CN107176932A - 苯并恶嗪酮衍生物及其制备方法和用途 - Google Patents
苯并恶嗪酮衍生物及其制备方法和用途 Download PDFInfo
- Publication number
- CN107176932A CN107176932A CN201710396333.4A CN201710396333A CN107176932A CN 107176932 A CN107176932 A CN 107176932A CN 201710396333 A CN201710396333 A CN 201710396333A CN 107176932 A CN107176932 A CN 107176932A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- aryl
- ketone derivatives
- straight chain
- side chain
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 Benzoxazine ketone Chemical class 0.000 title claims abstract description 49
- 238000004519 manufacturing process Methods 0.000 title description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 13
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 210000005036 nerve Anatomy 0.000 claims abstract description 6
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 6
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 5
- 230000004060 metabolic process Effects 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 25
- 125000000623 heterocyclic group Chemical group 0.000 claims description 18
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical group 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 229940002612 prodrug Drugs 0.000 claims description 5
- 239000000651 prodrug Substances 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 3
- 230000000118 anti-neoplastic effect Effects 0.000 claims description 3
- 208000019065 cervical carcinoma Diseases 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 2
- XMNIXWIUMCBBBL-UHFFFAOYSA-N 2-(2-phenylpropan-2-ylperoxy)propan-2-ylbenzene Chemical compound C=1C=CC=CC=1C(C)(C)OOC(C)(C)C1=CC=CC=C1 XMNIXWIUMCBBBL-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 229910052792 caesium Inorganic materials 0.000 claims description 2
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 229940125782 compound 2 Drugs 0.000 claims description 2
- 229940126214 compound 3 Drugs 0.000 claims description 2
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims description 2
- 150000002240 furans Chemical class 0.000 claims description 2
- 150000002460 imidazoles Chemical class 0.000 claims description 2
- 150000002475 indoles Chemical class 0.000 claims description 2
- 230000000977 initiatory effect Effects 0.000 claims description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- 150000003217 pyrazoles Chemical class 0.000 claims description 2
- 150000003233 pyrroles Chemical class 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N tert-butyl alcohol Substances CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 2
- 150000003852 triazoles Chemical class 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims 2
- 208000017897 Carcinoma of esophagus Diseases 0.000 claims 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 1
- 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
- 208000005718 Stomach Neoplasms Diseases 0.000 claims 1
- 150000001555 benzenes Chemical class 0.000 claims 1
