CN114605236A - 联芳基酚类化合物及其药物组合物、制备方法和应用 - Google Patents
联芳基酚类化合物及其药物组合物、制备方法和应用 Download PDFInfo
- Publication number
- CN114605236A CN114605236A CN202210259791.4A CN202210259791A CN114605236A CN 114605236 A CN114605236 A CN 114605236A CN 202210259791 A CN202210259791 A CN 202210259791A CN 114605236 A CN114605236 A CN 114605236A
- Authority
- CN
- China
- Prior art keywords
- substituted
- compound
- aryl
- chain
- heteroaryl
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 58
- -1 Biaryl phenol compound Chemical class 0.000 title claims abstract description 57
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 133
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 229940002612 prodrug Drugs 0.000 claims abstract description 10
- 239000000651 prodrug Substances 0.000 claims abstract description 10
- 239000012453 solvate Substances 0.000 claims abstract description 10
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 62
- 238000006243 chemical reaction Methods 0.000 claims description 42
- 125000003118 aryl group Chemical group 0.000 claims description 35
- 239000000758 substrate Substances 0.000 claims description 32
- 125000003107 substituted aryl group Chemical group 0.000 claims description 31
- 229910052736 halogen Inorganic materials 0.000 claims description 29
- 150000002367 halogens Chemical class 0.000 claims description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 23
- 125000003342 alkenyl group Chemical group 0.000 claims description 23
- 125000000304 alkynyl group Chemical group 0.000 claims description 23
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 23
- 125000006545 (C1-C9) alkyl group Chemical group 0.000 claims description 22
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000003172 aldehyde group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims description 3
- 238000011282 treatment Methods 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 229910004057 NO2F Inorganic materials 0.000 claims description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical class OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 150000001924 cycloalkanes Chemical class 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000011987 methylation Effects 0.000 claims description 2
- 238000007069 methylation reaction Methods 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 29
- 238000004440 column chromatography Methods 0.000 description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
- 238000004809 thin layer chromatography Methods 0.000 description 24
- 238000001035 drying Methods 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 239000004698 Polyethylene Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 238000000605 extraction Methods 0.000 description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 13
- 201000010099 disease Diseases 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 11
- 239000005457 ice water Substances 0.000 description 11
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 11
- 238000000926 separation method Methods 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- 238000001514 detection method Methods 0.000 description 10
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 238000010791 quenching Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 230000017858 demethylation Effects 0.000 description 7
- 238000010520 demethylation reaction Methods 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 6
- 230000000171 quenching effect Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 5
- XKZQKPRCPNGNFR-UHFFFAOYSA-N 2-(3-hydroxyphenyl)phenol Chemical compound OC1=CC=CC(C=2C(=CC=CC=2)O)=C1 XKZQKPRCPNGNFR-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 229940041181 antineoplastic drug Drugs 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 229940125810 compound 20 Drugs 0.000 description 3
- 229940125833 compound 23 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- 150000008052 alkyl sulfonates Chemical class 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000005228 aryl sulfonate group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N iodoform Chemical compound IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- 150000002611 lead compounds Chemical class 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000001476 sodium potassium tartrate Substances 0.000 description 2
