CN108309959A - The synthesis of N or O or C- diaryl substitutive derivatives and its pharmaceutical applications - Google Patents
The synthesis of N or O or C- diaryl substitutive derivatives and its pharmaceutical applications Download PDFInfo
- Publication number
- CN108309959A CN108309959A CN201810118546.5A CN201810118546A CN108309959A CN 108309959 A CN108309959 A CN 108309959A CN 201810118546 A CN201810118546 A CN 201810118546A CN 108309959 A CN108309959 A CN 108309959A
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- Prior art keywords
- alkyl
- group
- cancer
- substituted
- unsubstituted
- 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.)
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- 230000015572 biosynthetic process Effects 0.000 title abstract description 6
- 229910052760 oxygen Inorganic materials 0.000 title abstract description 5
- 238000003786 synthesis reaction Methods 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- -1 antiallergy Substances 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 13
- 229940079593 drug Drugs 0.000 claims abstract description 12
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 5
- 239000003146 anticoagulant agent Substances 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 230000003712 anti-aging effect Effects 0.000 claims abstract description 4
- 230000003266 anti-allergic effect Effects 0.000 claims abstract description 4
- 230000001093 anti-cancer Effects 0.000 claims abstract description 4
- 230000000078 anti-malarial effect Effects 0.000 claims abstract description 4
- 230000002785 anti-thrombosis Effects 0.000 claims abstract description 4
- 230000000767 anti-ulcer Effects 0.000 claims abstract description 4
- 239000003430 antimalarial agent Substances 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 125000004185 ester group Chemical group 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 208000032839 leukemia Diseases 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims 2
- 206010006187 Breast cancer Diseases 0.000 claims 1
- 208000026310 Breast neoplasm Diseases 0.000 claims 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 1
- 206010014759 Endometrial neoplasm Diseases 0.000 claims 1
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- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 claims 1
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- 206010035226 Plasma cell myeloma Diseases 0.000 claims 1
- 206010060862 Prostate cancer Diseases 0.000 claims 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims 1
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- 239000002260 anti-inflammatory agent Substances 0.000 claims 1
- 229940124599 anti-inflammatory drug Drugs 0.000 claims 1
- 208000019065 cervical carcinoma Diseases 0.000 claims 1
- 208000029742 colonic neoplasm Diseases 0.000 claims 1
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- 206010017758 gastric cancer Diseases 0.000 claims 1
- 208000015181 infectious disease Diseases 0.000 claims 1
- 201000007270 liver cancer Diseases 0.000 claims 1
- 208000014018 liver neoplasm Diseases 0.000 claims 1
- 201000005202 lung cancer Diseases 0.000 claims 1
- 208000020816 lung neoplasm Diseases 0.000 claims 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 1
- 201000000050 myeloid neoplasm Diseases 0.000 claims 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 claims 1
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 1
- 201000011549 stomach cancer Diseases 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 abstract description 7
- 230000002924 anti-infective effect Effects 0.000 abstract description 3
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 3
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 238000002875 fluorescence polarization Methods 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
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- 238000006243 chemical reaction Methods 0.000 description 4
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical class C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 3
- 208000006278 hypochromic anemia Diseases 0.000 description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 3
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- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- 108010032769 Autophagy-Related Protein 8 Family Proteins 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000005956 isoquinolyl group Chemical group 0.000 description 2
- 230000031700 light absorption Effects 0.000 description 2
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
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- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
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- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
- JHFAEUICJHBVHB-UHFFFAOYSA-N 1h-indol-2-ol Chemical compound C1=CC=C2NC(O)=CC2=C1 JHFAEUICJHBVHB-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- APRMCBSTMFKLEI-UHFFFAOYSA-N 2-chloro-5-methylpyrimidine Chemical class CC1=CN=C(Cl)N=C1 APRMCBSTMFKLEI-UHFFFAOYSA-N 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 1
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- RQQDJYROSYLPPK-UHFFFAOYSA-N N1=CC=CC2=CC=CC=C21.N1=CC=CC2=CC=CC=C21 Chemical compound N1=CC=CC2=CC=CC=C21.N1=CC=CC2=CC=CC=C21 RQQDJYROSYLPPK-UHFFFAOYSA-N 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
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- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
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- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
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- 239000007853 buffer solution Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
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- 230000006837 decompression Effects 0.000 description 1
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- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
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- 239000012894 fetal calf serum Substances 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical group O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 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 1
- 150000004820 halides Chemical class 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
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- 150000003951 lactams Chemical group 0.000 description 1
- 125000000686 lactone group Chemical group 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
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- 238000012986 modification Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
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- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
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- 230000008506 pathogenesis Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical class [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
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- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000003373 pyrazinyl group Chemical group 0.000 description 1
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- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
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- 230000004083 survival effect Effects 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical compound C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 description 1
- 125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000012549 training Methods 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/01—Hydrocarbons
- A61K31/015—Hydrocarbons carbocyclic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/02—Halogenated hydrocarbons
- A61K31/025—Halogenated hydrocarbons carbocyclic
- A61K31/03—Halogenated hydrocarbons carbocyclic aromatic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/075—Ethers or acetals
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Abstract
The present invention relates to the synthesis of N or O or C diaryl substitutive derivatives and its pharmaceutical applications, and in particular to compound or its pharmaceutically acceptable salt shown in lower formula (I) are independent or combine the purposes in the drug of the relevant diseases such as antiulcer, anti-infective, anticancer, antibacterial, anti-aging, antithrombotic, antiallergy, anti-malarial, resisting HIV, anti-inflammatory with other drugs.
