CN111909107A - Ido/hdac双重抑制剂及其药物组合物和应用 - Google Patents
Ido/hdac双重抑制剂及其药物组合物和应用 Download PDFInfo
- Publication number
- CN111909107A CN111909107A CN201910387782.1A CN201910387782A CN111909107A CN 111909107 A CN111909107 A CN 111909107A CN 201910387782 A CN201910387782 A CN 201910387782A CN 111909107 A CN111909107 A CN 111909107A
- Authority
- CN
- China
- Prior art keywords
- cancer
- compound
- heterocyclic
- pharmaceutically acceptable
- hydroxime
- 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
- 102000003964 Histone deacetylase Human genes 0.000 title claims abstract description 20
- 108090000353 Histone deacetylase Proteins 0.000 title claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 9
- 229940125436 dual inhibitor Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 45
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 16
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- 229940002612 prodrug Drugs 0.000 claims abstract description 9
- 239000000651 prodrug Substances 0.000 claims abstract description 9
- 239000012453 solvate Substances 0.000 claims abstract description 9
- 201000011510 cancer Diseases 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 102000016680 Dioxygenases Human genes 0.000 claims abstract description 5
- 108010028143 Dioxygenases Proteins 0.000 claims abstract description 5
- 208000030507 AIDS Diseases 0.000 claims abstract description 4
- 230000002159 abnormal effect Effects 0.000 claims abstract description 4
- 230000033228 biological regulation Effects 0.000 claims abstract description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 4
- 201000004792 malaria Diseases 0.000 claims abstract description 4
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 4
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 3
- 201000010881 cervical cancer Diseases 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 2
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 210000002919 epithelial cell Anatomy 0.000 claims description 2
- 230000003463 hyperproliferative effect Effects 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 201000005249 lung adenocarcinoma Diseases 0.000 claims description 2
- 201000005243 lung squamous cell carcinoma Diseases 0.000 claims description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 2
- 230000002062 proliferating effect Effects 0.000 claims description 2
- 201000000849 skin cancer Diseases 0.000 claims description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 2
- 230000007704 transition Effects 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 13
- 102000006639 indoleamine 2,3-dioxygenase Human genes 0.000 abstract description 11
- 108020004201 indoleamine 2,3-dioxygenase Proteins 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 10
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- 238000002474 experimental method Methods 0.000 abstract description 4
- 206010039966 Senile dementia Diseases 0.000 abstract description 2
- 239000004480 active ingredient Substances 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 40
- 210000004027 cell Anatomy 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- -1 amine compounds Chemical class 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 238000010189 synthetic method Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- NIQCNGHVCWTJSM-UHFFFAOYSA-N Dimethyl phthalate Chemical compound COC(=O)C1=CC=CC=C1C(=O)OC NIQCNGHVCWTJSM-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 101001037256 Homo sapiens Indoleamine 2,3-dioxygenase 1 Proteins 0.000 description 4
- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- 239000006285 cell suspension Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000009977 dual effect Effects 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- YPBKTZBXSBLTDK-PKNBQFBNSA-N (3e)-3-[(3-bromo-4-fluoroanilino)-nitrosomethylidene]-4-[2-(sulfamoylamino)ethylamino]-1,2,5-oxadiazole Chemical compound NS(=O)(=O)NCCNC1=NON\C1=C(N=O)/NC1=CC=C(F)C(Br)=C1 YPBKTZBXSBLTDK-PKNBQFBNSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 108091005772 HDAC11 Proteins 0.000 description 2
- 102100039385 Histone deacetylase 11 Human genes 0.000 description 2
- 102100038720 Histone deacetylase 9 Human genes 0.000 description 2
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 2
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 2
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion 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-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 150000007514 bases Chemical class 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000006196 deacetylation Effects 0.000 description 2
- 238000003381 deacetylation reaction Methods 0.000 description 2
- FBSAITBEAPNWJG-UHFFFAOYSA-N dimethyl phthalate Natural products CC(=O)OC1=CC=CC=C1OC(C)=O FBSAITBEAPNWJG-UHFFFAOYSA-N 0.000 description 2
- 229960001826 dimethylphthalate Drugs 0.000 description 2
- 229950006370 epacadostat Drugs 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 230000009036 growth inhibition Effects 0.000 description 2
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- HCZHHEIFKROPDY-UHFFFAOYSA-N kynurenic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC(=O)C2=C1 HCZHHEIFKROPDY-UHFFFAOYSA-N 0.000 description 2
- YGPSJZOEDVAXAB-UHFFFAOYSA-N kynurenine Chemical compound OC(=O)C(N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000031700 light absorption Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000037353 metabolic pathway Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229950006238 nadide Drugs 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 210000004940 nucleus Anatomy 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 239000011535 reaction buffer Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- QLWOUBCORTYSPP-UHFFFAOYSA-N 1h-imidazol-1-ium;hydroxide Chemical compound O.C1=CNC=N1 QLWOUBCORTYSPP-UHFFFAOYSA-N 0.000 description 1
- YQNRVGJCPCNMKT-LFVJCYFKSA-N 2-[(e)-[[2-(4-benzylpiperazin-1-ium-1-yl)acetyl]hydrazinylidene]methyl]-6-prop-2-enylphenolate Chemical compound [O-]C1=C(CC=C)C=CC=C1\C=N\NC(=O)C[NH+]1CCN(CC=2C=CC=CC=2)CC1 YQNRVGJCPCNMKT-LFVJCYFKSA-N 0.000 description 1
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 1
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 101100462537 Caenorhabditis elegans pac-1 gene Proteins 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 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
- 102100022537 Histone deacetylase 6 Human genes 0.000 description 1
- 102100038715 Histone deacetylase 8 Human genes 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 241000282412 Homo Species 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
