- 239000007787 solid Substances 0.000 description 29
- 125000003710 aryl alkyl group Chemical group 0.000 description 25
- 150000003248 quinolines Chemical class 0.000 description 21
- 125000003545 alkoxy group Chemical group 0.000 description 19
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 19
- 238000012360 testing method Methods 0.000 description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 125000004344 phenylpropyl group Chemical group 0.000 description 11
- 125000001424 substituent group Chemical group 0.000 description 10
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 9
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 125000001188 haloalkyl group Chemical group 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 125000000547 substituted alkyl group Chemical group 0.000 description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 7
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 6
- LTUZPODERZUPRD-UHFFFAOYSA-N 6-chloro-2-(1h-indol-3-yl)-4-phenylquinoline Chemical compound C12=CC(Cl)=CC=C2N=C(C=2C3=CC=CC=C3NC=2)C=C1C1=CC=CC=C1 LTUZPODERZUPRD-UHFFFAOYSA-N 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 6
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 5
- XMZQWZJMTBCUFT-UHFFFAOYSA-N 3-bromopropylbenzene Chemical compound BrCCCC1=CC=CC=C1 XMZQWZJMTBCUFT-UHFFFAOYSA-N 0.000 description 5
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 5
- 125000001589 carboacyl group Chemical group 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 125000004438 haloalkoxy group Chemical group 0.000 description 5
- MUJNAWXXOJRNGK-UHFFFAOYSA-N n-[3-(6-methyl-1,2,3,4-tetrahydrocarbazol-9-yl)propyl]cyclohexanamine Chemical compound C1=2CCCCC=2C2=CC(C)=CC=C2N1CCCNC1CCCCC1 MUJNAWXXOJRNGK-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 5
- 125000001701 trimethoxybenzyl group Chemical group 0.000 description 5
- APJSHECCIRQQDV-ZRDIBKRKSA-N (e)-3-[4-hydroxy-3-(5,5,8,8-tetramethyl-3-pentoxy-6,7-dihydronaphthalen-2-yl)phenyl]prop-2-enoic acid Chemical compound CCCCCOC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C1=CC(\C=C\C(O)=O)=CC=C1O APJSHECCIRQQDV-ZRDIBKRKSA-N 0.000 description 4
- DPRJPRMZJGWLHY-HNGSOEQISA-N (e,3r,5s)-7-[5-(4-fluorophenyl)-3-propan-2-yl-1-pyrazin-2-ylpyrazol-4-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)/C=C/C=1C(C(C)C)=NN(C=2N=CC=NC=2)C=1C1=CC=C(F)C=C1 DPRJPRMZJGWLHY-HNGSOEQISA-N 0.000 description 4
- 238000012449 Kunming mouse Methods 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 4
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- YRCHYHRCBXNYNU-UHFFFAOYSA-N n-[[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]carbamothioyl]-2-(4-fluorophenyl)acetamide Chemical compound N1=CC(CNCCOC)=CC=C1C1=CC2=NC=CC(OC=3C(=CC(NC(=S)NC(=O)CC=4C=CC(F)=CC=4)=CC=3)F)=C2S1 YRCHYHRCBXNYNU-UHFFFAOYSA-N 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 description 3
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 description 3
- 125000006711 (C2-C12) alkynyl group Chemical group 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 3
- 239000005977 Ethylene Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 231100000111 LD50 Toxicity 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 125000004423 acyloxy group Chemical group 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 125000002877 alkyl aryl group Chemical group 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 3
- 125000004175 fluorobenzyl group Chemical group 0.000 description 3
- 125000006005 fluoroethoxy group Chemical group 0.000 description 3
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 3
- 125000000262 haloalkenyl group Chemical group 0.000 description 3
- 125000002034 haloarylalkyl group Chemical group 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
- 125000001129 phenylbutoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- WZIYCIBURCPKAR-UHFFFAOYSA-N 4-(chloromethyl)pyridine Chemical compound ClCC1=CC=NC=C1 WZIYCIBURCPKAR-UHFFFAOYSA-N 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 102000016549 Vascular Endothelial Growth Factor Receptor-2 Human genes 0.000 description 2
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 2
- 210000000683 abdominal cavity Anatomy 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 230000005918 in vitro anti-tumor Effects 0.000 description 2
- 230000005917 in vivo anti-tumor Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 125000003396 thiol group Chemical class [H]S* 0.000 description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000009736 wetting Methods 0.000 description 2
- XEEQGYMUWCZPDN-DOMZBBRYSA-N (-)-(11S,2'R)-erythro-mefloquine Chemical compound C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-DOMZBBRYSA-N 0.000 description 1
- RBWMYPKAPIYTJQ-VMBFOHBNSA-N (1R,2S,5S)-6,6-dimethyl-N-[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]-3-[2-[4-(trifluoromethoxy)phenoxy]acetyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide Chemical compound CC1([C@@H]2[C@H]1[C@H](N(C2)C(=O)COC3=CC=C(C=C3)OC(F)(F)F)C(=O)N[C@@H](C[C@@H]4CCNC4=O)C=O)C RBWMYPKAPIYTJQ-VMBFOHBNSA-N 0.000 description 1
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 description 1
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 1
- RZFJBSIAXYEPBX-UHFFFAOYSA-N 1-[4-[4-[2-[4-chloro-3-(diethylsulfamoyl)anilino]pyrimidin-4-yl]pyridin-2-yl]phenyl]-3-methylurea Chemical compound C1=C(Cl)C(S(=O)(=O)N(CC)CC)=CC(NC=2N=C(C=CN=2)C=2C=C(N=CC=2)C=2C=CC(NC(=O)NC)=CC=2)=C1 RZFJBSIAXYEPBX-UHFFFAOYSA-N 0.000 description 1
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 1
- WIAAIYJUCDAKFY-UHFFFAOYSA-N 3-(4-methoxyphenyl)-9-(prop-2-ynylamino)pyrido[1,2]thieno[3,4-d]pyrimidin-4-one Chemical compound C1=CC(OC)=CC=C1N1C(=O)C(SC=2C3=C(NCC#C)C=CN=2)=C3N=C1 WIAAIYJUCDAKFY-UHFFFAOYSA-N 0.000 description 1
- AILRADAXUVEEIR-UHFFFAOYSA-N 5-chloro-4-n-(2-dimethylphosphorylphenyl)-2-n-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine Chemical compound COC1=CC(N2CCC(CC2)N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1P(C)(C)=O AILRADAXUVEEIR-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NZSQBRZWARZNQH-ZWOACCQCSA-N C1(CC1)NC(=O)O[C@H]1C(C2CC[C@]3([C@@]4(CC[C@@]5(C(C4CCC3[C@]2(CC1)C)[C@@H](CC5)[C@H](C)O)C(=O)O)C)C)(C)C Chemical compound C1(CC1)NC(=O)O[C@H]1C(C2CC[C@]3([C@@]4(CC[C@@]5(C(C4CCC3[C@]2(CC1)C)[C@@H](CC5)[C@H](C)O)C(=O)O)C)C)(C)C NZSQBRZWARZNQH-ZWOACCQCSA-N 0.000 description 1
- 125000006538 C11 alkyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006539 C12 alkyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
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- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
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- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- INDBQLZJXZLFIT-UHFFFAOYSA-N primaquine Chemical compound N1=CC=CC2=CC(OC)=CC(NC(C)CCCN)=C21 INDBQLZJXZLFIT-UHFFFAOYSA-N 0.000 description 1
- 229960005179 primaquine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
Classifications
-
- 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
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a quinoline derivative, a preparation method and application thereof, and belongs to the field of organic chemistry. The quinoline derivatives provided by the invention are compounds of formula I, pharmaceutically acceptable salts, hydrates, solvates, isomers or prodrugs thereof: Wherein R 1 is optionally substituted or unsubstituted alkyl, alkenyl or alkynyl; r 2 is 1 to 3 each independently optionally substituted or unsubstituted hydrogen, halogen, hydroxy, amino, alkyl, mercapto, cyano, nitro, sulfonyl or acyl; r 3 is optionally substituted or unsubstituted alkyl, alkenyl or alkynyl. The quinoline derivative provided by the invention has excellent anti-tumor activity, can be used for preparing medicaments for treating proliferative diseases, and can be used for effectively treating the proliferative diseases, in particular malignant tumors such as colorectal cancer, liver cancer, gastric cancer, lung cancer or glioma.
Description
Technical Field
The invention belongs to the field of organic chemistry, and particularly relates to a quinoline derivative, and a preparation method and application thereof.
Background
Quinoline compounds are an important class of nitrogen-containing heterocyclic compounds, and the skeleton structures thereof exist in the chemical structures of many clinical drugs, such as antimalarial drugs (quinine, chloroquine, mefloquine, primaquine, etc.), antiviral drugs (saquinavir), antibacterial drugs (quinolone drugs ciprofloxacin, seofloxacin, gatifloxacin, etc.), and the like.
