CN117843590A - 3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物、包含其的药物组合物及其制备方法、应用 - Google Patents
3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物、包含其的药物组合物及其制备方法、应用 Download PDFInfo
- Publication number
- CN117843590A CN117843590A CN202410006137.1A CN202410006137A CN117843590A CN 117843590 A CN117843590 A CN 117843590A CN 202410006137 A CN202410006137 A CN 202410006137A CN 117843590 A CN117843590 A CN 117843590A
- Authority
- CN
- China
- Prior art keywords
- carbonyl
- isopropylpiperazin
- piperazine
- phenyl
- naphthalene
- 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.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 64
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 201000007270 liver cancer Diseases 0.000 claims abstract description 11
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 101000730644 Homo sapiens Zinc finger protein PLAGL2 Proteins 0.000 claims abstract 4
- 102100032571 Zinc finger protein PLAGL2 Human genes 0.000 claims abstract 4
- -1 adamantyl acetyl Chemical group 0.000 claims description 55
- 238000004519 manufacturing process Methods 0.000 claims description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 claims description 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 4
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 claims description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 230000001404 mediated effect Effects 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- WHKWMTXTYKVFLK-UHFFFAOYSA-N 1-propan-2-ylpiperazine Chemical compound CC(C)N1CCNCC1 WHKWMTXTYKVFLK-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- SWBLLSQMOMPTMC-UHFFFAOYSA-N naphthalene-2-sulfonamide Chemical compound C1=CC=CC2=CC(S(=O)(=O)N)=CC=C21 SWBLLSQMOMPTMC-UHFFFAOYSA-N 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 150000001263 acyl chlorides Chemical class 0.000 claims description 2
- 150000001266 acyl halides Chemical class 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- 229960004106 citric acid Drugs 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 150000001993 dienes Chemical class 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 229960000448 lactic acid Drugs 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229940098895 maleic acid Drugs 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- DASJFYAPNPUBGG-UHFFFAOYSA-N naphthalene-1-sulfonyl chloride Chemical compound C1=CC=C2C(S(=O)(=O)Cl)=CC=CC2=C1 DASJFYAPNPUBGG-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229940107700 pyruvic acid Drugs 0.000 claims description 2
- 206010038038 rectal cancer Diseases 0.000 claims description 2
- 201000001275 rectum cancer Diseases 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 239000001384 succinic acid Substances 0.000 claims description 2
- 229960005137 succinic acid Drugs 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 229960001367 tartaric acid Drugs 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims 1
- 208000026310 Breast neoplasm Diseases 0.000 claims 1
- 125000003277 amino group Chemical group 0.000 claims 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- 239000012038 nucleophile Substances 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 10
- 201000011510 cancer Diseases 0.000 abstract description 8
- 230000002401 inhibitory effect Effects 0.000 abstract description 8
- 239000000463 material Substances 0.000 abstract description 5
- 230000004069 differentiation Effects 0.000 abstract description 4
- 238000011161 development Methods 0.000 abstract description 3
- 239000003937 drug carrier Substances 0.000 abstract description 3
- 206010058314 Dysplasia Diseases 0.000 abstract description 2
- 206010061218 Inflammation Diseases 0.000 abstract description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 2
- 208000012902 Nervous system disease Diseases 0.000 abstract description 2
- 208000025966 Neurological disease Diseases 0.000 abstract description 2
- 208000002193 Pain Diseases 0.000 abstract description 2
- 208000026278 immune system disease Diseases 0.000 abstract description 2
- 230000004054 inflammatory process Effects 0.000 abstract description 2
- 201000005202 lung cancer Diseases 0.000 abstract description 2
- 208000020816 lung neoplasm Diseases 0.000 abstract description 2
- 230000000926 neurological effect Effects 0.000 abstract description 2
- 208000020016 psychiatric disease Diseases 0.000 abstract description 2
- 208000023504 respiratory system disease Diseases 0.000 abstract description 2
- 230000002485 urinary effect Effects 0.000 abstract description 2
- 208000032612 Glial tumor Diseases 0.000 abstract 1
- 206010018338 Glioma Diseases 0.000 abstract 1
- 208000036142 Viral infection Diseases 0.000 abstract 1
- 208000030159 metabolic disease Diseases 0.000 abstract 1
- 238000004393 prognosis Methods 0.000 abstract 1
- 229940121649 protein inhibitor Drugs 0.000 abstract 1
- 239000012268 protein inhibitor Substances 0.000 abstract 1
- 208000017443 reproductive system disease Diseases 0.000 abstract 1
- 230000009385 viral infection Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 42
- 230000015572 biosynthetic process Effects 0.000 description 33
- 238000003786 synthesis reaction Methods 0.000 description 31
- 239000007787 solid Substances 0.000 description 29
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- AOTQGWFNFTVXNQ-UHFFFAOYSA-N 2-(1-adamantyl)acetic acid Chemical compound C1C(C2)CC3CC2CC1(CC(=O)O)C3 AOTQGWFNFTVXNQ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- OPECTNGATDYLSS-UHFFFAOYSA-N naphthalene-2-sulfonyl chloride Chemical compound C1=CC=CC2=CC(S(=O)(=O)Cl)=CC=C21 OPECTNGATDYLSS-UHFFFAOYSA-N 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 206010028980 Neoplasm Diseases 0.000 description 6
- 238000010609 cell counting kit-8 assay Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000012091 fetal bovine serum Substances 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 108010087230 Sincalide Proteins 0.000 description 5
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 230000035755 proliferation Effects 0.000 description 5