- 101000899330 Homo sapiens Histone deacetylase 6 Proteins 0.000 description 1
- 101001032113 Homo sapiens Histone deacetylase 7 Proteins 0.000 description 1
- 101001032118 Homo sapiens Histone deacetylase 8 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
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 101100117764 Mus musculus Dusp2 gene Proteins 0.000 description 1
- 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 description 1
- BYHJHXPTQMMKCA-QMMMGPOBSA-N N-formyl-L-kynurenine Chemical compound [O-]C(=O)[C@@H]([NH3+])CC(=O)C1=CC=CC=C1NC=O BYHJHXPTQMMKCA-QMMMGPOBSA-N 0.000 description 1
- 102100039388 Polyamine deacetylase HDAC10 Human genes 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- JJJCVLKKMCTDCH-UHFFFAOYSA-N acetic acid 2-(dimethylamino)benzaldehyde Chemical compound C(C)(=O)O.CN(C)C1=C(C=O)C=CC=C1 JJJCVLKKMCTDCH-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- QPQDOIAJMPGRCZ-UHFFFAOYSA-N anisole;isocyanic acid Chemical compound N=C=O.COC1=CC=CC=C1 QPQDOIAJMPGRCZ-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000004900 autophagic degradation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 230000010428 chromatin condensation Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000008406 drug-drug interaction Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 230000001973 epigenetic effect Effects 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 150000002669 lysines Chemical group 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- GJAWHXHKYYXBSV-UHFFFAOYSA-N quinolinic acid Chemical compound OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000002730 succinyl group Chemical group C(CCC(=O)*)(=O)* 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000037426 transcriptional repression Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- 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
- 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
- C07D413/12—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 linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Tropical Medicine & Parasitology (AREA)
- Biomedical Technology (AREA)
- Diabetes (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Virology (AREA)
- AIDS & HIV (AREA)
- Communicable Diseases (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Molecular Biology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了特定结构的杂环羟肟类化合物及其药学上可接受的盐、异构体、前体药物或溶剂合物，以及含有上述杂环羟肟类化合物作为有效成分的药物组合物，并进一步通过实验验证上述化合物和药物组合物具有对吲哚胺‑2,3‑双加氧酶和组蛋白去乙酰化酶的双重抑制作用，可应用于制备治疗2,3‑吲哚胺双加氧酶和组蛋白去乙酰化酶调节异常有关的疾病的药物，所述疾病包括癌症、神经变性疾病、艾滋病、老年痴呆、疟疾和糖尿病等，具有广阔的应用前景。
Description
技术领域
本发明属于化学医药领域，具体涉及特定结构的杂环羟肟类化合物及其药学上可接受的盐、异构体、前体药物或溶剂合物，以及含有这种化合物的药物组合物，以及它们在制备药物中的应用。
背景技术
吲哚胺-2,3-双加氧酶(Indoleamine-2,3-dioxygenase，简称IDO)是一种肝外含有亚铁血红素的单体酶，其催化色氨酸犬尿氨酸代谢途径的限速步骤，使得色氨酸发生氧化反应转化成N-甲酰犬尿氨酸，后者水解生成犬尿酸，进而进入犬尿酸代谢途径生成喹啉酸、犬尿喹啉酸等代谢产物。IDO表达过量，造成局部色氨酸耗竭，犬尿酸等代谢物增加，抑制了T细胞的增殖，活化调节性T细胞，进而造成免疫耐受的肿瘤微环境，使机体无法对肿瘤细胞进行识别和清除。另外，大量研究表明，IDO在多种肿瘤和抗原呈递细胞中高表达，与病人的预后性差和生存率低密切相关。因此，抑制IDO的活性可以有效地阻止肿瘤细胞周围色氨酸的降解，促进T细胞的增殖，从而增强机体对肿瘤细胞的攻击能力。但是，IDO抑制剂单独使用时只具有中等活性，而与化疗药物或其他免疫检查点抑制剂合用时，具有较好的疗效。然而，药物联合用药可能存在药代动力学性复杂，不能同时到达作用靶点以及药物-药物相互作用等问题。双靶点或多靶点药物能够降低耐药性的发生，增强药物活性、提高治疗指数。