In 1966, M.E.wall and M.C.Wani found camptothecine, thereby pulling open the prelude of quinoline derivatives for anti-tumor research, and then camptothecine analogs topotecan, irinotecan, etc. were synthesized and applied to the treatment of cancer; the FDA approved new anticancer drugs, bosutinib and cabotinib, both of which are derivatives of quinoline, the former being a tyrosine kinase inhibitor for the primary treatment of chronic, accelerated adult Ph chronic granulocytic leukemia (CML) resistant or intolerant to previous treatments, the latter being a tyrosine kinase inhibitor for inhibiting MET, vascular endothelial growth factor receptor 2 (VEGFR 2) and RET, and blocking tumor cell development and progression, and being clinically useful in the treatment of patients with progressive, metastatic thyroid medullary cancer (MTC) (Shang Zhongming FDA approved drug profile in 2012, journal of international pharmaceutical research, 2013,40 (1): 111-123). At present, more quinoline antitumor lead medicines are in different clinical test stages, and quinoline derivatives are attracting more and more attention of researchers.
There is still a need to find new quinoline compounds with antitumor activity for clinical application.
Disclosure of Invention
In order to overcome the problems of the prior art described above, it is an object of the present invention to provide a quinoline derivative having excellent antitumor activity.
The second object of the present invention is to provide a process for preparing the quinoline derivatives.
It is a further object of the present invention to provide a pharmaceutical composition comprising the quinoline derivatives as described above and a pharmaceutically acceptable carrier.
The fourth object of the invention is to provide an application of the quinoline derivative in preparing antitumor drugs.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
in a first aspect the present invention provides a quinoline derivative which is a compound of formula I:
Wherein R 1 is optionally substituted or unsubstituted alkyl, alkenyl or alkynyl;
R 2 is 1 to 3 each independently optionally substituted or unsubstituted hydrogen, halogen, hydroxy, amino, alkyl, mercapto, cyano, nitro, sulfonyl or acyl;
R 3 is optionally substituted or unsubstituted alkyl, alkenyl or alkynyl;
Each of the substituted substituents independently optionally being at least one from the group consisting of halogen, hydroxy, amino, alkyl, alkenyl, alkynyl, mercapto, cyano, nitro, sulfonyl, acyl, alkoxy, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl, alkylheterocyclyl, alkylamino, amido, alkylamido, alkanoylamino, alkanoyl, alkanoyloxy, or alkylthio; the substituents may be further substituted or unsubstituted.
Preferably, in the compounds of formula I, R 1 is optionally substituted or unsubstituted C2-C12 alkyl, C3-C12 alkenyl or C3-C12 alkynyl.
In some specific embodiments, R 1 is optionally substituted or unsubstituted ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, allyl, propargyl, or propargyl.
Further preferred, in the compounds of formula I, R 1 is optionally substituted or unsubstituted arylalkyl or heteroarylalkyl.
In some specific embodiments, R 1 is optionally substituted or unsubstituted arylmethyl, arylethyl, arylpropyl, arylbutyl, heteroarylmethyl, heteroarylethyl, heteroarylpropyl, or heteroarylbutyl.
In some more specific embodiments, R 1 is optionally benzyl, phenethyl, phenylpropyl, or phenylbutyl.
Still further preferred are compounds of formula I wherein R 1 is optionally substituted or unsubstituted arylalkyl or heteroarylalkyl, the substituents of said substituted arylalkyl or heteroarylalkyl being one or more optional halogen, alkyl, alkoxy, haloalkyl or haloalkoxy groups.
In some embodiments, the halogen is optionally fluorine, chlorine or bromine.
In some embodiments, the unsubstituted arylalkyl is optionally benzyl, phenethyl, phenylpropyl, or phenylbutyl.
In some specific embodiments, the substituted arylalkyl is an optional methoxyarylalkyl, dimethoxyarylalkyl, trimethoxyarylalkyl, ethoxyarylalkyl, diethoxyarylalkyl, or triethoxyarylalkyl.
In some more specific embodiments, the substituted arylalkyl is an optional methoxybenzyl, dimethoxybenzyl, trimethoxybenzyl, methoxyphenethyl, dimethoxyphenethyl or trimethoxyphenethyl.
In some specific embodiments, R 1 is optionally arylalkyl, heteroarylalkyl, methoxyarylalkyl, dimethoxyarylalkyl, trimethoxyarylalkyl, ethoxyarylalkyl, diethoxyarylalkyl, or triethoxyarylalkyl.
In some more specific embodiments, R 1 is optionally benzyl, phenethyl, phenylpropyl, phenylbutyl, methoxybenzyl, dimethoxybenzyl, trimethoxybenzyl, methoxyphenethyl, dimethoxyphenethyl or trimethoxyphenethyl.
In some specific embodiments, R 1 is optionally phenylpropyl or trimethoxybenzyl.
Preferably, in the compounds of formula I, R 2 is 1 to 3, each independently, optionally substituted or unsubstituted hydrogen, halogen, hydroxy, amino, alkyl, alkoxy, alkanoyloxy, alkylthio, alkylamino, cyano, nitro, carboxyl, sulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, amido, alkoxycarbonyl or alkanoyl.
In some embodiments, the halogen is optionally fluorine, chlorine or bromine.
Further preferred are compounds of formula I wherein R 2 is1 to 3 each independently optionally substituted or unsubstituted halogen, alkyl, alkoxy or nitro.
In some embodiments, R 2 is 1 to 3 each independently optionally substituted or unsubstituted fluoro, chloro, bromo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, or nitro.
Still more preferably, in the compounds of formula I, R 2 is 1 to 3 each independently optionally substituted or unsubstituted halogen, alkyl, alkoxy or nitro, the substituents of the substituted alkyl or alkoxy being one or more optionally halogen or aryl.
In some embodiments, the halogen is optionally fluorine, chlorine or bromine.
In some embodiments, unsubstituted alkyl or alkoxy is optionally methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, or butoxy.
In some embodiments, the substituted alkyl or alkoxy is an optional haloalkyl, haloalkoxy, arylalkyl, or arylalkoxy.
In some more specific embodiments, the substituted alkyl or alkoxy is an optional fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, fluoroethyl, chloroethyl, fluoromethoxy, fluoroethoxy, chloromethoxy, chloroethoxy, benzyloxy, phenethoxy, phenylpropoxy, or phenylbutoxy.
In some embodiments, R 2 is 1-2 each independently optional halogen, alkyl, alkoxy, nitro, haloalkyl, haloalkoxy, arylalkyl, or arylalkoxy
In some more specific embodiments, R 2 is 1-2 each independently optional fluoro, chloro, bromo, nitro, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, fluoroethyl, chloroethyl, fluoromethoxy, fluoroethoxy, chloromethoxy, chloroethoxy, benzyloxy, phenethoxy, phenylpropoxy, or phenylbutoxy.
In some specific embodiments, R 2 is 1-2 optional nitro, methoxy, trifluoromethyl, or phenylpropoxy groups.
Preferably, in the compounds of formula I, R 3 is optionally substituted or unsubstituted C1-C12 alkyl, C2-C12 alkenyl or C2-C12 alkynyl.
In some specific embodiments, R 3 is optionally substituted or unsubstituted methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, allyl, propargyl, or propargyl.
Further preferred, in the compounds of formula I, R 3 is optionally substituted or unsubstituted alkyl, alkenyl, arylalkyl or heteroarylalkyl.
In some specific embodiments, R 3 is optionally substituted or unsubstituted methyl, ethyl, propyl, butyl, pentyl, allyl, benzyl, phenethyl, phenylpropyl, phenylbutyl, pyrrolylmethyl, pyridylmethyl, or pyrimidinylmethyl.
Still further preferred are compounds of formula I wherein R 3 is optionally substituted or unsubstituted alkyl, alkenyl, arylalkyl or heteroarylalkyl, the substituents of the substituted alkyl, alkenyl, arylalkyl or heteroarylalkyl being one or more optional halogen, alkyl or alkoxy groups.
In some embodiments, the halogen is optionally fluorine, chlorine or bromine.
In some specific embodiments, the unsubstituted alkyl, alkenyl, arylalkyl, or heteroarylalkyl is optionally methyl, ethyl, propyl, butyl, ethylene, allyl, butadienyl, benzyl, phenethyl, phenylpropyl, picolyl, or pyridylethyl.
In some embodiments, the substituted alkyl, alkenyl, arylalkyl, or heteroarylalkyl is an optional haloalkyl, haloalkenyl, haloarylalkyl, haloheteroarylalkyl, alkylaryl, alkylheteroarylalkyl, alkoxyarylalkyl, or alkoxyheteroarylalkyl.
In some more specific embodiments, the substituted alkyl, alkenyl, arylalkyl, or heteroarylalkyl is an optional fluoromethyl, fluoroethyl, chloromethyl, fluorobenzyl, fluoropyridylmethyl, methylphenylmethyl, picolmethyl, methoxyphenylmethyl, or methoxypyridylmethyl.