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 description 4
- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 description 4
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 4
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 4
- 239000007821 HATU Substances 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical group OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 102000001301 EGF receptor Human genes 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 108010019160 Pancreatin Proteins 0.000 description 2
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical group OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid group Chemical group C(CCCC(=O)O)(=O)O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 229940055695 pancreatin Drugs 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- DOYOPBSXEIZLRE-UHFFFAOYSA-N pyrrole-3-carboxylic acid Chemical group OC(=O)C=1C=CNC=1 DOYOPBSXEIZLRE-UHFFFAOYSA-N 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- ZCMNOJJBYKLODK-UHFFFAOYSA-N tert-butyl 4-(4-chloro-3-nitrobenzoyl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 ZCMNOJJBYKLODK-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- 230000035899 viability Effects 0.000 description 2
- GAKUNXBDVGLOFS-DUZKARGPSA-N (1-acetyloxy-3-hexadecanoyloxypropan-2-yl) (9z,12z)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COC(C)=O)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC GAKUNXBDVGLOFS-DUZKARGPSA-N 0.000 description 1
- OTTYFDRFBJPGRW-ONEGZZNKSA-N (e)-pent-2-enoyl chloride Chemical group CC\C=C\C(Cl)=O OTTYFDRFBJPGRW-ONEGZZNKSA-N 0.000 description 1
- FBCCMZVIWNDFMO-OUBTZVSYSA-N 2,2-dichloroacetyl chloride Chemical group Cl[13CH](Cl)C(Cl)=O FBCCMZVIWNDFMO-OUBTZVSYSA-N 0.000 description 1
- FODBVCSYJKNBLO-UHFFFAOYSA-N 2,3-dimethoxybenzoic acid Chemical group COC1=CC=CC(C(O)=O)=C1OC FODBVCSYJKNBLO-UHFFFAOYSA-N 0.000 description 1
- WIWCHWGNONICJI-UHFFFAOYSA-N 2-[4-(1-adamantyl)phenoxy]acetic acid Chemical compound C1=CC(OCC(=O)O)=CC=C1C1(C2)CC(C3)CC2CC3C1 WIWCHWGNONICJI-UHFFFAOYSA-N 0.000 description 1
- NSTREUWFTAOOKS-UHFFFAOYSA-N 2-fluorobenzoic acid Chemical group OC(=O)C1=CC=CC=C1F NSTREUWFTAOOKS-UHFFFAOYSA-N 0.000 description 1
- RAAGZOYMEQDCTD-UHFFFAOYSA-N 2-fluorobenzoyl chloride Chemical group FC1=CC=CC=C1C(Cl)=O RAAGZOYMEQDCTD-UHFFFAOYSA-N 0.000 description 1
- ZPZDIFSPRVHGIF-UHFFFAOYSA-N 3-aminopropylsilicon Chemical compound NCCC[Si] ZPZDIFSPRVHGIF-UHFFFAOYSA-N 0.000 description 1
- SYVNVEGIRVXRQH-UHFFFAOYSA-N 3-fluorobenzoyl chloride Chemical group FC1=CC=CC(C(Cl)=O)=C1 SYVNVEGIRVXRQH-UHFFFAOYSA-N 0.000 description 1
- TUXYZHVUPGXXQG-UHFFFAOYSA-N 4-bromobenzoic acid Chemical group OC(=O)C1=CC=C(Br)C=C1 TUXYZHVUPGXXQG-UHFFFAOYSA-N 0.000 description 1
- CZKLEJHVLCMVQR-UHFFFAOYSA-N 4-fluorobenzoyl chloride Chemical group FC1=CC=C(C(Cl)=O)C=C1 CZKLEJHVLCMVQR-UHFFFAOYSA-N 0.000 description 1
- DFXQXFGFOLXAPO-UHFFFAOYSA-N 96-99-1 Chemical compound OC(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 DFXQXFGFOLXAPO-UHFFFAOYSA-N 0.000 description 1
- 101100067974 Arabidopsis thaliana POP2 gene Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 102000056372 ErbB-3 Receptor Human genes 0.000 description 1
- 101100118549 Homo sapiens EGFR gene Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 101000730643 Homo sapiens Zinc finger protein PLAGL1 Proteins 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 101150021023 PLAGL2 gene Proteins 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 description 1
- 102100029981 Receptor tyrosine-protein kinase erbB-4 Human genes 0.000 description 1
- 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 description 1
- 101100123851 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) HER1 gene Proteins 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
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102100032570 Zinc finger protein PLAGL1 Human genes 0.000 description 1
- 108091007916 Zinc finger transcription factors Proteins 0.000 description 1
- 102000038627 Zinc finger transcription factors Human genes 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical group COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 description 1
- 230000000181 anti-adherent effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000003911 antiadherent Substances 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- FYGUSUBEMUKACF-UHFFFAOYSA-N bicyclo[2.2.1]hept-2-ene-5-carboxylic acid Chemical group C1C2C(C(=O)O)CC1C=C2 FYGUSUBEMUKACF-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 201000007983 brain glioma Diseases 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- YTKRILODNOEEPX-NSCUHMNNSA-N crotyl chloride Chemical group C\C=C\CCl YTKRILODNOEEPX-NSCUHMNNSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- JPMJNRPHIMXRAP-UHFFFAOYSA-N cyclopropyl carbonochloridate Chemical compound ClC(=O)OC1CC1 JPMJNRPHIMXRAP-UHFFFAOYSA-N 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000008394 flocculating agent Substances 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Substances ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 208000004333 pleomorphic adenoma Diseases 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- DSAFUUFVQNUZMS-UHFFFAOYSA-N tert-butyl 1,3-diazinane-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCNC1 DSAFUUFVQNUZMS-UHFFFAOYSA-N 0.000 description 1
- WDPWEXWMQDRXAL-UHFFFAOYSA-N tert-butyl 1,4-diazepane-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCNCC1 WDPWEXWMQDRXAL-UHFFFAOYSA-N 0.000 description 1
- RBLOMFQUEUBEBG-UHFFFAOYSA-N tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate Chemical compound C1CC2N(C(=O)OC(C)(C)C)CC1NC2 RBLOMFQUEUBEBG-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical group OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供3‑氨基‑4‑(哌嗪‑1‑基)苯甲酰胺类衍生物、包含其的药物组合物及其制备方法、应用,该化合物作为PLAGL2蛋白抑制剂从而对一些疾病产生重要作用,包括但不限于疼痛、炎症、免疫功能障碍、神经和精神病症、呼吸道疾病、泌尿系统、生殖系统疾病、胚胎发育异常、细胞代谢紊乱、分化问题,以及病毒感染等。尤其是在肝癌、肺癌、脑胶质瘤等恶性肿瘤的发生、发展和预后中,PLAGL2起到了积极的作用。本发明化合物具有优良的PLAGL2抑制活性。本发明还提供包含所述化合物及其可药用的盐,药学上可接受的载体或辅料及其制备方法。