组蛋白去乙酰化酶(HDACs)催化组蛋白氨基端赖氨酸的去乙酰化，引起染色质凝缩和转录抑制。目前，已知组蛋白去乙酰化酶有18个不同的亚型，按种系分为4大类：I类包括HDAC1、HDAC2、HDAC3和HDAC8，只存在于细胞核中；II类包括HDAC4、HDAC5、HDAC6、HDAC7、HDAC9、HDAC10和HDAC11，在信号转导过程中穿梭于细胞核与细胞质之间；Ⅳ类是HDAC11；III类是SIRT1-SIRT7与I、II和IV类有很大的区别，其活性不依赖Zn2+，而是依赖辅酶I(NAD)，它不能被I和II类HDAC抑制剂所抑制。HDAC抑制剂能够引起肿瘤细胞凋亡、分化和自噬，抑制肿瘤细胞增殖，抑制肿瘤细胞的粘附和转移，抑制血管生成。目前，已经有四个HDAC抑制剂上市，用于治疗各种血液肿瘤。值得一提的是，最近的研究表明HDAC抑制剂可以提高免疫系统对肿瘤的识别能力，并且能够逆转肿瘤免疫抑制。因此，IDO/HDAC双重抑制剂可以有效地结合肿瘤免疫检查点抑制剂和表观遗传药物的优点，提高抗肿瘤疗效。
发明内容
发明目的：针对现有药物疗效不确切、毒副作用较大的缺陷等问题，本发明提供了一种杂环羟肟类化合物的吲哚胺-2,3-双加氧酶和组蛋白去乙酰化酶双重抑制剂，本发明还提供了该种吲哚胺-2,3-双加氧酶/组蛋白去乙酰化酶双重抑制剂的制备方法，以及含有该抑制剂的药物组合物，以及它们的制药用途。
技术方案：本发明所述的一种杂环羟肟类化合物，选自如下式I～VII所示的化合物：
及其药物上可接受的盐、异构体、前体药物或溶剂合物。
所述杂环羟肟类化合物的制备方法，包括以下步骤：
(1)将式(A)所示的化合物与异氰酸酯，在有机溶剂中反应，得到式(B)所示的化合物，反应过程如下所示：
(2)将式(B)所示的化合物在碱的作用下脱保护反应，得到式(C)所示的化合物，反应过程如下所示：
进一步地，步骤(1)中，所述有机溶剂选自二氯甲烷、四氢呋喃(THF)、N,N-二甲基甲酰胺(DMF)、乙二醇二甲醚、1,2-二氯乙烷、邻苯二甲酸二甲酯(DMP)、甲醇、乙醇、石油醚、正己烷和乙醚中的一种或多种。
步骤(2)中，所述碱选自碳酸钾、碳酸钠、碳酸氢钠、碳酸镁、碳酸钙、碳酸铯、氢氧化钠、氢氧化钾、氢氧化锂、氢氧化铯、氢氧化镁、氢氧化咪唑、三乙胺、二异丙基乙胺、哌啶、二甲基吡啶、N-甲基吗啉、DABCO和吡啶中的一种或多种。
本发明还提供了一种药物组合物，其中含有有效量的上述杂环羟肟类化合物或其药物上可接受的盐、前体药物或溶剂合物，以及药学上可接受的载体。
本发明还提供了上述杂环羟肟类化合物及其药学上可接受的盐或其前药分子在制备治疗或预防肿瘤的药物中的应用。
所述肿瘤包括淋巴瘤、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胃癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、白血病和宫颈癌等过渡增殖性疾病。
本发明涉及的杂环羟肟类化合物及其药学上可接受的盐，可以有效抑制多种肿瘤细胞的生长，并对2,3-吲哚胺双加氧酶和组蛋白去乙酰化酶产生双重抑制作用，可用于制备相应的抗肿瘤药物。如本领域人员所理解的，本申请所涉及的化合物及其药学可接受的盐可用于制备治疗人类及其它哺乳动物的肿瘤等过度增殖性疾病。
本发明涉及的杂环羟肟类化合物及其药学上可接受的盐所制备的药物可以用于治疗2,3-吲哚胺双加氧酶和组蛋白去乙酰化酶调节异常有关的哺乳动物疾病包括癌症、神经变性疾病、艾滋病、老年痴呆、疟疾和糖尿病等。
本领域的普通技术人员应当知道下列术语或缩写的含义。
术语“药物上可接受的盐”是指在合理医学判断范围内适用于与哺乳动物特别是人的组织接触而无过度毒性、刺激、过敏反应等并与合理的效益/风险比相称的盐，比如胺、羧酸和其它类型化合物的医学上可接受的盐在所属领域中是被熟知的。
术语“溶剂合物”是指化合物与溶剂组成的混合物，例如结晶体即是一种溶剂合物。
术语“前体药物”指通过在血液中水解而活体内快速转化产生具有上述化学式的母体化合物的化合物。
有益效果：本发明提供了特定结构的杂环羟肟类化合物及其药学上可接受的盐、异构体、前体药物或溶剂合物，以及含有上述杂环羟肟类化合物作为有效成分的药物组合物，并进一步通过实验验证上述化合物和药物组合物具有对吲哚胺-2,3-双加氧酶和组蛋白去乙酰化酶的双重抑制作用，可应用于制备治疗2,3-吲哚胺双加氧酶和组蛋白去乙酰化酶调节异常有关的疾病的药物，所述疾病包括癌症、神经变性疾病、艾滋病、老年痴呆、疟疾和糖尿病等，具有广阔的应用前景。
具体实施方式
下面结合具体实施例对本申请作出详细说明。
本发明包括式(I)～(VII)的游离形式，也包括药学上可接受的盐及立体异构体。文中一些特定的示例性化合物为胺类化合物的质子化了的盐。术语“游离形式”指以非盐形式的胺类化合物。包括药学上可接受的盐不仅包括本文所述特定化合物的示例性盐，也包括所有式(I)～(VII)所示化合物游离形式的典型的药学上可接收的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如，通过适当的碱稀水溶液如氢氧化钠稀水溶液，碳酸钠稀水溶液，稀氨水溶液及碳酸氢钾稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质如在极性溶剂中的溶解度上与其各自盐形式多少有些区别，但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常,通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的，通过和适当的无机或有机碱反应形成化合物的盐。
因此，本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如,常规无毒盐包括来自无机酸例如盐酸、硫酸、氢溴酸、氨基磺酸、磷酸、硝酸等的盐，也包括来自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、乙酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、富马酸、2-乙酰氧基-苯甲酸、富马酸、对甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
实施例1
反应式如下；
步骤1. 1-(4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-取代)-1,2,5-噁二唑-3-取代)-3-(3-甲氧基苯基)脲
在0℃，在氩气保护下，将间甲氧基苯异氰酸酯(14.9mg，0.10mmol)的四氢呋喃溶液(1mL)慢慢滴加到原料(30mg，0.0877mmol)的四氢呋喃溶液(1mL)中，升温至室温反应16h，浓缩，加入水(1mL)，再加入乙酸乙酯(1mL)，分层，水相用乙酸乙酯(2*2mL)萃取，合并有机相，用饱和食盐水(2mL)洗，无水硫酸钠干燥，浓缩，柱层析得目标物(322mg，66％)。MS(EI,m/z):491(M++1).
步骤2.(Z)-(N-(3-溴-4-氟苯基)-N’-羟基-4-(3-(3-甲氧基苯基)脲基)-1,2,5-噁二唑-3-甲咪
将上述原料(20mg)溶于四氢呋喃(1mL)，加入NaOH水溶液(0.5mL,2M)反应2h，加入水(1mL)，乙酸乙酯(5mL)，分层，水相用乙酸乙酯(2*5mL)萃取，合并有机相，用饱和食盐水(2mL)洗，无水硫酸钠干燥，浓缩，柱层析得目标化合物I(18mg，95％)。1H NMR(400MHz,DMSO):δ11.53(s,1H),9.85(s,1H),9.55(s，1H),9.01(s,1H),7.33(s,1H),7.28-7.26(m,2H),7.16-7.05(m,1H),6.94(t,J＝8.2Hz,1H),6.77(d,J＝6.2Hz,1H),6.65-6.60(m,1H),3.65(s,3H)ppm.13C NMR(125MHz,DMSO):δ163.9,162.3,158.3,154.1,148.3,146.1,136.6,133.8,128.7,119.6,118.2,117.8,115.8,113.2,110.8,109.3,58.3ppm.MS(EI,m/z):465(M++1).