In some specific embodiments, R 3 is optionally alkyl, alkenyl, arylalkyl, heteroarylalkyl, haloalkyl, haloalkenyl, haloarylalkyl, haloheteroarylalkyl, alkylaryl, alkylheteroarylalkyl, alkoxyarylalkyl, or alkoxyheteroarylalkyl.
In some more specific embodiments, R 3 is optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, ethylene, allyl, butadienyl, benzyl, phenethyl, phenylpropyl, picolyl, fluoromethyl, fluoroethyl, chloromethyl, fluorobenzyl, fluoropyridylmethyl, methylphenylmethyl, picolmethyl, methoxyphenylmethyl, or methoxypyridylmethyl.
In some specific embodiments, R 3 is optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, allyl, phenylpropyl, picolyl, or methoxyphenylmethyl.
Preferably, in the compounds of formula I, R 1 is optionally substituted or unsubstituted C2-C12 alkyl, C3-C12 alkenyl or C3-C12 alkynyl; r 2 is 1 to 3 each independently optionally substituted or unsubstituted hydrogen, halogen, hydroxy, amino, alkyl, alkoxy, alkanoyloxy, alkylthio, alkylamino, cyano, nitro, carboxy, sulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, amido, alkoxycarbonyl, or alkanoyl; r 3 is optionally substituted or unsubstituted C1-C12 alkyl, C2-C12 alkenyl or C2-C12 alkynyl.
Further preferred, in the compounds of formula I, R 1 is optionally substituted or unsubstituted arylalkyl or heteroarylalkyl; r 2 is 1 to 3 each independently optionally substituted or unsubstituted halogen, alkyl, alkoxy or nitro; r 3 is optionally substituted or unsubstituted alkyl, alkenyl, arylalkyl or heteroarylalkyl.
Still further preferred are compounds of formula I wherein R 1 is optionally substituted or unsubstituted arylalkyl or heteroarylalkyl, the substituents of said substituted arylalkyl or heteroarylalkyl being one or more optional halogen, alkyl, alkoxy, haloalkyl or haloalkoxy; r 2 is 1 to 3 each independently optionally substituted or unsubstituted halogen, alkyl, alkoxy or nitro, the substituents of the substituted alkyl or alkoxy being one or more optionally halogen or aryl; r 3 is optionally substituted or unsubstituted alkyl, alkenyl, arylalkyl, or heteroarylalkyl, the substituents of the substituted alkyl, alkenyl, arylalkyl, or heteroarylalkyl being one or more optional halogen, alkyl, or alkoxy groups.
More preferably, in the compounds of formula I, R 1 is optionally arylalkyl, heteroarylalkyl, methoxyarylalkyl, dimethoxyarylalkyl, trimethoxyarylalkyl, ethoxyarylalkyl, diethoxyarylalkyl or triethoxyarylalkyl; r 2 is 1-2 each independently optionally halogen, alkyl, alkoxy, nitro, haloalkyl, haloalkoxy, arylalkyl, or arylalkoxy; r 3 is optionally alkyl, alkenyl, arylalkyl, heteroarylalkyl, haloalkyl, haloalkenyl, haloarylalkyl, haloheteroarylalkyl, alkylaryl alkyl, alkylheteroarylalkyl, alkoxyarylalkyl, or alkoxyheteroarylalkyl.
Most preferably, in the compounds of formula I, R 1 is optionally benzyl, phenethyl, phenylpropyl, phenylbutyl, methoxybenzyl, dimethoxybenzyl, trimethoxybenzyl, methoxyphenethyl, dimethoxyphenethyl or trimethoxyphenethyl; r 2 is 1-2 each independently of the other optionally fluorine, chlorine, bromine, nitro, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, fluoroethyl, chloroethyl, fluoromethoxy, fluoroethoxy, chloromethoxy, chloroethoxy, benzyloxy, phenethoxy, phenylpropoxy or phenylbutoxy; r 3 is optionally methyl, ethyl, propyl, butyl, ethylene, allyl, butadienyl, benzyl, phenethyl, picolyl, fluoromethyl, fluoroethyl, chloromethyl, fluorobenzyl, fluoropyridylmethyl, methylphenylmethyl, picolmethyl, methoxyphenylmethyl or methoxypyridylmethyl.
In some specific embodiments, in the compound of formula I, R 1 is optionally phenylpropyl or trimethoxybenzyl; r 2 is 1-2 optional nitro, methoxy, trifluoromethyl and phenylpropoxy groups; r 3 is optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, allyl, phenylpropyl, picolyl, methoxyphenylmethyl.
In some embodiments of the invention, the compound of formula I is selected from at least one of the following compounds:
in a second aspect, the present invention provides a method for preparing a quinoline derivative according to the first aspect of the present invention, comprising the steps of:
1) Reacting a compound of formula II with R 1 X in the presence of a base to obtain a compound of formula III;
2) Reacting a compound of formula III with an R 2 substituted aniline in the presence of an acid to obtain a compound of formula IV;
3) Reacting a compound of formula IV with R 3 X in the presence of a base to obtain a compound of formula I;
wherein each X is independently halogen, R 1、R2 and R 3 are as defined in the first aspect of the invention.
Preferably, in the preparation method, the base in step 1) is selected from NaH.
Preferably, in the preparation method, the acid in step 2) is selected from concentrated hydrochloric acid.
Preferably, in the preparation method, the base in step 3) is selected from NaH.
In a third aspect the present invention provides a pharmaceutical composition comprising a quinoline derivative according to the first aspect of the invention and a pharmaceutically acceptable carrier.
In a fourth aspect, the present invention provides the use of a quinoline derivative according to the first aspect of the present invention in the manufacture of a medicament for the treatment of a proliferative disorder.
Preferably, the proliferative disease is a malignancy.
Preferably, the malignant tumor comprises at least one of colorectal cancer, liver cancer, gastric cancer, lung cancer or glioma.
The beneficial effects of the invention are as follows:
The quinoline derivative provided by the invention has excellent anti-tumor activity, can be used for preparing medicaments for treating proliferative diseases, and can be used for effectively treating the proliferative diseases, in particular malignant tumors such as colorectal cancer, liver cancer, gastric cancer, lung cancer or glioma.
Detailed Description
The terms used in the present application have conventional meanings in the related art. In particular, the specific meaning of some terms in the present application is given below. When these terms are interpreted differently in the related art, the definition in the present application controls.
The term "alkyl" in the present application means a straight or branched saturated hydrocarbon group, typically the alkyl group has 1 or more carbon atoms, for example, a C1-C12 alkyl group means an alkyl group having 1 to 12 carbon atoms. Similarly, the alkyl group may also be a C2-C12 alkyl group, a C2-C11 alkyl group, a C2-C10 alkyl group, a C2-C9 alkyl group, a C2-C8 alkyl group, a C2-C7 alkyl group, a C2-C6 alkyl group, a C2-C5 alkyl group, a C2-C4 alkyl group, such as a C2 alkyl (i.e., ethyl) group, a C3 alkyl group (including n-propyl, isopropyl), a C4 alkyl group (including n-butyl, isobutyl), a C5 alkyl group (including n-pentyl, isopentyl, neopentyl), a C6 alkyl group (including n-hexyl, various branched hexyl groups), a C7 alkyl group (heptyl) a C8 alkyl group (octyl group), a C9 alkyl group (nonyl group), a C10 alkyl group (decyl group), a C11 alkyl group (undecyl group), a C12 alkyl group (dodecyl group). In addition, in the present application, when alkyl is mentioned among other groups, such as alkoxy, alkanoyl, alkoxycarbonyl, wherein alkyl has the definition of alkyl herein, some groups (e.g., alkanoyl) include carbon atoms other than alkyl in the structure used to calculate the number of carbon atoms.
The term "alkenyl" in the present application means a straight or branched hydrocarbon group having one or more carbon-carbon double bonds. For example C2-C12 alkenyl, C3-C11 alkenyl, C3-C10 alkenyl, C3-C9 alkenyl, C3-C8 alkenyl, C3-C7 alkenyl, C3-C6 alkenyl, C3-C5 alkenyl, C3-C4 alkenyl, C4-C12 alkenyl, C4-C11 alkenyl, C4-C10 alkenyl, C4-C9 alkenyl, C4-C8 alkenyl, C4-C7 alkenyl, C4-C6 alkenyl, C4-C5 alkenyl. In particular, the alkenyl group may be a C3 alkenyl group (e.g., allyl), a C4 alkenyl group (e.g., 1, 3-butadienyl), a C5 alkenyl group, a C6 alkenyl group, a C7 alkenyl group, a C8 alkenyl group, a C9 alkenyl group, a C10 alkenyl group, a C11 alkenyl group, a C12 alkenyl group.