Description
Technical field
The present invention relates to biomedicine fields, and in particular to a kind of diphenyl ether analog derivative or its is pharmaceutically acceptable
Salt is independent or combines with other drugs in antiulcer, anti-infective, anticancer, antibacterial, anti-aging, antithrombotic, antiallergy, antimalarial
Purposes in the drug of the relevant diseases such as disease, resisting HIV, anti-inflammatory.
Background technology
It is well known that the features such as oneself its incidence of malignant tumour is high, lethality is high, cure rate is low, which becomes, threatens human health
With the important diseases of life.But due to its complicated pathogenesis and to human health composition the features such as seriously threatening, at
For the hot and difficult issue in drug development field in recent decades.The antitumor drug of early stage is largely cytotoxicity, is being killed
Prodigious influence is also resulted on human normal cell while hindering tumour cell, side effect is larger.Therefore, people are constantly grinding
While studying carefully Tumorigenesis, it is desirable to the antitumor drug that targeting can be found, it is secondary caused by oncotherapy to mitigate
Effect.
Derivative containing diphenyl ether class formation is a kind of very important medicine, pesticide and chemical intermediate.Very
More important drug contains the structural unit of diphenyl ether derivatives pesticide compound, such as a kind of oral vascular endothelial growth factor tyrosine kinase
Inhibitor C EP-11981, while it has also been found that diphenyl ether analog derivative has extensive bioactivity, such as antitumor, antibacterial, town
Bitterly, immune function, anti-platelet aggregation, anti-arrhythmia, decompression etc. are adjusted.
Invention content
The present invention carries out high flux screening by high flux screening platform, to known compound library, it was found that a kind of hexichol
Pyridyl ethers compound or its salt can be as the targeted drugs for the treatment of cancer.In addition, by molecular level active testing and carefully
The examination of cell space exterior measuring demonstrates this kind of compound and has good inhibiting effect to cancer cell, so as to be used to inhibit cancer cell with
And treatment relevant disease.
The first aspect of the present invention provide compound or its pharmaceutically acceptable salt shown in lower formula (I) individually or with
Other drugs are combined in antiulcer, anti-infective, anticancer, antibacterial, anti-aging, antithrombotic, antiallergy, anti-malarial, anti-human para-immunity
Purposes in the drug of the relevant diseases such as defective virus, anti-inflammatory.
Wherein：
R1, R2And R3It is each independently selected from：Hydrogen, hydroxyl, amino, cyano, formoxyl, halogen, C1-6Alkyl, C1-6Alkyl halide
Base, C1-6Alkoxy, C (=O) Ra, SO2Ra, substituted or unsubstituted-(CH2)m-C6-10Aryl or 5-10 unit's heteroaryls, substitution or
Unsubstituted-(CH2)m-C3-7Naphthenic base or 3-7 circle heterocyclic ring bases；The RaSelected from hydrogen, hydroxyl, C1-6Alkyl, C1-6Halogenated alkyl,
Substituted or unsubstituted C1-6Hydroxy alkyl, substituted or unsubstituted amino, substituted or unsubstituted phenyl, substitution or unsubstituted
Five to six membered heteroaryl；
X1, X2, X3, X4It is independently selected from C, the one or two of N, O with Y；
The halogen is selected from F, Cl, Br, I；It is preferably selected from F, Cl, Br；
The substitution indicates that the group is substituted by one or more substituents, and the substituent group is selected from：Hydroxyl, amino,
Cyano, halogen, nitro, trifluoromethyl, carboxyl, ester group, formoxyl, C1-6Alkyl, C1-6 halogenated alkyls, C1-6 hydroxy alkyls,
C1-6Alkoxy, 3-10 circle heterocyclic ring bases, C6-10Aryl and 5-10 unit's heteroaryls；
M is selected from 0,1,2 and 3, preferably 1 or 2.