实施例2
(Z)-(N-(3-溴-4-氟苯基)-N’-羟基-4-(3-(2-甲氧基苯基)脲基)-1,2,5-噁二唑-3-甲咪
合成方法参照实施例1。
1H NMR(400MHz,DMSO):δ11.56(s,1H),9.70(s,1H),9.50(s,1H),8.95(s,1H),7.89(t,J＝8.5Hz,1H),7.12-7.06(m,1H),6.87(t,J＝8.3Hz,1H),6.87(d,J＝6.2Hz,1H),6.69-6.63(m,1H),3.78(s,3H)ppm.13C NMR(125MHz,DMSO):δ13C NMR(125MHz,DMSO):δ163.1,156.3,152.1,149.3,147.1,141.3,135.8,128.7,124.1,121.2,120.3,113.2,110.8,109.3,58.4ppm.MS(EI,m/z):465(M++1).
实施例3
(Z)-(N-(3-溴-4-氟苯基)-N’-羟基-4-(3-(4-羟基苯基)脲基)-1,2,5-噁二唑-3-甲咪
合成方法参照实施例1。
1H NMR(400MHz,DMSO):δ11.23(s,1H),9.88(s,1H),9.55(s，1H),9.43(s,1H),9.21(s,1H),7.38(d,J＝5.3Hz,2H),6.93(t,J＝8.2Hz,1H),6.87(d,J＝6.2Hz,1H),6.75(d,J＝5.3Hz,2H)ppm.13C NMR(125MHz,DMSO):δ162.9,,155.3,153.1,150.2,147.5,142.1,134.6,132.2,123.5,119.5,117.5,117.8,116.8,115.2,109.9ppm.MS(EI,m/z):451(M++1).
实施例4
(Z)-(N-(3-溴-4-氟苯基)-4-(3-(3,4-二甲氧基苯基)脲基)-N’-羟基-1,2,5-噁二唑-3-甲咪
合成方法参照实施例1。
1H NMR(400MHz,DMSO):δ11.38(s,1H),9.88(s,1H),9.65(s,1H),9.05(s,1H),7.23(s,1H),6.94-6.89(m,2H),6.83(d,J＝6.2Hz,1H),6.69-6.62(m,1H),3.88(s,3H),3.62(s,3H)ppm.13C NMR(125MHz,DMSO):δ13C NMR(125MHz,DMSO):δ163.1,155.3,152.1,150.1,147.3,146.1,142.0,134.3,129.8,119.7,118.2,116.5,114.2,111.9,110.8,107.2,58.4,56.9ppm.MS(EI,m/z):495(M++1).
实施例5
(Z)-(N-(3-溴-4-氟苯基)-N’-羟基-4-(3-(4-三氟甲氧基)苯基)脲基)-1,2,5-噁二唑-3-甲咪
合成方法参照实施例1。
1H NMR(400MHz,DMSO):δ11.23(s,1H),9.89(s,1H),9.54(s,1H),9.02(s,1H),7.22(m,2H),6.96-6.93(m,3H),6.83(t,J＝8.5Hz,1H),6.72(m,1H)ppm.13C NMR(125MHz,CDCl3):δ165.4,155.8,151.2,148.0,146.4,142.3,134.6,132.6,130.2,119.3,118.0,117.2,114.5,110.8ppm.MS(EI,m/z):518(M++1).
实施例6
(Z)-(N-(3-溴-4-氟苯基)-N’-羟基-4-(3-(3-三氟甲氧基)苯基)脲基)-1,2,5-噁二唑-3-甲咪
合成方法参照实施例1。
1H NMR(400MHz,DMSO):δ11.28(s,1H),9.89(s,1H),9.43(s,1H),9.12(s,1H),7.34(s,1H),7.23-7.20(m,2H),6.93(t,J＝8.5Hz,1H),6.83-6.79(m,2H),6.68-6.65(m,1H)ppm.13C NMR(125MHz,DMSO):δ163.2,160.8,155.3,151.9,147.4,142.3,136.6,134.8,129.2,119.8,118.0,117.2,113.5,110.8,110.2,109.3ppm.MS(EI,m/z):518(M++1).