- 201000001531 bladder carcinoma Diseases 0.000 claims 1
- 206010017758 gastric cancer Diseases 0.000 claims 1
- 208000014829 head and neck neoplasm Diseases 0.000 claims 1
- 235000003642 hunger Nutrition 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
- 208000026037 malignant tumor of neck Diseases 0.000 claims 1
- 201000001441 melanoma Diseases 0.000 claims 1
- 201000000050 myeloid neoplasm Diseases 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims 1
- 125000004193 piperazinyl group Chemical group 0.000 claims 1
- 229910000160 potassium phosphate Inorganic materials 0.000 claims 1
- 235000011009 potassium phosphates Nutrition 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 201000001275 rectum cancer Diseases 0.000 claims 1
- 201000011549 stomach cancer Diseases 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 238000011287 therapeutic dose Methods 0.000 claims 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 abstract description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 57
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 208000030159 metabolic disease Diseases 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 208000016097 disease of metabolism Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000007306 functionalization reaction Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- 150000000183 1,3-benzoxazoles Chemical class 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- WWMRDJUFXRYJDM-UHFFFAOYSA-N 2-hydroxy-4h-1,2-benzoxazin-3-one Chemical class C1=CC=C2CC(=O)N(O)OC2=C1 WWMRDJUFXRYJDM-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- HQQTZCPKNZVLFF-UHFFFAOYSA-N 4h-1,2-benzoxazin-3-one Chemical compound C1=CC=C2ONC(=O)CC2=C1 HQQTZCPKNZVLFF-UHFFFAOYSA-N 0.000 description 1
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 description 1
- IZZIWIAOVZOBLF-UHFFFAOYSA-N 5-methoxysalicylic acid Chemical class COC1=CC=C(O)C(C(O)=O)=C1 IZZIWIAOVZOBLF-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 102000003964 Histone deacetylase Human genes 0.000 description 1
- 108090000353 Histone deacetylase Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- RXZHFCUEZIVFSF-UHFFFAOYSA-N P(Cl)(Cl)(Cl)(Cl)Cl.[Cl] Chemical compound P(Cl)(Cl)(Cl)(Cl)Cl.[Cl] RXZHFCUEZIVFSF-UHFFFAOYSA-N 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 235000014103 egg white Nutrition 0.000 description 1
- 210000000969 egg white Anatomy 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010490 three component reaction Methods 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/24—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in positions 2 and 4
- C07D265/26—Two oxygen atoms, e.g. isatoic anhydride
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于药物化学领域,具体涉及苯并恶嗪酮衍生物及制备方法和在相关的疾病中的应用。本发明提供了苯并恶嗪酮衍生物,具体结构为式I或式II所示。本发明还提供了式I或式II所示的合成方法及其在相关的疾病中的应用,主要涉及到肿瘤、心血管疾病、神经退行性疾病、代谢类疾病、炎性疾病等。
Description
技术领域
本发明属于药物化学领域,具体涉及式I或式II所示的苯并恶嗪酮衍生物及其制备方法和其在相关疾病中的应用,主要涉及肿瘤、心血管疾病、神经退行性疾病、代谢性疾病、炎性疾病等。