Terminology used in the present invention has its general sense in the art, in the case where there is conflict, be applicable in this
Definition in application.Chemical name, adopted name and chemical constitution may be used interchangeably to describe identical structure.No matter term
It is single use or is applied in combination with other terms, these definition are all suitable for.Therefore, " C1-6The definition of alkyl " is suitable for
“C1-6Alkyl " and " C1-6Hydroxy alkyl ", " C1-6Halogenated alkyl ", " C1-6" C1-6 alkyl " part of alkoxy " etc..
“C1-6Alkyl " refers to the linear or branched alkyl group containing 1 to 6 carbon atom, preferably 1 to 4 carbon atom it is straight
Chain or branched alkyl.Branch refers to that the alkyl such as methyl, ethyl or propyl etc. of one or more carbon atoms are connect with straight chained alkyl.
Preferred C1-6Alkyl includes but not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group and tertiary butyl etc..
“C1-6Halogenated alkyl " refers to C as defined above1-6Contain one or more halogen atom substituents in alkyl.It is preferred that
C1-6Halogenated alkyl includes but not limited to trifluoromethyl.
“C1-6Hydroxy alkyl " refers to C as defined above1-6Contain one or more hydroxyls in alkyl.Preferred C1-6Hydroxyl
Alkyl includes but not limited to methylol and 2- ethoxys.
“C1-6Alkoxy " refers to C1-6Allcyl-O-groups, wherein C bonded with parent fraction by oxygen1-6Alkyl institute as above
It states.Preferred C1-6Alkoxy includes but not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy and n-butoxy.
“C6-10Aryl " refers to aromatic monocyclic or multi-loop system containing 6 to 10 carbon atoms.Preferred C6-10Aryl includes
But it is not limited to phenyl and naphthalene.
“C3-7Naphthenic base " is to contain 3 to 7 carbon atoms, the non-aromatic saturation monocycle of preferably 3 to 6 carbon atoms on finger ring
Or polycyclic moiety.Preferred monocycle C3-7Naphthenic base includes but not limited to cyclopropyl, cyclopenta, cyclohexyl, suberyl etc..
" 5-10 unit's heteroaryls " refers to aromatic monocyclic or polycyclic moiety containing 5 to 10 annular atoms, and the 5-10 members are miscellaneous
Aryl includes 1 to 4 hetero atom in N, O and S.Preferred 5-10 unit's heteroaryls contain 5 to 6 annular atoms.5-10 members
The nitrogen-atoms of heteroaryl can optionally be oxidized to corresponding N- oxides.Preferred C5-10Heteroaryl includes but not limited to pyrrole
Piperidinyl, pyrazinyl, furyl, thienyl, pyrimidine radicals, pyridone, oxazolyls, isothiazolyl, oxazolyl, oxadiazolyls, thiazole
Base, thiadiazolyl group, pyrazolyl, furan cluck base (furazanyl), pyrrole radicals, triazolyl, 1,2,4- thiadiazolyl groups, pyridazinyl, quinoline
Quinoline base, phthalazinyl, hydroxyindole base, imidazo [1,2-a] pyridyl group, imidazo [2,1-b] thiazolyl, benzo furan cluck base
(benzofurazanyl), indyl, azaindolyl, benzimidazolyl, benzothienyl, quinolyl, imidazole radicals, thieno
Pyridyl group, quinazolyl, Thienopyrimidine base, pyrrolopyridinyl, imidazopyridine, isoquinolyl, benzo azine, 1,2,
Its oxide of 4- triazine radicals, benzothiazolyl etc..Term " 5-10 unit's heteroaryls " also refers to the 5-10 unit's heteroaryls of fractional saturation, example
Such as tetrahydro isoquinolyl, tetrahydric quinoline group etc..