实施例7
(Z)-(N-(3-溴-4-氟苯基)-N’-羟基-4-(3-(哌啶基-4-基)脲基)-1,2,5-噁二唑-3-甲咪
合成方法参照实施例1。
1H NMR(400MHz,DMSO):δ11.27(s,1H),9.88(s,1H),9.33(s,1H),9.09(s,1H),7.32(s,1H),7.23-7.20(m,2H),3.60(m,1H),2.80-2.77(m,2H),2.60-2.57(m,2H),1.87-1.83(m,2H),1.45-1.42(m,2H)ppm.13C NMR(125MHz,DMSO):δ163.1,156.3,154.9,147.3,142.3,134.6,120.8,118.8,117.2,110.7,49.5,48.5,32.9,31.2ppm.MS(EI,m/z):442(M++1).
实施例8
HDAC酶活性的测定
测定原理：化合物生化活的性测定是根据其抑制HDAC酶的去乙酰化作用程度来确定的。用荧光标记的含有乙酰化的赖氨酸侧链的底物和HDAC酶作用之后，该荧光底物被去乙酰化。去乙酰化后的荧光标记底物被酶裂解后，释放出荧光物质，该荧光物质在360nm光的激发下产生460nm的发射光。
具体步骤：HDAC的底物用反应缓冲液稀释至200M(反应浓度为20M)，将HDAC酶稀释至适当浓度，加入不同浓度的本发明制备的杂环脲类化合物，37℃反应30分钟，然后加入相同体积的2倍浓度底物发展液(developer)，室温孵育15分钟，最后用微孔板读板仪测定读数，激发光为360nm，发射光为460nm，数据用Prime 4软件处理。检测结果如表1所示。
实施例9
IDO1酶活性的测定
首先在微孔板孔内加入15μl磷酸氢钠的缓冲液(pH:7-8)，加入5μl含有适量IDO1酶的反应缓冲液和本发明制备的杂环脲类化合物，混匀，室温反应3小时后，用PE公司的Envision MultilabelReader多功能酶标仪进行检测320nm波长光吸收值，根据吸收比值计算杂环脲类化合物对酶反应的抑制率，用GraphPad软件进行分析计算出杂环脲类化合物的IC50值。检测结果如表1所示。
表1
上表中IC50是指被抑制一半时抑制剂的浓度(50％inhibitory concentration)。
从上表中结果可以看出：上述的化合物与SAHA相比，具有一定的HDAC酶抑制活性与INCB24360相比，具有较强的IDO1抑制活性。
实施例10
细胞水平IDO1酶活性的测定
37℃二氧化碳培养箱中，用添加抗生素的DMEM培养基培养及传代Hela细胞，接种到96孔板中过夜培养，然后每孔加入适当浓度的1μl杂环脲类化合物，再加入100μl的干扰素γ(终浓度为100ng/ml)。继续培养细胞72h后，取70μl细胞培养上清液加入96孔尖底板，每孔加入5μl三氯乙酸(6.1N)，50℃孵化30min后取出，25000rpm离心10min。将上述离心后的上清20μl/孔转移入384微孔板，然后每孔加入20μl的2％二甲氨基苯甲醛乙酸溶液，震荡混匀后，480nm下测光吸收,并测定数值。检测结果如表2所示。
表2
| sample | IC<sub>50</sub>(μM) |
| INCB24360 | 0.055 |
| I | 0.043 |
| II | 0.046 |
| III | 0.033 |
| IV | 0.039 |
| V | 0.021 |
| VI | 0.032 |
| VII | 0.018 |
实施例11
检测化合物对癌细胞活性实验
实验原理：化合物抑制癌细胞生长用MTT方法来检测。MTT法的原理是，黄色的噻唑兰可透过细胞膜进入细胞内，活细胞线粒体中的琥珀脱氢酶能使外源性MTT还原为难溶于水的蓝紫色的针状Formazan结晶并沉积在细胞中，结晶能被二甲基亚砜(DMSO)溶解，用酶联免疫检测仪在490nm/570nm波长处检测其光吸收值，可间接反映细胞数量。
实验材料：所使用的癌细胞系为Hela(人宫颈癌细胞)，MCF-7(人乳腺癌细胞)，BGC-823(人胃癌细胞)，A549(人肺癌细胞)，HT1080(人纤维肉瘤细胞)，A431(人表皮鳞状细胞癌细胞)，DU145(人前列腺癌细胞)，U937(人白血病细胞)，Pac-1(人胰腺癌细胞)，MOLT-4(人急性淋巴母细胞白血病细胞)；分别用DMEM+10％FBS培养基培养或者使用1640+10％FBS培养。
实验方法与结果分析：
实验组：190μl细胞悬液+10μl不同浓度的药物(终浓度为10-5～10-10M)
空白对照组：200μl PBS
阴性对照组：190μl细胞悬液+10μl 2％DMSO(DMSO终浓度为0.1％)
阳性对照组：190μl细胞悬液+10μl不同浓度的化合物
a)细胞接种于96孔板，接种量为1500个/孔，190μl/孔，37℃5％的CO2培养箱培养过夜；
b)次日每孔加入10μl不同药物，药物终浓度为10-5～10-10M，设三个平行孔；37℃、5％的CO2培养箱孵育72小时；
c)每孔加入20μl 5mg/ml的MTT，37℃5％的CO2培养箱孵育4小时；
d)弃上清，每孔加入100μl的DMSO，振荡；
e)570nm读数，计算细胞存活率，根据结果计算GI50，得下表3。
表3
上表中GI50表示的是细胞50％生长抑制所需的药物浓度(50％growthinhibition)。
从上表中结果可以看出：上述的药物与阳性对照(SAHA)相比，具有一定的细胞毒性。
Claims (5)
1.一种杂环羟肟类化合物，选自如下式I～VII所示的化合物：
及其药物上可接受的盐、异构体、前体药物或溶剂合物。
2.一种药物组合物，其特征在于，含有有效量的权利要求1所述的杂环羟肟类化合物或其药物上可接受的盐、前体药物或溶剂合物，以及药学上可接受的载体。
3.权利要求1所述杂环羟肟类化合物在制备治疗2,3-吲哚胺双加氧酶和组蛋白去乙酰化酶调节异常有关的疾病药物中的应用。
4.根据权利要求3所述应用，其特征在于，所述疾病包括过渡增殖性疾病、神经变性疾病、艾滋病、老年痴呆、疟疾和糖尿病等。
5.根据权利要求3所述应用，其特征在于，所述渡增殖性疾病包括淋巴瘤、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胃癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、白血病和宫颈癌等。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910387782.1A CN111909107B (zh) | 2019-05-10 | 2019-05-10 | Ido/hdac双重抑制剂及其药物组合物和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910387782.1A CN111909107B (zh) | 2019-05-10 | 2019-05-10 | Ido/hdac双重抑制剂及其药物组合物和应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111909107A true CN111909107A (zh) | 2020-11-10 |
