CN115160222B - Hydroxamic acid compound containing quinoline or isoquinoline and preparation and application thereof - Google Patents
Hydroxamic acid compound containing quinoline or isoquinoline and preparation and application thereof Download PDFInfo
- Publication number
- CN115160222B CN115160222B CN202210733176.2A CN202210733176A CN115160222B CN 115160222 B CN115160222 B CN 115160222B CN 202210733176 A CN202210733176 A CN 202210733176A CN 115160222 B CN115160222 B CN 115160222B
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- Prior art keywords
- phenyl
- sulfanyl
- hydroxy
- acrylamide
- acid
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title claims abstract description 26
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 239000002253 acid Substances 0.000 title claims abstract description 15
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 102000003964 Histone deacetylase Human genes 0.000 claims abstract description 12
- 108090000353 Histone deacetylase Proteins 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 7
- 201000010099 disease Diseases 0.000 claims abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 4
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 248
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 132
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- DAKIDYQCFJQMDF-UHFFFAOYSA-N dichloromethane;pyridine Chemical compound ClCCl.C1=CC=NC=C1 DAKIDYQCFJQMDF-UHFFFAOYSA-N 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 230000002265 prevention Effects 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 229940121372 histone deacetylase inhibitor Drugs 0.000 abstract description 4
- 239000003276 histone deacetylase inhibitor Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000007787 solid Substances 0.000 description 35
- 238000005160 1H NMR spectroscopy Methods 0.000 description 27
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 27
- 239000000243 solution Substances 0.000 description 13
- 125000003118 aryl group Chemical group 0.000 description 12
- 125000001072 heteroaryl group Chemical group 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 206010028980 Neoplasm Diseases 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 8
- -1 hydroxy, mercapto Chemical class 0.000 description 7
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 125000003373 pyrazinyl group Chemical group 0.000 description 5
- 125000004076 pyridyl group Chemical group 0.000 description 5
- GCMNJUJAKQGROZ-UHFFFAOYSA-N 1,2-Dihydroquinolin-2-imine Chemical compound C1=CC=CC2=NC(N)=CC=C21 GCMNJUJAKQGROZ-UHFFFAOYSA-N 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- ZGGPGWYMMZNPOY-ZZXKWVIFSA-N (e)-3-(4-chlorosulfonylphenyl)prop-2-enoic acid Chemical compound OC(=O)\C=C\C1=CC=C(S(Cl)(=O)=O)C=C1 ZGGPGWYMMZNPOY-ZZXKWVIFSA-N 0.000 description 3
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 108010033040 Histones Proteins 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 230000006195 histone acetylation Effects 0.000 description 2
- 230000006197 histone deacetylation Effects 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- PJGOLCXVWIYXRQ-UHFFFAOYSA-N 3-bromobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC(Br)=C1 PJGOLCXVWIYXRQ-UHFFFAOYSA-N 0.000 description 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000006947 Histones Human genes 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 229940124532 absorption promoter Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- NCNRHFGMJRPRSK-MDZDMXLPSA-N belinostat Chemical compound ONC(=O)\C=C\C1=CC=CC(S(=O)(=O)NC=2C=CC=CC=2)=C1 NCNRHFGMJRPRSK-MDZDMXLPSA-N 0.000 description 1
- 229960003094 belinostat Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000006364 cellular survival Effects 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000004076 epigenetic alteration Effects 0.000 description 1
- 230000006718 epigenetic regulation Effects 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 210000004088 microvessel Anatomy 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
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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
-
- 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
- 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
- C07D215/40—Nitrogen atoms attached in position 8
-
- 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
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
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Abstract
The invention relates to a hydroxamic acid compound containing quinoline or isoquinoline and preparation and application thereof, belongs to the technical field of medicines, and particularly comprises a pharmaceutical composition of the compound, and application of the pharmaceutical composition as a histone deacetylase inhibitor and application of the pharmaceutical composition in preventing and/or treating diseases related to histone deacetylase, wherein the structure of the hydroxamic acid compound containing quinoline or isoquinoline is shown as a general formula I:
Description
technical field:
the invention belongs to the technical field of medicines, and particularly relates to a hydroxamic acid compound containing quinoline or isoquinoline, and preparation and application thereof, and particularly relates to application of the compound serving as a histone deacetylase inhibitor for preventing and/or treating diseases related to histone deacetylase.
The background technology is as follows:
cancer, because of its high morbidity and mortality has become a leading cause of death worldwide, is one of the most fearful killers in humans.
In the emerging field of cancer research, epigenetic alterations have an indispensable function in the development, progression and invasive metastasis of tumors. Post-translational modification of histones is a key process for epigenetic regulation, and a large number of studies indicate that abnormal decrease in histone acetylation levels is closely related to cancer and various immune diseases. Histone deacetylase HDACs are one of the key enzymes regulating the balance of histone as well as non-histone acetylation and deacetylation in vivo, and abnormal expression of HDACs is found in a variety of cancers. It follows that HDACs have become an important target for cancer research.
HDACs mediated histone deacetylation plays an important role in regulating cellular differentiation, proliferation and survival processes. Histone hyperacetylation caused by HDACs mutation or abnormal expression is closely related to proliferation, invasion and migration of tumors. Numerous studies have shown that over-expression of HDACs is observed in different types of cancer and is in most cases closely related to poor prognosis. Related researches show that the HDACs inhibitor can exert the anti-tumor effect by inducing apoptosis of tumor cells, inhibiting formation of tumor tissue microvessels and the like, so that the HDACs inhibitor is developed as a novel anti-tumor medicament.
The invention comprises the following steps:
the invention aims to overcome the defects in the prior art and provide a hydroxamic acid compound containing quinoline or isoquinoline, preparation and application thereof, and application of the compound serving as a histone deacetylase inhibitor in preventing and/or treating tumors.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the invention provides a hydroxamic acid compound containing quinoline or isoquinoline as shown in a general formula I and pharmaceutically acceptable salts or hydrates thereof.