" 3-7 circle heterocyclic rings base " refer to containing 3 to 7 annular atoms, preferably 3 to 6 annular atoms, preferably 5 to 6 annular atoms
Non-aromatic monocyclic or polycyclic moiety, wherein the 3-10 circle heterocyclic rings base includes 1 to 4 hetero atom in N, O and S.It is described
The nitrogen or sulphur atom of 3-10 circle heterocyclic ring bases can optionally be oxidized to corresponding N- oxides, S- oxides or S- dioxide.
Therefore term " oxide " refers to corresponding N- oxides, S- oxides or S- dioxide in the present invention." 3-7 circle heterocyclic rings base "
Further include two available hydrogen atoms on ring in identical carbon atoms while being replaced by single group=O and (being formed carbonyl), this
Sample=O groups are properly termed as " oxo " in the present invention.Preferred monocycle 3-7 membered heterocycloalkyls include but not limited to piperidines
Base, oxetanyl, pyrrole radicals, piperazinyl, morpholinyl, thio-morpholinyl, thiazolidinyl, 1,4- alkyl dioxins, tetrahydrochysene furan
It mutters base, tetrahydro-thienyl, lactam group (such as pyrrolidone-base), lactone group and its oxide with 3 to 7 annular atoms.
" ester group " refer to by with 1-20 carbon atom aliphatic or aromatic carboxylic acid with 1-20 carbon atom
The group for removing a hydrogen atom in the ester that primary, secondary or tertiary alcohol is formed through esterification and obtaining.It is preferred that ester group includes but unlimited
In carbomethoxy, ethoxycarbonyl, isopropyl ester group, tert-butyl ester base, carbobenzoxy.
" amide groups " refer to by with 1-20 carbon atom aliphatic or aromatic carboxylic acid with 1-20 carbon atom
The amide that is formed through amidation process of primary or secondary amine in remove a hydrogen atom and the group that obtains.
In one preferred embodiment, the C5-10Aryl or 5-10 unit's heteroaryls are preferably selected to be lost by following ring
The group that one hydrogen atom is formed：
The C3-7Naphthenic base or 3-7 circle heterocyclic ring bases are preferably selected from and lose the group that a hydrogen atom is formed by following ring：
In one preferred embodiment, the compound of the logical formula (I) is selected from following compounds：
Specific implementation mode
Unless otherwise specified, agents useful for same is commercially available.
Detailed preparation process is illustrated by taking the compound 20 in upper table as an example.
The synthesis of 1 2- of embodiment (4- chloro-2-methyls phenoxy group) -5- methylpyrimidines
2g4- chloro-2-methyls phenol (compound ii) is dissolved in the DMF of 10mL, 1.34g NaH are added under ice bath, stir
The chloro- 5- methylpyrimidines 3.6g of 2- are added after mixing 30min, 100 DEG C are heated 12 hours, TLC monitoring reactions.After reaction, add water
It is quenched, EA extractions, anhydrous sodium sulfate drying, concentration, it is phonetic that column chromatography obtains 1.4g 2- (4- chloro-2-methyls phenoxy group) -5- methyl
Pyridine (compound III).HRMS(ESI):m/z calcd for C12H11N2OCl[M+H]+235.0560
The synthesis of 2 2- of embodiment (4- (4- chloros piperidin-1-yl) -2- methylphenoxies) -5- methylpyrimidines
0.5g4- chloros piperidines (compounds Ⅳ) and 1.2g 2- (4- chloro-2-methyls phenoxy group) -5- methylpyrimidines (are changed
Close object III) it is dissolved in the tetrahydrofuran of 10mL, 1.64g potassium tert-butoxides are slowly added under ice bath, room temperature stirs 3h, after reaction
It is adjusted to PH=6 with HCl.TLC monitoring reactions.EA is extracted, anhydrous sodium sulfate drying, concentration, and column chromatography obtains 1.0g 2- (4-
(4- chloros piperidin-1-yl) -2- methylphenoxies) -5- methylpyrimidines (compound V).HRMS(ESI):m/z calcd for
C17H20N3OCl[M+H]+318.1295
It is attached：The structural formula of all compounds, molecular formula and molecular weight
Embodiment 3
Adjusting of the compound of the present invention to autophagy GAP-associated protein GAP LC3B is tested using fluorescence polarization (FP) method.