背景技术
肿瘤是对人类健康危害最大的疾病之一,严重影响人们生活质量。近年来,化学药物作为治疗肿瘤的重要手段之一,已经取得巨大的进步和发展。目前,已开发出很多具有不同作用机制的抗肿瘤药物,但是这些药物在临床使用中表现出许多缺陷,比如选择性差、毒副作用大、快速产生耐药性等。因此,新型抗肿瘤药物的研究与开发尤为重要。
苯并恶嗪酮衍生物是一类重要的含氮杂环化合物,该骨架广泛存在于天然产物、生物活性分子和药物分子中。研究表明,此类化合物具有良好而广泛的药理活性,可用于抗炎、抗肿瘤、抗血栓形成、减肥、代谢紊乱和神经退行性疾病等的治疗。例如,化合物A是组蛋白去乙酰化酶(HDAC)抑制剂,用于治疗癌症和炎症。科特斯医药品公司开发的化合物CX-614正在处于研究阶段,有望成为帕金森综合症和阿尔茨海默症治疗药物。
由于苯并恶嗪酮衍生物在有机化学和医药领域具有重要的作用,因此关于该骨架的合成研究较多。传统的合成方法是利用官能化的邻羟基苯甲酰胺衍生物与醛或酮在酸性条件下反应。近年来,新的合成策略被报道,包括官能化邻羟基苯甲醛和亚胺的直接亚胺酰化反应(DIA),环化亚胺、邻氟代酰氯和含氧亲核试剂的三组分反应,以及过渡金属(如铜、钯、锡、钴等)催化的交叉脱氢偶联反应、分子内的多米诺反应、氧化脱芳化反应、脱乙酰化反应、自由化反应等。以上所述的合成方法由于反应条件苛刻、收率低、成本高、重金属残留等缺陷,无法实现工业化大量生产制备,限制了其在医药生产上的应用。
本发明合成一系列结构新颖的苯并恶嗪酮衍生物,并对其进行了肿瘤细胞毒性试验,证明该类苯并恶嗪酮衍生物具有肿瘤抑制活性。
苯并恶嗪酮衍生物结构新颖,表现出优良的抗肿瘤活性。目前还没有经济、高效的合成工艺,更无相关大批量生产制备工艺报道。本发明通过高效、经济、环保的合成方法提供苯并恶嗪酮衍生物,为肿瘤、心血管疾病、神经退行性疾病、代谢性疾病、炎性疾病等相关疾病的预防和治疗提供新策略。
发明内容
本发明针对现有技术的不足,提供了一系列结构新颖的苯并恶嗪酮衍生物及其制备方法和医药用途。
本发明提供的苯并恶嗪酮衍生物是式I或式II所示的化合物。
R1和R6相同或不相同代表氢、C1-C8直链饱和烷基、C2-C8直链不饱和烷基、C3-C8支链饱和烷基、C3-C8支链不饱和烷基、C3-C6的环烷基、芳基、杂环芳基、饱和杂环。
Y选自O或S中的一种。
Z选自O、NH或S中的一种。
X代表羟基、卤素、CN、OR7、OCF3、SCF3、SR7、NR7R8、NO2、C1-C8直链饱和烷基、C2-C8直链不饱和烷基、C3-C8支链饱和烷基、C3-C8支链不饱和烷基、C3-C6的环烷基、芳基、杂环芳基、饱和杂环;其中所述R7和R8同时或不同时为氢、C1-C8直链饱和烷基、C2-C8直链不饱和烷基、C3-C8支链饱和烷基、C3-C8支链不饱和烷基、C3-C6的环烷基、芳基、杂环芳基、饱和杂环。
R2、R3、R4与R5相同或不相同,分别独立代表氢、卤素、CN、CH3、CF3、OR9、OCF3、SCF3、SR9、NR9R10、NO2、COR9、COOR9、CONR9R10、SO3R9、SO2NR9R10、C1-C8直链饱和烷基、C2-C8直链不饱和烷基、C3-C8支链饱和烷基、C3-C8支链不饱和烷基、C3-C6的环烷基、芳基、杂环芳基、饱和杂环;其中所述R9和R10同时或不同时为氢、C1-C8直链饱和烷基、C2-C8直链不饱和烷基、C3-C8支链饱和烷基、C3-C8支链不饱和烷基、C3-C6的环烷基、芳基、杂环芳基、饱和杂环。
所述芳基为苯基、取代苯基,其中取代苯基的取代基位于苯环的各个位置,是单取代或多取代,取代基为卤素、C1-C4直链烷基、C1-C4支链烷基、C1-C4直链烷氧基、C1-C4支链烷氧基、氰基、硝基、羟基、氨基、羧基、甲酯基、乙酯基、三氟甲基。
所述杂环芳基为呋喃、嘧啶、咪唑、吡唑、吡啶、三唑、噻唑、吲哚、吲唑、苯并咪唑,杂环上的取代基位于杂环的各个位置,是单取代或多取代,取代基为卤素、C1-C4直链烷基、C1-C4支链烷基、C1-C4直链烷氧基、C1-C4支链烷氧基、氰基、羟基、氨基、羧基、甲酯基、乙酯基、三氟甲基。
所述饱和杂环为哌啶、哌嗪、甲基哌嗪、吡咯、吗啉,杂环上的取代基位于杂环的各个位置,是单取代或多取代,取代基为卤素、C1-C4直链烷基、C1-C4支链烷基、C1-C4直链烷氧基、C1-C4支链烷氧基、氰基、羟基、氨基、羧基、甲酯基、乙酯基、三氟甲基。
本发明另一个目的是提供式I或式II所示的化合物的制备方法:
式I或式II所示化合物的合成方法如下:
起始原料1与酰化试剂反应得到化合物2,其中所用酰化试剂选自氯化亚砜、草酰氯五氯化磷中的一种,用量为1-5当量;溶剂选自二氯甲烷、氯仿、四氢呋喃中的中的一种;温度为所用溶剂的回流温度。
中间体2与胺和碱在室温下反应得到化合物3,其中所用的碱选自三乙胺、N,N-二异丙基乙胺、吡啶中的一种,用量为4-6当量;溶剂选自二氯甲烷、氯仿、四氢呋喃中的中的一种;温度为室温。
中间体3与氧化剂和碱在加热条件下反应得到式I或式II化合物,其中所用的氧化剂选自过氧化氢、过氧化叔丁醇、过氧化二叔丁基、过氧化异丙苯、间氯过氧化苯甲酸、过硫酸钠中的一种,用量为2-10当量;碱选自氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、氢氧化锂、碳酸铯、甲醇钠、乙醇钠中的一种,用量为1-6当量;溶剂选自二氯甲烷、氯仿、四氢呋喃、乙酸乙酯、乙腈、1,2-二氯乙烷、1,4-二氧六环中的一种;温度为25~100℃。
本发明的又一目的在于提供上述化合物或其药学上可以接受的盐、酯或前药用于制备相关疾病的预防与治疗药物:主要涉及肿瘤、心血管疾病、神经退行性疾病、代谢类疾病、炎性疾病等。
具体实施方式
以下通过实施例对本发明作进一步阐述,但是本发明不限于下述的实施例。
实施例1本发明部分化合物合成,包括Ia-Ih,以化合物Ia为例
N-苄基-2-羟基-5-甲氧基苯甲酰胺的制备:
将5-甲氧基水杨酸1g(5.95mmol)溶于溶于30ml无水二氯甲烷中,加入氯化亚砜2.14g(10.7mmol),N,N-二甲基甲酰胺1滴,升温至回流反应2h后,冷却至室温,旋干除去溶剂,用无水二氯甲烷溶解,滴加到含有三乙胺1.85g(17.80mmol)和苄胺0.76g(7.14mmol)的无水二氯甲烷溶液中。滴加完毕后室温搅拌5min,旋干得粗品,柱层析纯化的白色固体N-苄基-2-羟基-5-甲氧基苯甲酰胺1.27g,收率83%。1H NMR(300MHz,DMSO)δ12.62(s,1H),7.36-7.32(m,5H),7.22(d,J=9.3Hz,1H),6.47(d,J=1.8Hz,1H),6.37(dd,J=9.0,2.4Hz,1H),6.33(s,1H),4.61(d,J=5.7Hz,2H),3.80(s,3H);ESI-MS(m/z):258.2[M+H]+.