Wherein:
x is N or CH, Y is CH or N; wherein, when X is N, Y is CH; when X is CH, Y is N;
w is carbonyl or (C) 3 -C 5 ) α, β -unsaturated carbonyl;
ring a is aryl or heteroaryl, wherein aryl or heteroaryl are each independently optionally substituted with one or more R, R is hydrogen, (C) 1 -C 6 ) Alkyl, cyano, halogen, halo (C) 1 -C 6 ) Alkyl, hydroxy, mercapto or alkoxy;
wherein the aryl is a 6-10 membered aryl; the heteroaryl is five-membered or six-membered heteroaryl, wherein 1-3 heteroatoms N, O or S are contained, and the rest ring atoms are C; the aryl is phenyl; the five-membered heteroaryl is pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl; the six-membered heteroaryl is pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl;
preferred compounds of the present invention are those of the following structure:
x is N, then Y is CH; or X is CH, then Y is N;
w is carbonyl or (C) 3 -C 5 ) α, β -unsaturated carbonyl;
ring a is aryl or heteroaryl;
wherein the aryl is phenyl; the five-membered heteroaryl is pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl; the six-membered heteroaryl is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl.
Preferred compounds of the present invention are those of the following structure:
x is N, then Y is CH; or X is CH, then Y is N;
w is carbonyl or (C) 3 -C 5 ) Alpha, beta-non-crystallineSaturated carbonyl groups;
ring a is aryl or heteroaryl;
wherein the aryl is phenyl; the heteroaryl is pyridinyl, pyrazinyl;
further, when the A ring is phenyl, the phenyl is
Further, when the ring A is a pyridyl group, the pyridyl group is
Further, when the A ring is pyrazinyl, pyrazinyl is
Preferred compounds of the present invention are those of the following structure:
x is N, then Y is CH; or X is CH, then Y is N;
w is carbonyl or (C) 3 -C 5 ) α, β -unsaturated carbonyl;
ring a is aryl;
wherein the aryl is phenyl;
further, when the A ring is phenyl, the phenyl is
Preferred compounds of the present invention are those of the following structure:
x is N, then Y is CH; or X is CH, then Y is N;
w is-ch=ch-CO-;
ring a is aryl;
wherein the aryl is phenyl;
further, when the A ring is phenyl, the phenyl is
Specifically, the present invention is preferably the following compounds:
(E) -N-hydroxy-3- (4- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylamide (I-1);
(E) -N-hydroxy-3- (4- (N- (quinolin-3-yl) sulfanyl) phenyl) acrylamide (I-2);
(E) -N-hydroxy-3- (4- (N- (quinolin-4-yl) sulfanyl) phenyl) acrylamide (I-3);
(E) -N-hydroxy-3- (4- (N- (quinolin-5-yl) sulfanyl) phenyl) acrylamide (I-4);
(E) -N-hydroxy-3- (4- (N- (quinolin-6-yl) sulfanyl) phenyl) acrylamide (I-5);
(E) -N-hydroxy-3- (4- (N- (quinolin-7-yl) sulfanyl) phenyl) acrylamide (I-6);
(E) -N-hydroxy-3- (4- (N- (quinolin-8-yl) sulfanyl) phenyl) acrylamide (I-7);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-1-yl) sulfanyl) phenyl) acrylamide (I-8);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-3-yl) sulfanyl) phenyl) acrylamide (I-9);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-4-yl) sulfanyl) phenyl) acrylamide (I-10);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-5-yl) sulfanyl) phenyl) acrylamide (I-11);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-6-yl) sulfanyl) phenyl) acrylamide (I-12);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-7-yl) sulfanyl) phenyl) acrylamide (I-13);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-8-yl) sulfanyl) phenyl) acrylamide (I-14);
(E) -N-hydroxy-3- (3- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylamide (I-15);
(E) -N-hydroxy-3- (3- (N- (quinolin-3-yl) sulfanyl) phenyl) acrylamide (I-16);
(E) -N-hydroxy-3- (3- (N- (quinolin-4-yl) sulfanyl) phenyl) acrylamide (I-17);
(E) -N-hydroxy-3- (3- (N- (quinolin-5-yl) sulfanyl) phenyl) acrylamide (I-18);
(E) -N-hydroxy-3- (3- (N- (quinolin-6-yl) sulfanyl) phenyl) acrylamide (I-19);
(E) -N-hydroxy-3- (3- (N- (quinolin-7-yl) sulfanyl) phenyl) acrylamide (I-20);
(E) -N-hydroxy-3- (3- (N- (quinolin-8-yl) sulfanyl) phenyl) acrylamide (I-21);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-1-yl) sulfanyl) phenyl) acrylamide (I-22);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-3-yl) sulfanyl) phenyl) acrylamide (I-23);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-4-yl) sulfanyl) phenyl) acrylamide (I-24);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-5-yl) sulfanyl) phenyl) acrylamide (I-25);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-6-yl) sulfanyl) phenyl) acrylamide (I-26);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-7-yl) sulfanyl) phenyl) acrylamide (I-27);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-8-yl) sulfanyl) phenyl) acrylamide (I-28);
or a salt or hydrate thereof;
the term "halogen" as used herein, unless otherwise indicated, refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine; "alkyl" refers to a straight or branched chain alkyl group.
According to the present invention, the pharmaceutically acceptable salt may be an inorganic acid salt or an organic acid salt; preferably, the inorganic acid salt is selected from any one of the following inorganic acid forming salts: hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; preferably, the organic acid salt is selected from any one of the following organic acid forming salts: acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, citric acid, salicylic acid, tartaric acid or p-toluenesulfonic acid.
The invention also includes prodrugs of the compounds of the invention. Pharmaceutically acceptable prodrugs mean that the prodrug itself may have a weaker activity or even no activity, but can be converted to-COOH, -NH under physiological conditions (e.g., by metabolism, solvolysis, or another form) after administration 2 Functional groups of-OH or the like, therebyA compound which forms the compound of the present invention.
