CN115073355A - 环庚烯并氮氧杂二萜衍生物及其药物组合物和其在制药中的应用 - Google Patents
环庚烯并氮氧杂二萜衍生物及其药物组合物和其在制药中的应用 Download PDFInfo
- Publication number
- CN115073355A CN115073355A CN202210820079.7A CN202210820079A CN115073355A CN 115073355 A CN115073355 A CN 115073355A CN 202210820079 A CN202210820079 A CN 202210820079A CN 115073355 A CN115073355 A CN 115073355A
- Authority
- CN
- China
- Prior art keywords
- acid
- cycloheptene
- pharmaceutically acceptable
- derivatives
- acceptable salts
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 Cycloheptene nitrogen oxygen hetero diterpene derivative Chemical class 0.000 title claims abstract description 46
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 239000003814 drug Substances 0.000 claims abstract description 25
- ZXIJMRYMVAMXQP-UHFFFAOYSA-N cycloheptene Chemical compound C1CCC=CCC1 ZXIJMRYMVAMXQP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 9
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 9
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 9
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 9
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 9
- 208000032839 leukemia Diseases 0.000 claims abstract description 9
- 201000005202 lung cancer Diseases 0.000 claims abstract description 9
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 9
- 201000007270 liver cancer Diseases 0.000 claims abstract description 7
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 7
- 239000003481 heat shock protein 90 inhibitor Substances 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims description 34
- 150000003839 salts Chemical class 0.000 claims description 28
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 150000007524 organic acids Chemical class 0.000 claims description 6
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 125000003107 substituted aryl group Chemical group 0.000 claims description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 5
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 claims description 4
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 4
- 239000004310 lactic acid Substances 0.000 claims description 4
- 235000014655 lactic acid Nutrition 0.000 claims description 4
- 235000005985 organic acids Nutrition 0.000 claims description 4
- 235000006408 oxalic acid Nutrition 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- 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 3
- 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 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 235000015165 citric acid Nutrition 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
- 229960000448 lactic acid Drugs 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 239000011664 nicotinic acid Substances 0.000 claims description 3
- 235000001968 nicotinic acid Nutrition 0.000 claims description 3
- 229960003512 nicotinic acid Drugs 0.000 claims description 3
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 2
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 claims description 2
- AWQSAIIDOMEEOD-UHFFFAOYSA-N 5,5-Dimethyl-4-(3-oxobutyl)dihydro-2(3H)-furanone Chemical compound CC(=O)CCC1CC(=O)OC1(C)C AWQSAIIDOMEEOD-UHFFFAOYSA-N 0.000 claims description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N Camphoric acid Natural products CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 claims description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-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
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 239000001361 adipic acid Substances 0.000 claims description 2
- 235000011037 adipic acid Nutrition 0.000 claims description 2
- 239000000783 alginic acid Substances 0.000 claims description 2
- 229920000615 alginic acid Polymers 0.000 claims description 2
- 229960001126 alginic acid Drugs 0.000 claims description 2