2-羟基-6-甲氧基-2-苯基-2,3-二氢-4H-苯并恶嗪酮的制备(Ia):
N-苄基-2-羟基-5-甲氧基苯甲酰胺1g(3.89mmol)溶于30ml1,2二氯乙烷中,加入过氧化氢2.20g(19.45mmol),碳酸钾1.07g(7.78mmol),升温至50℃反应2h后,冷却至室温,旋干得粗品,柱层析纯化的白色固体2-羟基-6-甲氧基-3-苯基-2,3-二氢-4H-苯并恶嗪酮0.97g,收率93%。M.P.202-203℃,1H NMR(300MHz,DMSO)δ11.95(brs,2H),8.13-8.02(m,4H),7.85(d,J=6.6,Hz,1H),7.46(t,J=6.9Hz,1H),7.03-6.95(m,2H),3.90(s,3H);13CNMR(75MHz,DMSO)δ165.5,164.7,156.9,137.9,134.3,133.0,131.0,129.6,128.2,119.7,119.0,117.2,52.6;HRMS(ESI)calculated for C15H14NO4 +[M+H]+272.0917,found272.0918.
2-羟基-6-硝基-2-苯基-2,3-二氢-4H-苯并恶嗪酮(Ib)
参照Ia的合成方法,产物为棕红色固体,收率90%.m.p.218-219℃;1H NMR(300MHz,DMSO)δ15.62(brs,2H),8.71(s,1H),8.07-7.95(m,3H),7.61(s,3H),6.49(d,J=5.4Hz,1H);13C NMR(75MHz,DMSO)δ177.5,165.1,165.0,134.0,132.7,129.0,128.8,128.4,127.8,122.9,118.6,116.9;HRMS(ESI)calculated for C14H11N2O5 +[M+H]+287.0662,found287.0665.
N-苄基-2-羟基-2-苯基-3,4-二氢-2H-苯并恶嗪酮-6-磺酸胺(Ic)
参照Ia的合成方法,产物为黄色固体,收率83%.m.p.169-172℃;1H NMR(300MHz,DMSO)δ14.52(brs,2H),8.22(s,1H),8.01(d,J=7.2Hz,2H),7.81-7.79(m,1H),6.64-7.53(m,4H),7.25(brs,5H),6.78(d,J=8.7Hz,1H),3.90(d,J=5.7Hz,2H);13C NMR(75MHz,DMSO)δ168.8,165.6,138.4,134.5,133.1,131.9,131.0,129.7,129.3,129.0,128.6,128.3,128.0,127.5,125.6,121.0,118.6,46.6;HRMS(ESI)calculated for C21H19N2O5S+[M+H]+411.1009,found 411.1013.
2-羟基-2-(4-甲氧基苯基)-2,3-二氢-4H-苯并恶嗪酮(Id)
参照Ia的合成方法,产物为白色固体,收率68.9%.M.P.85-87℃,1H-NMR(300MHz,DMSO),δ11.18(s,1H),9.01(s,1H),7.34-7.29(m,3H),7.06-7.04(m,1H),4.01-3.96(t,J=6.3Hz,2H),1.74-1.69(m,2H),1.41(m,2H),1.26(m,8H),0.86-0.38(m,3H);13C NMR(75MHz,DMSO):δ164.37,159.03,134.58,129.94,119.43,117.86,113.02,68.05,31.69,29.19,29.12,29.09,25.96,22.54,14.48;HRMS(ESI)calculated for C15H24NO3[M+H]+266.1751,found 266.1747.