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- NSFJAFZHYOAMHL-UHFFFAOYSA-N (4-nitrophenyl)boronic acid Chemical compound OB(O)C1=CC=C([N+]([O-])=O)C=C1 NSFJAFZHYOAMHL-UHFFFAOYSA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- ZZYYOHPHSYCHQG-UHFFFAOYSA-N 2-bromo-4-methylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C(Br)=C1 ZZYYOHPHSYCHQG-UHFFFAOYSA-N 0.000 description 1
- VBVUVYYPDRZXNH-UHFFFAOYSA-N 2-iodo-1,3-dimethoxy-5-methylbenzene Chemical compound COC1=CC(C)=CC(OC)=C1I VBVUVYYPDRZXNH-UHFFFAOYSA-N 0.000 description 1
- GPZXFICWCMCQPF-UHFFFAOYSA-N 2-methylbenzoyl chloride Chemical compound CC1=CC=CC=C1C(Cl)=O GPZXFICWCMCQPF-UHFFFAOYSA-N 0.000 description 1
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 description 1
- WNRGWPVJGDABME-UHFFFAOYSA-N 3,5-Dimethoxyaniline Chemical compound COC1=CC(N)=CC(OC)=C1 WNRGWPVJGDABME-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 208000024172 Cardiovascular disease 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
- 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
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical group [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
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 150000005347 biaryls Chemical group 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 238000006392 deoxygenation reaction Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000005040 ion trap Methods 0.000 description 1
- 239000003041 laboratory chemical Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005296 lung carcinoma 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
- 230000003211 malignant effect Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- MASRAGFWFYHMFI-UHFFFAOYSA-N methyl 3-bromo-4-methylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(Br)=C1 MASRAGFWFYHMFI-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 239000004711 α-olefin Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
- C07C205/20—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
- C07C205/26—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups and being further substituted by halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/39—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups
- C07C205/42—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/56—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C205/59—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于药物化学领域，公开一类联芳基酚类化合物，结构通式如式(I)或式(II)所示：
Description
技术领域
本发明属于药物化学领域，具体涉及一类联芳基酚类化合物及其药物组合物、制备方法和应用。
背景技术
癌症又称为恶性肿瘤，是一种严重威胁人类健康的恶性和常见疾病，已成为继心血管疾病后威胁人类健康的“第二大杀手”。。
2020年中国癌症死亡人数前2位的是肺癌(71万)和肝癌(39万)。尽管抗肿瘤药物的发展取得了重要进步，但现有的标准治疗手段仍然是手术切除、化疗和放疗。传统的化疗药物在临床上虽疗效明显，但毒副作用明显、易多药耐药导致患者的生存质量低。
发明内容
为此，需要提供一类联芳基酚类化合物及其药物组合物、制备方法和应用，解决现有肿瘤药毒副作用明显，易多药耐药导致患者的生存质量低的问题。
为实现上述目的，本发明提供了联芳基酚类化合物，其化学结构通式如式(I)或式(II)所示：
或该化合物的立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物，
其中：X、Y各自独立选自O、S、C、N；
R1，R2，R3，R4，R5，R6各自独立地选自：-H，羰基，酰基、C1-9烃基，取代C1-9烃基，，-CpHq-OD1,，-NH2，-CpHq-NHD1，-CpHq-NH-C(O)-D1， -CpHq-NHOH，-CpHq-NH-O-D1，-CpHq-C(O)-NH-D1，氰基，-CpHq-C(O)-D1，硝基，羧基，取代羧基，卤素，芳基，取代芳基，杂芳基，取代的杂芳基，其中，p＝0-5，q＝2p或p＝2-5，p＝2q-2；
R1＇，R2＇，R3＇，R4＇，R5＇，R6＇各自独立地选自：-H，卤素，1-3卤素取代甲基，硝基，氰基，-NH2，-NHD1，-ND1D1，-NH-C(O)-D1、C1-3的醛基、 C1-6烷基，C3-6环烷基，C2-6烯基，C2-6炔基，-COOH，-COOD1，-C(O)-NHD1， -OH或-(CH2)0-3-OD1，-C(O)-D1，芳基，取代芳基，杂芳基，取代杂芳基；
D1为选自：C1-9烷基链、末端被1～3个卤原子取代的C1-9烷基链，C3-6 的环烷基，C2-9烯基链，C2-9炔基链，C3-6环烯基，芳基，取代芳基，杂芳基，取代杂芳基。
本发明的另一个目的是提供上述化合物的制备方法。
本发明的另一个目的是提供包含上述化合物的药物组合物。
本发明的另一个目的是提供上述化合物及包含上述化合物的药物组合物在制备用于癌症及其他疾病的预防与治疗的药物中的用途。
上述技术方案具有以下有益效果：
本发明制备的联芳基酚类化合物具有较高的生物活性，能够有效抑制肿瘤细胞增殖，具有重大的药物研发潜力，可作为先导化合物用于抗癌药物的开发。
具体实施方式
为详细说明技术方案的技术内容、构造特征、所实现目的及效果，以下结合具体实施例详予说明。
本发明提供了联芳基酚类化合物，其化学结构通式如式(I)或式(II) 所示：
或该化合物的立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物，
其中：X、Y各自独立选自O、S、C、N；
R1，R2，R3，R4，R5，R6各自独立地选自：-H，羰基，酰基、C1-9烃基，取代C1-9烃基，，-CpHq-OD1,，-NH2，-CpHq-NHD1，-CpHq-NH-C(O)-D1， -CpHq-NHOH，-CpHq-NH-O-D1，-CpHq-C(O)-NH-D1，氰基，-CpHq-C(O)-D1 硝基，羧基，取代羧基，卤素，芳基，取代芳基，杂芳基，取代的杂芳基；其中，p＝0-5，q＝2p或p＝2-5，p＝2q-2；
R1＇，R2＇，R3＇，R4＇，R5＇，R6＇各自独立地选自：-H，卤素，1-3卤素取代甲基，硝基，氰基，-NH2，-NHD1，-ND1D1，-NH-C(O)-D1、C1-3的醛基、 C1-6烷基，C3-6环烷基，C2-6烯基，C2-6炔基，-COOH，-COOD1，-C(O)-NHD1， -OH或-(CH2)0-3-OD1，-C(O)-D1，芳基，取代芳基，杂芳基，取代杂芳基；
D1为选自：C1-9烷基链、末端被1～3个卤原子取代的C1-9烷基链，C3-6 的环烷基，C2-9烯基链，C2-9炔基链，C3-6环烯基，芳基，取代芳基，杂芳基，取代杂芳基。
进一步，所述X，Y，R1，R2，R3，R4，R5，R6优选自：
(1)当Y为O时：无R1、R2基团，R3选自：-H，-CpHq-C(O)-D1，C1-9 烷基链，被一个卤素取代的C1-C9烷基链，C2-9烯基链，C2-9炔基链，C3-6 环烷基，C3-C6环烯基，芳基，取代的芳基，杂芳基，取代的杂芳基，；