The present invention includes a pharmaceutical composition containing a hydroxamic acid compound having the above-described quinoline or isoquinoline structure as an active ingredient and a pharmaceutically acceptable adjuvant. The pharmaceutical excipients comprise diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants and the like which are conventional in the pharmaceutical field.
The pharmaceutical composition of the invention can be prepared into a plurality of dosage forms, such as injection, tablet, powder, granule, capsule, oral liquid, ointment, cream and the like. The medicaments of the various formulations can be prepared according to the conventional method in the pharmaceutical field.
The compounds of the present invention and pharmaceutical compositions comprising the compounds of the present invention may be formulated in a form suitable for intravenous, oral, rectal, parenteral, intranasal or transdermal administration, or in a form suitable for administration by inhalation or by suppository. Oral and intravenous administration are preferred.
The hydroxamic acid compounds containing quinoline or isoquinoline and the pharmaceutical compositions thereof are used as histone deacetylase inhibitors for preventing and/or treating diseases related to abnormal expression of histone deacetylase, such as various cancers including liver cancer, colon cancer, pancreatic cancer, lung cancer, gastric cancer, breast cancer, ovarian cancer and the like.
The preparation of the hydroxamic acid compound containing quinoline or isoquinoline adopts one of the following two routes:
route one:
each substituent is defined in the summary of the invention, reagents and conditions: HSO 3 Cl,12h;b.RNH 2 ,CH 2 Cl 2 ,pyridine, 1h;c.CH 3 OH,H 2 SO 4 ,4h;d.NH 2 OH,1N NaOH,CH 3 OH,1h.
Route two:
each substituent is defined in the summary of the invention, reagents and conditions: RNH (rnh) 2 ,CH 2 Cl 2 ,pyridine,2h;b.methyl acrylate,Pd(OAc) 2 ,POT,Et 3 N,CH 3 CN,60℃,12h;c.NH 2 OH,1N NaOH,CH 3 OH,1h.
The invention has the beneficial effects that:
the hydroxamic acid compounds containing quinoline or isoquinoline have good anti-tumor cell proliferation activity, and the preparation method is simple to operate and mild in condition.
The specific embodiment is as follows:
the present invention will be described in further detail with reference to examples.
Example 1: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylamide (I-1)
The structural formula of the compound (I-1)
Step A: (E) Preparation of 3- (4- (chlorosulfonyl) phenyl) acrylic acid
Cinnamic acid (1 g,6.76 mmol) was added slowly in portions to chlorosulfonic acid (7.84 g,67.6 mmol) with stirring at 0deg.C, and stirring was continued for 30min before slowly returning to room temperature and stirring was continued for a further 12h. After the reaction was completed, the reaction solution was slowly dropped into ice water, and after suction filtration, a yellow solid was obtained by vacuum drying, and the solid was added to 1, 4-dioxane, and recrystallized to give (E) -3- (4- (chlorosulfonyl) phenyl) acrylic acid as white crystals (0.55 g, yield 33%).
And (B) step (B): (E) Preparation of 3- (4- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylic acid
Pyridine (1 ml) and (E) -3- (4- (chlorosulfonyl) phenyl) acrylic acid (1 g,4.06 mmol) were added sequentially to a solution of 2-aminoquinoline (0.49 g,3.4 mmol) in methylene chloride (50 ml) at 0℃with stirring. After the addition, the reaction mixture was stirred at 0℃for 1 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give (E) -3- (4- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylic acid as a pale yellow solid (0.6 g, yield 50%).
Step C: preparation of methyl (E) -3- (4- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylate
To a solution of (E) -3- (4- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylic acid (0.6 g,1.7 mmol) in methanol (40 ml) was added 1 drop of concentrated H 2 SO 4 . After the addition, the reaction solution was heated to reflux for 4 hours. After completion of the reaction, ethyl acetate (50 ml. Times.3) was extracted, and the organic phases were combined, washed 3 times with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give methyl (E) -3- (4- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylate as a white solid (0.5 g, 80% yield).
Step D: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylamide
To a solution of methyl (E) -3- (4- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylate (0.5 g, 1.36 mmol) in methanol (20 ml) was slowly added dropwise a 1mol/L NaOH solution (3 ml) at 0℃with stirring, and after stirring for 10 minutes, NH was continuously slowly added dropwise thereto 2 OH solution (3 ml), after the addition, slowly returned to the chamberWarm and stir for 1h. After the completion of the reaction, the solvent was distilled off under reduced pressure, water (20 ml) was added thereto, pH was adjusted to neutrality with 2mol/L hydrochloric acid, and a solid was precipitated, suction filtration and vacuum drying were carried out to obtain (E) -N-hydroxy-3- (4- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylamide (I-1) as a white solid (0.36 g, yield 73%). Mp is 171.6-173.3 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ8.09(d,J=9.0Hz,1H),7.91(d,J =8.3Hz,2H),7.74(d,J=7.8Hz,1H),7.65(d,J=8.3Hz,2H),7.59(t,J=7.4Hz,1H),7.52(d,J=8.3Hz,1H),7.45(d,J=15.8Hz,1H),7.29(t,J=7.4Hz,2H),6.53(d,J=15.8Hz,1H). ESI-MS m/z:392.08[M+Na] + .
the compounds of examples 2-14 were prepared by the preparation method of example 1, with the appropriate choice of starting materials.