Description
技术领域
本发明属于医药技术领域,具体涉及3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物、包含其的药物组合物及其制备方法、应用。
背景技术
PLAGL2(Pleomorphic adenoma gene like 2)与PLAGL1同属PLAG基因家族,作为锌指蛋白转录因子,对多个重要基因的表达发挥调控作用,并参与多种生理学功能,包括细胞的生长、增殖和分化,在多种疾病的发生和发展中扮演关键角色。PLAGL2的表达失调在多种恶性肿瘤中常见,如肝癌、神经母细胞瘤、非小细胞肺癌、前列腺癌、结直肠癌和白血病等。
目前,大多数抗肿瘤药物主要通过作用于表皮生长因子受体(HER)来发挥作用,包括HER1(erbB1,EGFR)、HER2(erbB2,NEU)、HER3(erbB3)和HER4(erbB4)。HER家族在细胞生理过程中发挥重要调节作用,其中EGFR是其中的一员,分布于多种细胞表面,对细胞的生长、增殖和分化等过程发挥关键作用。尽管EGFR抑制剂在治疗恶性肿瘤中表现出满意的效果,但长期使用可能导致癌细胞对药物不敏感。PLAGL2基因表达的PLAGL2蛋白能够作为EGFR的转录因子,调控EGFR蛋白的正表达,从而增强癌细胞的生长,增殖和分化,并且PLAGL2蛋白能够恢复特定抗肿瘤药物的有效性,克服获得性耐药性。联合治疗可协同增加非小细胞肺癌细胞系的细胞凋亡并抑制体内肿瘤生长。因此,PLAGL2被认为是治疗各种癌症的潜在新靶点,PLAGL2抑制剂可能成为各种肿瘤疾病的新型治疗药物,值得进一步深入研究。
发明人CN115974766A公开了式(IX),但该化合物成药性差,故本发明在其基础上做了改进。
发明内容
发明的目的在于提供一种3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物及其应用,还提供包含3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物的药物组合物,3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物可抑制PLAGL2活性,对于多种恶性肿瘤的治疗具有应用前景。
为了实现上述目的,本发明所采用的技术方案为:
一种3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物及其药学上可接受的盐,其特征在于,其为式(VIII)所示结构的化合物
其中,
X选自羰基或砜基;
A选自N取代的五元环、六元环、七元环、双环或者桥环;
R1选自2-4位上取代芳甲酰基、芳杂甲酰基、不饱和或饱和长链乙酰基,金刚烷乙酰基,二氯乙酰基,环烷甲酰基;
R2选自2-4位上单取代或多取代的取代基,R2独立地选自卤素、羟基、硝基、氰基、胺基、取代或未取代的C1-6烷基、取代或未取代的C1-6烷氧基、取代或未取代的C1-环烷基,所述取代为单取代或多取代,R2的取代基独立地为卤素、羟基、硝基、氰基或胺基。
所述的3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物及其药学上可接受的盐,其特征在于:
A选自
R1选自
或者其他金刚烷类,共轭双烯,芳环类衍生物;
R2选自2,3,4位的卤素原子、甲氧基或芳环。
所述的3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物及其药学可接受的盐,其特征在于,所述的化合物为如下结构式中任意一种:
N-(5-(4-(环丙烷羰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
(E)-N-(5-(4-(丁-2-烯基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
(Z)-N-(5-(4-(3,7-二甲基-5-氧代辛烷-2,6-二烯基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
2-(4-(4-(-4-异丙基哌嗪-1-基)-3-(萘-2-磺酰胺基)苯甲酰基)哌嗪-1-酰基)-2-氧代乙酸甲酯;
N-(5-(4-(2,2-二氯乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
N-(5-(4-(2-(金刚烷-1-基)乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
4-(4-(4-异丙基哌嗪-1-基)-3-(萘-2-磺酰胺基)苯甲酰基)哌嗪-1-羰基氰化物;
5-(4-(4-(-4-异丙基哌嗪-1-基)-3-(萘-2-磺酰胺基)苯甲酰基)哌嗪-1-酰基)-5-氧代戊酸;
N-(5-(4-(4-溴苯甲酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
N-(5-(4-(2-氟苯甲酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
N-(2-(4-异丙基哌嗪-1-基)-5-(4-(噻吩-2-羰基)哌嗪-1-羰基)苯基)萘-2-磺酰胺;
N-(5-(4-(2,3-二甲氧基苯甲酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
N-(5-(4-(1H-吡咯-3-羰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
N-(5-(4-(呋喃-2-羰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
N-(5-(4-(2-(4-(金刚烷-1-基)苯氧基)乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
N-(5-(4-(2-(金刚烷-1-基)乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)-2-氟苯甲酰胺;
N-(5-(4-(2-(金刚烷-1-基)乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)-4-甲氧基苯甲酰胺;
N-(5-(4-(2-(金刚烷-1-基)乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)-3-氟苯甲酰胺;
N-(5-(4-(2-(金刚烷-1-基)乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)-4-氟苯甲酰胺;
N-(5-(4-(2-(金刚烷-1-基)乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)-2-萘酰胺;
N-(5-(4-((2S)-双环[2.2.1]庚-5-烯-2-羰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
N-(5-(4-(2-(金刚烷-1-基)乙酰基)-1,4-二氮杂-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
N-(5-(5-(2-(金刚烷-1-基)乙酰基)-2,5-二氮杂双环[2.2.2]辛烷-2-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
或N-(5-(3-(2-(金刚烷-1-基)乙酰基)六氢嘧啶-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺。
所述3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物及其药学可接受的盐,其特征在于,所述药学上可接受的盐包括与下列酸形成的盐:盐酸、硫酸、磷酸、氢溴酸、醋酸、三氟乙酸、丙酮酸、柠檬酸、酒石酸、乳酸、马来酸、苯磺酸或琥珀酸。
本发明公开一种药物组合物,其特征在于,所述的药物组合物包括所述3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物及其药学可接受的盐,及药学上可接受的辅料。
进一步而言,所述的药物组合物,它包含所述3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物及药学上可接受的载体或辅料。药学上可接受的辅料系指生产药品和调配处方时使用的赋形剂和附加剂,包括溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂、释放阻滞剂等。药学上可接受的载体,是指能改变药物进入人体的方式和在体内的分布、控制药物的释放速度并将药物输送到靶向器官的体系,包括微囊与微球、纳米粒、脂质体等。当药物组合物用于实体瘤肿瘤疾病时,优选组合物形式为有效成分+载体。
所述3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物因具有PLAGL2抑制活性,本发明还公开一种所述3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物的应用,3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物用于制备预防和/或治疗PLAGL2介导疾病的药物。
作为技术方法的进一步改进,所述的PLAGL2介导疾病包括疼痛、炎症、免疫功能障碍、神经和精神病症、呼吸道疾病、泌尿、生殖病症、胚胎发育异常、细胞代谢、分化异常和恶性肿瘤。
作为技术方法的进一步改进,所述恶性肿瘤为肝癌、直肠癌、胃癌、肺癌或脑胶质瘤。
所述3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物因具有PLAGL2抑制活性,本发明还公开一种所述3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物的应用,3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物用于制备PLAGL2抑制剂。
本发明还公开一种所述的3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物的制备方法,包括:
其中:
步骤一:化合物I与含Boc胺反应得到化合物II;
步骤二:化合物II在碱性碳酸钾的作用下与异丙基哌嗪回流得到化合物III;
步骤三:化合物III在钯碳及氢气的条件下转化为化合物IV;
步骤四:化合物IV在吡啶或三乙胺条件下与萘磺酰氯,取代酰氯反应得到化合物V;
步骤五:化合物V在三氟乙酸的作用下,将Boc脱去,得到化合物VI;
步骤六:化合物VI与酰卤、酸等亲核试剂反应得到本发明化合物VIII。
本发明相较于CN115974766A式(IX)具有如下优点:
首先,在结构上进行了优化改造,一是将式(IX)中A连接的烷烃连接替换成哌嗪衍生物,增加了化合物的水溶性,二是将芳环结构替换为脂肪烷结构,增加了化合物的活性。具体数据在表1中展示:
表1不同物质Ic50活性对比
由表1可知,本发明式(VIII)化合物相较于CN115974766A式(IX)化合物具有更高的IC50活性。且本发明式(VIII)化合物具有更低的LogP(脂水分配系数),说明其具有更高的水溶性。其次本发明对化合物的反应步骤进行了优化,这使反应处理过程更加简便,三是更便于式(VIII)类型化合物的合成。
有益效果
本发明相对现有技术具有突出的实质性特点和显著的进步,具体的说,本发明所述的化合物为全新的化合物,未见文献报道,其通过与PLAGL2蛋白结合,并抑制其转录调控作用,使其无法完成信号传导,达到阻断PLAGL2-EGFR-HIF-1/2α信号通路的目的。进一步说,本发明的化合物在400nM浓度下表现出较高的PLAGL2抑制作用,应用价值高。再一步说,本发明化合物的制备方法步骤简单,可实施性强。
具体实施方式:
下面通过具体实施方式,对本发明的技术方案做进一步的详细描述。
以下实施例中,“室温”是指大约10℃至大约35℃。混合溶剂表示的比例是体混合比例,除非另作说明,否则%是指wt%。
在硅胶柱色谱中,碱性硅胶是指使用氨基丙基硅烷结合的硅胶。在高效液相色谱(HPLC)中,C18是指使用十八烷基结合的硅胶。洗脱溶剂的比例是体积混合比例,除非另作说明。
在下面实施例和实验实施例中,使用下列缩写。
DCM:二氯甲烷,
MeOH:甲醇,
DMSO:二甲基亚砜,
DMF:N,N-二甲基甲酰胺,
DIEA:N,N-二异丙基乙胺,
HATU:2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯,
TFA:三氟乙酸,
M:摩尔浓度。
利用Fourier变换类型NMR,测定1H-NMR(质子核磁共振波谱)。对于分析,使用ACD/SpecManager等。不描述活性氢(例如羟基、氨基等等)的峰。
实施例1N-(5-(4-(环丙烷羰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺的合成。
步骤一,4-(4-氯-3-硝基苯甲酰基)哌嗪-1-羧酸叔丁酯的合成。
室温下将4-氯-3-硝基苯甲酸(1.69g,1.8mmol)、N-叔丁氧羰基哌嗪(1.7g,9.9mmol),HATU(3.8g,9.99mmol)和DIEA(2.94g,22.71mmol)在DCM(5mL)中溶解,室温反应三个小时。反应完成后,加入水萃取。经硅胶柱色谱纯化产物,得到白色固体1.96g,产率56.84%。
1H NMR(300MHz,Methanol-d4)δ6.98(d,J=8.0Hz,1H),6.74(d,J=2.0Hz,1H),6.70–6.63(m,1H),3.41(s,4H),2.91(s,4H),2.74–2.67(m,4H),1.41(s,10H),1.09(d,J=6.5Hz,6H).