- 235000010443 alginic acid Nutrition 0.000 claims description 2
- 150000004781 alginic acids Chemical class 0.000 claims description 2
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 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
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 claims description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 claims description 2
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 claims description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 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
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 229920003175 pectinic acid Polymers 0.000 claims description 2
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 claims description 2
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 claims description 2
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 claims description 2
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical class CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 3
- 230000005764 inhibitory process Effects 0.000 abstract description 10
- 230000000259 anti-tumor effect Effects 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 8
- 238000002474 experimental method Methods 0.000 abstract description 6
- 108060001084 Luciferase Proteins 0.000 abstract description 5
- 239000005089 Luciferase Substances 0.000 abstract description 5
- 230000001419 dependent effect Effects 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 4
- 238000004153 renaturation Methods 0.000 abstract description 3
- 238000004925 denaturation Methods 0.000 abstract 1
- 230000036425 denaturation Effects 0.000 abstract 1
- 230000009982 effect on human Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 101
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- 235000019439 ethyl acetate Nutrition 0.000 description 34
- 239000003921 oil Substances 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 19
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 18
- 239000003208 petroleum Substances 0.000 description 18
- 229920006395 saturated elastomer Polymers 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 239000007864 aqueous solution Substances 0.000 description 15
- 239000012267 brine Substances 0.000 description 15
- 238000003818 flash chromatography Methods 0.000 description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000000546 pharmaceutical excipient Substances 0.000 description 12
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 101001016865 Homo sapiens Heat shock protein HSP 90-alpha Proteins 0.000 description 10
- 125000003118 aryl group Chemical group 0.000 description 10
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 9
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- GHTDODSYDCPOCW-UHFFFAOYSA-N 1h-indole-6-carboxylic acid Chemical compound OC(=O)C1=CC=C2C=CNC2=C1 GHTDODSYDCPOCW-UHFFFAOYSA-N 0.000 description 3
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- YJQPYGGHQPGBLI-UHFFFAOYSA-N Novobiocin Natural products O1C(C)(C)C(OC)C(OC(N)=O)C(O)C1OC1=CC=C(C(O)=C(NC(=O)C=2C=C(CC=C(C)C)C(O)=CC=2)C(=O)O2)C2=C1C YJQPYGGHQPGBLI-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Substances CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000006166 lysate Substances 0.000 description 3
- YJQPYGGHQPGBLI-KGSXXDOSSA-N novobiocin Chemical compound O1C(C)(C)[C@H](OC)[C@@H](OC(N)=O)[C@@H](O)[C@@H]1OC1=CC=C(C(O)=C(NC(=O)C=2C=C(CC=C(C)C)C(O)=CC=2)C(=O)O2)C2=C1C YJQPYGGHQPGBLI-KGSXXDOSSA-N 0.000 description 3
- 229960002950 novobiocin Drugs 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 210000001995 reticulocyte Anatomy 0.000 description 3
- 229940014800 succinic anhydride Drugs 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 108090000331 Firefly luciferases Proteins 0.000 description 2