Example 2: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (quinolin-3-yl) sulfanyl) phenyl) acrylamide (I-2)
The structural formula of the compound (I-2)
(E) -N-hydroxy-3- (4- (N- (quinolin-3-yl) sulfanyl) phenyl) acrylamide (I-2) as a pale yellow solid in 85% yield. Mp 185.7-187.9 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.82(s,1H),9.10(s,1H),8.55(d,J=2.5Hz, 1H),7.83(dd,J=27.4,8.2Hz,6H),7.66(d,J=8.4Hz,2H),7.55(t,J=7.2Hz,1H),7.49(t,J=7.4Hz,1H),7.42(d,J=15.8Hz,1H),6.50(d,J=15.8Hz,1H).ESI-MS m/z:370.11[M+H] + .
example 3: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (quinolin-4-yl) sulfanyl) phenyl) acrylamide (I-3)
Compound (I-3) structural formula
(E) -N-hydroxy-3- (4- (N- (quinolin-4-yl) sulfanyl) phenyl) acrylamide (I-3) as a white solid in 79% yield. MP 228.9-230.1 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ8.39(d,J=8.1Hz,1H),8.18(d,J=6.3Hz,1H), 7.83(d,J=8.3Hz,2H),7.65(dd,J=8.9,1.4Hz,2H),7.61(d,J=8.2Hz,2H),7.41(ddd,J=11.8,8.6,8.1Hz,2H),6.98(d,J=6.3Hz,1H),6.49(d,J=15.8Hz,1H).ESI-MS m/z:370.11[M+H] + .
example 4: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (quinolin-5-yl) sulfanyl) phenyl) acrylamide (I-4)
Compound (I-4) structural formula
(E) -N-hydroxy-3- (4- (N- (quinolin-5-yl) sulfanyl) phenyl) acrylamide (I-4) as a pale yellow solid in 77% yield. Mp 199.0-201.7 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.84(s,1H),10.45(s,1H),9.12(s,1H),8.85 (dd,J=4.1,1.5Hz,1H),8.40(d,J=8.5Hz,1H),7.85(d,J=8.5Hz,1H),7.70–7.61(m,5H),7.47–7.41(m,2H),7.20(d,J=7.4Hz,1H),6.52(d,J=15.8Hz,1H).ESI-MS m/z:370.11[M+ H] + .
example 5: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (quinolin-6-yl) sulfanyl) phenyl) acrylamide (I-5)
Compound (I-5) structural formula
(E) -N-hydroxy-3- (4- (N- (quinolin-6-yl) sulfanyl) phenyl) acrylamide (I-5) as a white solid in 70% yield. MP 177.9-179.6 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.58(s,1H),8.60(d,J=3.0Hz,1H),8.05(d,J =8.2Hz,1H),7.79(d,J=8.3Hz,2H),7.74(d,J=8.8Hz,1H),7.60(d,J=8.2Hz,2H),7.43–7.36(m,3H),7.32(dd,J=8.3,4.1Hz,1H),6.48(d,J=15.8Hz,1H).ESI-MS m/z:370.11[M+ H] + .
example 6: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (quinolin-7-yl) sulfanyl) phenyl) acrylamide (I-6)
Compound (I-6) structural formula
(E) -N-hydroxy-3- (4- (N- (quinolin-7-yl) sulfanyl) phenyl) acrylamide (I-6) as a white solid in 73% yield. Mp 182.2-185.3 deg.c, 1 H-NMR(600MHz,DMSO-d 6 )δ8.76(dd,J=4.1,1.4Hz,1H),8.20(d,J=7.9Hz, 1H),7.83(t,J=9.8Hz,3H),7.69(d,J=8.3Hz,2H),7.62(d,J=0.8Hz,1H),7.41(d,J=15.8Hz, 1H),7.38(dd,J=8.8,1.9Hz,1H),7.35(dd,J=8.2,4.2Hz,1H),6.52(d,J=15.8Hz,1H).ESI-MS m/z:370.10[M+H] + .
example 7: (E) Preparation of-N-hydroxy-3- (4- (N- (quinolin-8-yl) sulfanyl) phenyl) acrylamide (I-7)
Compound (I-7) structural formula
(E) -N-hydroxy-3- (4- (N- (quinolin-8-yl) sulfanyl) phenyl) acrylamide (I-7) as a pale yellow solid in 85% yield. Mp is 158.2-160.6 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.20(s,1H),9.36(s,1H),8.81(d,J=2.3Hz, 1H),8.27(d,J=8.1Hz,1H),7.89(d,J=5.1Hz,2H),7.73–7.34(m,8H),6.49(d,J=15.8Hz,1H).ESI-MS m/z:370.10[M+H] + .
example 8: (E) Preparation of-N-hydroxy-3- (4- (N- (isoquinolin-1-yl) sulfanyl) phenyl) acrylamide (I-8)
Compound (I-8) structural formula
(E) -N-hydroxy-3- (4- (N- (isoquinolin-1-yl) sulfanyl) phenyl) acrylamide (I-8) as a pale yellow solid, yield 70%. Mp is 215.5-217.7 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ8.38(d,J=8.2Hz,1H),7.95(d,J=8.3Hz,2H), 7.72(t,J=8.5Hz,2H),7.65(d,J=8.1Hz,2H),7.59(d,J=6.7Hz,1H),7.56–7.50(m,1H),7.45(d,J=15.8Hz,1H),6.97(d,J=6.0Hz,1H),6.52(d,J=15.8Hz,1H).ESI-MS m/z:370.11[M+ H] + .
example 9: (E) Preparation of-N-hydroxy-3- (4- (N- (isoquinolin-3-yl) sulfanyl) phenyl) acrylamide (I-9)
Compound (I-9) structural formula
(E) -N-hydroxy-3- (4- (N- (isoquinolin-3-yl) sulfanyl) phenyl) acrylamide (I-9) as a pale yellow solid in 71% yield. Mp of 225.4-228.1 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ8.91(s,1H),7.88(t,J=7.9Hz,3H),7.69(d,J= 7.9Hz,1H),7.63(d,J=8.2Hz,2H),7.55(t,J=7.5Hz,1H),7.41(d,J=15.8Hz,1H),7.36–7.32(m,1H),7.29(s,1H),6.52(d,J=15.8Hz,1H). ESI-MS m/z:370.14[M+H] + .