(2)当Y为S时：R1、R2各自独立选自羰基，R3独立选自：H， -CpHq-C(O)-D1，-CpHq-OD1，C1-9烷基链，被一个卤素取代的C1-C9烷基链， C2-9烯基链，C2-9炔基链，C3-6环烷基，C3-C6环烯基，芳基，取代芳基，杂芳基，取代杂芳基；
(3)当Y为C时：
R1为羰基时，无R2基团，R3独立选自：-H，-CpHq-OD1，-NH2，-CpHq-NHD1， -CpHq-NH-C(O)-D1，-CpHq-NH-O-D1，C1-9烷基链，被一个卤素取代的C1-C9 烷基链，C2-9烯基链，C2-9炔基链，C3-6环烷基，C3-C6环烯基，芳基，取代的芳基，杂芳基，取代的杂芳基；
R1、R2、R3均不选自羰基时，各自独立取自：-H，-CpHq-OD1，-NH2， -CpHq-NHD1，-CpHq-NH-C(O)-D1，-CpHq-C(O)-NH-D1，-CpHq-NH-O-D1，-CN， -NO2，C1-9烷基链，被一个卤素取代的C1-C9烷基链，C2-9烯基链，C2-9 炔基链，C3-6环烷基，C3-C6环烯基，芳基，取代的芳基，杂芳基，取代的杂芳基，且R1、R2、R3不能同时两个或三个选自：-OH，NH2，-CN，-NO2；
(4)当Y为N时，无R2基团：
R1选自：-H，C1-9的烷基链，-C(O)-D1，-COOH，-COOD1，-OD1；
R3选自：-H，-(CH2)0-5-OD1，C1-9烷基链，被一个卤素取代的C1-C9烷基链，C2-9烯基链，C2-9炔基链，C3-6环烷基，C3-C6环烯基，芳基，取代芳基，杂芳基，取代杂芳基；
R1，R3均不选自-C(O)-D1，-COOH，-COOD1或-OD1时，各自独立选自：H，-(CH2)0-5-OD1，C1-9烷基链，被一个卤素取代的C1-C9烷基链，C2-9 烯基链，C2-9炔基链，C3-6环烷基，C3-C6环烯基，芳基，取代芳基，杂芳基，取代杂芳基；
(5)当X为C时，R5、R6独立选自：-H，-COOH，-COOD1，硝基，氰基，-NH2，-CpHq-NHD1，-CpHq-C(O)-D1，-CpHq-OD1，C1-9烷基链,被一个卤素取代的C1-C9烷基链，C2-9烯基链，C2-9炔基链，C3-6环烷基，C3-C6 环烯基，芳基，取代芳基，杂芳基，取代杂芳基，且R5、R6不同时选自-COOH， -COOD1，硝基，氰基，-CpHq-NHD1，-CpHq-C(O)-D1，-OH，-CpHq-OD1；
(6)当X为N时：R5、R6各自独立选自：-H，-COOH，-COOD1，-C(O)-D1， -OH，-OD1，C1-9烷基链，被一个卤素取代的C1-C9烷基链，C2-9烯基链， C2-9炔基链，C3-6环烷基，C3-C6环烯基，芳基，取代的芳基，杂芳基，取代的杂芳基，且R5、R6不同时选自-COOH，-COOD1，-C(O)-D1，-OH，-OD1；
(7)当X为S时：无R5基团，R6选自：-H，-C(O)-D1，C1-9烷基链，被一个卤素取代的C1-C9烷基链，C2-9烯基链，C2-9炔基链，C3-6环烷基， C3-C6环烯基，芳基，取代芳基，杂芳基，取代杂芳基；
(8)当X为O时：无R5基团，R6选自：-H，-C(O)-D1，-COOD1，C1-9 烷基链，被一个卤素取代的C1-C9烷基链，C2-9烯基链，C2-9炔基链，C3-6 环烷基，C3-C6环烯基，芳基，取代的芳基，杂芳基，取代的杂芳基；
进一步，所述X、Y、R1，R2，R3，R4，R5，R6优选自：
a)当Y为C时：R1为羰基，无R2基团，R3选自：-O(CH2)0-6-CH3，
-NH-(CH2)0-6-CH3；
b)当Y为C时：且R1，R2，R3都不选自羰基，各自独立选自：H， -(CH2)0-6-CH3，C1-6的环烷烃，-C(O)-NH-(CH2)0-6-CH3， -C(O)-NH-(CH2)0-3-(aryl)，-C(O)-NH-(CH2)0-6-CH2-(Cl、Br或I)， -(CH2)0-6-COO-(alkyl)，-(CH2)0-6-OH，-(CH2)0-6-O-C(O)-(alkyl)；
c)当Y为N时：无R2基团，R1取自：-H，C1-9的烷基链，-COOH， -COO-(CH2)0-3-CH3，-C(O)-(CH2)0-6-CH3；R3取自：C1-9的烷基链；
d)R4取Cl，Br，I，H；
e)当X为N时：R5，R6各自独立取自：-H、C1-6的烷基；
f)当X为O时：无R5基团，R6取自：-H，C1-6的烷基，-COO(CH2)0-6-CH3。
进一步，所述R1＇，R2＇，R3＇，R4＇，R5＇，R6＇优选自：
-H，-(CH2)0-3-CH3，-(CH2)0-3-OH，-O(CH2)0-3-CH3，-NO2，-COO-(CH2)0-3-CH3，-NH2；
进一步，所述芳基、取代芳基、杂芳基、取代杂芳基结构如下：
其中，n为0～3的整数；
D2选自：-N-[(CH2)0-3]2-，-OH，-O(alkyl)，-O(aryl)，-CF3，-NO2，F， Cl，Br，I，C1-4烷基，-COO(CH2)0-4；
E为六元苯环、含有N，O，S其中至少有一个杂原子的六元杂环或含有N，O，S其中一个杂原子的五元杂环；
进一步，所述F，E，D1，D2优选自：F为呋喃环；E为苯环；D1为选自：甲基、乙基、丁基、异戊基、3-氯-丙基、苄基，或胺取代的苄基；D2选自-H，-N(Me)2；
如本文所使用，术语“式(I)、式(II)化合物的药学上可以接受的盐”的例子是由形成药学上可以接受的阴离子的有机酸形成的有机酸加合盐，包括但不限于甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、α-酮戊二酸盐、α-甘油磷酸盐、烷基磺酸盐或芳基磺酸盐；优选地，所述烷基磺酸盐为甲基磺酸盐或乙基磺酸盐；所述芳基磺酸盐为苯磺酸盐或对甲苯磺酸盐。也可形成合适的无机盐，包括但不限于盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、碳酸氢盐和碳酸盐、硫酸盐或磷酸盐等。
药学上可以接受的盐可使用本领域熟知的标准程序获得，例如，通过将足量的碱性化合物和提供药学上可以接受的阴离子的合适的酸反应。
本文使用的术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据完全或部分地预防疾病或其症状，可以是预防性的；和/或根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)预防易感染疾病或症状但还没诊断出患病的患者所发生的疾病或症状；(b)抑制疾病的症状，即阻止其发展；或(c)缓解疾病的症状，即，导致疾病或症状退化。
按照本发明的一种具体技术方案，所述化合物、其立体异构体、其前药、或者其药学上可接受的盐或药学上可接受的溶剂合物，其中所述化合物为下面实施例中所述化合物之一。
另一方面，本发明提供了药物组合物，其包含上述任一技术方案所述的化合物、其立体异构体、其前药、或者其药学上可接受的盐或药学上可接受的溶剂合物，和药学上可接受的载体、稀释剂或赋形剂。
制备各种含有一定量的活性成分的药物组合物的方法是已知的，或根据本发明的公开内容对于本领域技术人员是显而易见的。如REMINGTON’S PHARMACEUTICAL SCIENCES,Martin,E.W.,ed.,Mack Publishing Company, 19th ed.(1995)所述，制备所述药物组合物的方法包括掺入适当的药学赋形剂、载体、稀释剂等。
另一方面，本发明还提供了上述任一技术方案所述式(I)或式(II)的制备方法，具体的：：
当R5＇不为-CH2-OH时，包括如下步骤：
反应条件：(a)将芳基取代硼酸和碘代物混合，加入碳酸铯和DMF，除氧后加入Pd催化剂。在合适的温度下，发生Suzuki偶联得到联芳基化合物； (b)联芳基底物溶解在合适的溶剂里，冰浴下缓慢滴加BBr3，得到脱甲基化合物。
当R5＇为-CH2-OH时，包括如下步骤：
其中，步骤(c):间三苯酚和邻溴苯甲酸类底物，发生Hurtley反应得到内酯化合物；(d)用硫酸二甲酯做甲基化试剂，得到酚甲基醚化合物；(e)将酚甲基醚内酯化合物，用氢化铝锂还原得到羟甲基化合物；
另一方面，本发明还提供了上述任一技术方案所述化合物、其立体异构体、其前药、或者其药学上可接受的盐或药学上可接受的溶剂合物及包含该化合物的药物组合物在制备用于癌症的预防与治疗的药物的用途。
化学物合成后，具体可通过以下方法进行纯化和分析：
在硅胶GF254预涂覆板(merck)上进行薄层色谱。在中压下经硅胶 (300-400目，Greagent)进行柱色谱分离。成分通过UV光(254nm)和通过碘蒸气、碱性KMnO4溶液(KMnO4：K2CO3：NaOH：H2O＝1.5g：10g：0.125g： 200ml)磷钼酸溶液(10g磷钼酸+200ml乙醇)显影。必要时，将化合物通过 HPLC纳谱分析(Chromcore 8-120C18,8um,10X250 mm)柱纯化，流动相为乙腈/H2O(70％～100％)，流速：10ml/min。
将1H-NMR谱在400MHz操作的Bruker Avance 400谱仪(对于1H而言)进行记录。将四甲基硅烷信号用作参比。化学位移以百万分率(ppm)进行报道且偶合常数(J)以Hz计。以下缩写用于峰裂分:s＝单；br.s.＝宽信号；d＝双；t＝三； m＝多重；dd＝双双。
电喷雾(ESI)质谱经Finnigan LCQ离子阱获得。
试剂纯化参考Purification of Laboratory Chemicals(Perrin,D.D.,Armarego, W.L.F.and Perrins Eds,D.R.；Pergamon Press:Oxford,1980)一书进行。石油醚是60-90℃馏分、乙酸乙酯、甲醇、二氯甲烷均为分析纯。
实施例1
目标化合物结构如下：
合成路线：
化合物1制备：100mL三口瓶，依次加入间三苯酚(1.17g，9.3mmol)， 2-溴-4-甲基-苯甲酸(1.0g，4.65mmol)，混合均匀加入0.4M的氢氧化钠23.25 mL，置于60℃油浴下反应15min。紧接着往体系里，滴加10％CuSO4，滴加完后升到95℃反应3h。停止加热冷却至室温，过滤得固体，用水洗固体三次，得到白色固体，减压干燥，得白色固体化合物1(1.0g)，收率：88％。