2-(1,3-苯并恶唑-5-基)-2-羟基--2,3-二氢-4H-苯并恶嗪酮(Ie)
参照Ia的合成方法,产物为黄色固体,收率91%.M.P.213-215℃;1H NMR(300MHz,DMSO)δ14.00(brs,2H),7.87-7.84(m,1H),7.62-7.60(m,1H),7.46(brs,1H),7.35-7.30(m,1H),7.07-7.04(m,1H),6.88-6.84(m,1H),6.78-6.74(m,1H),6.14(s,2H);13C NMR(75MHz,DMSO)δ166.3,151.0,147.8,134.0,132.2,130.5,123.3,118.6,118.1,117.3,116.8,115.9,108.2,107.6,102.0;HRMS(ESI)calculated for C15H12NO5 +[M+H]+286.0710,found286.0710.
2-羟基-2-(2-氯苯基)-2,3-二氢-4H-苯并恶嗪酮(If)
参照Ia的合成方法,产物为黄色固体,收率91%.M.P.137-138℃;1H NMR(300MHz,DMSO)δ11.99(brs,2H),7.71(d,J=7.8Hz,1H),7.50-7.42(m,3H),7.38-7.30(m,2H),6.86-6.77(m,2H);13C NMR(75MHz,DMSO)δ167.2,165.4,159.5,136.8,135.1,133.8,131.1,130.1,129.0,127.8,119.1,118.1,116.6;HRMS(ESI)calculated for C14H11ClNO3 +[M+H]+276.0422,found 276.0419.
4-(2-羟基-2,3-二氢-4H-苯并恶嗪酮)-苯甲酸甲酯(Ig)
参照Ia的合成方法,产物为黄色固体,收率98%.M.P.189-191℃;1H NMR(300MHz,DMSO)δ12.60(brs,2H),7.90(d,J=6.1Hz,2H),7.83(d,J=7.8Hz,1H),7.36(t,J=7.2Hz,1H),7.05(d,J=8.7Hz,2H),6.92(d,J=8.4Hz,1H),7.85(t,J=7.2Hz,1H);13C NMR(75MHz,DMSO)δ168.1,165.2,165.0,163.3,134.6,131.3,130.3,119.4,119.2,118.1,114.6,114.2,56.0;HRMS(ESI)calculated for C16H14NO5 +[M+H]+300.0866,found 300.0866.
2-羟基-2-(2-呋喃基)-2,3-二氢-4H-苯并恶嗪酮(Ih)
参照Ia的合成方法,产物为黄色固体,收率83%.M.P.202-203℃;1H NMR(300MHz,DMSO)δ14.00(brs,2H),7.87-7.85(m,1H),7.61(d,J=8.1Hz,1H),7.46(s,1H),7.35-7.30(m,1H),7.05-7.03(m,1H),6.87-6.84(m,1H),6.77-6.75(m,1H);13C NMR(75MHz,DMSO)δ151.5,148.3,134.5,130.9,124.0,119.1,118.6,117.8,116.5,108.6,108.2,102.5;HRMS(ESI)calculated for C12H9NO4Na+[M+Na]+254.0424,found 254.0426.
实施例2 化合物Ia-Ih抗肿瘤活性实验。
实验材料
细胞株:人宫颈癌细胞HeLa和人乳腺癌细胞MCF-7;样品:化合物Ia-Ih加入适量DMSO配置成浓度为10-2M溶液,临用前用培养基稀释至相应浓度。
实验方法
细胞消化、计数,每孔2.5×103个细胞,点在96孔板中,每孔总体积为100μl,培养24h;将待测样品用培养基稀释至适当的浓度,每孔100μl,设3复孔。培养72h后加入20μl 5mg/mlMTT溶液,孵育4h后,将孔内液体全部吸出,加入100μl DMSO,全波长酶标仪测吸光度;抑制率=(1-给药组平均吸光度值/对照组平均吸光度值)×100%。
实验结果
化合物Ia-Ih在10μM时对人宫颈癌细胞HeLa和人乳腺癌细胞MCF-7有抑制作用,表明该类化合物具有较好的抗肿瘤活性。
具体结果如表所示:
表:本发明部分化合物的抗肿瘤活性
Claims (9)
1.式I,式II所示的一种苯并恶嗪酮衍生物及其药学上可接受的盐、酯或前药,
其中R1和R6相同或不相同,分别独立代表氢、C1-C8直链饱和烷基、C2-C8直链不饱和烷基、C3-C8支链饱和烷基、C3-C8支链不饱和烷基、C3-C6的环烷基、芳基、杂环芳基、饱和杂环;
Y选自O或S中的一种;
Z选自O、NH或S中的一种;
X代表羟基、卤素、CN、OR7、OCF3、SCF3、SR7、NR7R8、NO2、C1-C8直链饱和烷基、C2-C8直链不饱和烷基、C3-C8支链饱和烷基、C3-C8支链不饱和烷基、C3-C6的环烷基、芳基、杂环芳基、饱和杂环;其中所述R7和R8同时或不同时为氢、C1-C8直链饱和烷基、C2-C8直链不饱和烷基、C3-C8支链饱和烷基、C3-C8支链不饱和烷基、C3-C6的环烷基、芳基、杂环芳基、饱和杂环;