example 10: (E) Preparation of-N-hydroxy-3- (4- (N- (isoquinolin-4-yl) sulfanyl) phenyl) acrylamide (I-10)
Compound (I-10) structural formula
(E) -N-hydroxy-3- (4- (N- (isoquinolin-4-yl) sulfanyl) phenyl) acrylamide (I-10) as a pale yellow solid, yield 83%. Mp is 110.1-112.2 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.87(s,1H),8.98(s,1H),8.08(d,J=10.0 Hz,1H),8.03(d,J=7.9Hz,1H),7.72–7.60(m,7H),7.43(d,J=15.7Hz,1H),6.53(d,J=15.8 Hz,1H).ESI-MS m/z:370.11[M+H] + .
example 11: (E) Preparation of-N-hydroxy-3- (4- (N- (isoquinolin-5-yl) sulfanyl) phenyl) acrylamide (I-11)
Compound (I-11) structural formula
(E) -N-hydroxy-3- (4- (N- (isoquinolin-5-yl) sulfanyl) phenyl) acrylamide (I-11) as a white solid in 80% yield. MP 170.7-172.8 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.81(s,1H),9.12(s,1H),8.33(d,J=5.8Hz, 1H),8.00(d,J=5.8Hz,1H),7.70(d,J=8.2Hz,3H),7.58(d,J=8.2Hz,3H),7.40(dd,J=15.0, 7.0Hz,2H),7.30(d,J=7.5Hz,1H),6.48(d,J=15.8Hz,1H).ESI-MS m/z:370.10[M+H] + .
example 12: (E) Preparation of-N-hydroxy-3- (4- (N- (isoquinolin-6-yl) sulfanyl) phenyl) acrylamide (I-12)
Compound (I-12) structural formula
(E) -N-hydroxy-3- (4- (N- (isoquinolin-6-yl) sulfanyl) phenyl) acrylamide (I-12) as a pale yellow solid, 77% yield. Mp is 166.0-168.2 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.84(s,1H),9.03(s,1H),8.30(d,J=5.8 Hz,1H),7.89(d,J=8.8Hz,1H),7.85(d,J=8.4Hz,2H),7.66(d,J=8.3Hz,2H),7.58(d,J=5.8Hz,1H),7.46(s,1H),7.41(d,J=15.8Hz,1H),7.35(dd,J=8.8,1.8Hz,1H),6.52(d,J=15.8Hz, 1H).ESI-MS m/z:370.11[M+H] + .
example 13: (E) Preparation of-N-hydroxy-3- (4- (N- (isoquinolin-7-yl) sulfanyl) phenyl) acrylamide (I-13)
Compound (I-13) structural formula
(E) -N-hydroxy-3- (4- (N- (isoquinolin-7-yl) sulfanyl) phenyl) acrylamide (I-13) as a pale yellow solid, yield 79%. Mp is 171.2-173.2 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.84(s,1H),9.15(s,1H),8.34(d,J=5.6 Hz,1H),7.82(t,J=7.6Hz,3H),7.71(s,1H),7.68–7.65(m,3H),7.49(dd,J=8.8,1.9Hz,1H),7.41(d,J=15.8Hz,1H),6.51(d,J=15.8Hz,1H).ESI-MS m/z:370.12[M+H] + .
example 14: (E) Preparation of-N-hydroxy-3- (4- (N- (isoquinolin-8-yl) sulfanyl) phenyl) acrylamide (I-14)
Compound (I-14) structural formula
(E) -N-hydroxy-3- (4- (N- (isoquinolin-8-yl) sulfanyl) phenyl) acrylamide (I-14) as a pale yellow solid, 75% yield. Mp is 175.2-177.9 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.85(s,1H),9.37(s,1H),8.43(d,J=5.6 Hz,1H),7.77–7.60(m,7H),7.44(d,J=15.8Hz,1H),7.27(d,J=7.5Hz,1H),6.52(d,J=15.9Hz,1H).ESI-MS m/z:370.11[M+H] + .
example 15: (E) Preparation of-N-hydroxy-3- (3- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylamide (I-15)
Compound (I-15) structural formula
Step A: preparation of 3-bromo-N- (quinolin-2-yl) benzenesulfonamide
To a solution of 2-aminoquinoline (0.47 g,3.26 mmol) in methylene chloride (50 ml) was added pyridine (1 ml) and 3-bromobenzenesulfonyl chloride (1 g,3.92 mmol) under stirring at 0 ℃. After the addition, the reaction mixture was stirred at 0℃for 2 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 3-bromo-N- (quinolin-2-yl) benzenesulfonamide as a pale yellow solid (0.91 g, yield 77%).
And (B) step (B): preparation of methyl (E) -3- (3- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylate
To acetonitrile (50 ml) was added 3-bromo-N- (quinolin-2-yl) benzenesulfonamide (1 g,2.76 mmol), methyl acrylate (0.28 g,3.31 mmol), palladium acetate (6.20 mg,0.0276 mmol), tris (o-methyl)Phenyl) phosphorus (25.20 mg,0.0828 mmol) and triethylamine (6.18 mg,5.52 mmol). At N 2 The reaction mixture was heated to 60℃under protection for reaction for 12h. After completion of the reaction, ethyl acetate (40 ml. Times.3) was extracted, and the organic phases were combined, washed 3 times with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give methyl (E) -3- (3- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylate as a white solid (0.89 g, 88% yield).