化合物2制备：25mL单口瓶，加入底物1(0.3g，1.24mmol),丙酮5mL，碳酸钾(514mg，3.72mmol)搅拌均匀后加入硫酸二甲酯(0.3mL，3.1mmol), 反应过夜，TLC检测反应完毕，加水，减压浓缩除去丙酮，加入EA萃取，无水硫酸钠干燥，减压浓缩，柱层析200～300目(DCM/Hexanes＝2:1),得化合物2(0.25g),收率：75％。
化合物I-1制备：25mL单口瓶，加入底物2(150mg，0.56mmol)，THF 10m，置于冰水浴中，缓慢滴加LiAlH4(1.0M in THF)0.83mL，滴加完毕后恢复到室温反应过夜，加入酒石酸钾钠淬灭反应，待体系澄清透明加入EA 分液萃取，合并有机相，无水硫酸钠干燥，减压浓缩，柱层析200～300目硅胶(Hexanes:EA＝2:1)，得化合物I-1(74mg)，收率：48％。1H NMR(400MHz, CDCl3)δ7.48(d,J＝7.8Hz,1H),7.26–7.21(m,1H),7.04(s,1H),6.24(d,J＝2.3Hz,1H),6.18(d,J＝2.3Hz,1H),4.37(dd,J＝11.9Hz,2H),3.82(s,3H),3.69 (s,3H),2.38(s,3H).GC-MS(EI)m/z：274.15[M]+。
实施例2-4
目标化合物结构如下：
合成路线：
硼试剂制备：取250ml三口瓶，加入3-溴-4-甲基-苯甲酸甲酯(2.0g，8.77 mmol)、频哪醇联硼酸酯(4.46g，17.54mmol)、PdCl2(dppf).DCM(143mg,0.175 mmol),KOAc(3.44g,35.08mmol)先置换Ar气，加入1,4-二氧六环(60ml), 除氧(隔膜泵抽体系，置换Ar气)，置于80℃油浴反应12h,TLC检测反应完毕。硅藻土过滤，减压除去溶剂，加入乙醚、水，分液萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，减压浓缩，柱层析分离纯化(Hexanes/EA ＝20:1)得到较纯硼酸酯化合物,在重结晶除去过量的硼试剂(Hexanes/EA)得白色固体化合物硼酸酯(1.81g,75％)。
碘代物制备：取100ml单口瓶，加入二酚化合物(1.02g，8.06mmol)，乙腈(16ml)置于冰水浴中(酯基底物溶剂换成甲醇)，分两次加入NIS(1.86 g，8.06mmol)加完后自然升温，反应2h，TLC检测反应完毕，加入饱和 NaHCO3，减压除去大部分乙腈，EA分液萃取，合并有机相，减压浓缩，柱层析分离纯化(Hexanes/EA＝4:1)，得二酚碘代物。
取25ml单口瓶，加入上述二酚碘代物(0.5g,2mmol)，丙酮(10ml)， K2CO3(0.83g，6mmol),硫酸二甲酯(0.47ml,5mmol)室温反应24h,TLC检测反应完毕。往体系加入10ml水，搅拌10min,减压除去丙酮，加入乙醚分液萃取，饱和食盐水洗，无水硫酸钠干燥，减压浓缩，柱层析分离纯化 (Hexanes/EA＝15:1)，得到醚化化合物。(含酯基碘代物，Hexanes/EA＝5:1)
化合物I-2，I-4制备：取25ml反应管，加入碘代物(0.22mmol)，硼酸酯(0.18mmol)，Cs2CO3(0.36mmol)，Pd(PPh3)4(0.02mmol)，1，4-二氧六环(2ml)置换Ar气后置于80℃油浴反应12h，TLC检测反应完毕。硅藻土过滤，减压除去溶剂，柱层析分离200～300目，(PE:EA＝10:1)纯化得联苯化合38mg，收率：70％。
取25mL反应瓶，加入上述联苯化合物(55mg，0.18mmol)，DCM 2mL 置于冰乙醇中，滴加入BBr3(2.0M in DCM)0.92mL，滴加完自然恢复到室温，反应2h。重新置于冰水浴中，滴加0.2mL甲醇淬灭，加入乙酸乙酯分液萃取，合并有机相，无水硫酸钠干燥，减压浓缩，柱层析200～300目， (HE:EA:AcOH＝4:1:0.1)，得化合物I-2(20mg)1H NMR(400MHz,MeOD)δ7.85(dd,J＝7.9,1.7Hz,1H),7.77(d,J＝1.6Hz,1H),7.32(d,J＝8.0Hz,1H), 6.27(s,2H),2.24(s,3H),2.18(s,3H).HRMS(ESI)m/z:[M+H]+Calcd for C15H15O4 +259.0965；Found259.0962；
化合物I-4(3.4mg)1H NMR(400MHz,CDCl3)δ8.04(dd,J＝8.0,1.8Hz, 1H),7.96(d,J＝1.6Hz,1H),7.48(d,J＝8.0Hz,1H),6.42(s,2H),3.90(s,3H), 2.31(s,3H),2.23(s,3H)；GC-MS(EI)m/z：272.12[M]+。
化合物I-3制备：以1,3-二甲氧基-2-碘-5-甲基苯为原料，参照化合物I-2 方法来获得化合物I-3(4.8mg)1H NMR(400MHz,MeOD)δ7.87(dd,J＝8.0, 1.8Hz,1H),7.70(d,J＝1.7Hz,1H),7.36(d,J＝8.0Hz,1H),7.24(dd,J＝12.2, 1.3Hz,2H),3.92(s,3H),3.88(s,3H),3.73(s,3H),2.16(s,2H),2.12(s,3H). HRMS(ESI)m/z:[M+H]+Calcd for C18H19O6 +331.1176；Found 331.1169。
实施例5-7
目标化合物结构如下：
合成路线：
化合物3制备：50mL单口瓶，依次加入氰基底物(0.95g，4.63mmol),2N NaOH 10mL，正丁醇5mL，加热回流过夜。冷却用EA萃取两次得到未完全水解的酰胺化合物4(200mg)，将水相加2N盐酸调pH至酸性，EA萃取得到羧酸化合物3(800mg)。
化合物5制备:100mL单瓶，加入化合物3(1.05g，4.41mmol)，DCM 44 ml，置于-15℃低温反应器中，缓慢滴加BBr3(2.0M in DCM)8.8mL，滴加完在该温度反应30min，升到室温反应1h，接着在置于-15℃中，缓慢滴加甲醇1mL，分液，乙酸乙酯萃取，无硫酸钠干燥，减压浓缩得二酚粗品，直接投下一步反应。
取50mL单口瓶，加入上一步二酚粗品，乙腈10mL，置于冰水浴中，限加入NIS(495mg)，10min后再加入NIS(495mg)，自然升温反应过夜，加入饱和硫代硫酸钠，减压除去大部分乙腈，水相用乙酸乙酯萃取几次，合并有机相，减压浓缩得碘代物粗品。
取50mL单口瓶，加入上述碘代物粗品，加入乙腈22mL，碳酸钾(3.05 g)，滴加入硫酸二甲酯(2.10mL)，反应过夜，过滤，减压浓缩，柱层析200～300 目，(H:EA＝5:1)得化合物5(1.18g)。
化合6制备：50mL单口瓶，加入碘代物(1.18g,3.24mmol)，MeOH 16 mL，THF 8mL，2NNaOH 5mL，混合均匀在室温下反应过夜。减压除去大部酚溶剂，用乙醚萃取一次，水相加2N HCl调pH 4～5，乙酸乙酯萃取，无水硫酸钠干燥，减压浓缩得到酸粗品，直接投下一步反应。
取50mL单口瓶，加入上述粗品酸底物，丙酮12ml，溶解完全后加入碳酸钾(672mg)，TBAI(120mg)，苄基溴(0.51mL)，室温下反应过夜。TLC 检测反应完毕，过滤，减压浓缩除去丙酮，加水和乙醚分液萃取，无水硫酸钠干燥，减压浓缩，柱层析分离200～300目，PE:EA＝10:1，得化合物6(1.45 g)。
化合物7制备：100mL双口瓶，加入底物6(1.45g，3.29mmol)，对硝基苯硼酸(1.1g，6.58mmol)，DMF 22mL，Cs2CO3(3.21g，9.87mmol)，除氧，加入催化剂Pd(PPh3)4(190mg，0.16mmol)在除一次氧，置于油浴中，先加热至40℃反应30min，后升至80℃反应6h，TLC检测反应完毕，过滤，加入水乙醚分液萃取，合并有机相，无水硫酸钠干燥，减压浓缩，柱层析分离，PE:EA＝8:1，得化合物7(1.24g)。
化合物I-5-I-7制备：化合物7脱甲基，参照化合物I-2脱甲基方法获得化合物I-5(57mg)1H NMR(600MHz,Acetone)δ8.38–8.36(m,2H),8.26– 8.20(m,2H),7.78–7.68(m,2H),6.58–6.56(m,2H),4.11(q,J＝7.1Hz,2H), 1.50(s,6H),1.19(t,J＝4.8Hz,3H)，LC-MS(ESI)m/z:[M+H]+346；
化合物I-6(90mg)1H NMR(600MHz,Acetone)δ8.37(s,2H),8.24–8.21 (m,2H),7.77–7.72(m,2H),6.56(s,2H),3.63(s,3H),1.50(s,6H).GC-MS(EI) m/z：331.03[M]+；
化合物I-7(0.62g)1H NMR(600MHz,Acetone)δ10.73(brs,1H),8.36(brs, 1H),8.26–8.20(m,2H),7.78–7.69(m,2H),6.63(s,2H),1.52(s,6H).LC-MS (ESI)m/z:[M+H]+318.3。
实施例8-10
合成路线：
化合物I-8制备：25mL单口瓶，加入底物I-6(50mg)，甲醇2mL，10％ Pd/C(5mg)，常压氢化，室温下搅拌过夜，TLC检测反应完毕，硅藻土过滤，减压浓缩，柱层析分离200～300目，PE:EA＝1:1，得化合物I-8(40mg) 1H NMR(400MHz,Acetone)δ7.31(s,2H),7.09–7.03(m,2H),6.72–6.67(m, 2H),6.45(s,2H),4.65(brs,2H),3.63(s,3H),1.50(s,6H).LC-MS(ESI)m/z: [M+H]+302.2。
化合物I-9制备：25mL单口瓶加入底物I-6(90mg)，THF 2mL，搅拌均匀后置于冰乙醇浴中，滴加入LiAlH4(1.0M in THF)1.36mL，加完自然升到室温，反应1h，将反应体系重新置于冰水浴中，缓慢滴加酒石酸钾钠，升到室温搅拌过夜，至体系澄清，加入乙酸乙酯分液，无水硫酸钠干燥，减压浓缩，柱层析分离200～300目，DCM:MeOH＝15:1，得化合物I-9(34mg)1H NMR(600MHz,Acetone)δ8.27–8.17(m,4H),7.79–7.69(m,2H),6.62(s, 2H),3.66(t,J＝5.8Hz,1H),3.54(d,J＝5.8Hz,1H),1.25(s,7H).GC-MS(EI) m/z：303.19[M]+。