Fluorescence polarization (FP) method test experiments
Histone GST-LC3B (final concentration 180nM) (SEQ ID NO:1) and N-terminal FITC marks peptide (SEQ ID NO:
2, sequence：FITC-GGDDDWTHLSSKEVD-NH2, final concentration 18nM) be placed in FP buffer solutions (50mM HEPES pH7.5,
0.1mg/mLBSA, 1mM DTT) in, it is added uses the diluted compound of FP buffer gradients thereto, then by above-mentioned mixing
Object is being protected from light incubation at 25 DEG C.Monitor fluorescence polarization value (PerkinElmer Envision, wavelength of transmitted light 480nm；It absorbs
Optical wavelength 535nm), it is used in combination 6.0 programs of GraphPad Prism to calculate IC50Value, test result are as shown in table 8.
The IC of compound50It is worth representation method：100μM<IC50≤ 1mM is considered active relatively low (+) to LC3B；Compound
15μM<IC50≤ 100 μM are considered as active medium (++) to LC3B；3μM<IC50≤ 15 μM be considered to LC3B activity compared with
High (+++)；IC50≤ 3 μM are considered having high activity (++++) to LC3B.The IC of the compounds of this invention50Value is as shown in table 8.
Table 8:Compound IC50
The compound of the present invention shows the activity to LC3B, and some compounds have high activity to LC3B.These
Compound is also active to other mammalian homologs of ATG8.Therefore, these compounds can adjust LC3B and
Other mammalian homologs of ATG8, for treating and the relevant disease of autophagy.
4 cell activity biological test of embodiment is tested
Measuring principle：Compound inhibits growth of cancer cells detail that can be measured with through MTT methods.The original of mtt assay
Reason is：Yellow Thiazolyl blue may pass through cell membrane and enter intracellular, and the succinate dehydrogenase in living cells mitochondria can allow external source
Property MTT be reduced into the royal purple crystallization first a ceremonial jade-ladle, used in libation being deposited in cell, however dead cell is but without this function.Dimethyl sulfoxide (DMSO) is used again
Dissolve first a ceremonial jade-ladle, used in libation.At 570nm wavelength, its light absorption value is measured with enzyme-linked immunosorbent assay instrument, obtains living cells quantity indirectly.
Experiment material：K562 (human chronic polymorpho nuclear leukemia cells), U937 (human leukemia cell), KBM-5 (the white blood of people
Sick chronic myelocytic), KBM5-T315I (human leukemia chronic myelocytic) respectively use DMEM+10%FBS medium cultures or
It is cultivated using 1640+10%FBS.
Test method and interpretation of result：
Experimental group：The drug (final concentration of 10 of+10 μ l various concentrations of 190 μ l cell suspensions-5-10-10)
Blank control group：200μl PBS
Negative control group：+ 10 μ l 2%DMSO (final concentration of 0.1%) of DMSO of 190 μ l cell suspensions
Positive controls：The compound of+10 μ l various concentrations of 190 μ l cell suspensions
MTT cell viability detecting steps
A) inoculating cell
In 37 DEG C, 5%CO2Under the conditions of, it is trained with the DMEM of the penicillin containing 10% fetal calf serum, 1% and streptomysin
Support cultured cell line in base.The upper layer culture medium in culture dish is discarded, cell is washed 2 times with PBS, adds pancreatin, be put into training
It supports in base and digests 1-2min, after cell takes off wall, add new culture medium, gently blow and beat, cell is made to completely fall off, wait for cell
Enter the new culture mediums of 5ml, gently blow and beat, calculates cell concentration with cell counting, be then inoculated in 96 orifice plates.
B) cell culture
96 orifice plates being inoculated with are positioned over 37 DEG C, 5% CO2It is incubated overnight in incubator, next day cell can be adherent.
C) dosing
The drug of various concentration is added according to different experimental designs, every group sets 3~4 multiple holes, and 10 μ l phases are added per hole
The drug of concentration is answered, then 96 orifice plates are put into incubator and continue to cultivate.
D) MTT viability examinations
After being cultivated 24 hours, 48 hours, 72 hours after administration, the MTT of 10 μ l 5mg/ml is added per hole, after by 96 orifice plates
It is positioned in incubator, is taken out after continuing culture 4 hours, the careful supernatant drawn per hole adds the diformazan of 100 μ l per hole
Base sulfoxide (DMSO) solution is placed after being incubated 10min in incubator, and concussion 40s or so makes first a ceremonial jade-ladle, used in libation crystal be completely dissolved.