| CN111909107B CN111909107B (zh) | 2023-02-03 |
Family
ID=73242190
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910387782.1A Active CN111909107B (zh) | 2019-05-10 | 2019-05-10 | Ido/hdac双重抑制剂及其药物组合物和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111909107B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113105366A (zh) * | 2021-03-04 | 2021-07-13 | 中国药科大学 | 一类含苯基羟肟结构衍生物及其制法与用途 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101212967A (zh) * | 2005-05-10 | 2008-07-02 | 因塞特公司 | 吲哚胺2,3-双加氧酶调节剂及其用法 |
| CN106866571A (zh) * | 2017-01-20 | 2017-06-20 | 中国药科大学 | 杂环脲类化合物及其药物组合物和应用 |
| CN108003111A (zh) * | 2017-12-14 | 2018-05-08 | 华东理工大学 | 一种hdac1和ido1双靶点抑制剂及其制备方法和应用 |
| WO2019057123A1 (zh) * | 2017-09-20 | 2019-03-28 | 杭州英创医药科技有限公司 | 作为ido抑制剂和/或ido-hdac双重抑制剂的多环化合物 |
-
2019
- 2019-05-10 CN CN201910387782.1A patent/CN111909107B/zh active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101212967A (zh) * | 2005-05-10 | 2008-07-02 | 因塞特公司 | 吲哚胺2,3-双加氧酶调节剂及其用法 |
| CN106866571A (zh) * | 2017-01-20 | 2017-06-20 | 中国药科大学 | 杂环脲类化合物及其药物组合物和应用 |
| WO2019057123A1 (zh) * | 2017-09-20 | 2019-03-28 | 杭州英创医药科技有限公司 | 作为ido抑制剂和/或ido-hdac双重抑制剂的多环化合物 |
| CN108003111A (zh) * | 2017-12-14 | 2018-05-08 | 华东理工大学 | 一种hdac1和ido1双靶点抑制剂及其制备方法和应用 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113105366A (zh) * | 2021-03-04 | 2021-07-13 | 中国药科大学 | 一类含苯基羟肟结构衍生物及其制法与用途 |
| CN113105366B (zh) * | 2021-03-04 | 2022-05-24 | 中国药科大学 | 一类含苯基羟肟结构衍生物及其制法与用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111909107B (zh) | 2023-02-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5400032B2 (ja) | ベンズイミダゾール及びその医薬組成物 | |
| CN103054869A (zh) | 含三唑基的氨基二硫代甲酸酯化合物在制备以lsd1为靶标药物中的应用 | |
| US10995096B2 (en) | 1,5-disubstituted 1,2,3-triazoles are inhibitors of Rac/Cdc42 GTPases | |
| Durgun et al. | Synthesis, characterization, in vitro cytotoxicity and antimicrobial investigation and evaluation of physicochemical properties of novel 4-(2-methylacetamide) benzenesulfonamide derivatives | |
| US20240327418A1 (en) | Multi-target inhibitor targeting hdac and nad synthesis and use of multi-target inhibitor | |
| Akolkar et al. | Click chemistry inspired syntheses of new amide linked 1, 2, 3-triazoles from naphthols: Biological evaluation and in silico computational study | |
| US9695181B2 (en) | Hydroximic acid derivatives and medical applications therof | |
| US8658655B2 (en) | Inhibition of activated cdc42-associated kinase 1 | |
| EP2313412B1 (fr) | Nouveaux derives de pyrroloindole inhibiteurs d'hsp90, compositions les contenant et utilisation | |