Step C: (E) Preparation of (E) -N-hydroxy-3- (3- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylamide
To a solution of methyl (E) -3- (3- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylate (0.5 g, 1.36 mmol) in methanol (20 ml) was slowly added dropwise a 1mol/L NaOH solution (3 ml) at 0℃with stirring. After stirring for 10 minutes, NH was slowly added dropwise thereto 2 OH solution (3 ml), after the addition was completed, slowly returned to room temperature and stirring was continued for 1h. After the completion of the reaction, the solvent was distilled off under reduced pressure, water (20 ml) was added thereto, pH was adjusted to neutrality with 2mol/L hydrochloric acid, and a solid was precipitated, suction filtration and vacuum drying were carried out to obtain (E) -N-hydroxy-3- (3- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylamide (I-15) as a white solid (0.42 g, yield 85%). Mp is 197.2-199.4 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ8.11(s,1H),8.08(d,J=6.5Hz, 1H),7.87(d,J=7.8Hz,1H),7.72(d,J=7.7Hz,1H),7.66(d,J=7.3Hz,1H),7.58(t,J=7.5Hz,1H),7.50(dd,J=16.6,9.0Hz,3H),7.33–7.23(m,2H),6.59(d,J=15.8Hz,1H).ESI-MS m/z: 370.11[M+H] + .
the compounds of examples 16-20 and examples 22-28 were prepared by the method of example 15 by selecting appropriate starting materials.
Example 16: (E) Preparation of-N-hydroxy-3- (3- (N- (quinolin-3-yl) sulfanyl) phenyl) acrylamide (I-16)
Compound (I-16) structural formula
(E) -N-hydroxy-3- (3- (N- (quinolin-3-yl) sulfanyl) phenyl) acrylamide (I-16) as a white solid in 83% yield. MP 182.7-184.4 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.81(s,1H),9.13(s,1H),8.54(d,J=2.4Hz, 1H),8.01(s,1H),7.87–7.73(m,4H),7.69(d,J=7.7Hz,1H),7.55–7.42(m,4H),6.52(d,J=15.8Hz,1H).ESI-MS m/z:370.10[M+H] + .
example 17: (E) Preparation of-N-hydroxy-3- (3- (N- (quinolin-4-yl) sulfanyl) phenyl) acrylamide (I-17)
Compound (I-17) structural formula
(E) -N-hydroxy-3- (3- (N- (quinolin-4-yl) sulfanyl) phenyl) acrylamide (I-17) as a pale yellow solid in 79% yield. Mp 203.1-205.6 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ8.39(d,J=8.1Hz,1H),8.18(d,J=6.2Hz,1H), 8.00(s,1H),7.79(d,J=6.3Hz,1H),7.66(d,J=8.1Hz,1H),7.64–7.59(m,2H),7.49–7.43(m,2H),7.38(t,J=7.3Hz,1H),6.96(d,J=6.1Hz,1H),6.54(d,J=15.8Hz,1H).ESI-MS m/z: 370.10[M+H] + .
example 18: (E) Preparation of-N-hydroxy-3- (3- (N- (quinolin-5-yl) sulfanyl) phenyl) acrylamide (I-18)
Compound (I-18) structural formula
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(E) -N-hydroxy-3- (3- (N- (quinolin-5-yl) sulfanyl) phenyl) acrylamide (I-18) as a pale yellow solid in 66% yield. MP 222.8-224.6 deg.C, 1 H-NMR(600MHz,DMSO-d 6 )δ10.79(s,1H),10.27(s,1H),9.11(s,1H),8.85 (dd,J=4.0,1.2Hz,1H),8.42(d,J=8.5Hz,1H),7.84(d,J=12.6Hz,2H),7.76(d,J=7.7Hz,1H),7.62(dd,J=15.2,7.3Hz,2H),7.52(t,J=7.8Hz,1H),7.48–7.40(m,2H),7.18(d,J=7.5 Hz,1H),6.45(d,J=15.8Hz,1H).ESI-MS m/z:370.10[M+H] + .
example 19: (E) Preparation of-N-hydroxy-3- (3- (N- (quinolin-6-yl) sulfanyl) phenyl) acrylamide (I-19)
Compound (I-19) structural formula
(E) -N-hydroxy-3- (3- (N- (quinolin-6-yl) sulfanyl) phenyl) acrylamide (I-19) as a pale yellow solid in 61% yield. Mp of 186.3-189.4 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.80(s,1H),9.13(s,1H),8.76–8.72(m,1H), 8.23(d,J=8.2Hz,1H),8.01(s,1H),7.88(d,J=9.0Hz,1H),7.80–7.72(m,2H),7.59(d,J=1.7 Hz,1H),7.54(t,J=7.8Hz,1H),7.50(dd,J=9.1,2.3Hz,1H),7.48–7.40(m,2H),6.51(d,J=15.8Hz,1H).ESI-MS m/z:370.11[M+H] + .
example 20: (E) Preparation of-N-hydroxy-3- (3- (N- (quinolin-7-yl) sulfanyl) phenyl) acrylamide (I-20)
Compound (I-20) structural formula
(E) -N-hydroxy-3- (3- (N- (quinolin-7-yl) sulfanyl) phenyl) acrylamide (I-20) as a pale yellow solid in 90% yield. Mp 170.5-173.5 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ8.74(dd,J=4.1,1.5Hz,1H),8.17(d,J=7.8Hz, 1H),8.02(s,1H),7.79(t,J=7.4Hz,2H),7.73(d,J=7.7Hz,1H),7.58(s,1H),7.54(t,J=7.8Hz,1H),7.45(d,J=15.8Hz,1H),7.36(dd,J=8.8,1.9Hz,1H),7.32(dd,J=8.1,4.2Hz,1H),6.53(d,J=15.9Hz,1H).ESI-MS m/z:370.09[M+H] + .
example 22: (E) Preparation of-N-hydroxy-3- (3- (N- (isoquinolin-1-yl) sulfanyl) phenyl) acrylamide (I-22)
Compound (I-22) structural formula
(E) -N-hydroxy-3- (3- (N- (isoquinolin-1-yl) sulfanyl) phenyl) acrylamide (I-22) as a white solid in 64% yield. Mp is 175.9-177.8 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.86(s,1H),9.10(s,1H),8.38(d,J=8.3Hz, 1H),8.16(s,1H),7.91(d,J=7.7Hz,1H),7.75–7.59(m,5H),7.48(d,J=15.6Hz,3H),6.94(s,1H),6.56(d,J=15.8Hz,1H).ESI-MS m/z:370.10[M+H] + .