化合物I-10制备：25mL单口瓶，加入底物I-9(30mg，0.1mmol)，THF 1mL，正丁酸(10mg，0.11mmol)，EDCI(25mg)，DMAP(2.4mg)室温下反应过夜，TLC检测，加入饱和氯化铵淬灭，加入DCM分液，无水硫酸钠干燥，减压浓缩，柱层析分离200～300目，DCM:MeOH＝15:1，得化合物 I-10(11mg)1H NMR(400MHz,Acetone)δ8.57(s,1H),8.30–8.23(m,2H), 7.65–7.58(m,2H),7.02(d,J＝1.7Hz,1H),6.77(d,J＝1.7Hz,1H),3.80(t,J＝ 5.7Hz,1H),3.58(d,J＝5.7Hz,2H),2.26(t,J＝7.2Hz,2H),1.50–1.40(m,2H), 1.29(s,6H),0.73(t,J＝7.4Hz,3H).HRMS(ESI)m/z:[M+H]+Calcd for C20H24NO6 +374.1598；Found 374.1593。
实施例11
目标化合物结构如下：
合成路线：
化合物8制备：250mL单口瓶,加入氰基底物(1.0g，5.65mmol)，THF 56 mL，置于-15℃，加入KHMDS(1.0M inTHF)17mL，滴加1,3-二溴丙烷(0.7 mL)，加完后在该温度下继续反应6h，TLC检测，反应完毕。加入饱和氯化铵淬灭，分液，水相乙醚萃取，合并有机相，无水硫酸钠干燥，减压浓缩，柱层析分离200～300目，PE:EA＝10:1,得化合物8(0.7g)。
化合物9制备：参照化合物5的合成方法，得到化合物9(360mg)。
化合物10制备：参照化合物7的合成方法(反应时间2h)，得到化合物 10(110mg)
化合物I-11制备：25mL单口瓶，加入化合物10(110mg)，MeOH 1mL， THF 1mL，置于冰水浴中加入LiCl(34mg)，NaBH4(30mg)自然升温反应过夜，TLC检测反应完毕，加入饱和氯化铵淬灭，减压除去溶剂，水相乙酸乙酯萃取，无水硫酸钠干燥，减压浓缩，柱层析200～300目，PE:EA＝2:1得还原醇化合物98mg。取25ml反应瓶，加入上述得到的醇底物，参照化物7到I-7的实验方法，最终获得化合物I-11(50mg)1H NMR(400MHz,Acetone) δ8.26–8.19(m,2H),7.79–7.69(m,2H),6.37(s,2H),3.65(s,3H),2.27–2.20 (m,4H),1.88–1.75(m,2H).LC-MS(ESI)m/z:[M+H]+316.0。
实施例12：
目标化合物结构如下：
合成路线：
化合物11制备：25mL单口瓶，加入底物4(127mg,0.57mmol)，DMF 2 mL，搅拌均匀后置于冰水浴中，加入NaH(30mg，0.74mmol)，反应30min。后往体系加入溴代物(115mg,0.74mmol)，TBAI(22mg，0.06mmol)升到室温反应15min，后置于油浴中加热至60℃，反应过夜。TLC检测反应完毕，加入饱和氯化铵淬灭，叫人水和乙醚分液萃取，合并有机相，无水硫酸钠干燥，减压浓缩，柱层析纯化，200～300目，PE:EA＝2:1,得化合物11(160 mg)。
化合物12制备：参照化合物3到5的制备方法，得化合物12(200mg)。
化合物I-12制备：参照化合物6到I-7的制备方法，得到化合物I-12(60 mg)1H NMR(400MHz,Acetone)δ8.42(s,2H),8.27–8.19(m,2H),7.78– 7.70(m,2H),6.56(s,3H),3.21–3.14(m,2H),1.57–1.49(m,1H),1.45(s,6H), 1.36–1.28(m,2H),0.85(d,J＝6.6Hz,6H).HRMS(ESI)m/z:[M+H]+Calcd for C21H27N2O5 +387.1914；Found 387.1906。
实施例13-16：
目标化合物结构如下：
合成路线：
化合物I-13制备：取25mL单口瓶，加入底物I-7(50mg，0.16mmol)， DCM 2ml，HATU(72mg，0.19mmol)，DIPEA(56μL，0.32mmol)室温下反应过夜，TLC检测反应完毕，加入饱和氯化铵淬灭，加入乙酸乙酯分液，无水硫酸钠干燥，减压浓缩，柱层析分离，200～300目，PE:EA＝1:1，得化合物I-13(32mg)1HNMR(400MHz,MeOD)δ8.26–8.17(m,2H),7.69–7.58(m, 2H),7.16(brs,1H),6.45(s,2H),3.23–3.11(m,2H),1.51(s,6H),1.48–1.41(m, 2H),1.33–1.24(m,2H),0.91(t,J＝7.3Hz,3H).HRMS(ESI)m/z:[M+H]+ Calcd for C20H25N2O5 +373.1758；Found 373.1753。
化合物I-14制备：参照化合I-13合成方法，得化合物I-14(39mg)
1H NMR(400MHz,MeOD)δ8.28–8.17(m,2H),7.70–7.61(m,2H),6.45(s, 2H),3.52(t,J＝6.6Hz,2H),3.30(t,J＝6.7Hz,3H),1.94(p,J＝6.6Hz,2H), 1.51(s,6H).HRMS(ESI)m/z:[M+H]+Calcd for C19H22ClN2O5 +393.1212， 395.1182；Found 393.1206，395.1176。
化合物I-15制备：参照化合I-13合成方法，得化合物I-15(35mg)
1H NMR(400MHz,MeOD)δ8.24–8.18(m,2H),7.68–7.61(m,2H),7.30– 7.23(m,2H),7.22–7.16(m,3H),6.49(s,2H),4.36(s,2H),1.54(s,6H).HRMS (ESI)m/z:[M+H]+Calcdfor C23H23N2O5 +407.1601；Found 407.1594。
化合物I-16制备：参照化合I-13合成方法，得化合物I-16(30mg)
1H NMR(400MHz,MeOD)δ8.27–8.16(m,2H),7.68–7.57(m,2H),7.43(d,J ＝4.0Hz,0.75H),7.13(d,J＝8.7Hz,0.75H),7.05(d,J＝8.7Hz,1.25H),6.72 (d,J＝2.4Hz,1.25H),6.70(d,J＝2.1Hz,0.75H),6.47(s,1.25H),4.25(d,J＝ 5.8Hz,2H),2.88(s,2H),2.87(s,4H),1.58(s,2H),1.52(s,4H).HRMS(ESI)m/z: [M+H]+Calcd for C25H28N3O5 +450.2023；Found 450.2018。
实施例17-19：
目标化合物结构如下：
合成路线：
化合物13制备：参照化合物7的合成方法(反应时间2h)，得到化合物 13(480mg)。
化合物14制备：50mL单口瓶，加入上述底物13(0.48g，1.53mmol)，甲醇10mL，THF10mL，2N NaOH 4mL，室温下反应过夜，TLC检测，反应完毕，减压除去溶剂，水相加乙醚洗两次，再用2N HCl调pH 4～5，乙酸乙酯萃取，无水硫酸钠干燥，减压浓缩，柱层析，100～200目，PE： EA:AcOH＝2:1:0.1得化合物14(450mg)。
化合物15制备：参照化合物I-13合成方法，得化合15(94mg)。
化合物I-17制备：参照化合物6到I-7的制备方法，得到化合物I-17(84 mg)1H NMR(400MHz,Acetone)δ8.66(s,2H),8.29–8.21(m,2H),7.76–7.69 (m,2H),7.64(brs,1H),7.05(s,2H),3.42–3.32(m,2H),1.64–1.52(m,2H), 1.47–1.33(m,2H),0.93(t,J＝7.4Hz,3H).HRMS(ESI)m/z:[M+H]+Calcd for C17H19N2O5 +331.1288；Found 331.1283.
化合物16制备：25mL单口瓶，加入底物14(100mg，0.33)，DMF 2mL， TBAI(12mg)，K2CO3(92mg),搅拌均匀加入1-溴正丁烷(87μL，0.82mmol) 搅拌10min,置于于油浴中，加热至80℃过夜，TLC检测反应完毕，加入1N HCl淬灭，加入乙醚萃取，无水硫酸钠干燥，减压浓缩，柱层析分离，PE:EA＝4:1, 得化合物16(115mg)。
化合物I-18,I-19制备：参照化合物6到I-7的制备方法，得到化合物I-18 (3.5mg)1H NMR(400MHz,Acetone)δ8.78(brs,2H),8.31–8.24(m,2H), 7.81–7.71(m,2H),7.24(s,2H),4.29(t,J＝6.5Hz,2H),1.79–1.70(m,2H), 1.55–1.43(m,2H),0.98(t,J＝7.4Hz,3H).LC-MS(ESI)m/z:[M+H]+332.0。
化合物I-19(45mg)1H NMR(400MHz,CDCl3)δ8.35–8.29(m,2H),7.61 –7.55(m,2H),7.33(d,J＝1.4Hz,1H),7.27(d,J＝1.4Hz,1H),5.29(brs,J＝7.4 Hz,1H),4.35(t,J＝6.6Hz,2H),3.80(s,3H),1.82–1.73(m,2H),1.48(dt,J＝ 14.7,7.4Hz,2H),0.99(t,J＝7.4Hz,3H).GC-MS(EI)m/z：345.20[M]+。
实施例20-24：
目标化合物结构如下：
合成路线：