| US10266489B2 (en) | Pyrrolic amide compound and preparation method and application thereof | |
| US20250074904A1 (en) | Nsd2-targeted checmical degraderts and compositions and methods of use thereof | |
| US20090286848A1 (en) | Novel n-(2-amino-phenyl)-acrylamides | |
| CN104230912A (zh) | 喹啉衍生物、其制备方法及其用途 | |
| CN111909107A (zh) | Ido/hdac双重抑制剂及其药物组合物和应用 | |
| US8470763B2 (en) | Alpha-amino-N-substituted amides, pharmaceutical composition containing them and uses thereof | |
| WO2015085860A1 (zh) | 杂环羟肟酸类化合物及其药用组合物和应用 | |
| US10065990B2 (en) | Cyclic peptide compound, and preparation method, pharmaceutical composition and use thereof | |
| CN111848629A (zh) | 一类mTOR/HDAC双重抑制剂及其应用 | |
| US20220024916A1 (en) | Heterocyclic comipound as cdk-hdac dual pathway inhibitor | |
| CN116589402A (zh) | 一种作为NAMPT-PDEδ双靶点抑制剂的化合物及其应用 | |
| Gopalakrishnan et al. | Unusual formation of N-hydroxy-3, 3-dimethyl-2, 6-diarylpiperidin-4-one and its thiosemicarbazide derivative—synthesis and antimicrobial activity | |
| CN106496132B (zh) | N-(4-取代苯基)-2-取代乙酰胺类化合物及其作为sirt2蛋白抑制剂的用途 | |
| Khudair et al. | SYNTHESIS, CHARACTERIZATION AND PRELIMINARY ANTIMICROBIAL EVALUATION OF NEW HYDRAZONES AND 1, 3, 4-OXADIAZOLE DERIVATIVES DERIVED FROM INDOLE-PROPIONIC ACID. | |
| CN110156704B (zh) | 1,2,4-三唑硫醚衍生物及其晶体结构与应用 | |
| US20190365711A1 (en) | Compound having anti-cancer effect, and preparation method therefor and use thereof |
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 | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20210809 Address after: 100036 Beijing city Haidian District Cuiwei Road No. 2, building A, room 1209, static source in Applicant after: Beijing Kexiang Zhongsheng Pharmaceutical Technology Co.,Ltd. Address before: No. 639 Jiangning longmian Road District of Nanjing City, Jiangsu province 211198 Applicant before: CHINA PHARMACEUTICAL University |
|
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20210819 Address after: 224500 4th floor, North building, building 2, enterprise accelerator, Xin'an Avenue, Binhai Pharmaceutical Industrial Park, Binhai County, Yancheng City, Jiangsu Province Applicant after: Yaokang Zhongtuo (Jiangsu) Pharmaceutical Technology Co.,Ltd. Address before: 100036 Beijing city Haidian District Cuiwei Road No. 2, building A, room 1209, static source in Applicant before: Beijing Kexiang Zhongsheng Pharmaceutical Technology Co.,Ltd. |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20230317 Address after: Room 628, 6th Floor, Building 2, Yard 30, Jinxing Road, Daxing District, Beijing, 100023 Patentee after: Yaokang Zhongtuo (Beijing) Pharmaceutical Technology Co.,Ltd. Address before: 224500 4th floor, North building, building 2, enterprise accelerator, Xin'an Avenue, Binhai Pharmaceutical Industrial Park, Binhai County, Yancheng City, Jiangsu Province Patentee before: Yaokang Zhongtuo (Jiangsu) Pharmaceutical Technology Co.,Ltd. |