R2、R3、R4与R5相同或不相同,分别独立代表氢、卤素、CN、CH3、CF3、OR9、OCF3、SCF3、SR9、NR9R10、NO2、COR9、COOR9、CONR9R10、SO3R9、SO2NR9R10、C1-C8直链饱和烷基、C2-C8直链不饱和烷基、C3-C8支链饱和烷基、C3-C8支链不饱和烷基、C3-C6的环烷基、芳基、杂环芳基、饱和杂环;其中所述R9和R10同时或不同时为氢、C1-C8直链饱和烷基、C2-C8直链不饱和烷基、C3-C8支链饱和烷基、C3-C8支链不饱和烷基、C3-C6的环烷基、芳基、杂环芳基、饱和杂环。
2.根据权利要求1所述的一种苯并恶嗪酮衍生物,其特征在于所述芳基为苯基、取代苯基,其中取代苯基的取代基位于苯环的各个位置,是单取代或多取代,取代基为卤素、C1-C4直链烷基、C1-C4支链烷基、C1-C4直链烷氧基、C1-C4支链烷氧基、氰基、硝基、羟基、氨基、羧基、甲酯基、乙酯基、三氟甲基。
3.根据权利要求1所述的一种苯并恶嗪酮衍生物,其特征在于所述杂环芳基为呋喃、嘧啶、咪唑、吡唑、吡啶、三唑、噻唑、吲哚、吲唑、苯并咪唑,杂环上的取代基位于杂环的各个位置,是单取代或多取代,取代基为卤素、C1-C4直链烷基、C1-C4支链烷基、C1-C4直链烷氧基、C1-C4支链烷氧基、氰基、羟基、氨基、羧基、甲酯基、乙酯基、三氟甲基。
4.根据权利要求1所述的一种苯并恶嗪酮衍生物,其特征在于所述饱和杂环为哌啶、哌嗪、甲基哌嗪、吡咯、吗啉,杂环上的取代基位于杂环的各个位置,是单取代或多取代,取代基为卤素、C1-C4直链烷基、C1-C4支链烷基、C1-C4直链烷氧基、C1-C4支链烷氧基、氰基、羟基、氨基、羧基、甲酯基、乙酯基、三氟甲基。
5.根据权利要求1所述的苯并恶嗪酮衍生物,其特征在于式I或式II所示化合物制备方法如下:
6.根据权利要求5,化合物的制备步骤为:
起始原料1与酰化试剂反应得到化合物2,其中所用酰化试剂选自氯化亚砜、草酰氯、五氯化磷中的一种,用量为1-5当量;溶剂选自二氯甲烷、氯仿、四氢呋喃中的一种;温度为所用溶剂的回流温度;
中间体2与胺和碱在室温下反应得到化合物3,其中所用的碱选自三乙胺、N,N-二异丙基乙胺、吡啶中的一种,用量为4-6当量;溶剂选自二氯甲烷、氯仿、四氢呋喃中的中的一种;温度为室温;
中间体3与氧化剂和碱在加热条件下反应得到式I或式II所示化合物,其中所用的氧化剂选自过氧化氢、过氧化叔丁醇、过氧化二叔丁基、过氧化异丙苯、间氯过氧化苯甲酸、过硫酸钠中的一种,用量为2-10当量;碱选自氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、氢氧化锂、碳酸铯、磷酸钾、甲醇钠、乙醇钠中的一种,用量为1-6当量;溶剂选自二氯甲烷、氯仿、四氢呋喃、乙酸乙酯、乙腈、1,2-二氯乙烷、1,4-二氧六环中的一种;温度为25~100℃。
7.根据权利要求1所述的任一苯并恶嗪酮衍生物、其药学上可接受的盐、酯或前药可以用于制备抗肿瘤药物,主要涉及胃癌、肝癌、骨髓瘤、膀胱癌、前列腺癌、乳腺癌、直肠癌、头颈癌、肺癌、黑色素瘤、卵巢癌、宫颈癌、食道癌等各类癌症。
8.根据权利要求1所述的任一苯并恶嗪酮衍生物、其药学上可接受的盐、酯或前药可以用于制备相关疾病的预防与治疗药物,主要涉及心血管疾病、神经退行性疾病、代谢类疾病、炎性疾病等。
9.药物组合物,其中含有有效治疗量的权利要求1所述的任一苯并恶嗪酮衍生物、其药学上可接受的盐、酯或前药。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710396333.4A CN107176932B (zh) | 2017-05-26 | 2017-05-26 | 苯并恶嗪酮衍生物及其制备方法和用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710396333.4A CN107176932B (zh) | 2017-05-26 | 2017-05-26 | 苯并恶嗪酮衍生物及其制备方法和用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107176932A true CN107176932A (zh) | 2017-09-19 |
CN107176932B CN107176932B (zh) | 2020-06-05 |
Family
ID=59836274
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710396333.4A Expired - Fee Related CN107176932B (zh) | 2017-05-26 | 2017-05-26 | 苯并恶嗪酮衍生物及其制备方法和用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN107176932B (zh) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108658887A (zh) * | 2018-06-20 | 2018-10-16 | 中南大学 | 苯并[d][1,3]噁嗪-2,4(1H)-二酮衍生物及其合成方法和用途 |