Similarly, the term "alkynyl" in the present application means a straight or branched hydrocarbon group having one or more carbon-carbon triple bonds. For example, C2-C12 alkynyl, C3-C11 alkynyl, C3-C10 alkynyl, C3-C9 alkynyl, C3-C8 alkynyl, C3-C7 alkynyl, C3-C6 alkynyl, C3-C5 alkynyl, C3-C4 alkynyl, C4-C12 alkynyl, C4-C11 alkynyl, C4-C10 alkynyl, C4-C9 alkynyl, C4-C8 alkynyl, C4-C7 alkynyl, C4-C6 alkynyl, C4-C5 alkynyl. Specifically, the alkynyl group may be a C3 alkynyl group (e.g., propargyl group), a C4 alkynyl group (e.g., 1, 3-butanediyl group), a C5 alkynyl group, a C6 alkynyl group, a C7 alkynyl group, a C8 alkynyl group, a C9 alkynyl group, a C10 alkynyl group, a C11 alkynyl group, a C12 alkynyl group.
The term "aryl" in the present application means a carbocyclic group having a cyclic conjugated structure. The aryl group may have 6 or more carbon atoms, for example, a C6-C14 aryl group, a C6-C12 aryl group, a C6-C10 aryl group. In particular, the aryl group may be phenyl, naphthyl, anthryl, phenanthryl.
The term "heteroaryl" in the present application means a cyclic group having one or more heteroatoms selected from N, O and S in the cyclic conjugated structure. The number of ring atoms in the heteroaryl group can be 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more. In particular, the heteroaryl group may be pyridinyl, thienyl, pyrazolyl, pyrimidinyl, indolyl, purinyl, thiazolyl, morpholinyl.
The term "heterocyclyl" in the present application denotes a cyclic group having one or more heteroatoms selected from N, O and S, such as piperidinyl, piperazinyl, pyrrolidinyl, pyranyl, oxacyclopentyl, dioxanyl.
The term "halogen" in the present application means fluorine, chlorine, bromine, iodine.
The term "substituted" in the present application may denote the substitution of any atom or group, except that the following two conditions are required: the valence is applicable; the system can be made chemically stable. The definition of any substituent or variable at a particular position in a molecule should be independent of the definition of other positions in the molecule. It will be appreciated that substituents and substitution patterns for the compounds of this application may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that are readily synthesized by techniques known in the art and described herein.
The term "treatment" in the present application means any treatment that allows the health of the subject to be treated to be alleviated, ameliorated, restored, eliminated from the disease state, and to prevent the risk of developing a disease and improve the prognosis of the disease. Including but not limited to, drug therapy, radiation therapy, chemotherapy, surgical therapy, and vaccination.
The present invention will be described in further detail with reference to specific examples. It is also to be understood that the following examples are given solely for the purpose of illustration and are not to be construed as limitations on the scope of the invention, since various modifications and adaptations may be made by those skilled in the art in light of the teachings herein. The specific process parameters and the like described below are also merely examples of suitable ranges, i.e., one skilled in the art can make a selection within the suitable ranges by the description herein and are not intended to be limited to the specific data described below. The starting materials, reagents or apparatus used in the following examples and comparative examples were obtained from conventional commercial sources or by known methods unless otherwise specified.
The general synthetic route for the quinoline derivatives according to the invention is shown below, the synthesis of compounds 10a-g being carried out according to the scheme disclosed in the prior art (scheme one of the examples in patent application publication number WO2017198196A1, corresponding to application number PCT/CN 2017/084929).
Preparation example
The general synthetic procedure for compounds 11a-11ab is as follows:
In a 100mL round bottom flask, the compounds 10a-g (1 mmol), DMF (10 mL) and sodium hydride (2 mmol) were added, stirred until the solid dissolved, heated to 60℃for 5min, and then the corresponding halogenated compound was added for a further reaction for 8h. The reaction solution was cooled to room temperature, then poured into water (50 mL), extracted 3 times with dichloromethane, the organic phases were combined, washed 2 times with water, washed 2 times with saturated brine, and dried over anhydrous sodium sulfate. Filtration, concentration to dryness under reduced pressure, column chromatography to remove reaction impurities, and use mobile phase dichloromethane: methanol=80: 1. dichloromethane: methanol=50: 1. dichloromethane: methanol=20: eluting 1, collecting target product, concentrating under reduced pressure to dry to obtain compound 11a-11ab.
Preparation example 1: compound 11a
Starting from compound 10a (0.45 g,1.0 mmol) and allyl bromide (0.18 g,1.5 mmol) a pale brown solid was obtained (0.38g,78.6％).MP：173.6-175.4℃;1H NMR(400MHz,CDCl3)δ8.95(d,J＝9.1Hz,1H),7.46(d,J＝7.6Hz,1H),7.14(t,J＝8.0Hz,1H),7.04(dd,J＝9.1,2.1Hz,1H),6.80(d,J＝2.1Hz,1H),6.76–6.67(m,3H),6.64–6.56(m,3H),6.24(d,J＝7.6Hz,1H),5.82–5.74(m,1H),5.17(d,J＝10.5Hz,1H),5.05(s,2H),4.72(s,2H),3.79(s,6H),3.77(s,3H),3.68(s,3H).13C NMR(100MHz,CDCl3)δ161.99,160.60,154.86,153.54,142.34,140.49,137.93,131.42,130.82,130.03,128.74,118.81,116.04,115.68,114.59,110.69,109.12,104.66,100.49,100.32,71.70,71.06,70.78,69.31,61.81,60.84,56.21,55.54,55.33.
Preparation example 2: compound 11b
Starting from compound 10a (0.45 g,1.0 mmol) and bromoethane (0.16 g,1.5 mmol) an off-white solid was obtained (0.28g,59.2％).MP：143.9-145.1℃;1H NMR(400MHz,CDCl3)δ8.78(d,J＝8.0Hz,1H),7.25(d,J＝8.0Hz,1H),7.16–7.09(m,1H),7.02–6.96(m,1H),6.78(s,1H),6.67–6.51(m,6H),6.11–6.06(m,1H),5.06(s,2H),4.02(dd,J＝8.0Hz,2H),3.80–3.78(m,6H),3.78–3.75(m,3H),3.70–3.67(m,3H),1.30–1.24(m,3H).13C NMR(100MHz,CDCl3)161.42,160.47,154.68,153.33,149.02,141.15,139.92,137.56,131.79,129.85,128.02,117.02,115.03,113.51,109.26,108.33,104.57,100.34,99.49,98.73,77.91,70.48,63.66,60.61,56.03,55.03,47.91,29.54.
Preparation example 3: compound 11c
Starting from compound 10a (0.45 g,1.0 mmol) and 1-bromo-3-phenylpropane (0.30 g,1.5 mmol), a brown solid (0.30 g, 52.8%) was obtained. MP: greater than 200℃;1H NMR(400MHz,CDCl3)δ9.44(d,J＝8.0Hz,1H),8.13(d,J＝7.6Hz,1H),7.27–7.22(m,1H),7.20–7.14(m,3H),7.13–7.05(m,3H),6.97(s,1H),6.90(d,J＝7.6Hz,1H),6.84(d,J＝1.6Hz,1H),6.67(dd,J＝8.0,2.4Hz,1H),6.61(s,2H),6.57(d,J＝7.2Hz,1H),4.41(t,J＝7.2Hz,2H),3.80(s,6H),3.76(s,3H),3.66(s,3H),3.48(q,J＝7.2Hz,2H),2.65(t,J＝7.2Hz,2H),2.14–2.05(m,2H).13C NMR(100MHz,CDCl3)δ163.00,160.42,154.79,153.46,145.69,140.09,139.94,138.38,137.94,130.87,130.16,129.22,128.61,128.46,128.32,126.39,117.45,117.36,113.32,112.76,111.30,104.90,99.84,99.36,70.96,62.97,60.77,56.20,55.38,53.88,52.75,32.28,29.89,29.61,27.86.
Preparation example 4: compound 11d
Starting from compound 10a (0.45 g,1.0 mmol) and p-methoxybenzyl chloride (0.23 g,1.5 mmol) a white solid was obtained (0.37g,65.0％).MP：167.5-170.2℃;1H NMR(400MHz,CDCl3)δ8.76(d,J＝9.2Hz,1H),7.45(d,J＝8.0Hz,1H),7.14(t,J＝8.0Hz,1H),7.01(d,J＝2.4Hz,1H),6.97(d,J＝8.8Hz,3H),6.78(d,J＝2.0Hz,1H),6.74(dd,J＝9.2,2.4Hz,2H),6.70(t,J＝2.0Hz,1H),6.67(d,J＝8.0Hz,1H),6.59(dd,J＝8.4,2.4Hz,1H),6.52(s,2H),5.14(s,2H),4.91(s,2H),3.76(s,3H),3.74(s,6H),3.68(s,3H),3.67(s,3H).13C NMR(100MHz,CDCl3)δ176.78,161.96,160.67,159.61,155.19,153.49,146.20,142.50,140.61,137.91,131.39,130.08,128.51,127.93,126.41,116.30,115.72,114.68,114.56,110.74,109.11,104.62,100.38,70.65,60.83,60.38,56.36,56.15,55.31,55.29,53.49,50.27,29.68,23.71.