步骤二,4-(4-(4-异丙基哌嗪-1-基)-3-硝基苯甲酰基)哌嗪-1-羧酸叔丁酯的合成。
室温下将(4-(4-氯-3-硝基苯甲酰基)哌嗪-1-羧酸叔丁酯,1.0g,3.88mmol)和1-异丙基哌嗪(0.54g,4.27mmol)在CH3CN(5mL)中溶解,加入K2CO3(1.34g,9.70mmol)中,80℃下反应6小时。反应完成后,冷却至室温。真空浓缩反应液。加入水萃取,合并有机相,加入无水硫酸钠干燥,真空除去残余溶剂。经硅胶柱色谱纯化产物,得到1.18g橙色固体,产率87.01%
步骤三,4-(3-氨基-4-(4-异丙基哌嗪-1-基)苯甲酰基)哌嗪-1-羧酸叔丁酯的合成。
室温下,将4-(4-(4-异丙基哌嗪-1-基)-3-硝基苯甲酰基)哌嗪-1-羧酸叔丁酯(1.0g,0.42mmol)溶于6mL甲醇中,加入10%Pd/C-H2,40℃反应5h。反应结束后,抽滤去除钯碳,收集滤液,真空浓缩得到淡黄色固体0.86g,产率91.97%。
步骤四,4-(4-(4-异丙基哌嗪-1-基)-3-(萘-2-磺酰胺基)苯甲酰基)哌嗪-1-羧酸叔丁酯的合成。
0℃下,将4-(3-氨基-4-(4-异丙基哌嗪-1-基)苯甲酰基)哌嗪-1-羧酸叔丁酯(0.80g,1.85mmol)溶于5mL吡啶中,加入2-萘磺酰氯(0.63g,2.78mmol),室温反应3小时。反应结束后,加入水萃取,经硅胶柱色谱纯化,得到0.68g白色固体,产率:59.0%。
步骤五,4-氟-N-(2-(4-异丙基哌嗪-1-基)-5-(哌嗪-1-羰基)苯基)苯甲酰胺的合成。
室温下,将4-(3-(4-氟苯甲酰胺基)-4-(4-异丙基哌嗪-1-基)苯甲酰基)哌嗪-1-羧酸叔丁酯(0.5g,0.80mmol)溶解于二氯甲烷(1mL)中,加入三氟乙酸(1mL,13.6mmol),室温搅拌2h。反应结束后加入饱和碳酸氢钠水溶液调节PH至8.00,加入DCM萃取,真空浓缩溶剂,得到浅绿色固体0.39g,产率94.9%。
f)N-(5-(4-(环丙烷羰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺
室温下,将N-(2-(4-异丙基哌嗪-1-基)-5-(哌嗪-1-羰基)苯基)萘-2-磺酰胺(0.20g,0.38mmol)和TEA(0.10g,1.00mmol)在DCM中溶解,0℃下,将环丙基甲酰氯(0.060g,0.58mmol)的DCM溶液在滴入上述溶液,0℃反应30min,转移至室温反应三个小时。反应完成后,加水萃取。再经硅胶柱色谱纯化产物,得到淡黄色固体0.15g,产率66.34%。
实验数据如下:
1H NMR(300MHz,Chloroform-d)δ8.45(s,1H),7.89(td,J=10.6,10.0,3.8Hz,3H),7.76(dd,J=8.7,2.0Hz,1H),7.68–7.59(m,3H),7.13(q,J=9.7,8.9Hz,2H),3.79(d,J=10.6Hz,4H),3.46(d,J=58.8Hz,4H),2.88(p,J=6.5Hz,1H),2.69(q,J=6.0Hz,8H),1.13(d,J=6.5Hz,6H),1.03(dd,J=4.6,2.8Hz,2H),0.94–0.90(m,1H),0.86–0.80(m,2H).
实施例2(E)-N-(5-(4-(丁-2-烯基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺的合成。
用(E)-丁-2-烯酰氯替换掉实施例1的步骤六中的环丙基甲酰氯,其它步骤参照实施例1中的制备方法,制得化合物(2),得固体0.15g,产率:63.03%。
实验数据如下:
1H NMR(300MHz,Chloroform-d)δ8.46(s,1H),7.90(s,3H),7.77(d,J=8.6Hz,1H),7.71–7.48(m,3H),7.29(s,1H),7.17(d,J=7.9Hz,1H),7.11(s,1H),7.01–6.79(m,1H),6.27(s,1H),4.03–3.48(m,6H),3.36(s,2H),2.93(s,1H),2.73(d,J=15.2Hz,8H),1.99–1.86(m,3H),1.15(d,J=5.4Hz,6H).
实施例3(Z)-N-(5-(4-(3,7-二甲基-5-氧代辛烷-2,6-二烯基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺的合成。
用甲基巴豆酰氯替换掉实施例1的步骤六中的环丙基甲酰氯,其它步骤参照实施例1中的制备方法,制得化合物(3),得固体0.13g,产率:45.19%。
实验数据如下:
1H NMR(300MHz,Chloroform-d)δ8.73(s,1H),7.99(d,J=25.1Hz,4H),7.61(d,J=30.2Hz,3H),7.28(s,3H),5.80(s,1H),5.35(s,1H),3.67(d,J=35.7Hz,8H),3.12(s,4H),2.81(s,1H),2.68(s,4H),2.07(s,3H),1.92(s,2H),1.86(s,3H),1.67(s,3H),1.10(s,6H).
实施例42-(4-(4-(-4-异丙基哌嗪-1-基)-3-(萘-2-磺酰胺基)苯甲酰基)哌嗪-1-酰基)-2-氧代乙酸甲酯的合成。
用草酰氯单甲酯替换掉实施例1的步骤六中的环丙基甲酰氯,其它步骤参照实施例1中的制备方法,制得化合物(4),得固体0.14g,产率:45.89%。
实验数据如下:
1H NMR(300MHz,Methanol-d4)δ8.42(s,1H),7.92(d,J=8.6Hz,2H),7.86(d,J=7.4Hz,1H),7.74(d,J=8.5Hz,1H),7.63–7.53(m,2H),7.50(s,1H),7.09(s,2H),3.82(s,3H),3.44(dd,J=57.8,32.0Hz,8H),2.65–2.58(m,1H),2.53(s,4H),2.50(s,4H),0.99(d,J=6.3Hz,6H).
实施例5N-(5-(4-(2,2-二氯乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺的合成。
用2,2-二氯乙酰氯替换掉实施例1的步骤六中的环丙基甲酰氯,其它步骤参照实施例1中的制备方法,制得化合物(5),得固体0.12g,产率:57.37%。
实验数据如下:
1H NMR(300MHz,Chloroform-d)δ8.44(d,J=1.9Hz,1H),7.98–7.83(m,3H),7.76(d,J=6.7Hz,1H),7.64(d,J=5.3Hz,3H),7.23–7.05(m,2H),6.20(s,1H),4.08–3.24(m,8H),2.86–2.73(m,1H),2.66(s,8H),1.12(d,J=6.5Hz,6H).