example 23: (E) Preparation of-N-hydroxy-3- (3- (N- (isoquinolin-3-yl) sulfanyl) phenyl) acrylamide (I-23)
Compound (I-23) structural formula
(E) -N-hydroxy-3- (3- (N- (isoquinolin-3-yl) sulfanyl) phenyl) acrylamide (I-23) as a pale yellow solid, 89% yield. Mp is 92.3-95.1 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.85(s,1H),8.96(s,1H),8.11(s,1H),7.91 (d,J=8.1Hz,1H),7.86(d,J=7.8Hz,1H),7.76(d,J=8.1Hz,1H),7.70(d,J=7.7Hz,1H),7.60(t,J=7.4Hz,1H),7.52(t,J=7.8Hz,1H),7.46(d,J=15.8Hz,1H),7.39(dd,J=15.9,8.6Hz, 2H),6.56(d,J=15.8Hz,1H).ESI-MS m/z:370.12[M+H] + .
example 24: (E) Preparation of-N-hydroxy-3- (3- (N- (isoquinolin-4-yl) sulfanyl) phenyl) acrylamide (I-24)
Compound (I-24) structural formula
(E) -N-hydroxy-3- (3- (N- (isoquinolin-4-yl) sulfanyl) phenyl) acrylamide (I-24) as a pale yellow solid, 82% yield. Mp is 175.4-177.7 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.81(s,1H),9.11(s,1H),9.07(s,1H), 8.09(s,1H),8.07(d,J=8.1Hz,1H),8.02(d,J=8.4Hz,1H),7.84(s,1H),7.74(d,J=7.6Hz,1H),7.68(t,J=7.5Hz,1H),7.66–7.61(m,2H),7.51(t,J=7.7Hz,1H),7.42(d,J=15.7Hz,1H), 6.46(d,J=15.8Hz,1H).ESI-MS m/z:370.09[M+H] + .
example 25: (E) Preparation of-N-hydroxy-3- (3- (N- (isoquinolin-5-yl) sulfanyl) phenyl) acrylamide (I-25)
Compound (I-25) structural formula
(E) -N-hydroxy-3- (3- (N- (isoquinolin-5-yl) sulfanyl) phenyl) acrylamide (I-25) as a pale yellow solid, yield 69%. Mp 173.0-176.3 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.77(s,1H),10.26(s,1H),9.20(s,1H), 8.37(d,J=5.9Hz,1H),7.90(d,J=5.8Hz,1H),7.84(s,1H),7.79(s,1H),7.70(d,J=7.5Hz,1H),7.64(d,J=7.8Hz,1H),7.49(dt,J=15.5,7.8Hz,2H),7.42(d,J=15.8Hz,1H),7.36(d,J= 7.5Hz,1H),6.45(d,J=15.8Hz,1H).ESI-MS m/z:370.09[M+H] + .
example 26: (E) Preparation of-N-hydroxy-3- (3- (N- (isoquinolin-6-yl) sulfanyl) phenyl) acrylamide (I-26)
Compound (I-26) structural formula
(E) -N-hydroxy-3- (3- (N- (isoquinolin-6-yl) sulfanyl) phenyl) acrylamide (I-26) as a white solid in 78% yield. Mp 205.3-207.7 deg.c, 1 H-NMR(600MHz,DMSO-d 6 )δ10.85(s,1H),9.12(s,1H),8.37(d,J=5.7Hz, 1H),8.06(s,1H),8.00(d,J=8.8Hz,1H),7.82(d,J=7.8Hz,1H),7.77(d,J=7.7Hz,1H),7.70(d,J=5.7Hz,1H),7.60–7.55(m,2H),7.47(d,J=16.3Hz,1H),7.44(d,J=8.9Hz,1H),6.54(d, J=15.9Hz,1H).ESI-MS m/z:370.11[M+H] + .
example 27: (E) Preparation of-N-hydroxy-3- (3- (N- (isoquinolin-7-yl) sulfanyl) phenyl) acrylamide (I-27)
Compound (I-27) structural formula
(E) -N-hydroxy-3- (3- (N- (isoquinolin-7-yl) sulfanyl) phenyl) acrylamide (I-27) as a white solid in 65% yield. Mp is 197.2-199.5 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.83(s,1H),9.19(s,1H),8.37(d,J=5.6Hz, 1H),8.02(s,1H),7.85(d,J=8.9Hz,1H),7.77(dd,J=11.6,7.6Hz,3H),7.69(d,J=5.6Hz,1H),7.56–7.51(m,2H),7.46(d,J=15.8Hz,1H),6.52(d,J=15.9Hz,1H).ESI-MS m/z:370.12[M+ H] + .
example 28: (E) Preparation of-N-hydroxy-3- (3- (N- (isoquinolin-8-yl) sulfanyl) phenyl) acrylamide (I-28)
Compound (I-28) structural formula
(E) -N-hydroxy-3- (3- (N- (isoquinolin-8-yl) sulfanyl) phenyl) acrylamide (I-28) as a pale yellow solid in 88% yield. MP 142.4-145.1 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.77(s,1H),9.46(s,1H),8.37(d,J=5.6 Hz,1H),7.89(s,1H),7.67(d,J=7.9Hz,2H),7.65(d,J=5.6Hz,1H),7.51(t,J=7.8Hz,1H),7.47(t,J=7.7Hz,2H),7.42(d,J=15.8Hz,1H),7.18(d,J=7.5Hz,1H),6.47(d,J=15.8Hz, 1H).ESI-MS m/z:370.13[M+H] + .