Preparation example 5: compound 11e
Starting from compound 10b (0.46 g,1.0 mmol) and allyl bromide (0.18 g,1.5 mmol), a yellow solid (0.43 g, 86.3%) was obtained. MP: greater than 200℃;1H NMR(400MHz,CDCl3)δ8.47(d,J＝8.8Hz,1H),7.74(s,2H),7.36(t,J＝8.0Hz,1H),7.22(d,J＝8.0Hz,1H),6.97–6.92(m,2H),6.65(d,J＝2.0Hz,1H),6.60(s,2H),5.86–5.78(m,2H),5.28–5.17(m,2H),5.00(s,2H),4.43(d,J＝8.2Hz,2H),3.80(s,6H),3.78(s,3H).13C NMR(100MHz,CDCl3)δ161.29,155.58,153.57,149.27,140.53,140.40,137.96,132.58,131.74,131.23,129.87,128.83,128.12,118.83,118.42,118.33,118.30,116.76,112.41,104.71,100.22,100.17,70.66,69.11,60.87,60.39,56.20,54.55.
Preparation example 6: compound 11f
Starting from compound 10b (0.46 g,1.0 mmol) and bromoethane (0.16 g,1.5 mmol) a pale brown solid was obtained (0.30g,61.7％).MP：164.0-166.2℃;1H NMR(400MHz,CDCl3)δ8.60(d,J＝8.8Hz,1H),7.78(d,J＝8.8Hz,2H),7.38(t,J＝8.0Hz,1H),7.34–7.27(m,1H),7.12(d,J＝7.6Hz,1H),7.00(dd,J＝8.8,2.0Hz,1H),6.76(d,J＝2.4Hz,1H),6.63(s,2H),5.93(d,J＝8.0Hz,1H),5.06(s,2H),3.96(d,J＝7.2Hz,2H),3.81(s,6H),3.78(s,3H),1.32(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ161.46,155.75,153.59,149.20,140.29,140.03,137.95,131.72,129.93,129.12,128.41,123.98,118.61,117.04,112.48,104.72,100.11,99.78,70.76,60.87,56.20,47.71,31.93,31.44,30.20,29.71,22.70.
Preparation example 7: compound 11g
Starting from compound 10b (0.46 g,1.0 mmol) and 1-bromo-3-phenylpropane (0.30 g,1.5 mmol), a beige solid was obtained (0.45g,77.2％).MP：158.1-161.7℃;1H NMR(400MHz,CDCl3)δ8.91(d,J＝9.2Hz,1H),7.95(s,1H),7.85(d,J＝8.0Hz,1H),7.60–7.49(m,2H),7.42(t,J＝8.0Hz,1H),7.25–7.17(m,3H),7.15–7.05(m,4H),6.73(s,1H),6.62(s,2H),6.18(d,J＝7.6Hz,1H),4.94(s,2H),4.13(t,J＝7.0Hz,2H),3.82(s,6H),3.78(s,3H),2.66(t,J＝7.2Hz,2H),2.15–2.05(m,2H).13CNMR(100MHz,CDCl3)δ162.39,155.10,153.59,148.92,143.30,140.23,139.86,138.09,131.17,130.28,130.15,128.76,128.35,126.57,119.06,118.28,115.25,104.96,99.81,99.51,70.93,60.87,56.27,53.21,32.51,31.93,31.52,31.44,30.20,30.15,29.71,29.47,29.36,22.70.
Preparation example 8: compound 11h
Starting from compound 10b (0.46 g,1.0 mmol) and p-methoxybenzyl chloride (0.23 g,1.5 mmol), a white solid (0.33 g, 56.3%) was obtained. MP: greater than 200℃;1H NMR(400MHz,CDCl3)δ8.54(d,J＝8.4Hz,1H),7.85(d,J＝6.8Hz,2H),7.45(t,J＝8.0Hz,1H),7.35–7.28(m,1H),7.08(d,J＝8.0Hz,3H),6.99(d,J＝8.0Hz,1H),6.88(d,J＝8.0Hz,2H),6.70(s,1H),6.60(s,1H),5.94(d,J＝6.4Hz,1H),5.05(s,2H),4.97(s,2H),3.85(s,3H),3.85(s,6H),3.78(s,3H).13C NMR(100MHz,CDCl3)δ171.14,162.61,161.46,159.54,155.71,153.50,152.54,149.20,141.24,140.66,137.91,131.59,129.96,129.14,128.14,127.65,126.85,118.51,117.20,117.08,114.56,113.09,104.61,100.38,100.02,70.56,60.82,60.37,56.14,55.77,55.29,36.48,31.42,29.67,21.01.
Preparation example 9: compound 11i
Starting from compound 10c (0.46 g,1.0 mmol) and allyl bromide (0.18 g,1.5 mmol) a white solid was obtained (0.28g,59.9％).MP：127.2-128.5℃;1H NMR(400MHz,CDCl3)δ8.44(d,J＝8.8Hz,1H),7.33(t,J＝7.6Hz,1H),7.25–7.10(m,7H),7.05(d,J＝8.0Hz,1H),6.88–6.80(m,2H),6.53(d,J＝2.4Hz,1H),5.94–5.74(m,2H),5.20(d,J＝10.4Hz,1H),5.09(d,J＝10.4Hz,1H),4.39(d,J＝4.4Hz,2H),3.95(t,J＝6.4Hz,2H),2.75(t,J＝7.6Hz,2H),2.10–2.00(m,2H).13C NMR(100MHz,CDCl3)δ161.53,155.33,141.26,140.57,139.89,131.68,131.51,131.36,129.64,128.54,128.51,127.98,126.08,125.38,123.10,118.81,118.50,118.26,111.92,100.38,99.57,67.17,54.42,32.10,31.53,30.69,29.72,29.29.
Preparation example 10: compound 11j
Starting from compound 10c (0.46 g,1.0 mmol) and bromoethane (0.16 g,1.5 mmol) a pale brown solid was obtained (0.33g,74.4％).MP：144.6-147.0℃;1H NMR(400MHz,CDCl3)δ9.52(d,J＝8.0Hz,1H),8.33(d,J＝6.4Hz,1H),7.76–7.64(m,2H),7.45(t,J＝8.0Hz,2H),7.32–7.19(m,3H),7.15(d,J＝7.6Hz,3H),6.93(d,J＝1.6Hz,1H),6.60(d,J＝6.8Hz,1H),4.48(d,J＝6.4Hz,2H),4.09(t,J＝6.0Hz,2H),2.78(t,J＝7.2Hz,2H),2.18–2.07(m,2H),1.47(t,J＝5.6Hz,3H).13C NMR(100MHz,CDCl3)δ163.17,160.57,154.97,153.47,150.43,149.85,148.85,147.92,145.82,140.36,138.14,137.91,137.12,134.71,130.76,130.36,130.09,128.93,123.92,117.63,117.19,113.16,113.05,111.19,104.55,100.37,100.24,70.99,60.96,60.83,56.21,55.48,55.44,44.83.
Preparation example 11: compound 11k
Starting from compound 10c (0.46 g,1.0 mmol) and 1-bromo-3-phenylpropane (0.30 g,1.5 mmol), a yellow solid was obtained (0.24g,44.1％).MP：183.5-184.8℃;1H NMR(400MHz,CDCl3)δ12.06(s,1H),9.47(d,J＝8.4Hz,1H),8.31(s,1H),7.63(s,2H),7.39(s,2H),7.26–7.01(m,12H),6.56(s,1H),6.51(s,1H),4.41(s,1H),3.79(s,2H),2.75(s,2H),2.70(s,2H),2.15(s,2H),2.06(s,2H).13C NMR(100MHz,CDCl3)δ162.36,158.28,153.43,153.49,151.42,148.64,148.79,146.02,145.98,141.17,138.84,137.42,136.30,133.48,130.88,130.25,130.12,129.63,122.45,116.71,116.34,115.71,113.72,112.12,107.38,103.75,101.63,73.07,61.37,60.19,58.97,56.67,53.29,42.20.
Preparation example 12: compound 11l
Starting from compound 10c (0.46 g,1.0 mmol) and p-methoxybenzyl chloride (0.23 g,1.5 mmol) a yellow solid was obtained (0.28g,52.3％).MP：157.1-159.5℃;1H NMR(400MHz,CDCl3)δ8.44(d,J＝9.2Hz,1H),7.33(t,J＝8.0Hz,1H),7.23–7.14(m,5H),7.09(d,J＝8.0Hz,3H),7.02(d,J＝8.0Hz,2H),6.96(d,J＝7.6Hz,1H),6.82–6.74(m,3H),6.49(s,1H),5.83(d,J＝7.6Hz,1H),4.92(s,2H),3.83(t,J＝6.4Hz,2H),3.68(s,3H),2.68(t,J＝7.6Hz,2H),2.06–1.90(m,2H).13C NMR(100MHz,CDCl3)δ161.48,159.47,155.38,153.22,145.38,141.22,140.66,140.36,129.67,128.50,127.97,127.64,127.35,126.06,125.47,124.39,123.51,118.86,118.62,114.57,112.28,100.28,99.78,67.12,55.57,55.32,35.03,32.06,31.54,30.54,30.20,29.73,29.39.
Preparation example 13: compound 11m
Starting from compound 10c (0.46 g,1.0 mmol) and 4-chloromethylpyridine (0.38 g,1.5 mmol), a black solid (0.18 g, 35.5%) was obtained. MP: greater than 200℃;1H NMR(400MHz,CDCl3)δ8.29(d,J＝8.8Hz,2H),7.70(d,J＝7.2Hz,1H),7.30–7.24(m,6H),7.22–7.15(m,6H),7.01(d,J＝2.0Hz,1H),6.96(dd,J＝8.8,2.4Hz,1H),6.26(d,J＝7.2Hz,2H),3.92(t,J＝6.4Hz,2H),2.76(t,J＝6.4Hz,2H),2.12–2.04(m,2H).13C NMR(100MHz,CDCl3)δ161.97,155.44,153.60,149.08,141.84,140.54,138.03,137.46,132.20,131.39,130.72,130.16,129.69,128.62,119.18,118.96,118.68,118.45,117.56,114.06,104.70,100.35,100.10,70.84,69.31,60.90,56.23,55.31,31.92,29.66,22.69.
Preparation example 14: compound 11n
Starting from compound 10d (0.43 g,1.0 mmol) and methyl iodide (0.21 g,1.5 mmol), a pale brown solid (0.25 g, 57.0%) was obtained. MP: greater than 200℃;1H NMR(400MHz,CDCl3)δ7.46(d,J＝8.6Hz,2H),7.31–7.21(m,6H),7.17(d,J＝6.2Hz,3H),7.06(dd,J＝8.6,2.2Hz,2H),4.17–4.07(m,2H),3.79(s,3H),2.80(s,3H),2.37(t,J＝7.4Hz,2H),2.27(t,J＝7.4Hz,2H).13C NMR(100MHz,CDCl3)δ163.47,159.19,155.18,147.11,145.56,141.07,140.97,138.47,128.57,128.51,126.19,124.48,123.98,119.09,116.78,111.70,98.85,68.01,56.65,42.34,34.88,34.53,31.93,31.44,30.20,29.70.
Preparation example 15: compound 11o
Starting from compound 10d (0.43 g,1.0 mmol) and bromoethane (0.16 g,1.5 mmol) a brown solid was obtained (0.16g,35.2％).MP：193.2-197.0℃;1H NMR(400MHz,CDCl3)δ7.99(s,1H),7.95(d,J＝8.0Hz,1H),7.53(t,J＝8.0Hz,2H),7.31(d,J＝8.6Hz,1H),7.11(d,J＝8.6Hz,3H),6.94–6.89(m,3H),6.63(s,2H),4.15(q,J＝7.2Hz,2H),3.88(d,J＝2.8Hz,6H),3.84(s,2H),3.82(s,3H),2.07(s,3H).13C NMR(100MHz,CDCl3)δ161.44,160.78,159.48,154.94,152.93,141.30,140.72,140.37,129.99,128.55,128.07,127.73,127.51,126.11,126.05,118.44,114.53,112.38,108.60,107.47,100.82,99.77,67.15,55.63,55.31,32.06,30.60.
Preparation example 16: compound 11p
Starting from compound 10d (0.43 g,1.0 mmol) and 1-bromopropane (0.18 g,1.5 mmol), a brown solid (0.20 g, 41.4%) was obtained. MP: greater than 200℃;1H NMR(400MHz,CDCl3)δ9.08(d,J＝7.6Hz,1H),8.10–8.02(m,2H),7.71(s,1H),7.36–7.22(m,6H),7.12(d,J＝8.8Hz,1H),7.01(d,J＝8.8Hz,1H),6.81(s,1H),6.10–5.94(m,2H),5.37(d,J＝9.2Hz,1H),5.26–5.19(m,1H),4.85(s,3H),4.10(t,J＝6.2Hz,2H),3.89(s,3H),2.86(t,J＝7.6Hz,2H),2.25–2.14(m,2H).13C NMR(100MHz,CDCl3)δ155.46,153.60,149.15,140.55,137.98,132.26,131.42,130.84,130.76,130.14,129.63,128.58,119.09,118.92,118.55,117.53,113.91,104.72,100.34,100.10,100.03,70.83,69.34,60.87,56.23,55.27,31.92,29.63.
Preparation example 17: compound 11q
Starting from compound 10d (0.43 g,1.0 mmol) and 2-bromopropane (0.18 g,1.5 mmol) a white solid was obtained (0.25g,54.1％).MP：176.3-178.7℃;1H NMR(400MHz,CDCl3)δ8.53(d,J＝4.4Hz,1H),8.25(d,J＝2.0Hz,1H),7.90(dd,J＝8.8,1.6Hz,1H),7.81(d,J＝9.2Hz,1H),7.25–7.10(m,7H),7.03(d,J＝4.8Hz,1H),6.94(d,J＝8.8Hz,1H),4.06(t,J＝5.6Hz,2H),3.97(s,3H),2.78(t,J＝8.0Hz,2H),2.16–2.07(m,2H),1.18(s,3H).13C NMR(100MHz,CDCl3)δ160.47,154.45,150.35,145.63,141.65,141.33,130.44,128.52,128.49,126.04,121.37,119.16,119.04,115.19,113.33,110.18,108.25,102.81,67.35,56.61,32.22,31.94,30.66,30.16,29.71,29.67,29.37,22.00.
Preparation example 18: compound 11r
Starting from compound 10d (0.43 g,1.0 mmol) and 1-bromobutane (0.20 g,1.5 mmol), a beige solid (0.21 g, 43.5%) was obtained. MP: greater than 200℃;1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.36(d,J＝9.2Hz,1H),7.91(d,J＝7.2Hz,1H),7.67–7.61(m,2H),6.80(d,J＝8.8Hz,2H),6.75(s,1H),6.61–6.55(m,3H),6.50(t,J＝6.8Hz,1H),5.67(d,J＝7.2Hz,1H),3.96(t,J＝6.4Hz,2H),3.63(t,J＝6.0Hz,2H),3.24(s,2H),2.72(s,3H),2.13(t,J＝7.6Hz,2H),1.50–1.40(m,2H),1.13–1.01(m,2H),0.21(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ163.49,160.17,154.82,147.09,141.64,141.09,140.52,140.45,128.83,127.87,126.38,126.17,125.57,124.34,118.23,114.11,113.74,112.76,101.02,100.42,69.42,68.56,57.40,54.28,31.87,31.59,31.00,30.54,30.28.
Preparation example 19: compound 11s
Starting from compound 10e (0.38 g,1.0 mmol) and allyl bromide (0.18 g,1.5 mmol) an off-white solid was obtained (0.29g,67.7％).MP：145.0-146.4℃;1H NMR(400MHz,CDCl3)δ8.60(d,J＝9.2Hz,1H),7.25–7.18(m,3H),7.16–7.11(m,4H),6.96(d,J＝7.6Hz,1H),6.86(dd,J＝9.2,2.0Hz,1H),6.57–6.49(m,4H),5.98(d,J＝8.0Hz,1H),5.20(d,J＝10.0Hz,1H),5.13–5.06(m,1H),4.45(d,J＝4.4Hz,2H),3.96(t,J＝6.0Hz,2H),3.74(s,3H),2.75(t,J＝7.2Hz,2H),2.13–1.98(m,2H).13CNMR(100MHz,CDCl3)δ161.70,160.70,154.87,141.23,140.59,140.21,131.47,129.92,128.55,128.52,128.50,128.23,126.08,118.35,117.91,114.62,112.39,108.95,107.67,100.81,99.56,67.27,55.25,54.65,35.00,32.09,30.65.
Preparation example 20: compound 11t
Starting from compound 10e (0.38 g,1.0 mmol) and 1-bromo-3-phenylpropane (0.30 g,1.5 mmol), preparation example 21 was obtained as a beige solid (0.25g,49.8％).MP：166.3-168.0℃;1H NMR(400MHz,CDCl3)δ8.51(d,J＝9.2Hz,1H),7.22–7.15(m,4H),7.15–7.09(m,5H),7.07(d,J＝7.6Hz,2H),6.85–6.78(m,2H),6.50(s,1H),6.49(s,2H),6.35(d,J＝1.6Hz,1H),5.87(d,J＝8.0Hz,1H),3.80(t,J＝6.0Hz,2H),3.75(t,J＝7.4Hz,2H),3.68(s,3H),2.74(t,J＝7.6Hz,2H),2.59(t,J＝7.2Hz,2H),2.09–1.92(m,4H).13C NMR(100MHz,CDCl3)δ161.62,160.79,155.03,153.16,141.36,140.46,140.27,130.02,128.88,128.70,128.62,128.57,128.49,128.08,126.39,126.14,118.39,114.63,112.31,108.42,107.68,100.54,98.58,72.07,71.06,67.02,61.57,55.18,51.54,32.62,32.14,31.83,30.76,29.69.: compound 11u
Starting from compound 10e (0.38 g,1.0 mmol) and p-methoxybenzyl chloride (0.23 g,1.5 mmol) an off-white solid was obtained (0.28g,55.0％).MP：173.9-176.5℃;1H NMR(400MHz,CDCl3)δ8.61(d,J＝8.4Hz,1H),7.32–7.14(m,7H),7.12–7.04(m,3H),6.87(t,J＝9.6Hz,3H),6.60(s,3H),6.05(d,J＝7.6Hz,1H),5.02(s,2H),3.93(t,J＝6.4Hz,2H),3.80(s,3H),3.77(s,3H),2.76(t,J＝7.6Hz,2H),2.13–2.01(m,2H).13C NMR(100MHz,CDCl3)δ161.45,160.73,159.42,154.90,152.79,141.25,140.67,140.40,129.95,128.51,128.23,128.00,127.68,127.45,126.06,124.42,123.54,118.91,118.39,114.53,112.40,108.63,107.51,100.75,99.78,67.16,55.59,55.32,55.24,32.06,31.56,30.53,29.74.
Preparation example 22: compound 11v
Starting from compound 10e (0.38 g,1.0 mmol) and 4-chloromethylpyridine (0.24 g,1.5 mmol), an off-white solid (0.15 g, 32.4%) was obtained. MP: greater than 200℃;1H NMR(400MHz,CDCl3)δ11.86(s,1H),9.35(d,J＝9.6Hz,1H),8.41(s,2H),7.58(d,J＝7.6Hz,1H),7.20(t,J＝3.6Hz,3H),7.16–7.12(m,2H),7.06(t,J＝7.6Hz,3H),7.00(s,1H),6.93(d,J＝7.6Hz,1H),6.81(s,1H),6.69(d,J＝8.0Hz,1H),6.64(d,J＝7.2Hz,1H),5.80(s,2H),3.91(t,J＝6.0Hz,3H),3.67(s,3H),2.66(t,J＝7.6Hz,2H),2.02–1.92(m,2H).13C NMR(100MHz,CDCl3)δ163.63,160.57,155.06,149.88,147.96,145.96,140.84,140.36,138.15,134.84,130.30,130.18,129.17,128.53,128.44,126.16,124.03,117.30,117.26,113.09,113.02,111.25,100.09,99.69,68.11,55.48,55.38,31.90,31.43,30.19,29.69.
Preparation example 23: compound 11w
Starting from compound 10f (0.40 g,1.0 mmol) and allyl bromide (0.18 g,1.5 mmol), a white solid (0.40 g, 91.3%) was obtained. MP: greater than 200℃;1H NMR(400MHz,CDCl3)δ8.41(d,J＝9.2Hz,1H),7.75–7.69(m,2H),7.34(t,J＝8.0Hz,1H),7.21(t,J＝7.2Hz,3H),7.15–7.09(m,3H),6.89(d,J＝7.6Hz,1H),6.82(dd,J＝9.2,2.0Hz,1H),6.53(d,J＝2.0Hz,1H),5.90–5.76(m,2H),5.24–5.16(m,1H),5.13–5.04(m,1H),4.40(d,J＝4.0Hz,2H),3.95(t,J＝6.0Hz,2H),2.74(t,J＝7.6Hz,2H),2.10–2.00(m,2H).13C NMR(100MHz,CDCl3)δ161.65,155.73,154.49,149.29,141.30,140.60,140.37,131.54,129.87,128.86,128.57,128.54,127.88,126.11,118.64,118.29,116.79,116.51,115.32,112.32,100.03,99.50,67.23,54.51,53.60,32.12,30.70.
Preparation example 24: compound 11x
Starting from compound 10f (0.40 g,1.0 mmol) and bromoethane (0.16 g,1.5 mmol), an off-white solid (0.30 g, 69.8%) was obtained. MP: greater than 200℃;1H NMR(400MHz,CDCl3)δ8.49(d,J＝9.2Hz,1H),7.76(d,J＝6.6Hz,2H),7.36(t,J＝8.4Hz,1H),7.23(t,J＝7.2Hz,3H),7.18–7.11(m,3H),6.97(d,J＝8.0Hz,1H),6.87(dd,J＝9.2,2.0Hz,1H),6.62(d,J＝2.4Hz,1H),5.83(d,J＝7.6Hz,1H),4.01(t,J＝6.4Hz,2H),3.90(q,J＝7.2Hz,2H),2.78(t,J＝7.6Hz,2H),2.15–2.02(m,2H),1.34(t,J＝8.8Hz,3H).13C NMR(100MHz,CDCl3)δ161.76,155.85,154.39,149.29,141.28,140.12,139.88,129.86,128.95,128.56,128.54,128.16,127.85,126.11,118.80,116.86,116.49,111.95,100.00,99.04,67.27,67.24,47.39,40.16,32.12,30.74.
Preparation example 25: compound 11y
Starting from compound 10f (0.40 g,1.0 mmol) and 1-bromo-3-phenylpropane (0.30 g,1.5 mmol), a yellow solid (0.30 g, 58.2%) was obtained. MP: greater than 200℃;1H NMR(400MHz,CDCl3)δ8.41(d,J＝9.2Hz,1H),7.72–7.67(m,2H),7.29(t,J＝8.0Hz,1H),7.20–7.15(m,4H),7.13(s,1H),7.13–7.08(m,4H),7.07–7.03(m,2H),6.83(d,J＝8.0Hz,1H),6.79(dd,J＝8.8,2.0Hz,1H),6.34(d,J＝2.0Hz,1H),5.74(d,J＝8.0Hz,1H),3.83–3.71(m,4H),2.72(t,J＝7.2Hz,2H),2.58(t,J＝7.2Hz,2H),2.07–1.94(m,4H).13C NMR(100MHz,CDCl3)δ161.81,155.80,154.23,149.32,141.35,140.61,140.30,140.26,129.93,129.04,128.78,128.65,128.60,128.48,128.34,128.15,127.84,126.50,126.17,118.94,118.69,116.94,116.59,112.55,99.78,98.64,67.09,51.75,32.68,32.17,30.77,29.83,29.69.
Preparation example 26: compound 11z
Starting from compound 10f (0.40 g,1.0 mmol) and p-methoxybenzyl chloride (0.23 g,1.5 mmol), a yellow solid (0.34 g, 65.3%) was obtained. MP: greater than 200℃;1H NMR(400MHz,CDCl3)δ8.42(d,J＝9.2Hz,1H),7.75(t,J＝4.0Hz,2H),7.36(t,J＝8.0Hz,1H),7.26–7.15(m,3H),7.15–7.07(m,3H),7.02(d,J＝8.0Hz,3H),6.83–6.76(m,3H),6.52(d,J＝2.0Hz,1H),5.84(d,J＝7.6Hz,1H),4.95(s,2H),3.84(t,J＝6.4Hz,2H),3.68(s,3H),2.68(t,J＝7.6Hz,2H),2.02–1.94(m,2H).13C NMR(100MHz,CDCl3)δ161.61,159.51,155.77,153.95,149.30,141.19,140.72,140.66,129.87,128.96,128.49,128.43,127.97,127.67,127.17,126.07,118.66,116.87,116.76,114.60,112.61,100.01,99.75,67.15,55.68,55.33,43.71,32.04,31.56,30.51,29.72,28.97.
Preparation example 27: compound 11aa
Starting from 10g (0.49 g,1.0 mmol) of the compound and allyl bromide (0.18 g,1.5 mmol), an off-white solid (0.19 g, 36.6%) was obtained. MP: greater than 200℃;1H NMR(400MHz,CDCl3)δ9.41(t,J＝10.0Hz,1H),7.82–7.56(m,1H),7.32–7.25(m,4H),7.24(s,1H),7.23–7.13(m,8H),7.05–6.82(m,4H),6.80–6.72(m,1H),6.60(t,J＝7.2Hz,1H),6.18–6.08(m,1H),4.14–4.04(m,2H),3.99–3.92(m,2H),2.86–2.74(m,4H),2.15(t,J＝5.2Hz,2H),2.06(t,J＝6.4Hz,2H),1.63(dd,J＝6.8,1.6Hz,1H).13C NMR(100MHz,CDCl3)δ163.38,163.21,160.05,155.16,155.07,142.79,142.38,141.53,141.00,140.76,140.43,130.12,129.62,129.44,129.38,128.83,128.53,128.49,128.41,128.01,126.14,125.90,116.66,112.97,110.98,100.43,100.09,99.82,99.60,67.89,67.21,40.98,32.16,32.01,30.83,30.49.