化合物18制备：取25mL单口瓶，加入底物17(0.56g,1.55mmol)，乙醇3mL，THF 3mL，混合均匀置于冰水浴中，加入LiCl(164mg),分批加入NaBH4(146mg)加完，自然升温反应过夜，TLC检测反应完毕，加入1N HCl淬灭，减压除去溶剂，乙酸乙酯萃取，无水硫酸钠干燥，柱层析分离， PE:EA＝2:1，得化合物18(450mg)。
化合物19制备：参照化合物6到7合成方法得到化合物19(350mg)
化合物I-20、I-21、I-22制备：25mL单口瓶，加入底物19(150mg)， DCM 3mL，三乙胺(0.26mL)，置于冰水浴中滴加入乙酰氯(0.1mL)，加恢复到室温反应1h，TLC检测反应完毕，加入饱和碳酸氢钠，DCM分液萃取，无水硫酸钠干燥，减压浓缩，柱层析分PE:EA＝4:1，得上Ac化合物160mg。
上述Ac底物脱甲基，参照化合物6到I-7的制备方法，得到化合物I-20 (72mg)1HNMR(400MHz,Acetone)δ8.29(s,2H),8.25–8.19(m,2H),7.76– 7.70(m,2H),6.44(s,2H),3.63–3.51(m,3H),2.61–2.54(m,2H),1.86–1.75 (m,2H).LC-MS(ESI)m/z:[M+H]+290.1。化合物I-21(16mg)1H NMR(400 MHz,Acetone)δ8.55(brs,1H),8.29–8.22(m,2H),7.74–7.64(m,2H),6.63(s, 1H),3.69–3.54(m,3H),2.81–2.75(m,2H),1.89–1.79(m,2H).LC-MS(ESI)m/z:[M+Na]+390、392。I-22(24mg)1H NMR(400MHz,Acetone)δ8.33(s,2H), 8.28–8.18(m,2H),7.78–7.70(m,2H),6.44(s,2H),4.06(t,J＝6.6Hz,1H), 2.63–2.53(m,2H),2.00(s,3H),1.96–1.88(m,2H).LC-MS(ESI)m/z:[M+H]+ 332.0。
化合物I-23制备：以I-20为底物，参照化合物I-10合成方法，得到化合化I-23(5.0mg)1H NMR(400MHz,Acetone)δ8.68(brs,1H),8.31–8.22(m, 2H),7.63–7.56(m,2H),6.82(d,J＝1.4Hz,1H),6.60(d,J＝1.5Hz,1H),3.67– 3.53(m,3H),2.74–2.64(m,2H),2.26(t,J＝7.2Hz,2H),1.89–1.78(m,2H), 1.52–1.41(m,2H),0.74(t,J＝7.4Hz,3H).GC-MS(EI)m/z：359.20[M]+。
化合物I-24制备：取25mL单口瓶，加入底物I-20(72mg，0.25mmol)，THF 2mL，置于冰水浴中，加入吡啶(42μL，0.5mmol)，滴加特戊酰氯(37 μL，0.30mmol)，缓慢升到室温反应2h。TLC检测反应完全，加入水，乙酸乙酯分液，无水硫酸钠干燥，减压浓缩，柱层析分离，200～300目，PE:EA＝4:1 得化合物I-24(17mg)1H NMR(400MHz,Acetone)δ8.32(s,2H),8.25–8.19 (m,2H),7.76–7.69(m,2H),6.44(s,2H),4.08(t,J＝6.4Hz,2H),2.68–2.54(m, 2H),1.93(tt,J＝13.1,6.5Hz,2H),1.19(s,9H).LC-MS(ESI)m/z:[M+H]+ 374.0。
实施例25～29：
目标化合物结构如下：
合成路线：
化合物20制备：50mL单口瓶加入底物3,5-二甲氧基苯胺(1.0g，6.54 mmol)，THF26ml，Boc2O(1.8mL，7.85mmol)加热回流过夜，TLC检测反应完毕，减压浓缩，柱层析，200～300目，PE:EA＝5:1，得化合物20(1.32 g)。
化合21和22制备：以化合物20为底物，参照化合物I-2里碘代物和偶联方法得到化合物21(772mg)和22(3.09g)。
化合物II-1制备：以化合物21(466mg，1.46mmol)为底物，参照化合物I-2脱甲基方法，得到脱甲基化合物(180mg)，DCM:MeOH＝15:1。
取25mL单口瓶，加入上述脱甲基底物(130mg，0.68mmol)，DMF 2 mL，TBAI(38mg)，Cs2CO3(243mg)先在室温下搅拌15min，加入正溴庚烷(120μL)，置于油浴加热至90℃反应过夜，TLC检测，反应完毕，先加1N HCl调至pH 3～5，在加碳酸氢钠调回pH 8～9，加入乙酸乙酯萃取，无水硫酸钠干燥，减压浓缩，柱层析分离，200～300目，PE:EA＝3:1，得化合物 II-1(23mg)，1H NMR(400MHz,CDCl3)δ7.63(t,J＝1.6Hz,1H),7.53(s,1H), 6.50(d,J＝0.9Hz,1H),6.01(d,J＝2.3Hz,1H),5.93(d,J＝2.3Hz,1H),5.02(s, 1H),3.90(t,J＝6.6Hz,2H),3.68(brs,2H),1.86–1.67(m,2H),1.47–1.26(m, 8H),0.89(t,J＝6.8Hz,3H).GC-MS(EI)m/z：289.13[M]+。
化合物23制备：50mL单口瓶，加入底物22(0.86g，2.7mmol)，DCM 14mL，TFA3 mL，苯甲醚0.88mL，在室温下反应过夜。TLC检测反应完毕，减压浓缩除去过量TFA，加入EA和饱和碳酸氢钠分液萃取，合并有机相，无水硫酸钠干燥，减压浓缩，柱层析分离，PE:EA＝2:1，得脱Boc化合物(560mg)。
取25mL单口瓶，加入上述脱Boc化合物(0.4g，1.83mmol)，DMSO 4 mL，TBAI 34mg，K2CO3271 mg，混合均匀后加入正溴庚烷(0.32mL)，置于油浴中加热至80℃反应过夜，TLC检测反应完毕，停止加热冷却后加入水和乙醚分液萃取，无水硫酸钠干燥，减压浓缩，柱层析，200～300目，PE:EA＝5:1，得化合物23(230mg)以及副产物24(160mg)。
化合物II-2制备：以化合物23为底物，参照化合物I-2方法脱去甲基，得化合物II-2(8mg)。1H NMR(400MHz,CDCl3)δ7.64(t,J＝1.5Hz,1H),7.58 (s,1H),6.52(d,J＝0.9Hz,1H),5.85(s,2H),4.96(brs,1H),3.08(t,J＝7.1Hz, 2H),1.72–1.53(m,2H),1.43–1.22(m,8H),0.89(t,J＝6.7Hz,3H).GC-MS (EI)m/z：303.12[M]+。
化合物II-3制备：25mL单口瓶，加入底物23(36mg，0.11mmol)，DCM 2mL，DMAP1.5mg，置于冰水浴中加入三乙胺(76μL)，缓慢滴甲乙酰氯 (40μL)升到室温反应2h，TLC检测反应完毕。加入水，DCM分液萃取，无水硫酸钠干燥，减压浓缩，柱层析，200～300目，DCM:MeOH＝20:1，得上 Ac化合物35mg。
取25mL单口瓶，加入上述上Ac底物(35mg),参照化合物I-2脱甲基方法，得到化合物II-3(6mg)。1H NMR(400MHz,CDCl3)δ7.72(s,1H),7.67 (s,1H),6.66(s,1H),6.35(s,2H),6.10(brs,2H),3.65(t,2H),1.91(s,3H),1.76– 1.58(m,2H),1.53(sm,2H),1.33–1.15(m,6H),0.85(t,J＝6.8Hz,3H).GC-MS (EI)m/z：331.14[M]+。
化合物II-4和II-5制备：以化合物24(160mg)为底物，参照化合物I-2 脱甲基方法，得到化合物II-4(8mg)1H NMR(400MHz,CDCl3)δ7.66–7.62 (m,1H),7.55(t,J＝1.6Hz,1H),6.83(s,1H),6.63(d,J＝1.0Hz,1H),6.61(s, 1H),6.57(d,J＝1.9Hz,1H),5.49(s,1H),4.16(t,J＝6.7Hz,2H),3.79(s,3H), 1.75–1.63(m,2H),1.43–1.27(m,8H),0.89(t,J＝6.8Hz,3H).LC-MS(ESI) m/z:[M+H]+348.2；化合物II-5(65mg)1H NMR(400MHz,CDCl3)δ7.70–7.57 (m,2H),6.68(s,2H),6.61(brs,1H),6.59(s,1H),5.52(s,2H),4.15(t,J＝6.6Hz, 2H),1.73–1.63(m,2H),1.46–1.22(m,8H),0.88(t,J＝6.7Hz,3H).LC-MS (ESI)m/z:[M+H]+334.2。
以上制备的化合物进行生物活性测试
具体试验方法如下：
1、种细胞
人肝癌细胞HepG2、HuH-7、MHCC97H、SMCC-7721，用DMEM完全培养液(含10％胎牛血清和1X青霉素-链霉素双抗溶液)在培养皿中培养。人肺癌细胞A549、人肺支气管癌细胞NCI-H1650用RPMI 1640完全培养液 (含10％胎牛血清和1X青霉素-链霉素双抗溶液)在培养皿中培养。取对数生长期的细胞，当细胞培养生长至70％-80％融合时，胰酶消化后用培养液重悬细胞并计数，配制成密度约7×104个/mL细胞悬液，以每孔100μL细胞悬液将细胞接种于96孔板，37℃培养箱中培养至细胞贴壁。
2、加药
以DMSO为溶剂配制浓度20mg/mL的受试化合物，实验时用培养液稀释至所需工作浓度。96孔板弃培养液后，实验组分别加入适当工作浓度的化合物溶液100μL，空白对照组加入培养液100μL，阳性对照组加入抗肿瘤药物顺铂100μL，将96孔板继续放置培养箱中培养。上述化合物和顺铂的工作浓度均为50μg/mL，
3、MTT检测法
培养48h后每孔加入10μL的MTT试剂，轻轻拍打培养板以帮助混匀， 37℃培养箱中孵育4小时，用酶标仪测定570nm吸光度值。实验重复3次后取平均值，结果如下表1所示。
表1.化合物50μg/mL对肝癌和肺癌细胞48h抑制率(％)