实施例6N-(5-(4-(2-(金刚烷-1-基)乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺的合成
步骤一-步骤七参考实施例1。
步骤七,N-(5-(4-(2-(金刚烷-1-基)乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺的合成。
室温下,将N-(2-(4-异丙基哌嗪-1-基)-5-(哌嗪-1-羰基)苯基)萘-2-磺酰胺(0.20g,0.38mmol),HATU(0.16g,0.42mmol)和DIEA(0.123g,0.96mmol)在DCM(5mL)中溶解,室温反应三个小时。反应完成后,加入水萃取。经硅胶柱色谱纯化产物,得到白色固体0.17g,产率69.09%。
实施例74-(4-(4-异丙基哌嗪-1-基)-3-(萘-2-磺酰胺基)苯甲酰基)哌嗪-1-羰基氰化物的合成。
用氰乙酸替换掉实施例6的步骤六中的1-金刚烷乙酸,其它步骤参照实施例6中的制备方法,制得化合物(7),得固体0.19g,产率:52.37%。
实验数据如下:
1H NMR(300MHz,Chloroform-d)δ8.39(s,1H),7.84(q,J=9.7,7.7Hz,3H),7.69(d,J=8.6Hz,1H),7.57(s,3H),7.22(s,1H),7.06(d,J=8.5Hz,2H),3.51(s,4H),3.42(s,4H),2.79–2.68(m,1H),2.58(s,8H),1.05(d,J=6.3Hz,6H).
实施例85-(4-(4-(-4-异丙基哌嗪-1-基)-3-(萘-2-磺酰胺基)苯甲酰基)哌嗪-1-酰基)-5-氧代戊酸的合成。
用戊二酸替换掉实施例6的步骤六中的1-金刚烷乙酸,其它步骤参照实施例6中的制备方法,制得化合物(8),得固体0.15g,产率:59.35%。
实验数据如下:
1H NMR(300MHz,Deuterium Oxide)δ8.19(s,1H),7.63(d,J=34.8Hz,4H),7.43–7.16(m,2H),7.05(d,J=24.6Hz,2H),3.26(d,J=41.1Hz,8H),2.88(d,J=38.8Hz,8H),2.18(s,4H),1.64(d,J=53.9Hz,2H),1.16(s,6H).
实施例9N-(5-(4-(4-溴苯甲酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺的合成。
用4-溴苯甲酸替换掉实施例6的步骤六中的1-金刚烷乙酸,其它步骤参照实施例6中的制备方法,制得化合物(9),得固体0.13g,产率:62.46%。
实验数据如下:
1H NMR(300MHz,DMSO-d6)δ8.48(s,1H),8.09(d,J=8.2Hz,2H),7.99(d,J=8.2Hz,1H),7.82(d,J=8.9Hz,1H),7.68(d,J=7.9Hz,3H),7.60(s,1H),7.37(d,J=7.9Hz,2H),7.25(s,1H),7.12(s,2H),3.50(s,4H),3.29(d,J=23.2Hz,6H),2.66(s,6H),0.98(d,J=6.1Hz,6H).
实施例10N-(5-(4-(2-氟苯甲酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺的合成。
用2-氟苯甲酸替换掉实施例6的步骤六中的1-金刚烷乙酸,其它步骤参照实施例6中的制备方法,制得化合物(10),得固体0.2g,产率:55.9%。
实验数据如下:
1H NMR(300MHz,Chloroform-d)δ8.69(s,1H),8.09(ddd,J=23.6,15.9,8.7Hz,4H),7.92–7.74(m,3H),7.66(p,J=7.3Hz,2H),7.52(dd,J=13.5,6.2Hz,2H),7.34(d,J=8.5Hz,3H),4.33–3.78(m,4H),3.60(s,4H),3.03(q,J=7.1Hz,1H),2.88(s,8H),1.52–1.22(m,6H).
实施例11N-(2-(4-异丙基哌嗪-1-基)-5-(4-(噻吩-2-羰基)哌嗪-1-羰基)苯基)萘-2-磺酰胺的合成。
用2-噻吩甲酸替换掉实施例6的步骤六中的1-金刚烷乙酸,其它步骤参照实施例6中的制备方法,制得化合物(11),得固体0.18g,产率:58.49%。
实验数据如下:
1H NMR(300MHz,Chloroform-d)δ8.37(s,1H),7.80(t,J=10.7Hz,3H),7.69(d,J=8.6Hz,1H),7.53(dd,J=16.6,9.3Hz,4H),7.34–7.25(m,1H),7.12(d,J=4.5Hz,1H),7.03(d,J=5.2Hz,2H),3.82–3.16(m,8H),2.81–2.71(m,1H),2.60(d,J=9.7Hz,8H),1.10–1.00(m,6H).
实施例12N-(5-(4-(2,3-二甲氧基苯甲酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺的合成。
/>
用2,3-二甲氧基苯甲酸替换掉实施例6的步骤六中的1-金刚烷乙酸,其它步骤参照实施例6中的制备方法,制得化合物(12),得固体0.15g,产率:56.02%。
实验数据如下:
1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.09(d,J=8.8Hz,2H),8.00(d,J=8.3Hz,1H),7.81(d,J=8.7Hz,1H),7.70–7.57(m,2H),6.79(dd,J=6.9,2.2Hz,1H),3.84(s,3H),3.74(s,3H),3.36(s,7H),2.67–2.59(m,5H),2.51(q,J=1.9Hz,5H),2.48–2.41(m,4H),1.22(dd,J=21.7,5.0Hz,4H),0.96(d,J=6.4Hz,6H).
实施例13N-(5-(4-(1H-吡咯-3-羰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺的合成。
用1H-吡咯-3-甲酸替换掉实施例6的步骤六中的1-金刚烷乙酸,其它步骤参照实施例6中的制备方法,制得化合物(13),得固体0.15g,产率:56.63%。
实验数据如下:
1H NMR(300MHz,Chloroform-d)δ9.40(s,1H),8.44(s,1H),7.88(t,J=10.1Hz,3H),7.76(d,J=8.6Hz,1H),7.61(dd,J=14.8,8.5Hz,3H),7.13(t,J=6.0Hz,3H),6.75(s,1H),6.34(s,1H),3.92–3.55(m,6H),3.40(s,2H),2.77(dt,J=12.9,6.2Hz,1H),2.63(s,8H),1.11(d,J=6.4Hz,6H).
实施例14N-(5-(4-(呋喃-2-羰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺的合成。
用2-呋喃甲酸替换掉实施例6的步骤六中的1-金刚烷乙酸,其它步骤参照实施例6中的制备方法,制得化合物(14),得固体0.18g,产率:56.04%。
实验数据如下:
1H NMR(300MHz,Chloroform-d)δ8.78(s,1H),8.03(d,J=7.2Hz,3H),7.95(s,1H),7.66(dd,J=15.6,8.4Hz,4H),7.51(s,1H),7.38(s,1H),7.34(s,1H),7.07(d,J=3.1Hz,1H),6.50(s,1H),6.25(s,1H),6.23–6.16(m,1H),3.78(d,J=71.3Hz,8H),3.63(s,1H),3.47–2.75(m,8H),1.37(d,J=6.4Hz,6H).
实施例15N-(5-(4-(2-(4-(金刚烷-1-基)苯氧基)乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺的合成。
用2-(4-(金刚烷-1-基)苯氧基)乙酸替换掉实施例6的步骤六中的1-金刚烷乙酸,其它步骤参照实施例6中的制备方法,制得化合物(15),得固体0.11g,产率:48.73%。
实验数据如下:
1H NMR(300MHz,Chloroform-d)δ8.43(s,1H),7.86(dd,J=15.2,8.0Hz,3H),7.76(d,J=8.6Hz,1H),7.65–7.49(m,
3H),7.29(s,2H),7.08(s,2H),6.88(d,J=7.6Hz,2H),4.67(s,2H),3.81–3.28(m,8H),2.92–2.82(m,1H),2.74(s,4H),2.62(s,4H),2.06(s,3H),1.85(s,6H),1.74(s,6H),1.12(d,J=5.5Hz,6H).
实施例16N-(5-(4-(2-(金刚烷-1-基)乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)-2-氟苯甲酰胺的合成。
用2-氟苯甲酰氯替换掉实施例1的步骤四中的2-萘磺酰氯,其它步骤参照实施例1中的制备方法,制得化合物(16),得固体0.18g,产率:54.97%。
实验数据如下:
1H NMR(300MHz,Chloroform-d)δ8.58(s,1H),8.02(s,3H),7.76(s,3H),7.23(s,2H),4.04–3.45(m,8H),2.90(s,1H),2.84–2.60(m,8H),2.30(s,2H),2.11(s,3H),1.88–1.67(m,12H),1.22(d,J=3.1Hz,0H).
实施例17N-(5-(4-(2-(金刚烷-1-基)乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)-4-甲氧基苯甲酰胺的合成。
用4-甲氧基苯甲酰氯替换掉实施例1的步骤四中的2-萘磺酰氯,其它步骤参照实施例1中的制备方法,制得化合物(17),得固体0.15g,产率:60.45%。
实验数据如下:
1H NMR(300MHz,Chloroform-d)δ9.04(s,1H),8.42(s,1H),7.89(d,J=8.4Hz,2H),7.20(s,2H),7.02(d,J=8.6Hz,
2H),3.89(s,3H),3.68(dt,J=12.8,6.5Hz,8H),3.13(t,J=7.6Hz,1H),2.98(s,4H),2.87(s,4H),2.18(s,2H),1.97(s,3H),1.66(d,J=10.2Hz,12H),1.25(d,J=6.5Hz,6H).
实施例18N-(5-(4-(2-(金刚烷-1-基)乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)-3-氟苯甲酰胺的合成。
用3-氟苯甲酰氯替换掉实施例1的步骤四中的2-萘磺酰氯,其它步骤参照实施例1中的制备方法,制得化合物(18),得固体0.19g,产率:58.79%。
实验数据如下:
1H NMR(300MHz,Chloroform-d)δ9.40–9.34(m,1H),8.55(s,1H),7.70(d,J=7.7Hz,1H),7.64(dt,J=9.4,2.3Hz,1H),7.52(td,J=8.0,5.5Hz,1H),7.30(d,J=5.7Hz,1H),7.26(d,J=5.0Hz,2H),3.72(s,4H),3.61(s,4H),2.99(t,J=4.7Hz,4H),2.92(d,J=6.4Hz,1H),2.85(s,4H),2.19(s,2H),1.98(s,3H),1.66(s,12H),1.18(d,J=6.5Hz,6H).
实施例19N-(5-(4-(2-(金刚烷-1-基)乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)-4-氟苯甲酰胺的合成。
用4-氟苯甲酰氯替换掉实施例1的步骤四中的2-萘磺酰氯,其它步骤参照实施例1中的制备方法,制得化合物(19),得固体0.14g,产率:59.19%。
实验数据如下:
1H NMR(300MHz,Chloroform-d)δ9.36(s,1H),8.58(s,1H),7.95(s,2H),7.47–7.06(m,5H),3.67(d,J=30.4Hz,8H),2.99(s,4H),2.78(s,5H),2.19(s,2H),1.98(s,3H),1.66(s,12H),1.15(d,J=3.9Hz,11H).
实施例20N-(5-(4-(2-(金刚烷-1-基)乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)-2-萘酰胺的合成。
用2-萘酰氯替换掉实施例1的步骤四中的2-萘磺酰氯,其它步骤参照实施例1中的制备方法,制得化合物(20),得固体0.11g,产率:62.74%。
实验数据如下:
1H NMR(300MHz,Chloroform-d)δ9.07(s,1H),8.76(s,1H),8.47(d,J=5.8Hz,1H),8.02(d,J=10.4Hz,1H),7.94(d,J=9.6Hz,1H),7.77(dd,J=7.5,3.7Hz,1H),7.60(s,2H),7.26(s,3H),3.69(d,J=24.7Hz,8H),3.03(s,4H),2.94(s,1H),2.68(s,4H),2.19(s,2H),1.98(s,3H),1.66(s,13H),1.08(d,J=6.5Hz,6H).
实施例21N-(5-(4-((2S)-双环[2.2.1]庚-5-烯-2-羰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺的合成。
用双环[2.2.1]庚-5-烯-2-羧酸替换掉实施例1的步骤六中的环丙基甲酰氯,其它步骤参照实施例1中的制备方法,制得化合物(21),得固体0.12g,产率:60.85%。
实验数据如下:
1H NMR(300MHz,DMSO-d6)δ8.52(s,1H),8.15(t,J=8.5Hz,2H),8.07–7.97(m,1H),7.85(d,J=8.7Hz,1H),7.77–7.60(m,2H),7.27(s,1H),7.14(s,2H),6.13–6.06(m,1H),5.99–5.90(m,1H),3.35(d,J=20.1Hz,8H),3.01(s,1H),2.88–2.84(m,1H),2.70(s,4H),2.56(s,4H),1.28(d,J=12.3Hz,4H),1.01(d,J=6.4Hz,6H).
实施例22N-(5-(4-(2-(金刚烷-1-基)乙酰基)-1,4-二氮杂-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺的合成。
用N-Boc高哌嗪替换掉实施例6的步骤一中的N-Boc哌嗪,其它步骤参照实施例6中的制备方法,制得化合物(22),得固体0.15g,产率:65.60%。
1H NMR(300MHz,Chloroform-d)δ8.42(s,1H),7.86(t,J=9.4Hz,3H),7.74(d,J=8.6Hz,1H),7.62(d,J=14.3Hz,3H),7.03(dt,J=19.2,9.8Hz,2H),3.73(d,J=18.0Hz,3H),3.53(d,J=15.6Hz,3H),3.32(d,J=17.3Hz,2H),2.82–2.70(m,1H),2.57(d,J=19.2Hz,8H),2.14(d,J=20.0Hz,2H),1.96(s,3H),1.66(s,12H),1.08(d,J=6.2Hz,6H).
实施例23N-(5-(5-(2-(金刚烷-1-基)乙酰基)-2,5-二氮杂双环[2.2.2]辛烷-2-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺的合成。
用N-Boc-2,5-二氮杂双环[2.2.2]辛烷替换掉实施例6的步骤一中的N-Boc哌嗪,其它步骤参照实施例6中的制备方法,制得化合物(23),得固体0.18g,产率:68.90%。
1H NMR(300MHz,Chloroform-d)δ9.68(s,1H),8.35(q,J=0.5Hz,1H),8.11(t,J=0.5Hz,1H),8.00(dq,J=1.0,0.5Hz,2H),7.92(d,J=2.0Hz,1H),7.85(d,J=0.5Hz,1H),7.75(dd,J=7.5,2.0Hz,1H),7.62(d,J=0.5Hz,1H),7.52(d,J=0.5Hz,1H),7.27(d,J=7.5Hz,1H),4.09(s,1H),3.97(s,1H),3.80(d,J=12.4Hz,2H),3.65(d,J=3.0Hz,2H),3.15(d,J=1.6Hz,4H),2.99(s,1H),2.77(s,2H),2.69(s,2H),2.41(d,J=12.4Hz,1H),2.33(d,J=12.4Hz,1H),1.98(s,3H),1.94–1.81(m,4H),1.65(d,J=9.8Hz,12H),1.16(d,J=15.1Hz,6H).
实施例24N-(5-(3-(2-(金刚烷-1-基)乙酰基)六氢嘧啶-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺的合成。
用N-Boc-六氢嘧啶替换掉实施例6的步骤一中的N-Boc哌嗪,其它步骤参照实施例6中的制备方法,制得化合物(24),得固体0.18g,产率:65.85%。
1H NMR(300MHz,Chloroform-d)δ9.72(s,1H),8.36(q,J=0.6Hz,1H),8.11(t,J=0.5Hz,1H),8.04–7.91(m,3H),7.84(d,J=0.5Hz,1H),7.76(dd,J=7.5,2.0Hz,1H),7.63(d,J=0.5Hz,1H),7.52(d,J=0.5Hz,1H),7.37(d,J=7.5Hz,1H),4.87(s,1H),4.74(s,1H),3.70(d,J=8.1Hz,4H),3.15(s,4H),2.99(s,1H),2.77(s,2H),2.69(s,2H),2.53(d,J=12.4Hz,1H),2.40(d,J=12.4Hz,1H),1.98(s,3H),1.85(s,2H),1.67(d,J=15.3Hz,12H),1.16(s,6H).
实施例25CCK-8法测定肿瘤细胞的存活率
实验原理:PLAGL2抑制剂可以抑制肝癌细胞中PLAGL2的表达,从使肝癌细胞死亡。因此,我们可以通过高转移人肝癌细胞(HCCLM3/Huh7)的细胞毒活性实验,间接反映PLAGL2抑制剂的抑制能力,PLAGL2抑制剂抑制能力越强,人肝癌细胞存活率越低,对应的IC50值越小。
实验材料与仪器
(1)细胞:人肝癌HCCLM3和Huh7细胞购自中国科学院典型培养物保藏中心。
(2)实验耗材见表2
表2实验耗材表
试剂名称 | 厂家 |
Pen Strep | 美国Gibco公司 |
DMEM培养基 | BI |
胰酶消化液 | BI |
FBS(10%胎牛血清 | 陶术 |
CCK-8试剂盒 | 陶术 |
DMSO | 陶术 |
PBS缓冲液 | 陶术 |
试剂配制和测定
(A)HCCLM3细胞系的测定
HCCLM3细胞培养基的配制:HCCLM3细胞使用含有10%胎牛血清(FBS)和1%双抗的DMEM培养基进行细胞培养,具体配制过程如下:无菌条件下精确吸取55mL FBS,5.5mL P双抗,加入500mL瓶装DMEM培养基中混匀置于4℃冰箱备用。
受试化合物的配制:依据受试化合物的分子量,采用DMSO配制成20mM的母液储备于-80℃冰箱。
实验方法:
(1)取处于对数生长期的HCCLM3细胞,弃培养液,经含EDTA的0.25%Trypsin消化细胞,制成单细胞悬液。
(2)用DMEM培养基(含10%(V/V)FBS,1%Pen Strep)调整细胞密度为30000个/mL,接种至96孔板,100μL/孔,每孔细胞数量约为3000个,置37℃,5%CO2细胞培养箱中培养24h直至贴壁。
(3)含药培养基的配制:将受试化合物进行100倍稀释使其终浓度为200μM,并依次等比稀释,使其终浓度为200μM,100μM,50μM,25μM,12.5μM,6.25μM,0.313μM,0.156μM。。
(4)溶剂组加入含1%DMSO的DMEM培养基10μL,使DMSO终浓度为0.01%;给药组加入步骤(3)的不同浓度的受试化合物10μL使终浓度为20μM,10μM,5μM,2.5μM,1.25μM,0.625μM,0.313μM,0.156μM。
(5)72h后,在每个孔中加入10μL的CCK-8溶液,继续置37℃,5%CO2细胞培养箱中孵育2h。孵育结束后使用酶标仪在450nm的波长下测定其吸光度(OD)值。同时,利用Graphpad prism统计软件,计算受试化合物的IC50值。
(B)HCCLM3细胞系的测定
将实施例25步骤(A)的MHCC-97H细胞系替换为Huh7细胞系,其他实验操作一致,最终计算受试化合物在Huh7细胞系的IC50值.
细胞活力(%)=[A(加药)-A(空白)]/[A(加药)-A(空白)]×100%
A(加药):具有细胞、CCK-8溶液和药物溶液的孔的OD值
A(0加药):具有细胞、CCK-8溶液而没有药物溶液的孔的OD值
A(空白):没有细胞的孔的OD值。
细胞活力:细胞增殖活力或细胞毒性活力结果展示于表3中。
表3不同物质对细胞的细胞活力结果
表2的测试结果表明,上述化合物对HCCLM3/Huh7细胞系显示出较高的细胞活性,其中以实施例5,6,16和20效果最好,说明了部分本发明化合物在抑制肝癌细胞的增殖方面表现出有益的效果。
实施例26克隆形成法评估肿瘤细胞的侵袭能力
对CCK-8测定法筛选出的抗增殖活性较好的实施例5,6进行克隆形成实验,以评估其对肝癌细胞侵袭能力的影响。
实验方法:
取生长状态良好且处于对数生长期的HCCLM3细胞,PBS洗涤后,用胰酶消化,离心收集后,加入相应培养基重悬。向六孔板中加入1μL、0.5μL、0.25μL、0.1μL、0.05μL浓度为20mM的化合物溶液,配置为每孔浓度为10μM、5μM、2.5μM、1μM、0.5μM,0μM加入1μL DMSO。每孔加入2mL培养基含5×103个细胞的培养基。摇匀后,37℃、5%CO2的恒温培养箱中培养14天。
弃置培养基,PBS轻轻清洗1次,加入4%多聚甲醛固定40min,然后弃去固定液,再用PBS清洗3次,加入2.5%结晶紫染色1h,纯水轻轻清洗至不脱色。然后拍照,ImageJ统计克隆数量,结果按照0μM时细胞数量百分比进行计算,结果展示于表4中:
表4不同物质对细胞的细胞侵袭能力结果
实施例5 | 实施例6 | |
0μM | 100.00% | 100.00% |
0.5μM | 0.05% | 89.55% |
1μM | 0.01% | 61.28% |
2.5μM | 0.04% | 20.55% |
5μM | 0.06% | 0.53% |
10μM | 0.09% | 0.07% |
表3的测试结果表明,实施例5能够显著抑制HCCLM3细胞系的转移侵袭能力,说明了部分本发明化合物在抑制肝癌细胞的侵袭方面表现出有益的效果。
以上药理学数据显示:本发明化合物通过作用于PLAGL2靶点从而抑制肝癌细胞的增殖与恶性发展,展现出了较强的抑制恶性肿瘤的作用。
最后应当说明的是:以上实施例仅用以说明本发明的技术方案而非对其限制;尽管参照较佳实施例对本发明进行了详细的说明,所属领域的普通技术人员应当理解,依然可以对本发明的具体实施方式进行修改或者对部分技术特征进行等同替换;而不脱离本发明技术方案的精神,其均应涵盖在本发明请求保护的技术方案范围当中。
Claims (8)
1.一种3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物及其药学上可接受的盐,其特征在于,其为式(VIII)所示结构的化合物:
其中,
X选自羰基或砜基;
A选自N取代的五元环、六元环、七元环、双环或者桥环;
R1选自2-4位上取代芳甲酰基、芳杂甲酰基、不饱和或饱和长链乙酰基,金刚烷乙酰基,二氯乙酰基,环烷甲酰基;
R2选自2-4位上单取代或多取代的取代基,R2独立地选自卤素、羟基、硝基、氰基、胺基、取代或未取代的C1-6烷基、取代或未取代的C1-6烷氧基、取代或未取代的C1-环烷基,所述取代为单取代或多取代,R2的取代基独立地为卤素、羟基、硝基、氰基或胺基。
2.根据权利要求1所述的3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物及其药学上可接受的盐,其特征在于:
A选自
R1选自
或者其他金刚烷类,共轭双烯,芳环类衍生物;
R2选自2,3,4位的卤素原子、甲氧基或芳环。
3.根据权利要求1或2所述的3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物及其药学可接受的盐,其特征在于,所述的化合物为如下结构式中任意一种:
N-(5-(4-(环丙烷羰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
(E)-N-(5-(4-(丁-2-烯基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
(Z)-N-(5-(4-(3,7-二甲基-5-氧代辛烷-2,6-二烯基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
2-(4-(4-(-4-异丙基哌嗪-1-基)-3-(萘-2-磺酰胺基)苯甲酰基)哌嗪-1-酰基)-2-氧代乙酸甲酯;
N-(5-(4-(2,2-二氯乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
N-(5-(4-(2-(金刚烷-1-基)乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
4-(4-(4-异丙基哌嗪-1-基)-3-(萘-2-磺酰胺基)苯甲酰基)哌嗪-1-羰基氰化物;
5-(4-(4-(-4-异丙基哌嗪-1-基)-3-(萘-2-磺酰胺基)苯甲酰基)哌嗪-1-酰基)-5-氧代戊酸;
N-(5-(4-(4-溴苯甲酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
N-(5-(4-(2-氟苯甲酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
N-(2-(4-异丙基哌嗪-1-基)-5-(4-(噻吩-2-羰基)哌嗪-1-羰基)苯基)萘-2-磺酰胺;
N-(5-(4-(2,3-二甲氧基苯甲酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
N-(5-(4-(1H-吡咯-3-羰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
N-(5-(4-(呋喃-2-羰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
N-(5-(4-(2-(4-(金刚烷-1-基)苯氧基)乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
N-(5-(4-(2-(金刚烷-1-基)乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)-2-氟苯甲酰胺;
N-(5-(4-(2-(金刚烷-1-基)乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)-4-甲氧基苯甲酰胺;
N-(5-(4-(2-(金刚烷-1-基)乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)-3-氟苯甲酰胺;
N-(5-(4-(2-(金刚烷-1-基)乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)-4-氟苯甲酰胺;
N-(5-(4-(2-(金刚烷-1-基)乙酰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)-2-萘酰胺;
或N-(5-(4-((2S)-双环[2.2.1]庚-5-烯-2-羰基)哌嗪-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
N-(5-(4-(2-(金刚烷-1-基)乙酰基)-1,4-二氮杂-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
N-(5-(5-(2-(金刚烷-1-基)乙酰基)-2,5-二氮杂双环[2.2.2]辛烷-2-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺;
N-(5-(3-(2-(金刚烷-1-基)乙酰基)六氢嘧啶-1-羰基)-2-(4-异丙基哌嗪-1-基)苯基)萘-2-磺酰胺。
4.根据权利要求1-3任意一项所述的3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物及其药学可接受的盐,其特征在于,所述药学上可接受的盐包括与下列酸形成的盐:盐酸、硫酸、磷酸、氢溴酸、醋酸、三氟乙酸、丙酮酸、柠檬酸、酒石酸、乳酸、马来酸、苯磺酸或琥珀酸。
5.权利要求1-4任意一项所述的3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物或其药学可接受的盐的制备方法,其特征在于:
其中X选自羰基或砜基;
A选自N取代的五元环、六元环、七元环、双环或者桥环;
R1选自2-4位上取代芳甲酰基、芳杂甲酰基、不饱和或饱和长链乙酰基,金刚烷乙酰基,二氯乙酰基,环烷甲酰基;
R2选自2-4位上单取代或多取代的取代基,R2独立地选自卤素、羟基、硝基、氰基、胺基、取代或未取代的C1-6烷基、取代或未取代的C1-6烷氧基、取代或未取代的C1-环烷基,所述取代为单取代或多取代,R2的取代基独立地为卤素、羟基、硝基、氰基或胺基;
步骤一:化合物I与含Boc胺反应得到化合物II;
步骤二:化合物II在碱性碳酸钾的作用下与异丙基哌嗪反应得到化合物III;
步骤三:化合物III在钯碳及氢气的条件下转化为化合物IV;
步骤四:化合物IV在吡啶或三乙胺条件下与萘磺酰氯,取代酰氯反应得到化合物V;
步骤五:化合物V在三氟乙酸的作用下,将Boc脱去,得到化合物VI;
步骤六:化合物VI与卤素、酰卤、酸亲核试剂反应得到化合物VIII。
6.一种药物组合物,其特征在于,所述的药物组合物包括权利要求1-4任意一项所述的3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物及其药学可接受的盐,及药学上可接受的辅料。
7.一种根据权利要求1-4任一项所述3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物及其药学可接受的盐或权利要求6所述的药物组物在制备预防或治疗PLAGL2介导疾病的药物中的应用。
8.根据权利要求7所述的应用,其特征在于,所述的PLAGL2介导疾病包括肝癌、乳腺癌、直肠癌、胃癌或前列腺癌。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202410006137.1A CN117843590A (zh) | 2024-01-03 | 2024-01-03 | 3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物、包含其的药物组合物及其制备方法、应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202410006137.1A CN117843590A (zh) | 2024-01-03 | 2024-01-03 | 3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物、包含其的药物组合物及其制备方法、应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117843590A true CN117843590A (zh) | 2024-04-09 |
Family
ID=90545443
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202410006137.1A Pending CN117843590A (zh) | 2024-01-03 | 2024-01-03 | 3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物、包含其的药物组合物及其制备方法、应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117843590A (zh) |
-
2024
- 2024-01-03 CN CN202410006137.1A patent/CN117843590A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2997051C (en) | Novel pyrazolo[3,4-d]pyrimidine compound or salt thereof | |
CA2924206C (en) | Pyrimidine fgfr4 inhibitors | |
RU2719428C2 (ru) | Индазольные соединения в качестве ингибиторов киназы fgfr, их получение и применение | |
TR201802632T4 (tr) | 6-(5-hidroksi-1H-pirazol-1-il)nikotinamid türevleri ve bunların PHD inhibitörleri olarak kullanımı. | |
JP6704422B2 (ja) | キナゾリン誘導体の塩およびその製造方法 | |
MX2010013843A (es) | Pirazolo-quinazolinas. | |
KR20190038485A (ko) | Fgfr4 저해제인 헤테로 고리 화합물 | |
CN112851663B (zh) | 一种并杂环化合物及其用途 | |
CN110563703B (zh) | 基于crbn配体诱导parp-1降解的化合物及制备方法和应用 | |
KR20060015283A (ko) | 신규한 피리도피라진 및 키나제 억제제로서의 이의 용도 | |
JP2008528564A (ja) | 抗ウイルス剤としてのキナゾリン誘導体 | |
JP2019520367A (ja) | 新規なヘテロサイクリック誘導体化合物およびその用途 | |
CN112745335A (zh) | 一种三并杂环化合物及其用途 | |
CN114516832B (zh) | 一种微管蛋白抑制剂及其制备方法与应用 | |
US20190169163A1 (en) | Quinoline derivative and use thereof | |
CN107903185B (zh) | 新型eEF2K抑制剂的制备及应用 | |
CN115819418B (zh) | Plk1激酶抑制剂及其制备方法和应用 | |
CN117843590A (zh) | 3-氨基-4-(哌嗪-1-基)苯甲酰胺类衍生物、包含其的药物组合物及其制备方法、应用 | |
CN112243437A (zh) | 含丙烯酰基的核转运调节剂及其用途 | |
US20230126473A1 (en) | Phosphorus imidazoquinoline amine derivatives, pharmaceutical compositions and therapeutic methods thereof | |
CN112979659B (zh) | 一类HIF-2α小分子抑制剂的制备及用途 | |
KR102606167B1 (ko) | 불소 함유 치환 벤조티오펜 화합물, 그의 약학적 조성물 및 응용 | |
AU2021398704A1 (en) | Heterocyclic jak inhibitor | |
KR20230065986A (ko) | Bcl-2 억제제로서의 헤테로시클릭 화합물 | |
WO2016127949A1 (zh) | 作为t790变异抑制剂的嘧啶衍生物 |
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 |