EXAMPLE 29 in vitro anti-tumor cell proliferation Activity test of the Compounds of interest
The MTT method is adopted to test the in vitro antiproliferative activity of the target compound on two cell lines, namely A549 and MCF-7. Cells were placed in RPMI-1640 medium containing 10% Fetal Bovine Serum (FBS) and in a medium containing 5% CO 2 Is cultured in an incubator at 37 ℃. Taking cells in logarithmic growth phase at 3×10 per well 3 Density of individual cells were seeded in 96-well plates and placed in a chamber containing 5% CO 2 The culture is continued for about 18-24 hours at 37 ℃. According to the experimental design, 100 mu L of compounds with different concentration gradients are added into each hole, a blank control group is not added with compounds, a positive control group is added with Belinostat with the same concentration gradient, and the culture is continued in an incubator for 48 hours. When the acting time of the medicine reaches, avoiding each holeLight was added to 20. Mu.L of MTT solution at a concentration of 5mg/ml, incubated in an incubator for 4-6h, the culture broth was then discarded, 100. Mu.L of DMSO solution was added to each well, and shaking was performed in the absence of light for 5min. The inhibition ratio of the test compound was calculated by measuring the OD value at 570nm wavelength of a 96-well plate in a microplate reader, respectively, inhibition ratio (%) = (100% absorbance average value-compound absorbance average value)/(100% absorbance average value-blank group absorbance average value) ×100, and IC was calculated by SPSS software 50 Values.
TABLE 1 antiproliferative activity results of target compounds on two classes of cancer cell lines
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Claims (6)
1. The hydroxamic acid compound containing quinoline or isoquinoline as shown in the formula I and pharmaceutically acceptable salt thereof are characterized in that:
wherein,,
x is N, Y is CH; or X is CH, then Y is N;
w is-ch=ch-CO-;
ring A is
The pharmaceutically acceptable salt refers to an acid addition salt formed by the hydroxamic acid compound containing quinoline or isoquinoline and an inorganic acid or an organic acid; the inorganic acid is selected from one of hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; the organic acid is selected from acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, citric acid, salicylic acid, tartaric acid and p-toluenesulfonic acid.
2. The compound and pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is specifically one of the following compounds:
(E) -N-hydroxy-3- (4- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylamide (I-1);
(E) -N-hydroxy-3- (4- (N- (quinolin-3-yl) sulfanyl) phenyl) acrylamide (I-2);
(E) -N-hydroxy-3- (4- (N- (quinolin-4-yl) sulfanyl) phenyl) acrylamide (I-3);
(E) -N-hydroxy-3- (4- (N- (quinolin-5-yl) sulfanyl) phenyl) acrylamide (I-4);
(E) -N-hydroxy-3- (4- (N- (quinolin-6-yl) sulfanyl) phenyl) acrylamide (I-5);
(E) -N-hydroxy-3- (4- (N- (quinolin-7-yl) sulfanyl) phenyl) acrylamide (I-6);
(E) -N-hydroxy-3- (4- (N- (quinolin-8-yl) sulfanyl) phenyl) acrylamide (I-7);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-1-yl) sulfanyl) phenyl) acrylamide (I-8);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-3-yl) sulfanyl) phenyl) acrylamide (I-9);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-4-yl) sulfanyl) phenyl) acrylamide (I-10);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-5-yl) sulfanyl) phenyl) acrylamide (I-11);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-6-yl) sulfanyl) phenyl) acrylamide (I-12);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-7-yl) sulfanyl) phenyl) acrylamide (I-13);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-8-yl) sulfanyl) phenyl) acrylamide (I-14);
(E) -N-hydroxy-3- (3- (N- (quinolin-2-yl) sulfanyl) phenyl) acrylamide (I-15);
(E) -N-hydroxy-3- (3- (N- (quinolin-3-yl) sulfanyl) phenyl) acrylamide (I-16);
(E) -N-hydroxy-3- (3- (N- (quinolin-4-yl) sulfanyl) phenyl) acrylamide (I-17);
(E) -N-hydroxy-3- (3- (N- (quinolin-5-yl) sulfanyl) phenyl) acrylamide (I-18);
(E) -N-hydroxy-3- (3- (N- (quinolin-6-yl) sulfanyl) phenyl) acrylamide (I-19);
(E) -N-hydroxy-3- (3- (N- (quinolin-7-yl) sulfanyl) phenyl) acrylamide (I-20);
(E) -N-hydroxy-3- (3- (N- (quinolin-8-yl) sulfanyl) phenyl) acrylamide (I-21);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-1-yl) sulfanyl) phenyl) acrylamide (I-22);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-3-yl) sulfanyl) phenyl) acrylamide (I-23);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-4-yl) sulfanyl) phenyl) acrylamide (I-24);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-5-yl) sulfanyl) phenyl) acrylamide (I-25);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-6-yl) sulfanyl) phenyl) acrylamide (I-26);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-7-yl) sulfanyl) phenyl) acrylamide (I-27);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-8-yl) sulfanyl) phenyl) acrylamide (I-28).
3. The preparation of a quinoline-or isoquinoline-containing hydroxamic acid compound according to claim 1, wherein one of the following two routes is adopted:
route one:
the substituents are defined in the claims, reagents and conditions: HSO 3 Cl,12h;b.RNH 2 ,CH 2 Cl 2 Pyridine, 1h; c.CH 3 OH,H 2 SO 4 ,4h;d.NH 2 OH,1N NaOH,CH 3 OH,1h;
Route two:
the substituents are defined in the claims, reagents and conditions: RNH (rnh) 2 ,CH 2 Cl 2 Pyridine, 2h; b. methyl acrylate, pd (OAc) 2 ,POT,Et 3 N,CH 3 CN,60℃,12h;c.NH 2 OH,1N NaOH,CH 3 OH,1h。
4. A pharmaceutical composition comprising a compound according to any one of claims 1-2 and a pharmaceutically acceptable carrier therefor.
5. Use of a compound according to any one of claims 1-2, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 4, for the manufacture of a medicament for the prevention and/or treatment of diseases associated with histone deacetylase.
6. Use of a compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 4, for the manufacture of a medicament for the prevention and/or treatment of liver cancer, colon cancer, pancreatic cancer, lung cancer, gastric cancer, breast cancer or ovarian cancer.
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