由表1可知，联芳基酚类化合物在50μg/mL浓度下作用肿瘤细胞48h，其中：化合物I-4,I-5,I-10,I-18,I-19,I-24,II-1,II-3,II-4和II-5对HepG2的抑制率大于70％；化合物I-4,I-10,I-18,I-19,I-24,II-1,II-3和II-5对HuH-7抑制率大于80％；化合物I-17,I-24,II-1,II-3和II-5对A549抑制率大于80％；化合物I-18,I-19,II-1,II-3和II-5对NCI-1650抑制率大于75％；化合物I-18,I-19, I-24,II-1,II-3和II-5对MHCC97H抑制率大于80％；化合物I-10,I-18,I-19和 I-24对SMCC-7721抑制率大于75％。综上所述：其中，化合物I-18，I-19， I-24，II-1，II-3和II-5对上述六株细胞均有较高抑制率，且效果优于阳性药物顺铂。
由以上实验结果可知，本发明提供的具有生物活性的联芳基酚类化合物具有抑制肿瘤细胞增殖的活性，具有重大的药物研发潜力，可作为先导化合物用于抗癌药物的开发。
需要说明的是，在本文中，诸如第一和第二等之类的关系术语仅仅用来将一个实体或者操作与另一个实体或操作区分开来，而不一定要求或者暗示这些实体或操作之间存在任何这种实际的关系或者顺序。而且，术语“包括”、“包含”或者其任何其他变体意在涵盖非排他性的包含，从而使得包括一系列要素的过程、方法、物品或者终端设备不仅包括那些要素，而且还包括没有明确列出的其他要素，或者是还包括为这种过程、方法、物品或者终端设备所固有的要素。在没有更多限制的情况下，由语句“包括……”或“包含……”限定的要素，并不排除在包括所述要素的过程、方法、物品或者终端设备中还存在另外的要素。此外，在本文中，“大于”、“小于”、“超过”等理解为不包括本数；“以上”、“以下”、“以内”等理解为包括本数。
尽管已经对上述各实施例进行了描述，但本领域内的技术人员一旦得知了基本创造性概念，则可对这些实施例做出另外的变更和修改，所以以上所述仅为本发明的实施例，并非因此限制本发明的专利保护范围，凡是利用本发明说明书内容及实施例所作的等效结构或等效流程变换，或直接或间接运用在其他相关的技术领域，均同理包括在本发明的专利保护范围之内。
Claims (10)
1.联芳基酚类化合物，其特征在于，其化学结构通式如式(I)或式(II)所示：
或该化合物的立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物，
其中：X、Y各自独立选自O、S、C、N；
R1，R2，R3，R4，R5，R6各自独立地选自：-H，羰基，酰基、C1-9烃基，取代C1-9烃基，，-CpHq-OD1,，-NH2，-CpHq-NHD1，-CpHq-NH-C(O)-D1，-CpHq-NHOH，-CpHq-NH-O-D1，-CpHq-C(O)-NH-D1，氰基，-CpHq-C(O)-D1，硝基，羧基，取代羧基，卤素，芳基，取代芳基，杂芳基，取代的杂芳基，其中，p＝0-5，q＝2p或p＝2-5，p＝2q-2；
R1＇，R2＇，R3＇，R4＇，R5＇，R6＇各自独立地选自：-H，卤素，1-3卤素取代甲基，硝基，氰基，-NH2，-NHD1，-ND1D1，-NH-C(O)-D1、C1-3的醛基、C1-6烷基，C3-6环烷基，C2-6烯基，C2-6炔基，-COOH，-COOD1，-C(O)-NHD1，-OH，-(CH2)0-3-OD1，-C(O)-D1，芳基，取代芳基，杂芳基，取代杂芳基；
D1为选自：-H、C1-9烷基链、末端被1-3个卤原子取代的C1-9烷基链，C3-6的环烷基，C2-9烯基链，C2-9炔基链，C3-6环烯基，芳基，取代芳基，杂芳基，取代杂芳基；
2.如权利要求1所述的联芳基酚类化合物，其特征在于，所述X，Y，R1，R2，R3，R4，R5，R6优选自：
(1)当Y为O时：无R1、R2基团，R3选自：-H，-CpHq-C(O)-D1，C1-9烷基链，被一个卤素取代的C1-C9烷基链，C2-9烯基链，C2-9炔基链，C3-6环烷基，C3-C6环烯基，芳基，取代的芳基，杂芳基，取代的杂芳基；
(2)当Y为S时：R1、R2各自独立选自羰基，R3独立选自：H，-CpHq-C(O)-D1，-CpHq-OD1，C1-9烷基链，被一个卤素取代的C1-C9烷基链，C2-9烯基链，C2-9炔基链，C3-6环烷基，C3-C6环烯基，芳基，取代芳基，杂芳基，取代杂芳基；
(3)当Y为C时：
R1为羰基时，无R2基团，R3独立选自：-H，-CpHq-OD1，-NH2，-CpHq-NHD1，-CpHq-NH-C(O)-D1，-CpHq-NH-O-D1，C1-9烷基链，被一个卤素取代的C1-C9烷基链，C2-9烯基链，C2-9炔基链，C3-6环烷基，C3-C6环烯基，芳基，取代的芳基，杂芳基，取代的杂芳基；
R1、R2、R3均不选自羰基时，各自独立取自：-H，-CpHq-OD1，-NH2，-CpHq-NHD1，-CpHq-NH-C(O)-D1，-CpHq-C(O)-NH-D1，，-CpHq-NH-O-D1，-CN，-NO2，C1-9烷基链，被一个卤素取代的C1-C9烷基链，C2-9烯基链，C2-9炔基链，C3-6环烷基，C3-C6环烯基，芳基，取代的芳基，杂芳基，取代的杂芳基，且R1、R2、R3不能同时两个或三个选自：-OH，NH2，-CN，-NO2；
(4)当Y为N时，无R2基团：
R1选自：-H，C1-9的烷基链，-C(O)-D1，-COOH，-COOD1，-OD1；
R3选自：-H，-(CH2)0-5-OD1，C1-9烷基链，被一个卤素取代的C1-C9烷基链，C2-9烯基链，C2-9炔基链，C3-6环烷基，C3-C6环烯基，芳基，取代芳基，杂芳基，取代杂芳基；
R1，R3均不选自-C(O)-D1，-COOH，-COOD1或-OD1时，各自独立选自：H，-(CH2)0-5-OD1，C1-9烷基链，被一个卤素取代的C1-C9烷基链，C2-9烯基链，C2-9炔基链，C3-6环烷基，C3-C6环烯基，芳基，取代芳基，杂芳基，取代杂芳基；
(5)当X为C时，R5、R6独立选自：-H，-COOH，-COOD1，硝基，氰基，-NH2，-CpHq-NHD1，-CpHq-C(O)-D1，-CpHq-OD1,，C1-9烷基链,被一个卤素取代的C1-C9烷基链，C2-9烯基链，C2-9炔基链，C3-6环烷基，C3-C6环烯基，芳基，取代芳基，杂芳基，取代杂芳基，且R5、R6不同时选自-COOH，-COOD1，硝基，氰基，-CpHq-NHD1，-CpHq-C(O)-D1，-OH，-CpHq-OD1；
(6)当X为N时：R5、R6各自独立选自：-H，-COOH，-COOD1，-C(O)-D1，-OH，-OD1，C1-9烷基链，被一个卤素取代的C1-C9烷基链，C2-9烯基链，C2-9炔基链，C3-6环烷基，C3-C6环烯基，芳基，取代的芳基，杂芳基，取代的杂芳基，且R5、R6不同时选自-COOH，-COOD1，-C(O)-D1，-OH，-OD1；
(7)当X为S时：无R5基团，R6选自：-H，-C(O)-D1，C1-9烷基链，被一个卤素取代的C1-C9烷基链，C2-9烯基链，C2-9炔基链，C3-6环烷基，C3-C6环烯基，芳基，取代芳基，杂芳基，取代杂芳基；
(8)当X为O时：无R5基团，R6选自：-H，-C(O)-D1，-COOD1，C1-9烷基链，被一个卤素取代的C1-C9烷基链，C2-9烯基链，C2-9炔基链，C3-6环烷基，C3-C6环烯基，芳基，取代的芳基，杂芳基，取代的杂芳基；
3.如权利要求2所述的联芳基酚类化合物，其特征在于，所述X、Y、R1，R2，R3，R4，R5，R6优选自：
a)当Y为C时：R1为羰基，无R2基团，R3选自：-O(CH2)0-6-CH3，
-NH-(CH2)0-6-CH3；
b)当Y为C时：且R1，R2，R3都不选自羰基，各自独立选自：H，-(CH2)0-6-CH3，C1-6的环烷烃，-C(O)-NH-(CH2)0-6-CH3，-C(O)-NH-(CH2)0-3-(aryl)，-C(O)-NH-(CH2)0-6-CH2-(Cl、Br或I)，-(CH2)0-6-COO-(alkyl)，-(CH2)0-6-OH，-(CH2)0-6-O-C(O)-(alkyl)；
c)当Y为N时：无R2基团，R1取自：-H，C1-9的烷基链，-COOH，-COO-(CH2)0-3-CH3，-C(O)-(CH2)0-6-CH3；R3取自：C1-9的烷基链；
d)R4取Cl，Br，I，H；
e)当X为N时：R5，R6各自独立取自：-H、C1-6的烷基；
f)当X为O时：无R5基团，R6取自：-H，C1-6的烷基，-COO(CH2)0-6-CH3。
4.如权利要求1所述的联芳基酚类化合物，其特征在于，所述R1＇，R2＇，R3＇，R4＇，R5＇，R6＇优选自：
-H，-(CH2)0-3-CH3，-(CH2)0-3-OH，-O(CH2)0-3-CH3，-NO2，-COO-(CH2)0-3-CH3，-NH2；
5.如权利要求1所述的联芳基酚类化合物，其特征在于，所述芳基、取代芳基、杂芳基、取代杂芳基结构如下：
其中，n为0～3的整数；
D2选自：-N-[(CH2)0-3]2-，-OH，-O(alkyl)，-O(aryl)，-CF3，-NO2，F，Cl，Br，I，C1-4烷基，-COO(CH2)0-4；
E为六元苯环、含有N，O，S其中至少有一个杂原子的六元杂环或含有N，O，S其中一个杂原子的五元杂环。
6.如权利要求5所述的联芳基酚类化合物，其特征在于，所述F，E，D1，D2优选自：F为呋喃环；E为苯环；D1为选自：H、甲基、乙基、丁基、异戊基、3-氯-丙基、苄基，或胺取代的苄基；D2选自-H，-N(Me)2；
7.如权利要求1所述的联芳基酚类化合物，其特征在于，具体选自以下结构式化合物：
或上述化合物的立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物。
8.制备权利要求1-7任一所述联芳基酚类化合物的合成方法，其特征在于，
当R5＇不为-CH2-OH时，包括如下步骤：
其中，步骤(a)：将芳基取代硼酸和碘代物混合，加入碳酸铯和DMF，除氧后加入Pd催化剂，发生Suzuki偶联得到联芳基化合物；(b)联芳基化合物溶解在溶剂里，冰浴下缓慢滴加BBr3，得到脱甲基化合物。
方法二：当R5＇为-CH2-OH时，包括如下步骤