Preparation example 28: compound 11ab
Starting from 10g (0.49 g,1.0 mmol) of the compound and p-methoxybenzyl chloride (0.23 g,1.5 mmol), a beige solid (0.25 g, 41.7%) was obtained. MP: greater than 200℃;1H NMR(400MHz,CDCl3)δ9.60(d,J＝9.2Hz,1H),7.99(d,J＝7.6Hz,1H),7.31–7.24(m,6H),7.23–7.18(m,4H),7.16(d,J＝7.6Hz,3H),7.11(d,J＝8.4Hz,2H),7.03(d,J＝7.6Hz,1H),6.92(d,J＝2.0Hz,1H),6.86(d,J＝8.4Hz,2H),6.79(dd,J＝8.4,2.0Hz,1H),6.72(d,J＝7.6Hz,1H),5.51(s,2H),3.97(q,J＝6.0Hz,4H),3.78(s,3H),2.82–2.72(m,4H),2.14–2.01(m,4H).13C NMR(100MHz,CDCl3)δ163.43,160.04,159.95,154.95,144.72,141.51,140.86,140.60,138.42,130.14,129.75,128.54,128.51,128.47,128.44,126.17,125.92,125.31,117.09,114.79,113.58,113.27,111.59,99.87,99.74,67.92,67.29,57.70,55.34,32.16,31.94,30.80,30.21.
Comparative example 1 was prepared: compound 10f
Compound 10f was used as a comparative example .MP：149.1-150.3℃;1H NMR(400MHz,CDCl3)δ8.60(1H,d,J＝5.2Hz),8.11(1H,s),7.96(1H,d,J＝8.0Hz),7.84(1H,d,J＝9.2Hz),7.59–7.52(2H,m),7.38(1H,s),7.33–7.27(2H,m),7.24–7.19(4H,m),7.01(1H,d,J＝5.2Hz),6.75(1H,s),4.12(2H,t,J＝6.4Hz),2.86(2H,t,J＝7.6Hz),2.24–2.14(2H,m).13C NMR(100MHz,DMSO-d6)δ159.5,151.0,148.6,146.0,142.8,141.4,130.6,128.4,126.2,125.9,123.6,117.5,116.7,115.0,114.4,108.5,102.2,67.0,31.5,30.3.
Table 1 below shows the correspondence of the quinoline derivative code number of the present invention with the structural formula and basic parameters.
TABLE 1 correspondence between quinoline derivative codes and structural formulas and basic parameters
Test examples
Test example 1
In vitro antitumor Activity test
Pharmacological research of the quinoline derivatives as medicaments for treating cancers. All tested compounds are prepared into a hydrochloride form before the test, and an antitumor drug-cisplatin commonly used in clinic is used as a positive control drug.
The inhibitory activities of the compounds 11a-ab on the cancer cell lines HCT-116, hepG2, BGC-823, A549 and U251 were evaluated by MTT method, respectively, using human colorectal cancer cell line (HCT-116), human liver cancer cell line (HepG 2), human gastric cancer cell line (BGC-823), human lung cancer cell line (A549) and human glioma cell line (U251). Inoculating tumor cells on a 96-well plate at a concentration of 1×10 4/mL, culturing in a CO 2 incubator at 37 ℃ until the culture reaches a logarithmic phase, changing fresh culture medium, adding sterilized test compounds, setting 6-8 dose groups for each test compound, setting at least three parallel wells for each group, continuing culturing for 72 hours, discarding supernatant, adding 200 mu L of culture medium containing 50 mu g/mLMTT for each well, continuing culturing for 4 hours, removing supernatant in the well plate, adding 200 mu L of DMSO for each well, oscillating for about 10 minutes to dissolve precipitate, measuring Optical Density (OD) at 570nm by using an enzyme-labeling instrument, and determining cell survival rate at each sample concentration by using solvent-treated tumor cells as a control group by using the following formula:
survival% = sample group mean OD/control group mean OD x 100%.
The IC 50 values for each sample were plotted against the log drug concentration and the results are shown in Table 2 below.
Table 2 in vitro antitumor Activity evaluation table of quinoline derivatives
Test example 2
Acute toxicity test in mice
Kunming mice (supplied by the university of Wuhan laboratory animal center) weigh 19-20g, and are male and female halves. One group of 10 mice each. The solvent adopts physiological saline and 0.5 percent CMC-Na solution; according to the pre-test results, five doses were designed for each sample, with a dose interval of 0.8 times. After weighing each sample, a small amount of Tween 80 is added for wetting and dissolving in the test, and then 0.5% CMC-Na solution is gradually added to reach the required concentration. The experimental volume was 0.5mL/20g mice. Single intraperitoneal administration was used. The Kunming mice were taken and randomly grouped by sex, each group was given intraperitoneally separately in a dosing setting, and the immediate response of the mice after administration was observed. The animals that were dead were anatomically observed, and the animals that were surviving were observed for two weeks and the death of the animals was recorded for two weeks. Two weeks later, the surviving animals were dissected, and the lesions of the parenchymal organs were observed, and the organs with the parenchymal lesions were examined for pathology. The semi-lethal dose (LD 50 value) of the drug was calculated by the Bliss method based on the number of deaths of each group of animals.
The test results are shown in Table 3 below.
Test example 3
In vivo anti-tumor test
Kunming mice (supplied by the university of Wuhan laboratory animal center) all had a weight of 18-20g, and were both male and female, each experiment using the same sex. Anti-tumor experiment C57BL/6 mice and Kunming mice are one group of 8-10 mice, and negative controls are two groups respectively; the tumor source adopts mouse Lewis lung cancer and S180 sarcoma (maintained by the cell molecular biology research laboratory of the university of Wuhan student' S Ming Seisakusho); the solvent adopts physiological saline and 0.5 percent CMC-Na solution; the test medicine is provided with a high dose group and a low dose group, and 1/5 of the LD50 value of the medicine for single abdominal cavity administration is taken as a reference; weighing each sample to be tested, adding a small amount of Tween-80 for wetting and dissolving, and gradually adding 0.5% CMC-Na solution to the required concentration. The experimental volume was 0.5mL/20g mice. The medicine is administered to the abdominal cavity 1 time a day for 10 days continuously for 10 times. The negative control was given an equal volume of the corresponding solvent, and the regimen was the intraperitoneal route, 1 time per day for 10 consecutive days. The positive control CTX was dosed at 30mg/kg once daily for 7 consecutive days. An in vivo anti-tumor underarm subcutaneous inoculation model is adopted: taking a tumor source with vigorous growth under aseptic condition, preparing a cell suspension with a homogenization method of about 1X 107/mL, subcutaneously inoculating 0.2 mL/mouse to the corresponding host axilla, administering according to an experimental design scheme the next day, killing each group of animals about three weeks, taking tumors, weighing, and calculating tumor inhibition rate according to the following formula:
tumor inhibition rate% = [ (average tumor weight of negative control group-average tumor weight of administration group)/average tumor weight of negative control group ] ×100%.
The test results are shown in Table 3 below.
TABLE 3 results of mouse acute toxicity and anti-tumor Activity test of quinoline derivatives
The quinoline derivative provided by the invention has excellent anti-tumor activity, can be used for preparing medicaments for treating proliferative diseases, and can be used for effectively treating the proliferative diseases, in particular malignant tumors such as colorectal cancer, liver cancer, gastric cancer, lung cancer or glioma.
Claims (5)
1. A quinoline derivative, which is a compound of formula I:
（I）；
The compound of formula I is selected from one of the following compounds:
、、、、、、、、。
2. The process for preparing quinoline derivatives according to claim 1, comprising the steps of:
1) Contacting a compound of formula II with R 1 X in the presence of a base to obtain a compound of formula III;
（II）
（III）
2) Contacting a compound of formula III with an R 2 substituted aniline in the presence of an acid to obtain a compound of formula IV;
（IV）
3) Contacting a compound of formula IV with R 3 X in the presence of a base to obtain a compound of formula I;
Wherein each X is independently halogen, R 1、R2 and R 3 are as defined in claim 1.
3. A pharmaceutical composition comprising a quinoline derivative of claim 1 and a pharmaceutically acceptable carrier.
4. Use of a quinoline derivative according to claim 1 for the preparation of a medicament for the treatment of malignant tumors.
5. The use according to claim 4, wherein the malignancy is at least one of colorectal cancer, liver cancer, gastric cancer, lung cancer or glioma.
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