CN108997244A (zh) * | 2018-07-05 | 2018-12-14 | 遵义医学院 | 一种噁嗪酮类化合物及其合成方法 |
CN110204506A (zh) * | 2019-02-20 | 2019-09-06 | 常州大学 | Co2作为c1来源合成1,4-二氢-2h-3,1-苯并恶嗪-2-酮衍生物 |
CN113135884A (zh) * | 2020-01-20 | 2021-07-20 | 西华大学 | 一种新型异色烯类化合物及其制备方法和用途 |
WO2021203811A1 (zh) * | 2020-04-08 | 2021-10-14 | 苏州大学 | 苯并噻嗪酮化合物及其制备方法与作为抗结核药物的应用 |
US11427558B1 (en) | 2019-07-11 | 2022-08-30 | ESCAPE Bio, Inc. | Indazoles and azaindazoles as LRRK2 inhibitors |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3257397A (en) * | 1963-07-26 | 1966-06-21 | Rexall Drug Chemical | Substituted 2, 3-dihydro-4(1h)-quinazolinones |
CN105061333A (zh) * | 2015-08-18 | 2015-11-18 | 陕西师范大学 | 一种乙醇促进的二氯二茂钛催化高效制备喹唑啉酮衍生物的方法 |
-
2017
- 2017-05-26 CN CN201710396333.4A patent/CN107176932B/zh not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3257397A (en) * | 1963-07-26 | 1966-06-21 | Rexall Drug Chemical | Substituted 2, 3-dihydro-4(1h)-quinazolinones |
CN105061333A (zh) * | 2015-08-18 | 2015-11-18 | 陕西师范大学 | 一种乙醇促进的二氯二茂钛催化高效制备喹唑啉酮衍生物的方法 |
Non-Patent Citations (3)
Title |
---|
J. SUBBA RAO,ET AL.,: "Synthesis of 2-hydroxy-3-alkyl-2-phenyl-2,3-dihydroquinazolin-4(1H)-one via molybdenum hexacarbonyl mediated CO gas- and ligand free carbonylative reactions", 《RSC ADVANCES》 * |
SUMAN KR GHOSH,ET AL.,: "Deep eutectic solvent mediated synthesis of quinazolinones and dihydroquinazolinones:synthesis of natural products and drugs", 《RSC ADVANCES》 * |
刘辰: "STN检索过程", 《STN检索报告》 * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108658887A (zh) * | 2018-06-20 | 2018-10-16 | 中南大学 | 苯并[d][1,3]噁嗪-2,4(1H)-二酮衍生物及其合成方法和用途 |
CN108658887B (zh) * | 2018-06-20 | 2022-04-05 | 中南大学 | 苯并[d][1,3]噁嗪-2,4(1H)-二酮衍生物及其合成方法和用途 |
CN108997244A (zh) * | 2018-07-05 | 2018-12-14 | 遵义医学院 | 一种噁嗪酮类化合物及其合成方法 |
CN108997244B (zh) * | 2018-07-05 | 2022-04-29 | 遵义医科大学 | 一种噁嗪酮类化合物及其合成方法 |
CN110204506A (zh) * | 2019-02-20 | 2019-09-06 | 常州大学 | Co2作为c1来源合成1,4-二氢-2h-3,1-苯并恶嗪-2-酮衍生物 |
CN110204506B (zh) * | 2019-02-20 | 2022-10-28 | 常州大学 | Co2作为c1来源合成1,4-二氢-2h-3,1-苯并恶嗪-2-酮衍生物 |
US11427558B1 (en) | 2019-07-11 | 2022-08-30 | ESCAPE Bio, Inc. | Indazoles and azaindazoles as LRRK2 inhibitors |
CN113135884A (zh) * | 2020-01-20 | 2021-07-20 | 西华大学 | 一种新型异色烯类化合物及其制备方法和用途 |
CN113135884B (zh) * | 2020-01-20 | 2023-03-10 | 西华大学 | 一种异色烯类化合物及其制备方法和用途 |
WO2021203811A1 (zh) * | 2020-04-08 | 2021-10-14 | 苏州大学 | 苯并噻嗪酮化合物及其制备方法与作为抗结核药物的应用 |
Also Published As
Publication number | Publication date |
---|---|
CN107176932B (zh) | 2020-06-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107176932A (zh) | 苯并恶嗪酮衍生物及其制备方法和用途 | |
CN106916101B (zh) | Nampt/hdac双靶点抑制剂及其制备方法 | |
US8946439B2 (en) | Amide compounds, compositions and uses thereof | |
CN106928206B (zh) | 醛基类化合物及其制法和用途 | |
JP7046968B2 (ja) | 2-(置換フェニルヘテロ)芳香族カルボン酸系fto阻害剤、その製造方法およびその使用 | |
JP5608655B2 (ja) | P2x3受容体活性のモジュレーター | |
JP7175888B2 (ja) | 選択的hdac1、2阻害剤としてのピペラジン誘導体 | |
CN104080455A (zh) | 某些化学实体、组合物及方法 | |
Zhou et al. | Synthesis, cytotoxicity and topoisomerase II inhibitory activity of lomefloxacin derivatives | |
CN107286113A (zh) | 一种异喹啉酮衍生物及其制备方法和用途 | |
Xu et al. | Synthesis and biological evaluation of marine alkaloid-oriented β-carboline analogues | |
Moghimi et al. | Design and synthesis of novel pyridazine N-aryl acetamides: In-vitro evaluation of α-glucosidase inhibition, docking, and kinetic studies | |
Kaur et al. | Synthesis of 1, 4-dihydropyrazolo [4, 3-b] indoles via intramolecular C (sp2)-N bond formation involving nitrene insertion, DFT study and their anticancer assessment | |
Abbhi et al. | Design and synthesis of benzimidazole-based Rho kinase inhibitors for the treatment of glaucoma | |
CN107879975A (zh) | 组蛋白去乙酰化酶抑制剂及其应用 | |
CN103992236A (zh) | 一种新型靶向性抗肿瘤药物及其制备方法与应用 | |
Singh et al. | Synthesis, molecular docking and biological evaluation of some newer 2-substituted-4-(benzo [d][1, 3] dioxol-5-yl)-6-phenylpyridazin-3 (2H)-ones as potential anti-inflammatory and analgesic agents | |
CN102688234B (zh) | 吲哚酮衍生物作为rsk2抑制剂的合成与应用 | |
JP6454413B2 (ja) | アミノスルホニル系化合物、その製造方法、および使用 | |
CN103980252A (zh) | 制备含1,2,4-三氮唑的吡唑类席夫碱治疗肿瘤的药物 | |
CA2739488A1 (en) | Fused heteroaryl diamide compounds useful as mmp-13 inhibitors | |
RO108869B1 (ro) | DERIVATI DE 6-ARIL-5,6-DIHIDROIMIDAZO-/2,1-b/-TIAZOL, PROCEDEU PENTRU PREPARAREA LOR SI INTERMEDIARI PENTRU REALIZAREA ACESTORA | |
CN115197221B (zh) | 二氢吡唑并嘧啶酮类大环衍生物及其用途 | |
CN102617478B (zh) | 苯并咪唑、噁唑和噻唑衍生物的合成及其应用 | |
CN108530337A (zh) | 一种可选择性抑制胃癌细胞的吲哚酰胺类化合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20200605 |