E) it surveys absorbance and calculates IC50Value
96 orifice plates are placed in microplate reader, Detection wavelength is the light absorption value at 570nm.With every 3~4 multiple holes absorbances
Its relative inhibition of mean value calculation.The inhibiting rate of disease cells, calculating half are effectively inhibited according under different pharmaceutical concentration
Concentration (IC50).Every group of sample will do 3 parallel laboratory tests.
570nm is read, and calculates cell survival rate, and IC is calculated according to result50, as a result such as the following table 1.
The structure and activity data (μm ol) of 1. micromolecular inhibitor of table
The compound of the present invention shows the activity to kinds of tumor cells, and some compound on tumor cell have
High activity.Therefore, these compounds can be used for, but be not limited to treatment and the relevant disease of tumour.
It should be understood that without departing from the scope and spirit of the present invention, those skilled in the art can to the present invention into
The various changes of row or modification, this is apparent to those skilled in the art, and such equivalent forms equally fall within the application
The appended claims limited range.
Claims (4)
1. compound or its pharmaceutically acceptable salt shown in lower formula (I) are independent or combine with other drugs in antiulcer, resist
The relevant diseases such as infection, anticancer, antibacterial, anti-aging, antithrombotic, antiallergy, anti-malarial, resisting HIV, anti-inflammatory
Drug in purposes：
Wherein：
R1, R2And R3It is each independently selected from：Hydrogen, hydroxyl, amino, cyano, formoxyl, halogen, C1-6Alkyl, C1-6Halogenated alkyl,
C1-6Alkoxy, C (=O) Ra, SO2Ra, substituted or unsubstituted-(CH2) m-C6-10Aryl or 5-10 unit's heteroaryls, substitution or not
Substitution-(CH2)m-C3-7Naphthenic base or 3-7 circle heterocyclic ring bases；The RaSelected from hydrogen, hydroxyl, C1-6Alkyl, C1-6Halogenated alkyl takes
Generation or unsubstituted C1-6Hydroxy alkyl, substituted or unsubstituted amino, substituted or unsubstituted phenyl are substituted or unsubstituted
Five to six membered heteroaryl；
X1, X2, X3, X4It is independently selected from C, the one or two of N, O with Y；
The halogen is selected from F, Cl, Br, I；It is preferably selected from F, Cl, Br；
The substitution indicates that the group is substituted by one or more substituents, and the substituent group is selected from：Hydroxyl, amino, cyano,
Halogen, nitro, trifluoromethyl, carboxyl, ester group, formoxyl, C1-6Alkyl, C1-6 halogenated alkyls, C1-6 hydroxy alkyls, C1-6Alcoxyl
Base, 3-10 circle heterocyclic ring bases, C6-10Aryl and 5-10 unit's heteroaryls；
M is selected from 0,1,2 and 3, preferably 1 or 2.
2. purposes according to claim 1, wherein the C6-10Aryl or 5-10 unit's heteroaryls are selected to be lost by following ring
The group that one hydrogen atom is formed：
And/or the C3-7Naphthenic base or 3-7 circle heterocyclic ring bases are selected from loses the group that a hydrogen atom is formed by following ring：
。
3. purposes according to claim 1 or 2, wherein the compound of the logical formula (I) is selected from following compounds：
。
4. according to the purposes described in claim 1-3, wherein the tumour is selected from lung cancer, colon cancer, liver cancer, breast cancer, pancreas
Cancer, cervical carcinoma, carcinoma of endometrium, colorectal cancer, gastric cancer, nasopharyngeal carcinoma, oophoroma, prostate cancer, leukaemia, lymthoma, myeloma.
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| JP2021534212A (en) * | 2018-08-24 | 2021-12-09 | ゼニオプロ ゲーエムベーハー | Aromatic molecules for use in the treatment of pathological conditions |
| WO2022148317A1 (en) * | 2021-01-11 | 2022-07-14 | 广州市力鑫药业有限公司 | 2-aminopyrimidine compound and pharmaceutical composition thereof and application thereof |
| CN115087641A (en) * | 2021-01-11 | 2022-09-20 | 广州市力鑫药业有限公司 | 2-aminopyrimidine compound and pharmaceutical composition and application thereof |
| CN115087641B (en) * | 2021-01-11 | 2024-06-18 | 广州力鑫生物科技有限公司 | 2-Aminopyrimidine compound, and pharmaceutical composition and application thereof |
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