其中，步骤(c):间三苯酚和邻溴苯甲酸类底物，发生Hurtley反应得到内酯化合物；(d)用硫酸二甲酯做甲基化试剂，得到酚甲基醚化合物；(e)将酚甲基醚内酯化合物，用氢化铝锂还原得到羟甲基化合物；
9.药物组合物，其特征在于，包含权利要求1-7中任一项所述联芳基酚类化合物、其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物以及任选的药学上可以接受的赋形剂。
10.权利要求1-7中任一项所述的联芳基酚类化合物、其立体异构体、其前药、其药学上可接受的盐、其药学上可接受的溶剂合物或者权利要求9所述的药物组合物在制备用于预防或治疗肿瘤的药物的用途。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210259791.4A CN114605236B (zh) | 2022-03-16 | 2022-03-16 | 联芳基酚类化合物及其药物组合物、制备方法和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210259791.4A CN114605236B (zh) | 2022-03-16 | 2022-03-16 | 联芳基酚类化合物及其药物组合物、制备方法和应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114605236A true CN114605236A (zh) | 2022-06-10 |
| CN114605236B CN114605236B (zh) | 2023-12-29 |
Family
ID=81863346
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210259791.4A Active CN114605236B (zh) | 2022-03-16 | 2022-03-16 | 联芳基酚类化合物及其药物组合物、制备方法和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114605236B (zh) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1671639A (zh) * | 2002-08-23 | 2005-09-21 | 康涅狄格大学 | 新型联苯大麻素和类似联苯的大麻素 |
| CA2658887A1 (en) * | 2006-07-28 | 2008-01-31 | University Of Connecticut | Fatty acid amide hydrolase inhibitors |
| EP2150534A1 (en) * | 2007-04-26 | 2010-02-10 | H. Lundbeck A/S | Isoquinolinone derivatives as nk3 antagonists |
| CN101668425A (zh) * | 2007-03-02 | 2010-03-10 | 田纳西州立大学研究基金会 | 三芳基/杂芳族大麻素类和其应用 |
| CN108341739A (zh) * | 2017-01-23 | 2018-07-31 | 中国科学院上海有机化学研究所 | 一种α-芳基、杂芳基或烯基-α,α-二氟甲基类化合物的制备方法 |
| CN110590557A (zh) * | 2019-08-28 | 2019-12-20 | 上海师范大学 | 一种芳基酚类或芳基醚类衍生物的硝化方法 |
| CN112500293A (zh) * | 2020-12-10 | 2021-03-16 | 福建省中科生物股份有限公司 | 1,1′-联苯-2,6-二酚类化合物及其应用 |
-
2022
- 2022-03-16 CN CN202210259791.4A patent/CN114605236B/zh active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1671639A (zh) * | 2002-08-23 | 2005-09-21 | 康涅狄格大学 | 新型联苯大麻素和类似联苯的大麻素 |
| CA2658887A1 (en) * | 2006-07-28 | 2008-01-31 | University Of Connecticut | Fatty acid amide hydrolase inhibitors |
| WO2008013963A2 (en) * | 2006-07-28 | 2008-01-31 | University Of Connecticut | Fatty acid amide hydrolase inhibitors |
| CN101668425A (zh) * | 2007-03-02 | 2010-03-10 | 田纳西州立大学研究基金会 | 三芳基/杂芳族大麻素类和其应用 |
| EP2150534A1 (en) * | 2007-04-26 | 2010-02-10 | H. Lundbeck A/S | Isoquinolinone derivatives as nk3 antagonists |
| CN108341739A (zh) * | 2017-01-23 | 2018-07-31 | 中国科学院上海有机化学研究所 | 一种α-芳基、杂芳基或烯基-α,α-二氟甲基类化合物的制备方法 |
| CN110590557A (zh) * | 2019-08-28 | 2019-12-20 | 上海师范大学 | 一种芳基酚类或芳基醚类衍生物的硝化方法 |
| CN112500293A (zh) * | 2020-12-10 | 2021-03-16 | 福建省中科生物股份有限公司 | 1,1′-联苯-2,6-二酚类化合物及其应用 |
Non-Patent Citations (3)
| Title |
|---|
| "Structure Activity Relationships of Tetrahydrocanabinol Analogs on Human Cannabinoid Receptors，Yves Gareau" * |
| F. MINUTOLO: "Metabolically Labile Cannabinoid Esters: A \'Soft Drug\' Approach for the Development of Cannabinoid-Based Therapeutic Drugs" * |
| YVES GAREAU: "Structure Activity Relationships of Tetrahydrocanabinol Analogs on Human Cannabinoid Receptors" * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114605236B (zh) | 2023-12-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104211683B (zh) | 咪唑二酮类化合物及其用途 | |
| CN111961034A (zh) | 用作ret激酶抑制剂的化合物及其应用 | |
| CN110590796B (zh) | 喜树碱衍生物及其制备方法和应用 | |
| EP2805954B1 (en) | 7-substituted hanfangichin b derivative, and preparation method and use thereof | |
| TW202304927A (zh) | 用作shp2抑制劑的化合物及其應用 | |
| CN114195814B (zh) | 羟基萘酮-苯硼酸类化合物、制备方法和用途 | |
| CN112500293B (zh) | 1,1′-联苯-2,6-二酚类化合物及其应用 | |
| CN112110897B (zh) | 一种氘代克里唑蒂尼及其衍生物的制备方法 | |
| CN114605236A (zh) | 联芳基酚类化合物及其药物组合物、制备方法和应用 | |
| CN107573336B (zh) | 苯并杂环-甲酰胺-吡啶酮衍生物及其制备方法和用途 | |
| US8815940B2 (en) | Coumarin-chalcones as anticancer agents | |
| WO2022148439A1 (zh) | 作为bcl-2抑制剂的杂环化合物 | |
| WO2013023620A1 (zh) | 高三尖杉酯碱的胺化衍生物、及其制备方法和应用 | |
| CN108358858B (zh) | 氘标记1-取代苯基-4-取代苯胺甲基-1,2,3-三氮唑衍生物及其制备方法和应用 | |
| CN102516066B (zh) | Ostopanic acid类似物及制备方法及用途 | |
| CN114746426B (zh) | 作为acc1和acc2抑制剂的晶型及其制备方法和应用 | |
| WO2013079017A1 (zh) | 2-位烷基或芳香基取代的丹参酮衍生物、及其制备方法和应用 | |
| CN115010642B (zh) | β-榄香烯酰亚胺类衍生物及其应用 | |
| CN114940696B (zh) | 一种川楝素衍生物及其在乳腺癌治疗中的应用 | |
| CN113683613B (zh) | 一种多环吡啶肟基化合物及其药物组合物和用途 | |
| WO2021110138A1 (zh) | 噻吩并[2,3-c]哒嗪-4(1H)-酮类化合物的晶型及其制备方法和应用 | |
| CN117185908A (zh) | 一种具有抗肿瘤活性的毛兰素衍生物、其药物组合物及用途 | |
| CN111533738A (zh) | 含吲哚结构的化合物或其药学上可接受的盐、制备方法和用途 | |
| CN117567457A (zh) | 噻唑酮亚砜和砜类化合物及其制备方法和应用 | |
| WO2023061263A1 (zh) | Shp2抑制剂、包含其的药物组合物及其用途 |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |