CN109574936A - 一种具有hdac6抑制活性的异羟肟酸类化合物及其应用 - Google Patents
一种具有hdac6抑制活性的异羟肟酸类化合物及其应用 Download PDFInfo
- Publication number
- CN109574936A CN109574936A CN201811402954.XA CN201811402954A CN109574936A CN 109574936 A CN109574936 A CN 109574936A CN 201811402954 A CN201811402954 A CN 201811402954A CN 109574936 A CN109574936 A CN 109574936A
- Authority
- CN
- China
- Prior art keywords
- methyl
- indazol
- hydroxybenzamide
- dihydropyrazolo
- phenyl
- 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
- 150000001875 compounds Chemical class 0.000 title claims abstract description 59
- 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 16
- 239000002253 acid Substances 0.000 title claims abstract description 16
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 16
- 102100022537 Histone deacetylase 6 Human genes 0.000 title claims abstract description 10
- 101000899330 Homo sapiens Histone deacetylase 6 Proteins 0.000 title claims abstract description 10
- WWGBHDIHIVGYLZ-UHFFFAOYSA-N N-[4-[3-[[[7-(hydroxyamino)-7-oxoheptyl]amino]-oxomethyl]-5-isoxazolyl]phenyl]carbamic acid tert-butyl ester Chemical compound C1=CC(NC(=O)OC(C)(C)C)=CC=C1C1=CC(C(=O)NCCCCCCC(=O)NO)=NO1 WWGBHDIHIVGYLZ-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 54
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 54
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 39
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 35
- 125000001424 substituent group Chemical group 0.000 claims description 28
- 125000003545 alkoxy group Chemical group 0.000 claims description 27
- 102000003964 Histone deacetylase Human genes 0.000 claims description 21
- 108090000353 Histone deacetylase Proteins 0.000 claims description 21
- 125000001797 benzyl group Chemical class [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 19
- -1 methoxyethyl Chemical group 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 14
- 150000004677 hydrates Chemical class 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- ACYDAXAFFLOQDF-UHFFFAOYSA-N 4-[(3-benzyl-7-ethyl-4,5-dihydropyrazolo[3,4-e]indazol-1-yl)methyl]-N-hydroxybenzamide Chemical compound ONC(C1=CC=C(C=C1)CN1N=C(C2=C1C1=CN(N=C1CC2)CC)CC1=CC=CC=C1)=O ACYDAXAFFLOQDF-UHFFFAOYSA-N 0.000 claims description 3
- PTKFBCCFXNVGBH-UHFFFAOYSA-N 4-[(3-benzyl-7-ethyl-4,5-dihydropyrazolo[3,4-e]indazol-2-yl)methyl]-N-hydroxybenzamide Chemical compound ONC(C1=CC=C(C=C1)CN1N=C2C3=CN(N=C3CCC2=C1CC1=CC=CC=C1)CC)=O PTKFBCCFXNVGBH-UHFFFAOYSA-N 0.000 claims description 3
- MSXZGOSCQZBOCC-UHFFFAOYSA-N 4-[(3-benzyl-7-methyl-4,5-dihydropyrazolo[3,4-e]indazol-1-yl)methyl]-N-hydroxybenzamide Chemical compound CN1C=C2C(=N1)CCC3=C2N(N=C3CC4=CC=CC=C4)CC5=CC=C(C=C5)C(=O)NO MSXZGOSCQZBOCC-UHFFFAOYSA-N 0.000 claims description 3
- UUKPCYXDULDYNP-UHFFFAOYSA-N 4-[(3-benzyl-7-methyl-4,5-dihydropyrazolo[3,4-e]indazol-2-yl)methyl]-N-hydroxybenzamide Chemical compound CN1C=C2C(=N1)CCC3=C(N(N=C32)CC4=CC=C(C=C4)C(=O)NO)CC5=CC=CC=C5 UUKPCYXDULDYNP-UHFFFAOYSA-N 0.000 claims description 3
- RRYYYJBEQKKKAN-UHFFFAOYSA-N 4-[(7-ethyl-3-methyl-4,5-dihydropyrazolo[3,4-e]indazol-1-yl)methyl]-N-hydroxybenzamide Chemical compound ONC(C1=CC=C(C=C1)CN1N=C(C2=C1C1=CN(N=C1CC2)CC)C)=O RRYYYJBEQKKKAN-UHFFFAOYSA-N 0.000 claims description 3
- VCRKOWDLUIEFMD-UHFFFAOYSA-N 4-[(7-ethyl-3-phenyl-4,5-dihydropyrazolo[3,4-e]indazol-1-yl)methyl]-N-hydroxybenzamide Chemical compound ONC(C1=CC=C(C=C1)CN1N=C(C2=C1C1=CN(N=C1CC2)CC)C1=CC=CC=C1)=O VCRKOWDLUIEFMD-UHFFFAOYSA-N 0.000 claims description 3
- ASCIVFQVPSMNCF-UHFFFAOYSA-N 4-[(7-ethyl-3-phenyl-4,5-dihydropyrazolo[3,4-e]indazol-2-yl)methyl]-N-hydroxybenzamide Chemical compound ONC(C1=CC=C(C=C1)CN1N=C2C3=CN(N=C3CCC2=C1C1=CC=CC=C1)CC)=O ASCIVFQVPSMNCF-UHFFFAOYSA-N 0.000 claims description 3
- URDLOTVDJPLNPF-UHFFFAOYSA-N 4-[[3-benzyl-7-(2-methoxyethyl)-4,5-dihydropyrazolo[3,4-e]indazol-1-yl]methyl]-N-hydroxybenzamide Chemical compound ONC(C1=CC=C(C=C1)CN1N=C(C2=C1C1=CN(N=C1CC2)CCOC)CC1=CC=CC=C1)=O URDLOTVDJPLNPF-UHFFFAOYSA-N 0.000 claims description 3
- KVPDXHFYIOVAGG-UHFFFAOYSA-N 4-[[3-benzyl-7-(2-methoxyethyl)-4,5-dihydropyrazolo[3,4-e]indazol-2-yl]methyl]-N-hydroxybenzamide Chemical compound ONC(C1=CC=C(C=C1)CN1N=C2C3=CN(N=C3CCC2=C1CC1=CC=CC=C1)CCOC)=O KVPDXHFYIOVAGG-UHFFFAOYSA-N 0.000 claims description 3
- CYALUHQUKUXWOZ-UHFFFAOYSA-N N-hydroxy-4-[(7-methyl-3-phenyl-4,5-dihydropyrazolo[3,4-e]indazol-1-yl)methyl]benzamide Chemical compound CN1C=C2C(=N1)CCC3=C2N(N=C3C4=CC=CC=C4)CC5=CC=C(C=C5)C(=O)NO CYALUHQUKUXWOZ-UHFFFAOYSA-N 0.000 claims description 3
- UEJXKQSQSQYMKG-UHFFFAOYSA-N N-hydroxy-4-[(7-methyl-3-phenyl-4,5-dihydropyrazolo[3,4-e]indazol-2-yl)methyl]benzamide Chemical compound CN1C=C2C(=N1)CCC3=C(N(N=C32)CC4=CC=C(C=C4)C(=O)NO)C5=CC=CC=C5 UEJXKQSQSQYMKG-UHFFFAOYSA-N 0.000 claims description 3
- VYDPQOSKFFVJCC-UHFFFAOYSA-N N-hydroxy-4-[[7-(2-methoxyethyl)-3-methyl-4,5-dihydropyrazolo[3,4-e]indazol-1-yl]methyl]benzamide Chemical compound ONC(C1=CC=C(C=C1)CN1N=C(C2=C1C1=CN(N=C1CC2)CCOC)C)=O VYDPQOSKFFVJCC-UHFFFAOYSA-N 0.000 claims description 3
- CEDFTIUFOPINDM-UHFFFAOYSA-N N-hydroxy-4-[[7-(2-methoxyethyl)-3-methyl-4,5-dihydropyrazolo[3,4-e]indazol-2-yl]methyl]benzamide Chemical compound ONC(C1=CC=C(C=C1)CN1N=C2C3=CN(N=C3CCC2=C1C)CCOC)=O CEDFTIUFOPINDM-UHFFFAOYSA-N 0.000 claims description 3
- APPMZHSUNGGHSU-UHFFFAOYSA-N N-hydroxy-4-[[7-(2-methoxyethyl)-3-phenyl-4,5-dihydropyrazolo[3,4-e]indazol-1-yl]methyl]benzamide Chemical compound ONC(C1=CC=C(C=C1)CN1N=C(C2=C1C1=CN(N=C1CC2)CCOC)C1=CC=CC=C1)=O APPMZHSUNGGHSU-UHFFFAOYSA-N 0.000 claims description 3
- DMJMWAOUSVYZED-UHFFFAOYSA-N N-hydroxy-4-[[7-(2-methoxyethyl)-3-phenyl-4,5-dihydropyrazolo[3,4-e]indazol-2-yl]methyl]benzamide Chemical compound ONC(C1=CC=C(C=C1)CN1N=C2C3=CN(N=C3CCC2=C1C1=CC=CC=C1)CCOC)=O DMJMWAOUSVYZED-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 238000011282 treatment Methods 0.000 claims 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims 1
- 230000001594 aberrant effect Effects 0.000 claims 1
- 230000000118 anti-neoplastic effect Effects 0.000 claims 1
- 229940034982 antineoplastic agent Drugs 0.000 claims 1
- 201000010881 cervical cancer Diseases 0.000 claims 1
- 208000032839 leukemia Diseases 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 10
- JAAGHUBILRENEC-UHFFFAOYSA-N 1h-benzo[g]indazole Chemical class C1=CC2=CC=CC=C2C2=C1C=NN2 JAAGHUBILRENEC-UHFFFAOYSA-N 0.000 abstract description 3
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 239000003560 cancer drug Substances 0.000 abstract 1
- 239000000470 constituent Substances 0.000 abstract 1
- MWGQUKJMKCGPCH-UHFFFAOYSA-N pyrazolo[3,4-e]indazole Chemical class C1=CC2=CN=NC2=C2C=NN=C21 MWGQUKJMKCGPCH-UHFFFAOYSA-N 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 68
- 238000005160 1H NMR spectroscopy Methods 0.000 description 34
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 239000002207 metabolite Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000012453 solvate Substances 0.000 description 8
- 210000004881 tumor cell Anatomy 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 3
- NLWBJPPMPLPZIE-UHFFFAOYSA-N methyl 4-(bromomethyl)benzoate Chemical compound COC(=O)C1=CC=C(CBr)C=C1 NLWBJPPMPLPZIE-UHFFFAOYSA-N 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- FUVZDXDCPRQZSQ-UHFFFAOYSA-N 1,5,6,7-tetrahydroindazol-4-one Chemical compound O=C1CCCC2=C1C=NN2 FUVZDXDCPRQZSQ-UHFFFAOYSA-N 0.000 description 2
- LGENYAPWLPIWFN-UHFFFAOYSA-N 2-(dimethylamino)-4-methylidenecyclohexane-1,3-dione Chemical compound CN(C)C1C(=O)CCC(=C)C1=O LGENYAPWLPIWFN-UHFFFAOYSA-N 0.000 description 2
- CMRRIPRABGYABK-UHFFFAOYSA-N 4-[(7-ethyl-3-methyl-4,5-dihydropyrazolo[3,4-e]indazol-2-yl)methyl]-N-hydroxybenzamide Chemical compound ONC(C1=CC=C(C=C1)CN1N=C2C3=CN(N=C3CCC2=C1C)CC)=O CMRRIPRABGYABK-UHFFFAOYSA-N 0.000 description 2
- 102100038720 Histone deacetylase 9 Human genes 0.000 description 2
- 108010033040 Histones Proteins 0.000 description 2
- 229910017833 NH2NH2.H2O Inorganic materials 0.000 description 2
- 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 2
- 108050002485 Sirtuin Proteins 0.000 description 2
- 102000011990 Sirtuin Human genes 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 230000001973 epigenetic effect Effects 0.000 description 2
- 230000004049 epigenetic modification Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 2
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 2
- POCUPXSSKQAQRY-UHFFFAOYSA-N hydroxylamine;hydrate Chemical compound O.ON POCUPXSSKQAQRY-UHFFFAOYSA-N 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000012049 topical pharmaceutical composition Substances 0.000 description 2
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 2
- 229960000237 vorinostat Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- KZVAAIRBJJYZOW-LMVFSUKVSA-N (2r,3s,4s)-2-(hydroxymethyl)oxolane-3,4-diol Chemical compound OC[C@H]1OC[C@H](O)[C@@H]1O KZVAAIRBJJYZOW-LMVFSUKVSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- LJKVZKZQXCLXFT-UHFFFAOYSA-N 2-ethyl-6,7-dihydro-5h-indazol-4-one Chemical compound C1CCC(=O)C=2C1=NN(CC)C=2 LJKVZKZQXCLXFT-UHFFFAOYSA-N 0.000 description 1
- MNALUTYMBUBKNX-UHFFFAOYSA-N 6-methoxy-3,4-dihydro-2h-naphthalen-1-one Chemical compound O=C1CCCC2=CC(OC)=CC=C21 MNALUTYMBUBKNX-UHFFFAOYSA-N 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 101100123577 Caenorhabditis elegans hda-1 gene Proteins 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 101100506416 Drosophila melanogaster HDAC1 gene Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102100039996 Histone deacetylase 1 Human genes 0.000 description 1
- 102100039999 Histone deacetylase 2 Human genes 0.000 description 1
- 102100021455 Histone deacetylase 3 Human genes 0.000 description 1
- 102100021454 Histone deacetylase 4 Human genes 0.000 description 1
- 102100021453 Histone deacetylase 5 Human genes 0.000 description 1
- 101001035024 Homo sapiens Histone deacetylase 1 Proteins 0.000 description 1
- 101001035011 Homo sapiens Histone deacetylase 2 Proteins 0.000 description 1
- 101000899282 Homo sapiens Histone deacetylase 3 Proteins 0.000 description 1
- 101000899259 Homo sapiens Histone deacetylase 4 Proteins 0.000 description 1
- 101000899255 Homo sapiens Histone deacetylase 5 Proteins 0.000 description 1
- 101001032113 Homo sapiens Histone deacetylase 7 Proteins 0.000 description 1
- 101001032092 Homo sapiens Histone deacetylase 9 Proteins 0.000 description 1
- 101001035694 Homo sapiens Polyamine deacetylase HDAC10 Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 101000654471 Mus musculus NAD-dependent protein deacetylase sirtuin-1 Proteins 0.000 description 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- QGZYDVAGYRLSKP-UHFFFAOYSA-N N-[7-(hydroxyamino)-7-oxoheptyl]-2-(N-phenylanilino)-5-pyrimidinecarboxamide Chemical compound N1=CC(C(=O)NCCCCCCC(=O)NO)=CN=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 QGZYDVAGYRLSKP-UHFFFAOYSA-N 0.000 description 1
- BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-O 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 102100039388 Polyamine deacetylase HDAC10 Human genes 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- HJSLFCCWAKVHIW-UHFFFAOYSA-N cyclohexane-1,3-dione Chemical compound O=C1CCCC(=O)C1 HJSLFCCWAKVHIW-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 230000008995 epigenetic change Effects 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000012239 gene modification Methods 0.000 description 1
- 230000030279 gene silencing Effects 0.000 description 1
- 238000012226 gene silencing method Methods 0.000 description 1
- 230000005017 genetic modification Effects 0.000 description 1
- 235000013617 genetically modified food Nutrition 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- ZSRCGGBALFGALF-VOTSOKGWSA-N methyl (e)-3-[4-(bromomethyl)phenyl]prop-2-enoate Chemical compound COC(=O)\C=C\C1=CC=C(CBr)C=C1 ZSRCGGBALFGALF-VOTSOKGWSA-N 0.000 description 1
- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- SUTRDULVNIPNLW-SFHVURJKSA-N tert-butyl n-[(2s)-6-acetamido-1-[(4-methyl-2-oxochromen-7-yl)amino]-1-oxohexan-2-yl]carbamate Chemical compound CC1=CC(=O)OC2=CC(NC(=O)[C@@H](NC(=O)OC(C)(C)C)CCCCNC(=O)C)=CC=C21 SUTRDULVNIPNLW-SFHVURJKSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于医药技术领域，涉及一种具有HDAC6抑制活性和抗肿瘤活性的异羟肟酸类化合物，具体涉及含有苯并吲唑类母核和吡唑并吲唑类母核的异羟肟酸类化合物，及其药学上可接受的盐、水合物，和以该化合物为活性成分的药物组合物，以及在制备组蛋白去乙酰化酶抑制剂及其在制备用于治疗和/或预防癌症药物中的用途。所述的化合物结构如式I或II所示，其中，X、R、A如权利要求和说明书所述。
Description
技术领域：
本发明属于医药技术领域，涉及一种具有HDAC6抑制活性和抗肿瘤活性的异羟肟酸类化合物，具体涉及含有苯并吲唑类母核和吡唑并吲唑类母核的异羟肟酸类化合物，及其药学上可接受的盐、水合物，和以该化合物为活性成分的药物组合物，以及在制备组蛋白去乙酰化酶抑制剂及其在制备用于治疗和/或预防癌症药物中的用途。
背景技术：
表观遗传研究正成为人类攻克肿瘤的希望。表观遗传改变多发生在肿瘤发生的早期，此时肿瘤细胞尚未对人体造成实质性伤害，此时进行干预，很有可能将其扼杀在摇篮里。另外，相比遗传修饰几乎是不可逆转而言，表观遗传修饰异常可以逆转，是肿瘤细胞恢复为正常状态。因而，表观遗传研究具有更为广阔的应用前景。组蛋白修饰是表观遗传修饰的一种重要方式，人类绝大多数肿瘤细胞都存在组蛋白修饰异常，这种异常能引起抑癌基因沉默致使肿瘤形成。组蛋白去乙酰化酶(Histone deacetylase,HDAC)是一个包含多个成员的酶家族，目前已知有18种亚型，按其种系及与酵母同源性不同分为以下四类：与酵母Rpd3，HoS1，HoSt2同源的Ⅰ类，包括HDAC1、HDAC2、HDAC3、HDAC8；与酵母Hda1，HoS3同源的Ⅱa类，包括HDAC4、HDAC5、HDAC7、HDAC9，Ⅱb类包括HDAC6、HDAC10；与酵母Sir2同源的Ⅲ类，包括SIRT1～SIRT7；与Ⅰ和Ⅱ类HDAC都有部分同源性，但其种系不同的Ⅳ类，包括HDAC11。其中Ⅰ、Ⅱ、Ⅳ类为经典的Zn2+依赖的HDACs，而第Ⅲ类属于Sirtuin家族，为NAD+依赖的HDACs。研究表明，第Ⅰ和Ⅱ类HDACs能够抑制肿瘤细胞分化和凋亡、促进肿瘤细胞增殖等，其与肿瘤的发生、发展密切相关，以HDACs为靶点的抑制剂研究已经成为抗肿瘤药物研究的热点之一。
本发明在参考文献的基础上，设计并合成了一系列含有苯并吲唑类母核和吡唑并吲唑类母核的异羟肟酸类化合物，体外抗肿瘤活性测试结果表明，其具有良好的抗肿瘤活性，并表现出优异的HDAC抑制作用。
发明内容：
本发明旨在提供一种具有HDAC抑制活性且具有良好抗肿瘤活性的异羟肟酸类化合物及其制备方法，以及该类化合物作为组蛋白去乙酰化酶抑制剂在制备预防和/或治疗肿瘤药物中的应用。
本发明所述的异羟肟酸类化合物包含以下片段：苯并吲唑类片段和吡唑并吲唑类片段。
本发明涉及式Ⅰ或II所示的化合物、及其药学上可接受的盐、水合物、溶剂化物、代谢化物：
其中，
A环选自一个或多个取代或未取代的5-6元芳环或杂芳环，所述杂芳环含有1-3个N、O或S的杂原子；所述的取代基为H、卤素、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烷氧基(C1-C4)烷基、(C6-C10)芳基、(C1-C4)烷基取代的苯基、(C1-C4)烷氧基取代的苯基或苄基；
X选自一个或多个如下取代基：羰基、(C3-C5)α，β-不饱和羰基；
R选自一个或多个如下取代基：H、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、(C6-C10)芳基、(C1-C4)烷基取代的苯基、(C1-C4)烷氧基取代的苯基或苄基。
本发明优选式Ⅰ或II所示的化合物、及其药学上可接受的盐、水合物、溶剂化物、代谢化物：
其中，
A环选自一个或多个如下环系：
R1选自一个或多个如下取代基：H、卤素、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烷氧基(C1-C4)烷基；
R2选自一个或多个如下取代基：H、(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、(C6-C10)芳基、(C1-C4)烷基取代的苯基、(C1-C4)烷氧基取代的苯基或苄基；
R3选自一个或多个如下取代基：H、(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、(C6-C10)芳基、(C1-C4)烷基取代苯基、(C1-C4)烷氧基取代苯基或苄基；
R选自一个或多个如下取代基：H、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、(C6-C10)芳基、(C1-C4)烷基取代的苯基、(C1-C4)烷氧基取代的苯基或苄基；
X选自一个或多个如下取代基：羰基、(C3-C5)α，β-不饱和羰基。
本发明优选定义如式Ⅰ或II的化合物、及其药学上可接受的盐、水合物、溶剂化物、代谢化物：
其中，
A环为
R1选自一个或多个如下取代基：H、卤素、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烷氧基(C1-C4)烷基；
R2选自一个或多个如下取代基：H、(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、(C6-C10)芳基、(C1-C4)烷基取代苯基、(C1-C4)烷氧基取代苯基或苄基；
R3选自一个或多个如下取代基：H、(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、(C6-C10)芳基、(C1-C4)烷基取代苯基、(C1-C4)烷氧基取代苯基或苄基；
R选自一个或多个如下取代基：H、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、(C6-C10)芳基、(C1-C4)烷基取代苯基、(C1-C4)烷氧基取代苯基或苄基；
X选自一个或多个如下取代基：羰基、(C3-C5)α，β-不饱和羰基。
本发明还优选定义如式Ⅰ或II的化合物、及其药学上可接受的盐、水合物、溶剂化物、代谢化物：
其中，
A环为
R1为H或(C1-C4)烷氧基；
R2选自一个或多个如下取代基：H、(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、(C6-C10)芳基、(C1-C4)烷基取代苯基、(C1-C4)烷氧基取代苯基或苄基；
R3选自一个或多个如下取代基：H、(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、(C6-C10)芳基、(C1-C4)烷基取代苯基、(C1-C4)烷氧基取代苯基或苄基；
R选自一个或多个如下取代基：H、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、(C6-C10)芳基、(C1-C4)烷基取代苯基、(C1-C4)烷氧基取代苯基或苄基；
X选自一个或多个如下取代基：羰基、(C3-C5)α，β-不饱和羰基。
本发明还特别优选定义如式Ⅰ或II的化合物、及其药学上可接受的盐、水合物、溶剂化物、代谢化物：
其中，
A环为
R1为H或甲氧基；
R2、R3为(C1-C4)烷基或(C1-C4)烷氧基(C1-C4)烷基；
R选自一个或多个如下取代基：H、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、(C6-C10)芳基、(C1-C4)烷基取代苯基、(C1-C4)烷氧基取代苯基或苄基；
X选自一个或多个如下取代基：羰基、(C3-C5)α，β-不饱和羰基。
本发明还特别优选定义如式Ⅰ或II的化合物、及其药学上可接受的盐、水合物、溶剂化物、代谢化物：
其中，
A环为
R1为H或甲氧基；
R2、R3为甲基、乙基或甲氧乙基；
R为甲基、苯基或苄基；
X选自一个或多个如下取代基：羰基、(C3-C5)α，β-不饱和羰基。
本发明还特别优选定义如式Ⅰ或II的化合物、及其药学上可接受的盐、水合物、溶剂化物、代谢化物：
其中，
A环为
R1为H或甲氧基；
R2、R3为甲基、乙基或甲氧乙基；
R为甲基、苯基或苄基；
X为：-CO-或-CH＝CH-CO-。
具体的，本发明优选如下化合物：
4-[(7-甲氧基-3-苯基-4,5-二氢-1H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-甲氧基-4,5-二氢-2H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-4,5-二氢-2H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-4,5-二氢-2H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
(E)-3-{4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
4-[(7-乙基-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(7-乙基-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(7-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(7-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(6-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(6-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
或其水合物、溶剂化物、代谢化物以及药学上可接受的盐。
此外，本发明还包括本发明化合物的前药。依据本发明，它们自身可能具有较弱的活性甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或者另外的方式)被转化成相应的生物活性形式。
本发明包括药物组合物，该组合物含有上式Ⅰ或II所示的异羟肟酸类化合物和药学上可接受的赋形剂。所述药学上可接受的赋形剂是指任何可用于药物领域的稀释剂、辅助剂和/或载体。本发明的化合物可以与其他活性成分组合使用，只要他们不产生其他不利的作用，例如过敏反应。
本发明的药物组合物可配制成若干种剂型，其中含有药物领域中常用的一些赋形剂，例如，口服制剂(如片剂，胶囊剂，溶液或混悬液)；可注射的制剂(如可注射的溶液或者混悬液，或者是可注射的干燥粉末，在注射前加入注射用水可立即使用)；局部制剂(例如软膏或溶液)。
用于本发明药物组合物的载体是药物领域中可得到的常见类型，包括：口服制剂用的粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、色素、矫味剂等；可注射制剂用的防腐剂、加溶剂、稳定剂等；局部制剂用的基质、稀释剂、润滑剂、防腐剂等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药，如果某些药物在胃部条件下是不稳定的，可将其配制成肠衣片剂。
通过体外抑酶试验筛选，我们发现本发明化合物可抑制组蛋白去乙酰化酶活力，因此，本发明化合物可用于制备治疗与组蛋白去乙酰化酶活性异常表达相关的疾病的药物中的应用，如各种癌症。
通过体外活性筛选及体内药效学研究，我们发现本发明化合物具有抗肿瘤活性，因此本发明化合物可以用于制备治疗和/或预防各种癌症的药物，如乳腺、肺、结肠、直肠、胃、前列腺、膀胱、子宫、胰腺和卵巢癌。
本发明活性化合物可作为唯一抗癌药物使用，或者与一种或多种其他抗肿瘤药物联合使用。联合治疗通过将各个治疗组分同时、顺序或隔开给药来实现。
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解，下述实施例和制备例的范围并不以任何方式限制本发明的范围。
下面的合成路线描述了本发明的式Ⅰ或II化合物的制备，所有的原料都是通过这些路线中描述的方法、通过有机化学领域普通技术人员熟知的方法制备的或者可商购。本发明的全部最终化合物都是通过这些路线中描述的方法或通过与其类似的方法制备的，这些方法是有机化学领域普通技术人员熟知的。这些路线中应用的全部可变因数如下文的定义或如权利要求中的定义。
按照本发明的式I化合物，路线一中，各取代基如发明内容部分所定义。
路线一
试剂和条件：a.R2COCl,LiHMDS,dry THF,N2,r.t.,6h；b.NH2NH2.H2O,AcOH,100℃,1h；c.methyl 4-(bromomethyl)benzoate,Cs2CO3,MeCN,70℃,4h；d.NH2OH.H2O,NaOH,MeOH,r.t.,6h.
按照本发明的式Ⅰ或II的化合物，路线二中，各取代基如发明内容部分所定义。
路线二
试剂和条件：a.DMF-DMA,95℃,1h；b.NH2NH2.HCl,MeOH,70℃,3h；c.R1X,Cs2CO3,MeCN,70℃,4h；d.R2COCl,LiHMDS,dry THF,N2,r.t.,6h；e.NH2NH2.H2O,AcOH,100℃,1h；f.methyl 4-(bromomethyl)benzoate or(E)-methyl 3-(4-(bromomethyl)phenyl)acrylate,Cs2CO3,MeCN,70℃,4h；g.NH2OH.H2O,NaOH,MeOH,r.t.,6h.
本发明制备方法操作简单、条件温和，所得化合物均具有组蛋白去乙酰化酶抑制活性，抗肿瘤作用显著。
具体实施方式：
下面通过具体的实施例对本发明进行详细说明，但这些例举性实施方式的用途和目的仅用来例举本发明，并非对本发明的实际保护范围构成任何形式的任何限定，更非将本发明的保护范围局限于此。
实施例1：4-[(7-甲氧基-3-苯基-4,5-二氢-1H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺的制备
步骤A：2-苯甲酰基-6-甲氧基-3,4-二氢萘-1(2H)-酮的制备
在40ml四氢呋喃中加入0.5g(2.84mmol)6-甲氧基-1-萘满酮，5.7ml(5.68mmol)双三甲基硅基胺基锂，在0℃下加入0.4ml(3.41mmol)苯甲酰氯，滴毕，转移至室温反应6h。反应结束后，将溶剂直接蒸干得黄色固体0.75g。不经纯化，直接进行下一步反应。
步骤B：3-苯基-7-甲氧基-4,5-二氢-2H-苯并[g]吲唑的制备
在50ml冰醋酸中加入0.75g 2-苯甲酰基-6-甲氧基-3,4-二氢萘-1(2H)-酮粗品，溶解后，加入0.23ml(3.58mmol)80％水合肼溶液，100℃反应1h。反应结束后，将反应液倒入大量水中，用乙酸乙酯萃取(30ml×3)，合并有机相，用饱和碳酸氢钠溶液洗涤有机相，至没有气泡产生，用无水硫酸钠干燥有机相，浓缩得粗品。以石油醚：乙酸乙酯(V/V)为洗脱剂进行柱层析，得白色固体0.64g，两步总收率为82.1％。
步骤C：4-[(7-甲氧基-3-苯基-4,5-二氢-1H-苯并[g]吲唑-2-基)甲基]苯甲酸甲酯的制备
在50ml乙腈中加入0.3g(1.09mmol)3-苯基-7-甲氧基-4,5-二氢-2H-苯并[g]吲唑，0.5g 4-溴甲基苯甲酸甲酯(2.18mmol)以及0.27g(2.18mmol)碳酸钾，70℃反应4h。反应结束后，向反应液中加入硅胶，以石油醚：乙酸乙酯(V/V)为洗脱剂进行柱层析，得白色固体0.35g，收率为76.1％。
步骤D：4-[(7-甲氧基-3-苯基-4,5-二氢-1H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺的制备
在20ml甲醇中加入0.2g(0.47mmol)4-[(7-甲氧基-3-苯基-4,5-二氢-1H-苯并[g]吲唑-2-基)甲基]苯甲酸甲酯，在0℃下加入2M NaOH溶液，使其pH>10，再加入4ml羟胺水溶液，转移至室温反应3h。反应结束后，将甲醇蒸干，在0℃下加入2M盐酸，使其pH为6-7，析出白色固体，抽滤，滤饼用水淋洗(5ml×2)，红外灯下干燥后，得白色固体0.17g，收率为85.0％。ESI-MS:m/z,424.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.16(s,1H),9.02(s,1H),7.63(d,J＝8.0Hz,2H),7.46-7.42(m,5H),7.39-7.30(m,3H),7.07(d,J＝8.1Hz,2H),5.39(s,2H),3.77(s,3H),2.90(t,J＝7.9Hz,2H),2.67(t,J＝8.1Hz,2H).
按照实施例1的制备方法，选择适当的原料，制得实施例2-实施例4的化合物。
实施例2：4-[(3-苄基-7-甲氧基-4,5-二氢-2H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,438.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.14(s,1H),9.00(s,1H),7.63(d,J＝8.0Hz,2H),7.28(d,J＝7.1Hz,2H),7.13-7.08(m,5H),6.92-6.75(m,3H),5.30(s,2H),4.01(s,2H),3.76(s,3H),2.84(t,J＝7.3Hz,2H),2.55(t,J＝7.4Hz,2H).
实施例3：4-[(3-苄基-4,5-二氢-2H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,408.1[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.15(s,1H),9.01(s,1H),7.66-7.62(m,2H),7.26(m,2H),7.24-7.14(m,5H),7.14-7.08(m,4H),5.33(s,2H),4.03(s,2H),2.86(t,J＝7.3Hz,2H),2.57(t,J＝8.1Hz,2H).
实施例4：4-[(3-苯基-4,5-二氢-2H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,394.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.18(s,1H),9.06(s,1H),7.71-7.69(m,2H),7.50-7.45(m,5H),7.40-7.36(m,4H),7.21-7.18(m,2H),5.81(s,2H),2.92(t,J＝8.2Hz,2H),2.69(t,J＝7.3Hz,2H).
实施例5：4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
步骤A：2-(二甲基氨基)亚甲基-1,3-环己二酮的制备
在250ml茄形瓶中加入10.0g(89.2mmol)1,3-环己二酮和30ml N,N-二甲基甲酰胺二甲基缩醛(DMF-DMA)，95℃反应1h。反应结束，减压蒸馏回收过量未反应的DMF-DMA得到14.9g红棕色固体。不经纯化直接进行下一步反应。
步骤B：2,5,6,7-四氢-4H-吲唑-4-酮的制备
在150ml甲醇中加入14.9g 2-(二甲基氨基)亚甲基-1,3-环己二酮粗品和11.2g(107.0mmol)盐酸肼，65℃反应3h。反应结束，蒸干甲醇的黄色固体。用60ml二氯甲烷淋洗固体，红外灯下干燥，得到11.5g淡黄色固体。两步总收率为95.0％。
步骤C：2-乙基-2,5,6,7-四氢-4H-吲唑-4-酮的制备
在150ml乙腈中加入5.8g(42.6mmol)2,5,6,7-四氢-4H-吲唑-4-酮，6.4ml(85.2mmol)溴乙烷和11.8g(85.2mmol)碳酸钾，加热至80℃反应4h。反应结束后，抽滤，收集滤液。以石油醚：乙酸乙酯(V/V)为洗脱剂进行柱层析，得淡黄色固体2.96g，收率为42.3％。
步骤D：2-乙基-5-(2-苯乙酰基)-2,5,6,7-四氢-4H-吲唑-4-酮的制备
在50ml四氢呋喃中加入0.5g(3.0mmol)2-乙基-2,5,6,7-四氢-4H-吲唑-4-酮，在0℃下加入6.0ml(6.0mmol)双三甲基硅基胺基锂溶液(LiHMDS)，逐滴加入0.8ml(4.5mmol)苯乙酰氯，室温搅拌6h。反应结束后，直接将溶剂蒸除，得0.75g黄色固体，不经纯化直接进行下一步反应。
步骤E：3-苄基-7-乙基-1,4,5,7-四氢吡唑并[3,4-e]吲唑的制备
在50ml冰醋酸中加入0.75g 2-乙基-5-(2-苯乙酰基)-2,5,6,7-四氢-4H-吲唑-4-酮粗品，0.25ml(5.0mmol)水合肼(80％)，100℃反应1h。反应结束后，将反应液倒入大量水中，用乙酸乙酯萃取(30ml×3)，合并有机相，用饱和碳酸氢钠溶液洗涤有机相，至没有气泡产生，用无水硫酸钠干燥有机相，浓缩得5-3粗品。以石油醚：乙酸乙酯(V/V)为洗脱剂进行柱层析，得白色固体0.42g，两步总收率为49.5％。
步骤F：4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯甲酸甲酯和4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯甲酸甲酯的制备
在50ml乙腈中加入0.4g(1.4mmol)3-苄基-7-乙基-1,4,5,7-四氢吡唑并[3,4-e]吲唑，0.34g(2.8mmol)碳酸钾和0.48g(2.1mmol)4-溴甲基苯甲酸甲酯，70℃反应4h。反应完毕后，反应液中加入硅胶，以石油醚：丙酮(V/V)为洗脱剂进行柱层析，得白色固体，4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯甲酸甲酯80mg，收率为13.1％；4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯甲酸甲酯70mg，收率为11.5％。
步骤G：4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
在10ml甲醇中加入80mg(0.19mmol)4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯甲酸甲酯，0℃下，加入1M氢氧化钠溶液，使其pH>11，滴入2ml羟胺水溶液，滴毕，转移至室温反应6h。反应完毕后，将甲醇蒸干，在0℃下加入2M盐酸，使其pH为6-7，析出白色固体，抽滤，滤饼用水淋洗(5ml×2)，红外灯下干燥后，得白色固体35mg，收率为43.6％。ESI-MS:m/z,425.9[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.18(s,1H),9.01(s,1H),7.95(s,1H),7.68(d,J＝8.0Hz,2H),7.26(d,J＝7.3Hz,2H),7.24-7.13(m,5H),5.41(s,2H),4.04(q,J＝7.2Hz,2H),3.88(s,2H),2.69(t,J＝7.4Hz,2H),2.55(t,J＝7.7Hz,2H),1.33(t,J＝7.2Hz,3H).
按照实施例5的制备方法，选择适当的原料，制得实施例6-实施例34的化合物。
实施例6：4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,426.4[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.12(s,1H),9.01(s,1H),7.95(s,1H),7.68(d,J＝7.9Hz,2H),7.26(d,J＝7.4Hz,2H),7.24-7.14(m,5H),5.42(s,2H),4.04(q,J＝7.3Hz,2H),3.88(s,2H),2.69(t,J＝7.7Hz,2H),2.55(t,J＝7.9Hz,2H),1.33(t,J＝7.2Hz,3H).
实施例7：4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,412.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.15(s,1H),8.93(s,1H),8.03(s,1H),7.70(d,J＝6.1Hz,2H),7.68(d,J＝6.8Hz,2H),7.47-7.24(m,5H),5.52(s,2H),4.09(q,J＝7.2Hz,2H),2.99(t,J＝7.6Hz,2H),2.81(t,J＝7.6Hz,2H),1.36(t,J＝7.2Hz,3H).
实施例8：4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,412.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.14(s,1H),9.00(s,1H),7.89(s,1H),7.64(d,J＝8.0Hz,2H),7.47-7.37(m,5H),7.04(d,J＝7.9Hz,2H),5.31(s,2H),4.10(q,J＝7.2Hz,2H),2.76(d,J＝5.9Hz,2H),2.72(d,J＝6.0Hz,2H),1.38(t,J＝7.2Hz,3H).
实施例9：4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,412.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.14(s,1H),9.01(s,1H),7.90(s,1H),7.67(d,J＝8.1Hz,2H),7.27(t,J＝7.5Hz,2H),7.23-7.19(m,4H),7.17(t,J＝7.3Hz,1H),5.41(s,2H),3.88(s,2H),3.75(s,3H),2.68(t,J＝7.6Hz,2H),2.55(t,J＝7.6Hz,2H).
实施例10：4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,412.4[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.15(s,1H),9.00(s,1H),7.75(s,1H),7.62(d,J＝8.1Hz,2H),7.25(t,J＝7.5Hz,2H),7.18(t,J＝7.3Hz,1H),7.11(d,J＝7.4Hz,2H),7.06(d,J＝8.1Hz,2H),5.24(s,2H),4.00(s,2H),3.79(s,3H),2.71(t,J＝7.3Hz,2H),2.61(t,J＝7.2Hz,2H).
实施例11：4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,397.7[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.14(s,1H),9.02(s,1H),7.98(s,1H),7.69(t,J＝8.5Hz,4H),7.43(t,J＝7.7Hz,2H),7.33(t,J＝7.4Hz,1H),7.28(d,J＝8.3Hz,2H),5.52(s,2H),3.80(s,3H),2.99(t,J＝7.6Hz,2H),2.80(t,J＝7.6Hz,2H).
实施例12：4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,397.7[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.15(s,1H),9.00(s,1H),7.84(s,1H),7.64(d,J＝8.3Hz,2H),7.49(t,J＝7.3Hz,2H),7.44(t,J＝7.9Hz,1H),7.39-7.36(m,2H),7.04(d,J＝8.3Hz,2H),5.31(s,2H),3.81(s,3H),2.75(t,J＝6.6Hz,2H),2.70(t,J＝6.8Hz,2H).
实施例13：4-[(3-苄基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,455.8[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.15(s,1H),9.03(s,1H),7.90(s,1H),7.68(d,J＝8.0Hz,2H),7.27(t,J＝7.5Hz,2H),7.21(d,J＝7.6Hz,4H),7.17(t,J＝7.2Hz,1H),5.41(s,2H),4.16(t,J＝5.1Hz,2H),3.89(s,2H),3.63(t,J＝5.2Hz,2H),3.18(s,3H),2.69(t,J＝7.5Hz,2H),2.55(t,J＝7.6Hz,2H).
实施例14：4-[(3-苄基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,455.8[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.15(s,1H),9.00(s,1H),7.76(s,1H),7.62(d,J＝7.8Hz,2H),7.25(t,J＝7.3Hz,2H),7.18(t,J＝7.2Hz,1H),7.11(d,J＝7.5Hz,2H),7.05(d,J＝7.9Hz,2H),5.23(s,2H),4.20(t,J＝5.2Hz,2H),4.00(s,2H),3.66(t,J＝5.2Hz,2H),3.23(s,3H),2.73(t,J＝7.3Hz,2H),2.62(t,J＝7.3Hz,2H).
实施例15：4-[(3-苯基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,441.9[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.14(s,1H),9.01(s,1H),7.99(s,1H),7.69(t,J＝7.5Hz,4H),7.44(t,J＝7.5Hz,2H),7.33(t,J＝7.3Hz,1H),7.28(d,J＝7.9Hz,2H),5.53(s,2H),4.20(t,J＝5.1Hz,2H),3.67(t,J＝5.1Hz,2H),3.21(s,3H),2.99(t,J＝7.5Hz,2H),2.81(t,J＝7.6Hz,2H).
实施例16：4-[(3-苯基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,441.8[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.15(s,1H),8.99(s,1H),7.85(s,1H),7.64(d,J＝7.8Hz,2H),7.49(t,J＝7.4Hz,2H),7.44(t,J＝7.0Hz,1H),7.38(d,J＝7.9Hz,2H),7.04(d,J＝7.9Hz,2H),5.32(s,2H),4.23(t,J＝5.1Hz,2H),3.68(t,J＝5.1Hz,2H),3.25(s,3H),2.77(t,J＝7.2Hz,2H),2.72(t,J＝7.0Hz,2H).
实施例17：4-[(3-苄基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,456.0[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.14(s,1H),9.00(s,1H),7.67(d,J＝8.0Hz,2H),7.60(s,1H),7.28(t,J＝7.5Hz,2H),7.23(t,J＝6.4Hz,4H),7.18(t,J＝6.5Hz,1H),5.47(s,2H),4.18(t,J＝5.0Hz,2H),3.89(s,2H),3.60(t,J＝5.0Hz,2H),3.16(s,3H),2.82(t,J＝8.0Hz,2H),2.57(t,J＝7.9Hz,2H).
实施例18：4-[(3-苄基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,455.9[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.18(s,1H),9.00(s,1H),7.63(d,J＝8.2Hz,2H),7.54(s,1H),7.25(t,J＝7.5Hz,2H),7.18(t,J＝7.3Hz,1H),7.12(d,J＝7.3Hz,2H),7.06(d,J＝8.2Hz,2H),5.23(s,2H),4.22(t,J＝5.3Hz,2H),4.00(s,2H),3.64(t,J＝5.3Hz,2H),3.20(s,3H),2.86(t,J＝7.6Hz,2H),2.65(t,J＝7.6Hz,2H).
实施例19：4-[(3-苯基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,442.0[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.14(s,1H),9.01(s,1H),7.69(m,5H),7.44(t,J＝7.5Hz,2H),7.33(t,J＝7.3Hz,1H),7.30(d,J＝7.9Hz,2H),5.58(s,2H),4.24(t,J＝5.0Hz,2H),3.64(t,J＝5.1Hz,2H),3.19(s,3H),3.03(t,J＝7.7Hz,2H),2.95(t,J＝7.8Hz,2H).
实施例20：4-[(3-苯基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,441.8[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.15(s,1H),8.99(s,1H),7.67-7.60(m,3H),7.49(t,J＝7.4Hz,2H),7.44(t,J＝7.1Hz,1H),7.38(d,J＝7.5Hz,2H),7.04(d,J＝8.0Hz,2H),5.31(s,2H),4.24(t,J＝5.0Hz,2H),3.65(t,J＝5.0Hz,2H),3.20(s,3H),2.91(t,J＝7.5Hz,2H),2.76(t,J＝7.6Hz,2H).
实施例21：(E)-3-{4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺的制备
ESI-MS:m/z,452.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:10.76(s,1H),9.03(s,1H),7.94(s,1H),7.50(d,J＝8.1Hz,3H),7.42(d,J＝15.8Hz,1H),7.27(t,J＝7.5Hz,3H),7.17(m,3H),6.42(d,J＝15.8Hz,1H),5.39(s,2H),4.05(q,J＝7.3Hz,2H),3.88(s,2H),2.69(t,J＝7.6Hz,2H),2.54(t,J＝7.6Hz,2H),1.33(t,J＝7.2Hz,3H).
实施例22：(E)-3-{4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺的制备
ESI-MS:m/z,452.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:10.75(s,1H),9.02(s,1H),7.81(s,1H),7.44(d,J＝8.0Hz,2H),7.40(d,J＝15.8Hz,1H),7.24(t,J＝7.5Hz,2H),7.18(d,J＝7.2Hz,1H),7.11(d,J＝7.3Hz,2H),7.03(d,J＝8.0Hz,2H),6.40(d,J＝15.8Hz,1H),5.21(s,2H),4.08(q,J＝7.2Hz,2H),4.00(s,2H),2.72(t,J＝7.3Hz,2H),2.61(t,J＝7.3Hz,2H),1.36(t,J＝7.2Hz,3H).
实施例23：(E)-3-{4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺的制备
ESI-MS:m/z,438.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:10.74(s,1H),9.02(s,1H),8.03(s,1H),7.68(d,J＝7.2Hz,2H),7.52(d,J＝8.1Hz,2H),7.42(m,3H),7.32(m,1H),7.27(d,J＝8.1Hz,2H),6.42(d,J＝15.8Hz,1H),5.50(s,2H),4.09(q,J＝7.2Hz,2H),2.99(t,J＝7.6Hz,2H),2.81(t,J＝7.6Hz,2H),1.37(t,J＝7.3Hz,3H).
实施例24：(E)-3-{4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺的制备
ESI-MS:m/z,438.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:10.75(s,1H),9.02(s,1H),7.89(s,1H),7.46(m,5H),7.39(t,3H),7.01(d,J＝8.1Hz,2H),6.40(d,J＝15.8Hz,1H),5.29(s,2H),4.10(q,J＝7.2Hz,2H),2.76(t,J＝6.7Hz,2H),2.71(t,J＝6.8Hz,2H),1.38(t,J＝7.2Hz,3H).
实施例25：(E)-3-{4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺的制备
ESI-MS:m/z,438.4[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:10.78(s,1H),9.02(s,1H),7.90(s,1H),7.50(d,J＝7.8Hz,2H),7.40(d,J＝16.0Hz,1H),7.27(t,J＝5.7Hz,2H),7.22(t,J＝6.1Hz,2H),7.20-7.16(m,3H),6.43(d,J＝15.6Hz,1H),5.38(s,2H),3.87(s,2H),3.76(s,3H),2.68(t,J＝7.5Hz,2H),2.56(t,J＝7.3Hz,2H).
实施例26：(E)-3-{4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺的制备
ESI-MS:m/z,438.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:10.74(s,1H),9.02(s,1H),7.75(s,1H),7.43(d,J＝7.8Hz,2H),7.39(d,J＝15.7Hz,1H),7.24(t,J＝5.6Hz,2H),7.18(t,J＝7.2Hz,1H),7.11(d,J＝7.5Hz,2H),7.03(d,J＝7.8Hz,2H),6.40(d,J＝15.8Hz,1H),5.21(s,2H),4.00(s,2H),3.79(s,3H),2.71(t,J＝5.3Hz,2H),2.60(t,J＝5.3Hz,2H).
实施例27：(E)-3-{4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺的制备
ESI-MS:m/z,423.7[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:10.76(s,1H),9.12(s,1H),7.98(s,1H),7.68(d,J＝7.4Hz,2H),7.52(d,J＝7.9Hz,2H),7.43(t,J＝7.6Hz,2H),7.38(d,J＝15.8Hz,1H),7.33(t,J＝7.3Hz,1H),7.25(d,J＝7.9Hz,2H),6.41(d,J＝15.8Hz,1H),5.49(s,2H),3.80(s,3H),2.98(t,J＝7.6Hz,2H),2.80(t,J＝7.6Hz,2H).
实施例28：(E)-3-{4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺的制备
ESI-MS:m/z,423.7[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:10.78(s,1H),9.02(s,1H),7.84(s,1H),7.51-7.42(m,6H),7.38(d,J＝7.0Hz,2H),7.01(d,J＝7.9Hz,2H),6.42(d,J＝15.8Hz,1H),5.28(s,2H),3.81(s,3H),2.75(t,J＝6.5Hz,2H),2.70(t,J＝6.7Hz,2H).
实施例29：4-[(7-乙基-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,350.2[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.14(s,1H),9.00(s,1H),7.94(s,1H),7.67(d,J＝8.1Hz,2H),7.20(d,J＝8.1Hz,2H),5.36(s,2H),4.05(q,J＝7.1Hz,2H),2.74(t,J＝7.6Hz,2H),2.65(t,J＝7.4Hz,2H),2.10(s,3H),1.34(t,J＝7.2Hz,3H).
实施例30：4-[(7-乙基-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,350.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.16(s,1H),9.01(s,1H),7.79(s,1H),7.69(d,J＝8.3Hz,2H),7.17(d,J＝8.3Hz,2H),5.28(s,2H),4.07(q,J＝7.2Hz,2H),2.73(t,J＝7.2Hz,2H),2.64(t,J＝7.3Hz,2H),2.14(s,3H),1.36(t,J＝7.3Hz,3H).
实施例31：4-[(7-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,380.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.07(s,1H),9.03(s,1H),7.90(s,1H),7.67(d,J＝8.1Hz,2H),7.20(d,J＝7.9Hz,2H),5.36(s,2H),4.17(t,J＝5.2Hz,2H),3.65(t,J＝5.2Hz,2H),3.20(s,3H),2.74(t,J＝7.5Hz,2H),2.66(t,J＝7.4Hz,2H),2.10(s,3H).
实施例32：4-[(7-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,380.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.16(s,1H),9.00(s,1H),7.75(s,1H),7.69(d,J＝8.0Hz,2H),7.17(d,J＝8.0Hz,2H),5.29(s,2H),4.20(t,J＝5.2Hz,2H),3.67(t,J＝5.2Hz,2H),3.24(s,3H),2.73(t,J＝7.2Hz,2H),2.65(t,J＝7.2Hz,2H),2.14(s,3H).
实施例33：4-[(6-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,379.6[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.14(s,1H),8.98(s,1H),7.90(s,1H),7.68-7.65(m,2H),7.21(t,J＝8.1Hz,2H),5.36(s,2H),4.17(t,J＝5.3Hz,2H),3.65(t,J＝5.3Hz,2H),3.19(s,3H),2.74(t,J＝7.5Hz,2H),2.66(t,J＝7.5Hz,2H),2.10(s,3H).
实施例34：4-[(6-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,379.6[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.15(s,1H),9.00(s,1H),7.69(d,J＝8.0Hz,2H),7.53(s,1H),7.17(d,J＝8.0Hz,2H),5.28(s,2H),4.22(t,J＝5.3Hz,2H),3.64(t,J＝5.3Hz,2H),3.20(s,3H),2.86(t,J＝7.6Hz,2H),2.68(t,J＝7.6Hz,2H),2.14(s,3H).
实施例35.本发明产物的药理作用研究
实验设阳性对照组(伏立诺他和ACY-1215)。以HeLa细胞核提取物(Enzo LifeSciences,USA)为HDACs酶源，重组rHDAC1、2、3及rHDAC6蛋白(BPS Bioscience,USA)为亚型酶源。所有反应均在96孔板中进行。反应缓冲液包含25mM Tris-HCl(pH 8.0)，137mMNaCl，2.7mM KCl，1mM MgCl2及0.1mg/mL BSA。梯度浓度的化合物溶液(5μL)及酶(5μL)于25℃预孵育15min，随后加入荧光底物Boc–Lys(Ac)–AMC(5μL)起始反应，于37℃孵育60min。最后向体系中加入含Trypsin及SAHA的终止缓冲液(25μL)，再孵育10min。以激发波长355nm，发射波长460nm，测量荧光强度(Thermo Scientific Varioskan Flash Station)。以GraphPad计算IC50。目标化合物对HDAC的抑制活性见表1。
表1目标化合物对HDAC酶的抑制活性
抗肿瘤细胞增殖的体外抑制活性实验
采用MTT法，对所得的目标化合物进行了乳腺癌细胞MCF-7的抗肿瘤活性的测试。MCF-7培养于H-DMEM培养基，且培养基中添加10％FBS，添加双抗(100units/mL青霉素G及100ng/mL链霉素)，细胞培养于恒温培养箱(5％CO2,37℃,Thermo/Forma Scientific)。
将2.8×104个乳腺癌细胞MCF-7接种于96孔板中，贴壁、伸展24h后，加入各浓度受试药。培养96h后，每孔加入50μL MTT溶液(2mg/mL)，继续孵育3.5小时，甩板去除培养液，加入DMSO将产生的结晶溶解，于570nm下测其吸光度。通过加药组与空白对照组的吸光度比值(％)求得受试药所致的细胞生长抑制率。
以伏立诺他为阳性对照药，进行目标化合物的抗肿瘤细胞增殖的体外抑制活性实验。实验结果见表2。
表2目标化合物对乳腺癌细胞MCF-7的抗肿瘤活性
上述实验结果表明，本发明要保护的通式的化合物具有良好的抗肿瘤活性和HDAC6抑制作用。本发明的化合物具有很好的工业应用前景。
Claims (10)
1.如式I或II所示的具有HDAC6抑制活性的异羟肟酸类化合物及其药学上可接受的盐或水合物：
其中，
A环选自一个或多个取代或未取代的5-6元芳环或杂芳环，所述杂芳环含有1-3个N、O或S的杂原子；所述的取代基为H、卤素、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烷氧基(C1-C4)烷基、(C6-C10)芳基、(C1-C4)烷基取代的苯基、(C1-C4)烷氧基取代的苯基或苄基；
X选自一个或多个如下取代基：羰基、(C3-C5)α，β-不饱和羰基；
R选自一个或多个如下取代基：H、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、(C6-C10)芳基、(C1-C4)烷基取代的苯基、(C1-C4)烷氧基取代的苯基或苄基。
2.权利要求1所述的式I或II所示的具有HDAC6抑制活性的异羟肟酸类化合物及其药学上可接受的盐或水合物：
其中，
A环选自一个或多个如下环系：
R1选自一个或多个如下取代基：H、卤素、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烷氧基(C1-C4)烷基；
R2选自一个或多个如下取代基：H、(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、(C6-C10)芳基、(C1-C4)烷基取代的苯基、(C1-C4)烷氧基取代的苯基或苄基；
R3选自一个或多个如下取代基：H、(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、(C6-C10) 芳基、(C1-C4)烷基取代苯基、(C1-C4)烷氧基取代苯基或苄基。
3.权利要求1或2所述的式Ⅰ或II所示的具有HDAC6抑制活性的异羟肟酸类化合物及其药学上可接受的盐或水合物：
其中，
A环为
R1为H或甲氧基；
R2、R3为甲基或乙基或甲氧乙基；
R为甲基或苯基或苄基。
4.权利要求1-3任何一项所述的式Ⅰ或II所示的具有HDAC6抑制活性的异羟肟酸类化合物及其药学上可接受的盐或水合物：
其中，X为-CO-或-CH＝CH-CO-。
5.根据权利要求1-4任何一项所述的化合物及其药学上可接受的盐或水合物：选自，
4-[(7-甲氧基-3-苯基-4,5-二氢-1H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-甲氧基-4,5-二氢-2H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-4,5-二氢-2H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-4,5-二氢-2H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
(E)-3-{4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
4-[(7-乙基-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(7-乙基-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(7-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(7-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(6-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(6-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺。
6.一种药物组合物，包含权利要求1-5中任何一项的化合物、及其药学上可接受的盐或水合物以及药学上可接受的赋形剂。
7.如权利要求1所述的化合物、及其药学上可接受的盐或水合物的制备方法，其特征在于，
式I化合物通过如下流程制备：
或式Ⅰ或II的化合物通过如下流程制备：
8.权利要求1-5中任何一项的化合物、及其药学上可接受的盐或水合物或权利要求6所述的药物组合物在制备治疗与组蛋白去乙酰化酶活性异常表达相关的疾病药物中的应用。
9.权利要求1-5中任何一项的化合物、及其药学上可接受的盐或水合物或权利要求6所述的药物组合物在制备抗肿瘤药物中的应用。
10.权利要求1-5中任何一项的化合物、及其药学上可接受的盐或水合物或权利要求6所述的药物组合物在制备治疗和/或预防前列腺癌、乳腺癌、宫颈癌或白血病药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811402954.XA CN109574936B (zh) | 2018-11-23 | 2018-11-23 | 一种具有hdac6抑制活性的异羟肟酸类化合物及其应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811402954.XA CN109574936B (zh) | 2018-11-23 | 2018-11-23 | 一种具有hdac6抑制活性的异羟肟酸类化合物及其应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109574936A true CN109574936A (zh) | 2019-04-05 |
| CN109574936B CN109574936B (zh) | 2022-02-22 |
Family
ID=65924070
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811402954.XA Active CN109574936B (zh) | 2018-11-23 | 2018-11-23 | 一种具有hdac6抑制活性的异羟肟酸类化合物及其应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109574936B (zh) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113773258A (zh) * | 2020-06-09 | 2021-12-10 | 兰州大学 | 人源lrrk2蛋白小分子抑制剂及其应用 |
| CN113896725A (zh) * | 2021-09-22 | 2022-01-07 | 沈阳药科大学 | 一种吡唑并喹啉类化合物及其制备方法和应用 |
| CN114621194A (zh) * | 2022-03-09 | 2022-06-14 | 沈阳药科大学 | 一种4-亚甲基-n-羟基苯甲酰胺类化合物及其应用 |
| CN114763356A (zh) * | 2021-01-11 | 2022-07-19 | 沈阳药科大学 | 吡咯并苯并二氮杂䓬类化合物及其制备方法和应用 |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1450991A (zh) * | 2000-09-01 | 2003-10-22 | 诺瓦提斯公司 | 脱乙酰酶抑制剂 |
| US20050176796A1 (en) * | 2002-02-19 | 2005-08-11 | D'alessio Roberto | Tricyclic pyrazole derivatives, process for their preparation and their use as antitumor agents |
| CN1764648A (zh) * | 2003-01-13 | 2006-04-26 | 安斯泰来制药有限公司 | 作为组蛋白脱乙酰酶(hdac)抑制剂的异羟肟酸衍生物 |
| CN101918389A (zh) * | 2007-11-02 | 2010-12-15 | 梅特希尔基因公司 | 组蛋白脱乙酰酶抑制剂 |
| CN103906732A (zh) * | 2011-10-28 | 2014-07-02 | 株式会社钟根堂 | 用作hdac抑制剂的异羟肟酸酯衍生物以及包含所述衍生物的药物组合物 |
| WO2018200608A1 (en) * | 2017-04-26 | 2018-11-01 | The Board Of Trustees Of The University Of Illinois | Nrf and hif activators/hdac inhibitors and therapeutic methods using the same |
-
2018
- 2018-11-23 CN CN201811402954.XA patent/CN109574936B/zh active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1450991A (zh) * | 2000-09-01 | 2003-10-22 | 诺瓦提斯公司 | 脱乙酰酶抑制剂 |
| US20050176796A1 (en) * | 2002-02-19 | 2005-08-11 | D'alessio Roberto | Tricyclic pyrazole derivatives, process for their preparation and their use as antitumor agents |
| CN1764648A (zh) * | 2003-01-13 | 2006-04-26 | 安斯泰来制药有限公司 | 作为组蛋白脱乙酰酶(hdac)抑制剂的异羟肟酸衍生物 |
| CN101918389A (zh) * | 2007-11-02 | 2010-12-15 | 梅特希尔基因公司 | 组蛋白脱乙酰酶抑制剂 |
| CN103906732A (zh) * | 2011-10-28 | 2014-07-02 | 株式会社钟根堂 | 用作hdac抑制剂的异羟肟酸酯衍生物以及包含所述衍生物的药物组合物 |
| WO2018200608A1 (en) * | 2017-04-26 | 2018-11-01 | The Board Of Trustees Of The University Of Illinois | Nrf and hif activators/hdac inhibitors and therapeutic methods using the same |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113773258A (zh) * | 2020-06-09 | 2021-12-10 | 兰州大学 | 人源lrrk2蛋白小分子抑制剂及其应用 |
| CN113773258B (zh) * | 2020-06-09 | 2023-08-25 | 兰州大学 | 人源lrrk2蛋白小分子抑制剂及其应用 |
| CN114763356A (zh) * | 2021-01-11 | 2022-07-19 | 沈阳药科大学 | 吡咯并苯并二氮杂䓬类化合物及其制备方法和应用 |
| CN113896725A (zh) * | 2021-09-22 | 2022-01-07 | 沈阳药科大学 | 一种吡唑并喹啉类化合物及其制备方法和应用 |
| CN114621194A (zh) * | 2022-03-09 | 2022-06-14 | 沈阳药科大学 | 一种4-亚甲基-n-羟基苯甲酰胺类化合物及其应用 |
| CN114621194B (zh) * | 2022-03-09 | 2023-08-29 | 沈阳药科大学 | 一种4-亚甲基-n-羟基苯甲酰胺类化合物及其应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109574936B (zh) | 2022-02-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109574936B (zh) | 一种具有hdac6抑制活性的异羟肟酸类化合物及其应用 | |
| US10729678B2 (en) | Preparation of and formulation comprising a MEK inhibitor | |
| US20200181115A1 (en) | Method for preparing 2-hydroxyl-4-(2, 3-disubstituted benzyloxy)-5-substituted benzaldehyde derivative | |
| WO2019042444A1 (zh) | 一类抑制并降解酪氨酸蛋白激酶alk的化合物 | |
| WO2018157842A1 (zh) | 2-(取代苯氨基)苯甲酸类fto抑制剂治疗白血病的用途 | |
| CN107445896B (zh) | 一种具有抗肿瘤活性的苯基异羟肟酸类化合物及其应用 | |
| JP2016500080A (ja) | ビスβ−カルボリン系化合物、その製造方法、医薬組成物および用途 | |
| WO2020221006A1 (zh) | 一种bet蛋白抑制剂、其制备方法及用途 | |
| CN111777501A (zh) | 咖啡酸苯乙酯类衍生物，其制法和其药物组合物与用途 | |
| CN113880772A (zh) | 一类cdk激酶抑制剂及其应用 | |
| CN111943906B (zh) | 脒类衍生物、及其制法和药物组合物与用途 | |
| CN109096272B (zh) | 一种具有抗肿瘤活性的吲哚异羟肟酸类化合物及其应用 | |
| TWI832361B (zh) | 具有高口服生物利用度的ｊａｋ抑制劑 | |
| CN109384793B (zh) | 一种具有hdac6抑制活性的硫醇类化合物及其应用 | |
| CN107311933B (zh) | 一类苯并咪唑衍生物，及其制备方法和用途 | |
| CN113493414B (zh) | 一种氘代取代丁烯酰胺及其制备方法与应用 | |
| CN105102447B (zh) | 双环取代的嘧啶类pde‑5抑制剂的前药 | |
| JP2018087173A (ja) | 悪性脳腫瘍治療薬 | |
| KR101965348B1 (ko) | N'-히드록시인다졸카르복시이미다미드 유도체 화합물, 이의 광학이성질체, 또는 이의 약학적으로 허용가능한 염, 및, 이를 유효성분으로 포함하는 항암용 조성물 | |
| KR20210151849A (ko) | 퀴놀린 유도체 및 암의 치료를 위한 그의 용도 | |
| CN107556315B (zh) | 含四元环的咪唑衍生物 | |
| CN111548286B (zh) | 一种具有hdac3抑制活性的psa衍生物及其应用 | |
| WO2017097215A1 (zh) | 内嵌脲类结构的wnt通路抑制剂 | |
| WO2020114455A1 (zh) | 含有哌嗪酮的喹唑啉二酮盐类化合物、其制备方法、药物组合物和用途 | |
| CN101602750A (zh) | (取代)萘基、(取代)芳基、哌嗪基脒类化合物 |
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 |