- 101710113864 Heat shock protein 90 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 229930004069 diterpene Natural products 0.000 description 2
- 150000002611 lead compounds Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- WHKWMTXTYKVFLK-UHFFFAOYSA-N 1-propan-2-ylpiperazine Chemical compound CC(C)N1CCNCC1 WHKWMTXTYKVFLK-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- SMBXWJIRCAXTNE-UHFFFAOYSA-N 2-[[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]azaniumyl]acetate hydrochloride Chemical compound Cl.OCC(CO)(CO)NCC(O)=O SMBXWJIRCAXTNE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction 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
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 1
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 108010006519 Molecular Chaperones Proteins 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 238000010256 biochemical assay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 125000004639 dihydroindenyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000005046 dihydronaphthyl group Chemical group 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- RTIKCEKESDRWAE-UJVKWQRCSA-N eriocalyxin b Chemical class C([C@@H]1C[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(=O)C=CC(C)(C)[C@H]1[C@H](O)[C@@]3(O)OC2 RTIKCEKESDRWAE-UJVKWQRCSA-N 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 238000013537 high throughput screening Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000004650 oncogenic pathway Effects 0.000 description 1
- 102000027450 oncoproteins Human genes 0.000 description 1
- 108091008819 oncoproteins Proteins 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000000165 tricyclic carbocycle group Chemical group 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- 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
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供一种Hsp90抑制剂环庚烯并氮氧杂二萜衍生物及其药物组合物和其在制药中的应用，属于药物技术领域。所述的环庚烯并氮氧杂二萜衍生物具有如式(I)，(II)所示的化学结构，它们能用于制备治疗或预防肝癌、白血病、结肠癌、乳腺癌及肺癌的药物。本发明提供的环庚烯并氮氧杂二萜衍生物，Hsp90依赖性荧光素酶变性再复性实验结果显示良好的抑制活性。本发明环庚烯并氮氧杂二萜衍生物结构新颖，具有较强的抗肿瘤活性，尤其是对人乳腺癌细胞、人肝癌细胞和人白血病细胞，人结肠癌细胞，人肺癌细胞具有很好的抑制作用。该类化合物对抗肿瘤活性化合物发现具有重要意义，在抗肿瘤作用方面具有重要的应用价值。
Description
技术领域：
本发明属于药物技术领域，具体地，涉及环庚烯并氮氧杂二萜衍生物及其有机和无机酸盐，以其为药物有效成分的药物组合物，以及它们在制备治疗或预防癌症药物中的应用。
背景技术：
化疗是治疗癌症的重要手段，但对化疗药物来讲，不可避免面临耐药性与毒性问题。因此寻找高效低毒的抗癌药物及抗癌辅助药物是当前癌症研究的重要内容。
热休克蛋白90(Hsp90)作为一种ATP依赖性伴侣分子，是研究最多的热休克蛋白之一。在肿瘤细胞中，Hsp90的水平和功能会得到增加，其表达水平是正常细胞的2-10倍。在Hsp90抑制后，参与多种致癌途径的30多种癌蛋白同时被破坏，从而导致对癌症的组合攻击[Clin Cancer Res,2012,18(1):64-76]。因此，在过去的几十年中，为了发现治疗癌症的新药，Hsp90抑制剂已被广泛研究。
杂二萜化合物是较好的药物来源库，世界传统医学中使用的药物含有较多杂二萜物质，现代医学应用的化学药物中杂二萜化合物也占较高的比例，有不少药物是以杂二萜为先导化合物经过结构修饰和改造产生的，产物结构和生物活性的多样性可以提供新药或药物先导化合物。目前，现有技术未见有本发明涉及的环庚烯并氮氧杂二萜衍生物及其活性的报道。
发明内容：
针对现有技术存在的上述不足之处，本发明的目的在于：提供环庚烯并氮氧杂二萜衍生物，以及利用其单体或者有机酸(酒石酸，柠檬酸，甲酸，乙二酸等) 或无机酸(盐酸，硫酸，磷酸等)制成的盐；以及环庚烯并氮氧杂二萜衍生物及其药用盐的制备方法，它们在制备预防或治疗包括但不限于：肝癌、白血病、结肠癌、乳腺癌及肺癌的药物中的应用。
本发明的上述目的是通过如下的技术方案得以实现的：
通式(I)所示的二萜环庚烯并氮氧杂二萜衍生物或其药用盐，
R2为O，a和b为双键时，R1选自-OH、-F、-Cl、-OC＝OCH2COOH、-NHR、 -NR(R选自单取代芳基、C4-7的含杂原子环烷基)；R2为O，a，b为单键时，R4选自-OH，R1为-OH。
R2为N时，R1选自-OH、-F、-OC＝OCH2COOH、-NHR、-NR(R选自单取代芳基、C4-7的含杂原子环烷基)，R1为-CHO时、R3选自F、Cl。
通式(II)所示的二萜环庚烯并氮氧杂二萜衍生物或其药用盐，
R选自-OH、-F、-Cl、-OC＝OCH2COOH、-NHR、-NR(R为C4-7的含杂原子环烷基或芳基)。
通式(I)和(II)环庚烯并氮氧杂二萜衍生物或其药学上容许的盐，包括但不限于下述结构式所示的化合物：
如所述的通式(I)和(II)环庚烯并氮氧杂二萜衍生物或其药用盐，其中，所述的药用盐是指药学上可接受的盐，指与有机酸形成的盐，所述的有机酸包括但不限于酒石酸、柠檬酸、甲酸、乙酸、乙二酸、丁酸、草酸、马来酸、琥珀酸、己二酸、藻酸、天冬氨酸、苯磺酸、樟脑酸、樟脑磺酸、二葡糖酸、环戊烷丙酸、十二烷基硫酸、乙磺酸、葡庚糖酸、甘油磷酸、半硫酸、庚酸、己酸、延胡索酸、 2-羟基乙磺酸、乳酸、甲磺酸、烟酸、2-萘磺酸、扑酸、果胶酯酸、3-苯基丙酸、苦味酸、新戊酸、丙酸、硫代氰酸、对甲苯磺酸盐、十一烷酸盐。
本发明同时提供了一种药物组合物，含有所述的环庚烯并氮氧杂二萜衍生物或其药用盐任其一或任其组合及可药用载体。
本发明还提供了所述的环庚烯并氮氧杂二萜衍生物或其药用盐在制备抗肿瘤药物中的应用。
以及，所述的环庚烯并氮氧杂二萜衍生物或其药用盐在制备治疗或预防乳腺癌、肝癌、白血病、肺癌、结肠癌的药物中的应用。
再及，所述的环庚烯并氮氧杂二萜衍生物或其药用盐在制备Hsp90活性抑制剂中的应用。
除非另作说明，本发明使用的术语“环烷基”是指环状饱和桥和/或非桥的一价烃基，其可以任选地被一个或多个本发明所述的取代基取代。在某些实施方式中，环烷基具有从3到20(C3-20)、从3到15(C3-15)、从3到12(C3-12)、从3到10(C3-10)、或者从3到7(C3-7)个碳原子。环烷烃基的实施方式包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、十氢萘基和金刚烷基。
除非另作说明，本发明使用的术语“杂原子”是指除了碳或者氢以外的其他任何原子。在某些实施方式中，术语“杂原子”是指N、O、S、Si或P。在其他实施方式中，术语“杂原子”是指N、O或者S。
除非另作说明，本发明使用的术语“芳基”是指单环芳基和/或包含至少一个芳香烃环的多环单价芳基。在某些实施方式中，芳基具有从6到20(C6-20)、从6 到15(C6-15)、或者从6到10(C6-10)个环原子。芳基的实施方式包括苯基、萘基、芴基、薁基(azulenyl)、蒽基、菲基、芘基、联苯基和三联苯基。芳基也指其中一个环是芳香族的和其他环可以是饱和的，部分不饱和的或者芳香族的二环或者三环的碳环，例如二氢萘基、茚基、二氢茚基或者四氢萘基(萘满基(tetralinyl))。在某些实施方式中，芳基也可以任选地被一个或多个取代基取代。
除非另作说明，本发明使用的术语“药学上可接受的盐”是指由药学上可接受的无毒的酸制备而成的盐，主要是有机酸。本发明的组合物可以是任何合适形式，例如固体，半固体，液体或气溶胶形式。一般情况下，药物含有本发明的化合物或提取物作为活性成分，与适合外部，肠道，或肠胃外给药的有机或无机载体或赋形剂混合。活性成分可以是复方的，所述药物组合物还包括药学上可接受的助剂；优选地，所述抗癌药物为片剂、胶囊粉、针剂、或注射剂。
本发明化合物用作药物时，可以直接使用，或者以药物组合物的形式使用。该药物组合物含有0.1-99％，优选0.5-90％的本发明化合物，其余为药物学上可接受的，对人和动物无毒和惰性的可药用载体和/或赋形剂。
所述的药用载体或赋形剂是一种或多种固体、半固体和液体稀释剂、填料以及药物制品辅剂。将本发明的药物组合物以单位体重服用量的形式使用。本发明的药物可经多种形式(液体制剂、固体制剂、注射剂、外用制剂、喷剂、复方制剂)给药。
与现有技术相比，本发明具备如下的优益性：
1.本发明提供了一类新的环庚烯并氮氧杂二萜衍生物或其药用盐，填补了现有技术的空白。
2.本发明提供了制备环庚烯并氮氧杂二萜衍生物或其药用盐的方法，该方法原料易得，易于操作，收率高，适于工业化生产。
3.本发明提供了环庚烯并氮氧杂二萜衍生物或其药用盐作为有效成分的药物组合物，为新的抗肿瘤药物提供了具有较好药用作用的新的药物。
4.本发明环庚烯并氮氧杂二萜衍生物对包括人乳腺癌细胞株(SK-BR-3),人肝癌细胞株(SMMC7721),人白血病细胞株(HL-60),人结肠癌细胞株(SW480)，人肺癌细胞株(A549)生长的半数抑制浓度(IC50)在2.878-40μM之间。显示此类结构新颖的环庚烯并氮氧杂二萜衍生物具有较好的抗肿瘤应用前景。
5.本发明环庚烯并氮氧杂二萜衍生物具有明显的抑制Hsp90活性。
6.本发明环庚烯并氮氧杂二萜衍生物或其药用盐可作为药物用于治疗相关的疾病。可用于制备抗肿瘤药物，用于制备治疗或预防肝癌、结肠癌、肺癌、乳腺癌、白血病的药物。
7.本发明环庚烯并氮氧杂二萜衍生物对Hsp90蛋白具有较强抑制活性(见表 1)。目前未曾见过报道环庚烯并氮氧杂二萜衍生物类似的应用，因此环庚烯并氮氧杂二萜衍生物具有极高的应用价值。
附图说明
图1为本发明环庚烯并氮氧杂二萜衍生物通式结构式I和II示意图。
具体实施方式：
下面结合附图，用本发明的实施例来进一步说明本发明的实质性内容，但并不以此来限定本发明。
实施例1
化合物2的制备
黄色油状物；产率：54％。将1(50.0mg,0.12mmol)和(1mL)DCM装入5 mL圆底烧瓶。然后加入DCC(51.9mg,0.25mmol)、DMAP(10.7mg,0.06mmol) 和吲哚-6-羧酸(40.54mg,0.25mmol)并在室温下搅拌12小时。加入NaHCO3饱和水溶液和乙酸乙酯(10mL)淬灭反应，将有机层用盐水(10mL×3)洗涤，经Na2SO4干燥，并在真空下浓缩。残余物通过硅胶快速色谱法纯化(石油醚/乙酸乙酯2:1 v/v)。1H NMR(600MHz,CDCl3)δ8.65(brs,1H),8.43(brs,1H),8.16(s,1H),7.82– 7.79(m,1H),7.65(d,J＝8.3Hz,1H),7.36(d,J＝2.7Hz,1H),7.09(d,J＝12.3Hz, 1H),6.59(s,1H),5.72–5.69(m,1H),5.66(s,1H),5.63(dd,J＝6.9,3.6Hz,1H),5.57(dd,J＝12.2,9.2Hz,1H),5.20(d,J＝12.0Hz,1H),5.00(d,J＝12.0Hz,2H), 3.19(d,J＝9.1Hz,1H),2.42(dd,J＝18.2,3.2Hz,1H),2.22(d,J＝8.9Hz,1H),2.18 (s,3H),2.14–2.09(m,1H),1.94(d,J＝13.4Hz,2H),1.91(s,3H),1.59(s,3H),1.48 (s,3H),1.27(dd,J＝17.2,8.3Hz,4H),1.00(s,3H).13C NMR(150MHz,CDCl3)δ 168.2,163.6,158.9,135.9,135.1,131.7,130.9,127.6,127.5,126.5,126.4,125.1, 124.0,123.6,123.3,120.9,120.3,116.6,115.2,113.9,109.7,103.0,68.9,46.6,38.7, 36.5,29.7,27.6,25.9,25.7,22.6,20.4,17.3,13.1.HRMS(ESI):m/z calcd.for C34H41N2O4[M+H]+:541.3061；found:541.3058。
实施例2
化合物3的制备
黄色油状物；产率：40％。将1(100.0mg,0.25mmol)和(1mL)DCM装入5mL 圆底烧瓶。然后加入Ph3P(127.4mg，0.50mmol)、NCS(64.9mg，0.50mmol)并在0℃搅拌2h。加入NaHCO3饱和水溶液和乙酸乙酯(10mL)淬灭反应，有机相用盐水(10mL×3)洗涤层，用Na2SO4干燥，并在真空下浓缩。残余物通过硅胶快速色谱法纯化(石油醚/乙酸乙酯2:1v/v)，得到黄色油状物。1H NMR(400MHz, CDCl3)δ10.29(brs,1H),9.35(s,1H),7.04(d,J＝12.3Hz,1H),6.28(dd,J＝7.5, 3.1Hz,1H),5.72–5.54(m,1H),5.36(dd,J＝12.3,8.8Hz,1H),4.94(t,J＝7.1Hz, 1H),3.38(dd,J＝8.9,2.2Hz,1H),2.74(dd,J＝20.5,3.2Hz,1H),2.42(ddd,J＝20.5, 7.5,2.3Hz,1H),2.22(s,3H),2.17(d,J＝1.3Hz,3H),1.90(d,J＝1.3Hz,3H),1.86(s,1H),1.59(s,3H),1.41(s,3H),1.27–1.25(m,1H),1.12(s,3H),0.86(qd,J＝7.5, 6.3,3.9Hz,4H).13C NMR(100MHz,CDCl3)δ196.6,163.3,159.6,149.4,137.2, 131.5,131.4,124.4,124.3,120.9,119.4,114.9,114.2,110.8,42.9,40.9,38.5,35.6, 27.6,26.5,25.7,22.2,20.5,17.1,11.0.HRMS(ESI):m/z calcd.for C25H33ClNO3 [M+H]+:430.2143；found:430.2145。
实施例3
化合物4的制备
黑色油状物；产率：51％。将1(50.0mg,0.12mmol)和(1mL)DCM装入 5mL圆底烧瓶。然后，加入DAST(0.03mL，0.24mmol)并在-78℃搅拌反应3 小时。反应完成后加入NaHCO3饱和水溶液和乙酸乙酯(10mL)淬灭反应，将有机层用盐水(10mL×3)洗涤，经Na2SO4干燥，并在真空下浓缩。残余物通过硅胶快速色谱法纯化(石油醚/乙酸乙酯10:1v/v)。1H NMR(600MHz,CDCl3)δ8.01(s, 1H),7.10(d,J＝12.4Hz,1H),5.71(s,1H),5.64(s,1H),5.46(dd,J＝20.4,9.4Hz, 2H),5.21–5.06(m,2H),4.99(d,J＝9.1Hz,1H),3.16(d,J＝9.7Hz,1H),2.38(dd, J＝19.7,10.2Hz,1H),2.20(d,J＝22.6Hz,3H),2.09(d,J＝18.8Hz,1H),1.90(s, 3H),1.61(s,3H),1.48(s,3H),1.26(d,J＝12.3Hz,4H),0.97(s,3H),0.91–0.76(m, 2H).13C NMR(150MHz,CDCl3)δ163.7,159.4,135.9,131.2,128.0,126.2,126.1,125.2,124.3,123.9,116.5,115.3,109.7,88.7(d,J＝161.1Hz),46.7,39.0,36.4,29.9,27.8,26.1,25.9,22.7,20.7,17.5.HRMS(ESI):m/z calcd.for C25H35FNO2[M+H]+:400.2646；found:400.2650。
实施例4
化合物5的制备
黄色油状物；产率：42％。将1(50.0mg,0.12mmol)和DCM(1mL)装入 5mL圆底烧瓶。然后加入Et3N(35.3μl，0.25mmol)、DMAP(0.31mg，2.51μmol) 和琥珀酸酐(25.1mg，0.25mmol)并在室温下搅拌3h。加入NaHCO3饱和水溶液和乙酸乙酯(10mL)淬灭反应，有机层用盐水(10mL×3)洗涤，经Na2SO4干燥，真空浓缩。残余物通过硅胶快速色谱法纯化(石油醚/乙酸乙酯1:1v/v)。1H NMR (400MHz,CDCl3)δ8.82(brs,1H),7.10(d,J＝12.2Hz,1H),5.69(s,1H),5.65(s, 1H),5.49(t,J＝10.8Hz,2H),5.01(s,1H),4.81(q,J＝11.8Hz,2H),3.16(s,1H), 3.09(m,3H),2.6(s,3H),2.35(dd,J＝18.2,3.8Hz,1H),2.19(s,3H),2.11–2.02(m, 1H),1.91(s,3H),1.61(s,3H),1.49(s,3H),1.28(t,J＝7.1Hz,6H),0.96(s,2H).13CNMR(100MHz,CDCl3)δ176.78,173.69,163.57,159.10,135.40,130.94,127.92, 126.37,125.89,125.12,123.83,123.73,116.59,115.07,109.42,69.30,46.68,45.43, 38.79,38.49,36.46,30.69,30.36,27.57,25.73,22.59,20.43,17.32,12.99. HRMS(ESI):m/zcalcd.for C29H38NO6[M-H]-:496.2705；found:496.2707。
实施例5
化合物6的制备
黄色油状物；产率：45％。将1(100.0mg,0.20mmol)和(1mL)DCM装入 5mL圆底烧瓶。然后加入EDCI(76.6mg,0.40mmol)、DMAP(12.3mg,0.10mmol) 和4-氟-苯胺(44.7mg,0.40mmol)并在室温搅拌12小时。加入NaHCO3饱和水溶液和乙酸乙酯(10mL)淬灭反应，将有机层用盐水(10mL×3)洗涤，经Na2SO4干燥，并在真空下浓缩。残余物通过硅胶快速色谱法纯化(石油醚/乙酸乙酯4:1v/v)，得到黄色油状物(40mg，40％)。1H NMR(600MHz,CDCl3)δ8.39(brs,1H),7.68(s, 1H),7.40(d,J＝4.1Hz,1H),6.99(dd,J＝10.1,7.8Hz,2H),5.66(s,1H),5.64(s, 1H),5.57(dd,J＝12.2,8.7Hz,1H),5.47(dd,J＝6.9,3.4Hz,1H),4.99(d,J＝7.1 Hz,1H),4.95(d,J＝12.1Hz,1H),4.73(d,J＝11.9Hz,1H),3.17(d,J＝8.7Hz,1H),2.81–2.76(m,1H),2.68(d,J＝6.8Hz,1H),2.36(dd,J＝18.3,3.4Hz,1H),2.15(s, 3H),2.06(s,3H),2.04(d,J＝6.4Hz,1H),1.91(s,3H),1.65(s,4H),1.60(s,3H), 1.47(s,3H),1.23(ddt,J＝28.5,11.9,4.7Hz,4H),0.99(s,3H).13C NMR(150MHz, CDCl3)δ173.3,169.7,163.8,159.3(JC,F＝235.2),159.4,136.3,133.7,131.0,128.0, 126.2,125.9,125.1,123.7,123.4,121.8,121.8,116.5,115.5,115.4,115.1,109.6, 69.4,46.3,38.9,38.7,36.3,31.9,29.7,27.6,25.9,25.7,22.5,20.5,17.3,12.9. HRMS(ESI):m/z calcd.forC35H44FN2O5[M+H]+:591.3229；found:591.3235。
实施例6
化合物8的制备
黄色油状物；产率：63％。将化合物7(50.0mg,0.12mmol)和(1.5mL)DCM 装入5mL圆底烧瓶。然后加入DCC(51.9mg,0.25mmol)、DMAP(7.7mg,0.06 mmol)和吲哚-6-羧酸(40.5mg,0.25mmol)并在室温下搅拌12小时。加入NaHCO3饱和水溶液和乙酸乙酯(10mL)淬灭反应，将有机层用盐水(10mL×3)洗涤，经 Na2SO4干燥，并在真空下浓缩。残余物通过硅胶快速色谱法纯化(石油醚/乙酸乙酯5:1v/v)。1H NMR(600MHz,CDCl3)δ8.90(brs,1H),8.13(s,1H),7.82(d,J＝ 8.3Hz,1H),7.64(d,J＝8.3Hz,1H),7.34(t,J＝2.6Hz,1H),7.06(d,J＝12.3Hz, 1H),6.58(s,1H),5.85(s,1H),5.72(dd,J＝7.1,3.3Hz,1H),5.69(s,1H),5.55(dd,J ＝12.3,8.4Hz,1H),5.31(d,J＝12.7Hz,1H),5.01(t,J＝6.9Hz,1H),4.97(d,J＝11.9Hz,1H),3.14(d,J＝8.3Hz,1H),2.42(d,J＝18.2Hz,1H),2.20(s,3H),2.15(s, 3H),1.93(s,3H),1.68(dd,J＝13.7,3.8Hz,2H),1.60(s,3H),1.49(s,3H),1.25(t,J ＝5.3Hz,2H),1.10(m,1H),1.02(s,3H).13C NMR(150MHz,CDCl3)δ167.6, 163.6,159.4,150.6,145.9,136.9,135.2,131.3,131.2,127.3,126.7,125.5,124.7, 123.9,123.4,120.9,120.0,115.7,115.1,113.8,110.3,102.7,66.0,49.1,44.7,38.5, 38.0,35.9,33.9,27.6,24.9,22.5,20.5,17.3.HRMS(ESI):m/z calcd.for C34H39NO5Na[M+Na]+:564.2720；found:564.2727。
实施例7
化合物9的制备
黄色油状物；产率：43％。化合物7(100.0mg,0.25mmol)和(1mL)DCM 装入5mL圆底烧瓶。然后加入Ph3P(127.5mg,0.50mmol)、NCS(64.9mg,0.50 mmol)并在0℃搅拌2小时。加入NaHCO3饱和水溶液和乙酸乙酯(10mL)淬灭反应，将有机层用盐水(10mL×3)洗涤，经Na2SO4干燥，并在真空下浓缩。残余物通过硅胶快速色谱法纯化(石油醚/乙酸乙酯2:1v/v)。1HNMR(400MHz,CDCl3)δ 7.03(dd,J＝12.4,2.2Hz,1H),5.80(s,1H),5.63(dt,J＝6.5,2.8Hz,1H),5.59(s, 1H),5.33(ddd,J＝12.0,9.3,2.2Hz,1H),4.94(t,J＝7.3Hz,1H),4.37–4.28(m, 2H),3.00(d,J＝9.5Hz,1H),2.29(dd,J＝17.9,4.0Hz,1H),2.19(s,3H),2.12(s, 3H),2.00(dd,J＝18.2,7.4Hz,1H),1.84(s,3H),1.55(s,3H),1.45(s,3H),1.25– 1.13(m,3H),0.89(d,J＝2.2Hz,3H),0.85–0.62(m,1H).13C NMR(100MHz, CDCl3)δ163.4,159.7,150.7,144.7,137.2,137.1,136.5,131.3,126.6,124.7,115.6, 114.9,110.8,46.1,45.2,38.6,37.4,35.8,27.6,25.7,25.5,22.6,20.5,17.5,13.6. HRMS(ESI):m/z calcd.forC25H33ClO3Na[M+Na]+:439.2010；found:439.2017。
实施例8
化合物10的制备
黄色油状物；产率：40％。将7(50.0mg,0.12mmol)和(1.5mL)DCM装入 5mL圆底烧瓶。然后加入DAST(0.03mL,0.25mmol)，在0℃搅拌5h。加入 NaHCO3饱和水溶液和乙酸乙酯(10mL)淬灭反应，有机层用盐水(10mL×3)，用Na2SO4干燥，真空浓缩。残余物通过硅胶快速色谱法纯化(石油醚/乙酸乙酯10:1 v/v)。1H NMR(600MHz,CDCl3)δ7.09(d,J＝12.3Hz,1H),5.86(s,1H),5.70– 5.67(m,1H),5.66(s,1H),5.40(dd,J＝12.3,9.5Hz,1H),5.18(s,1H),5.10(s,1H), 5.00(t,J＝7.2Hz,1H),3.08(d,J＝9.5Hz,1H),2.39(dd,J＝16.5,7.8Hz,1H),2.24 (s,3H),2.19(s,3H),2.11(d,J＝17.9Hz,1H),1.92(s,3H),1.62(s,3H),1.51(s,3H), 1.25(t,J＝11.0Hz,4H),0.98(s,3H).13C NMR(150MHz,CDCl3)δ163.4,159.7, 150.6,145.0,136.4,131.3,127.4,126.3,124.6,124.3,115.6,114.9,110.6,84.0(d, JC,F＝166.9Hz),45.0,38.5,37.6,35.6,29.7,27.6,25.7,22.5,20.5,17.4,13.6. HRMS(ESI):m/z calcd.for C25H33FO3Na[M+Na]+:423.2306；found:423.2308。
实施例9
化合物11的制备
黄色油状物；产率63％。将9(45.0mg,0.10mmol)和(1mL)THF装入5mL 圆底烧瓶。然后加入NaI(32.3mg，0.20mmol)并在室温搅拌10分钟。加入4-氟苯胺(24.0mg，0.20mmol)，将所得混合物在50℃搅拌12小时。完成后，将所得混合物真空浓缩，并通过硅胶色谱法纯化(石油醚/乙酸乙酯1:1v/v)。1H NMR(500 MHz,CDCl3)δ7.05(s,1H),6.85(td,J＝9.3,8.8,2.9Hz,3H),6.58–6.47(m,2H), 6.32(t,J＝6.5Hz,1H),5.67(s,1H),5.59–5.50(m,1H),5.02(s,1H),4.51(d,J＝ 15.4Hz,1H),4.39(d,J＝15.5Hz,1H),2.83(d,J＝11.0Hz,1H),2.68(s,3H),2.19 (s,3H),2.13–2.07(m,1H),1.94(s,4H),1.89–1.84(m,1H),1.67(s,3H),1.57(s, 3H),1.52(d,J＝5.2Hz,1H),1.24(dt,J＝16.6,8.3Hz,3H),0.82(s,3H).13C NMR(125MHz,CDCl3)δ162.8,160.5,157.5,157.4,156.0(JC,F＝235.2Hz),144.0,142.7,138.3,136.7,132.0,131.8,125.9,124.1,115.7,115.5,115.2,115.1,114.5,109.0,48.9,47.8,39.4,37.0,27.6,27.6,25.7,23.2,22.5,22.2,20.6,17.6.HRMS(ESI):m/zcalcd.for C31H39FNO3[M+H]+:492.2908；found:492.2912。
实施例10
化合物12的制备
黄色油状物；产率：52％。将9(20.0mg,0.05mmol)和(1mL)THF装入5mL 圆底烧瓶。然后，加入NaI(14.4mg，0.10mmol)并在室温搅拌10分钟。加入咪唑 (6.8mg，0.10mmol)在50℃搅拌12小时。反应完成后，将所得混合物真空浓缩，并通过硅胶色谱法纯化(石油醚/乙酸乙酯2:1v/v)。1H NMR(400MHz,CDCl3) δ7.55(s,1H),7.06(d,J＝12.3Hz,1H),7.01(s,1H),6.93(s,1H),5.83(s,1H),5.66 (s,1H),5.44–5.30(m,2H),4.98(t,J＝7.2Hz,1H),4.90–4.78(m,2H),3.05(d,J＝ 9.4Hz,1H),2.34(dd,J＝17.8,3.9Hz,1H),2.19(d,J＝4.5Hz,6H),2.10–2.01(m, 1H),1.92(s,3H),1.63(s,3H),1.50(s,3H),1.35–1.08(m,4H),0.95(s,3H).13C NMR(100MHz,CDCl3)δ163.4,159.8,150.7,144.9,136.6,131.3,131.3,127.4,124.7,124.7,124.6,124.6,115.5,114.8,114.8,110.9,49.8,45.2,38.5,37.2,35.6,27.6,25.7,25.5,22.6,20.5,17.5,13.5.HRMS(ESI):m/z calcd.for C28H37N2O3 [M+H]+:449.2799；found:449.2795。
实施例11
化合物13的制备
黄色油状物；产率：63％。将7(50.0mg,0.12mmol)和(1.5mL)DCM装入 5mL圆底烧瓶。然后加入Et3N(35.2μl，0.25mmol)、DMAP(0.3mg，2.51μmol) 和琥珀酸酐(24.1mg，0.25mmol)并在室温下搅拌5h。加入NaHCO3饱和水溶液淬灭反应和乙酸乙酯(10mL)，有机层用盐水(10mL×3)洗涤，经Na2SO4干燥，真空浓缩。残余物通过硅胶快速色谱法纯化(石油醚/乙酸乙酯1:1v/v)。1H NMR (600MHz,CH3OD)δ7.00(d,J＝12.3Hz,1H),5.90(s,1H),5.69(s,1H),5.66(d,J ＝3.7Hz,1H),5.41(dd,J＝12.3,9.2Hz,1H),4.99(t,J＝7.1Hz,1H),4.09(d,J＝ 7.1Hz,2H),3.14(d,J＝9.0Hz,1H),2.61–2.56(m,3H),2.36(d,J＝18.3Hz,1H),2.23(s,2H),2.17(s,3H),2.00(s,3H),1.93(s,3H),1.61(s,3H),1.49(s,3H),1.28 (m,2H),1.23(t,J＝7.1Hz,2H),0.98(s,3H).13C NMR(150MHz,MeOD)δ176.0, 174.1,164.8,161.4,151.9,146.9,138.0,132.0,127.7,127.2,125.8,125.5,116.8, 115.6,111.6,66.8,45.9,39.7,38.8,36.7,30.2,27.5,26.2,25.9,23.5,20.5,17.5,14.5, 13.4.HRMS(ESI):m/z calcd.for C29H38O7Na[M+Na]+:521.2510；found:521.2515。
实施例12
化合物14的制备
黄色油状物；产率：47％。将13(50.0mg,0.10mmol)和(1mL)DCM装入 5mL圆底烧瓶。然后加入EDCI(37.3mg,0.20mmol)、DMAP(6.0mg,0.20mmol) 和4-氟苯胺(21.8mg,0.20mmol)并在室温搅拌12小时。加入NaHCO3饱和水溶液和乙酸乙酯(10mL)淬灭反应，将有机层用盐水(10mL×3)洗涤，经Na2SO4干燥，并在真空下浓缩。残余物通过硅胶快速色谱法纯化(石油醚/乙酸乙酯1:1v/v)。1H NMR(600MHz,CDCl3)δ7.92(s,1H),7.46–7.42(m,2H),7.01–6.96(m,3H), 5.80(s,1H),5.67(s,1H),5.59(dd,J＝7.2,3.5Hz,1H),5.48(dd,J＝12.3,8.6Hz, 1H),5.02(d,J＝11.8Hz,1H),4.98(s,1H),4.79(d,J＝11.8Hz,1H),3.09(d,J＝8.6 Hz,1H),2.83(dt,J＝17.4,6.6Hz,1H),2.77–2.72(m,1H),2.65–2.61(m,2H), 2.34(dd,J＝18.4,3.1Hz,1H),2.16(s,3H),2.12(s,3H),2.05(dd,J＝17.9,6.8Hz, 1H),1.93–1.91(m,3H),1.87(dd,J＝11.5,5.8Hz,2H),1.62(s,3H),1.49(s,3H), 1.22–1.19(m,2H),0.98(s,3H).13C NMR(150MHz,CDCl3)δ173.0,170.0,163.8, 160.2,159.4(JC,F＝235.2Hz),150.9,145.8,137.2,134.3,131.5,126.6,126.3,124.8, 123.9,121.7,121.6,115.7,115.7,115.6,115.0,110.7,66.6,44.8,38.7,38.2,36.0, 32.3,30.1,27.9,26.0,25.9,22.7,20.7,17.6,13.7.HRMS(ESI):m/z calcd.for C35H42FNO6Na[M+Na]+:614.2888；found:614.2893。
实施例13
化合物16的制备
无色油状物；产率：43％。将15(100.0mg,0.25mmol)和(1.5mL)DCM装入5mL圆底烧瓶。然后加入Et3N(0.07mL，0.50mmol)、DMAP(6.9mg，0.05mmol) 和琥珀酸酐(48.8mg，0.50mmol)并在室温下搅拌5小时。然后通过加入NaHCO3饱和水溶液淬灭反应和乙酸乙酯(10mL)，有机层用盐水(10mL×3)洗涤，经 Na2SO4干燥，真空浓缩。残余物通过硅胶快速色谱法纯化(DCM/乙酸乙酯1:1v/v)。1H NMR(600MHz,CD3OD)δ7.50(s,1H),7.21(d,J＝12.3Hz,1H),6.56(t,J＝ 6.8Hz,1H),5.90–5.82(m,1H),5.73(s,1H),5.22(q,J＝12.6Hz,2H),5.07(t,J＝ 7.5Hz,1H),3.66(s,1H),2.66(s,3H),2.58–2.52(m,4H),2.30–2.22(m,1H),2.18(s,3H),1.95(s,3H),1.65(s,3H),1.59(s,2H),1.37(dd,J＝11.9,4.5Hz,2H),1.33– 1.25(m,3H),1.16(d,J＝7.1Hz,1H),0.92(s,3H).13C NMR(150MHz,MeOD)δ 175.8,174.0,164.5,162.3,159.5,158.2,145.0,139.7,135.8,135.3,132.5,128.5, 125.4,115.2,110.9,66.9,40.9,38.3,30.0,29.8,29.7,29.7,27.6,25.9,24.3,23.3, 21.6,20.6,17.7.HRMS(ESI):m/z calcd.for C29H37N2O6[M-H]-:509.2657；found: 509.2658。
实施例14
化合物17的制备
黄色油状物；产率：50％。将16(100.0mg,0.20mmol)和(1mL)DCM装入 5mL圆底烧瓶。然后加入EDCI(76.5mg，0.40mmol)、DMAP(12.1mg，0.10mmol) 和4-氟苯胺(44.6mg，0.40mmol)并在室温搅拌12小时。加入NaHCO3饱和水溶液和乙酸乙酯(10mL)淬灭反应，将有机层用盐水(10mL×3)洗涤，经Na2SO4干燥，并在真空下浓缩。残余物通过硅胶快速色谱法纯化(石油醚/乙酸乙酯3:1v/v)。1H NMR(600MHz,CDCl3)δ8.14(s,1H),7.47(dd,J＝8.8,4.8Hz,2H),7.20(d,J ＝12.3Hz,1H),7.10(s,1H),6.95(t,J＝8.6Hz,2H),6.47(t,J＝6.8Hz,1H),5.76–5.67(m,2H),5.31(d,J＝12.3Hz,1H),5.20(d,J＝12.3Hz,1H),5.02(t,J＝6.8Hz, 1H),3.14(d,J＝11.0Hz,1H),2.74–2.70(m,1H),2.68(s,3H),2.56(tt,J＝15.2,8.5Hz,2H),2.17(s,3H),2.02–1.97(m,1H),1.95(s,3H),1.90(q,J＝6.3Hz,1H), 1.66(s,3H),1.57(s,3H),1.33(ddt,J＝26.6,12.2,6.7Hz,3H),1.26(d,J＝11.2Hz, 2H),0.89(s,3H).13C NMR(150MHz,CDCl3)δ173.0,170.0,163.4,161.4,159.4 (JC,F＝242.8Hz),158.0,156.8,142.5,138.4,134.8,134.7,134.4,132.0,126.3,124.2, 121.9,121.9,115.6,115.5,114.6,109.6,66.9,48.7,39.5,37.2,32.6,30.2,29.9,27.9, 25.9,23.3,22.8,22.3,20.9,17.8.HRMS(ESI):m/z calcd.for C35H43FN3O5[M+H]+: 604.3187；found:604.3185。
实施例15
化合物18的制备
黄色油状物；产率：67％。将15(50.0mg,0.12mmol)和(1mL)DCM装入 5mL圆底烧瓶。然后，加入Ph3P(63.9mg，0.25mmol)、NCS(36.0mg，0.25mmol) 并在0℃搅拌2小时。加入NaHCO3饱和水溶液和乙酸乙酯(10mL)淬灭反应，有机相用盐水(10mL×3)洗涤层，用Na2SO4干燥，并在真空下浓缩。残余物通过硅胶快速色谱法纯化(石油醚/乙酸乙酯2:1v/v)。1HNMR(400MHz,CDCl3)δ7.20 (d,J＝12.3Hz,1H),7.13(s,1H),6.51(t,J＝7.0Hz,1H),5.77–5.67(m,2H),5.07 (t,J＝6.7Hz,1H),4.99(d,J＝11.3Hz,1H),4.63(d,J＝11.3Hz,1H),3.18(d,J＝ 11.1Hz,1H),2.71(s,3H),2.20(s,3H),2.19–2.13(m,2H),1.95(s,3H),1.68(s, 3H),1.60(s,3H),1.45–1.34(m,2H),1.26(s,2H),0.88(s,3H).13C NMR(150MHz,CDCl3)δ162.8,160.7,158.0,156.2,142.4,138.4,136.7,133.5,131.8,125.7,124.0,114.4,108.9,49.3,47.9,46.2,39.3,36.6,27.6,25.6,23.2,22.4,22.2,20.5,17.6. HRMS(ESI):m/z calcd.for C25H34ClN2O2[M+H]+:429.2303；found:429.2303。
实施例16
化合物19的制备
黄色油状物；产率：63％。将18(30.0mg,0.07mmol)和(1mL)THF装入 5mL圆底烧瓶。然后加入NaI(21.0mg，0.14mmol)并在室温搅拌10分钟。加入 4-氟苯胺(15.6mg，0.14mmol)，将所得混合物在50℃搅拌12小时。反应完成后，将所得混合物真空浓缩，并通过硅胶色谱法纯化(石油醚/乙酸乙酯5:1v/v)。1H NMR(500MHz,CDCl3)δ7.05(d,J＝12.4Hz,1H),6.85(t,J＝8.7Hz,2H),6.61– 6.51(m,2H),5.85(s,1H),5.66(d,J＝1.2Hz,1H),5.52(dd,J＝7.1,3.7Hz,1H), 5.38(dd,J＝12.4,9.3Hz,1H),4.93(t,J＝6.5Hz,1H),4.06(d,J＝6.5Hz,2H),3.05 (d,J＝9.3Hz,1H),2.30(d,J＝16.0Hz,1H),2.23(s,3H),2.19(s,3H),2.05–1.99 (m,1H),1.92(s,3H),1.89–1.83(m,2H),1.63(s,3H),1.50(s,3H),1.26–1.13(m, 3H),0.93(s,3H).13C NMR(125MHz,CDCl3)δ163.5,159.7,155.9(JC,F＝242.6Hz),150.2,146.3,144.4,136.5,131.1,127.9,124.8,124.0,123.0,115.6,115.5,115.4,114.9,114.4,114.3,110.7,47.9,45.1,38.6,37.4,35.7,27.6,25.6,25.6,22.5,20.5,17.4,13.6.HRMS(ESI):m/z calcd.for C31H39FN3O2[M+H]+:504.3021； found:504.3023。
实施例17
化合物20的制备
黄色油状物；产率：40％。将15(40.0mg,0.09mmol)和(1mL)DCM装入 5mL圆底烧瓶中。加入DCC(39.6mg，0.18mmol)、DMAP(2.3mg，0.02mmol)和吲哚-6-羧酸(31.0mg，0.18mmol)并在室温搅拌12小时。加入NaHCO3饱和水溶液和乙酸乙酯(10mL)淬灭反应，将有机层用盐水(10mL×3)洗涤，经Na2SO4干燥，并在真空下浓缩。残余物通过硅胶快速色谱法纯化(石油醚/乙酸乙酯2:1v/v)。1H NMR(600MHz,CDCl3)δ9.54(brs,1H),7.79(s,1H),7.72(d,J＝8.4Hz,1H), 7.55(d,J＝8.3Hz,1H),7.29(d,J＝12.3Hz,1H),7.23(t,J＝2.7Hz,1H),7.05(s, 1H),6.51(t,J＝7.2Hz,1H),6.47(s,1H),5.80(t,J＝11.7Hz,1H),5.70(s,1H),5.66 (d,J＝11.5Hz,1H),5.08(d,J＝11.5Hz,1H),5.01(t,J＝6.9Hz,1H),3.35(d,J＝11.1Hz,1H),2.63(s,3H),2.22(s,3H),2.15–2.11(m,1H),1.93(s,3H),1.87(m, 1H),1.58(s,3H),1.50(s,3H),1.28(dd,J＝13.6,3.4Hz,2H),1.05–1.00(m,2H), 0.84(s,3H).13CNMR(150MHz,CDCl3)δ167.3,163.8,162.1,158.0,157.5,142.6, 138.3,135.9,135.2,134.3,132.1,131.7,127.8,125.5,124.2,123.5,121.1,120.4, 114.6,113.3,109.8,102.7,67.1,49.4,48.0,39.6,36.3,34.2,28.1,25.9,25.2,23.5, 22.5,21.9,20.9,17.8.HRMS(ESI):m/z calcd.for C34H40N3O4[M+H]+:554.3013； found 554.3021。
实施例18
化合物21的制备
黄色油状物；产率39％。将18(30.0mg,0.07mmol)和(1mL)THF装入5mL 圆底烧瓶。加入NaI(21.0mg，0.14mmol)并在室温搅拌10分钟。随后加入异丙基哌嗪(17.93mg，0.14mmol)并将所得混合物在50℃搅拌12小时。反应完成后将所得混合物真空浓缩，并通过硅胶色谱法纯化(石油醚/乙酸乙酯3:1v/v)。1H NMR(600MHz,CDCl3)δ7.15(d,J＝12.3Hz,1H),7.08(s,1H),6.31(t,J＝7.1Hz, 1H),5.79–5.68(m,2H),5.09(s,1H),3.96(d,J＝14.1Hz,1H),3.77–3.72(m,2H), 3.45(d,J＝14.2Hz,1H),3.12(d,J＝11.2Hz,1H),2.68(s,3H),2.64–2.63(m,1H), 2.54(s,3H),2.20(d,J＝0.9Hz,3H),2.12(dd,J＝14.2,7.9Hz,1H),1.95–1.95(m, 3H),1.87–1.84(m,2H),1.71(s,2H),1.69(s,3H),1.61(s,3H),1.46–1.33(m,3H), 1.26–1.25(m,1H),1.04(d,J＝6.4Hz,6H),0.85(s,3H).13C NMR(150MHz,CDCl3)δ163.1,160.8,158.8,157.4,142.1,138.3,137.1,132.0,131.3,125.4,124.5,114.7,109.5,68.2,61.5,54.7,53.9,50.2,48.8,47.8,39.6,36.8,27.9,25.9,25.8,23.5,22.4,22.2,20.8,18.9,17.9,17.9.HRMS(ESI):m/z calcd.for C32H49N4O2[M+H]+:521.3850；found:521.3857。
实施例19
化合物22的制备
黄色油状物；产率：40％。将15(100.0mg,0.25mmol)和(1mL)DCM装入 5mL圆底烧瓶。然后加入DAST(0.05mL,0.50mmol)，在-78℃搅拌2h。然后加入NaHCO3饱和水溶液和乙酸乙酯(10mL)淬灭反应，有机层用盐水(10mL)洗涤×3)，用N2SO4干燥，真空浓缩。残余物通过硅胶快速色谱纯化(石油醚/乙酸乙酯 2:1v/v)。1H NMR(600MHz,CDCl3)δ7.21(d,J＝12.3Hz,1H),7.10(s,1H),6.47 (ddt,J＝7.2,5.5,3.1Hz,1H),5.71–5.60(m,3H),5.47(dd,J＝47.2,11.6Hz,1H), 5.02–4.98(m,1H),3.14(d,J＝10.9Hz,1H),2.69(s,3H),2.27(dd,J＝16.0,7.3Hz, 1H),2.19(d,J＝1.3Hz,3H),1.99(dq,J＝12.4,6.5,6.0Hz,1H),1.94(d,J＝1.3Hz, 3H),1.79(dt,J＝16.0,5.1Hz,1H),1.65(s,3H),1.55(s,3H),1.34–1.25(m,3H),0.93(s,3H).13C NMR(150MHz,CDCl3)δ163.1,161.0,158.2,155.9,142.0,138.4, 134.8,132.8,132.7,126.5,124.2,114.6,109.7,84.0(d,J＝167.8Hz),49.8,39.3,37.7, 27.9,25.9,23.5,23.1,22.3,22.3,20.8,17.8.HRMS(ESI):m/z calcd.for C25H34FN2O2[M+H]+:413.2599；found:413.2597。
实施例20
本发明化合物环庚烯并氮氧杂二萜衍生物具有明显的抑制Hsp90活性，实验方法和结果如下：
一、材料与方法：
热变性萤火虫萤光素酶的复性取决于兔网织红细胞裂解物中Hsp90的活性，因此基于兔网织红细胞裂解物中萤火虫萤光素酶的Hsp90依赖性重折叠生化分析方法是稳健、灵敏、简单的Hsp90抑制剂的高通量筛选方法。
将荧光素酶添加到准备好的稳定缓冲液(25mM Tricine-HCl、pH7.8、8mM MgSO4、50％(v/v)甘油、0.1M EDTA和10％(v/v)Triton X-100和10mg/mL BSA) 中，41℃下变性10分钟，不同浓度的化合物、阳性对照(Novobiocin)加入到变性的荧光素酶中。将10μL稀释的兔网织红细胞裂解液加入混合物体系中，24℃孵育3h。96孔板中加入40μL检测缓冲液和40μL混合物样品，用Perkin Elmer EnVision板读取荧光素酶活性，仪器每3分钟测量一次，对照组(TBS/HbBSA) 设为100％抑制，对照组(2.5％DMSO)设为0％抑制，计算化合物不同浓度点对HSP90酶活性的抑制，采用GraphPad Prism软件对抑制率数据进行非线性拟合分析得到化合物的半数抑制浓度IC50值。
阳性对照：Novobiocin
二、结果
表1.环庚烯并氮氧杂二萜衍生物对Hsp90蛋白的半数抑制浓度(IC50,μM)
三、结论
在本实验条件下，对本发明化合物进行了Hsp90依赖性荧光素酶变性再复性抑制实验。其中，化合物10、13、16、22的IC50值分别为0.26、0.18、0.27、0.37μM。通过修饰，可以提高环庚烯并氮氧杂二萜衍生物的抑制Hsp90活性。
实施例21：
本发明化合物环庚烯并氮氧杂二萜衍生物具有明显的抗肿瘤活性，实验方法和结果如下：
一、材料与方法：
1.样品及制备：
样品呈无色或淡黄色，二甲基亚砜(DMSO)溶解配制为10mg/mL浓度的贮存液避光保存备用。
二、细胞株：
MCF-7,人乳腺癌细胞株
SMMC7721,人肝癌细胞株
HL-60,人白血病细胞株
SW-480，人结肠癌细胞株
A549，人肺癌细胞株
三、实验方法：
将细胞接种于96孔板，细胞于5％二氧化碳、37℃的细胞培养箱中提前12-24 小时接种培养。化合物用DMSO溶解，加入不同浓度的待测化合物(40、8、1.6、 0.32、0.064、0μM)，每个浓度均设置3个复孔。加药培养48小时后，每孔加入20μL MTT(5mg/mL)和培养液100μL，继续培养4小时，反应充分后用酶标仪在492nm下检测各孔的OD值，并用Prism5.0软件计算IC50值，实验重复三次。
阳性对照：Novobiocin和Taxol。
二、结果：
表2.环庚烯并氮氧杂二萜衍生物对人肿瘤细胞株生长的半数抑制浓度(IC50,μM)
三、结论
在本实验条件下，本发明化合物环庚烯并氮氧杂二萜衍生物对包括人乳腺癌细胞株(SK-BR-3),人肝癌细胞株(SMMC7721),人白血病细胞株(HL-60),人结肠癌细胞株(SW480)，人肺癌细胞株(A549)生长的半数抑制浓度(IC50)在2.878-40μM 之间。显示此类结构新颖的环庚烯并氮氧杂二萜衍生物具有较好的抗肿瘤应用前景。
制剂实施例
在以下制剂实施例中，选择常规试剂，并按照现有常规方法进行制剂制备，本应用例仅体现本发明所述毛萼内酯素B衍生物制备成不同的制剂，对具体试剂和操作不作具体限定。
1.将本发明化合物环庚烯并氮氧杂二萜衍生物任其一种或任其组合，用 DMSO溶解后，按常规方法加注射用水，精滤，灌封灭菌制成注射液，所述注射液的浓度为0.5～5mg/mL。
2.将本发明化合物环庚烯并氮氧杂二萜衍生物任其一或任其组合，用 DMSO溶解后，将其溶于无菌注射用水中，搅拌使其溶解，用无菌抽滤漏斗过滤，再无菌精滤，分装于安瓿中，低温冷冻干燥后无菌熔封，得粉针剂。
3.将本发明化合物环庚烯并氮氧杂二萜衍生物任其一或任其组合，按其与赋形剂质量比为9:1的比例加入赋形剂，制成粉剂。
4.将本发明化合物环庚烯并氮氧杂二萜衍生物任其一或任其组合，按其与赋形剂质量比为5:1的比例加入赋形剂，制粒压片。
5.将本发明化合物环庚烯并氮氧杂二萜衍生物任其一或任其组合，按常规口服液制备方法制成口服液。
6.将本发明化合物环庚烯并氮氧杂二萜衍生物任其一或任其组合，按其与赋形剂质量比为5:1的比例加入赋形剂，制成胶囊。
7.将本发明化合物环庚烯并氮氧杂二萜衍生物任其一或任其组合，按其与赋形剂质量比为5:1的比例加入赋形剂，制成颗粒剂。
以上所述仅为本申请的优选实施例而已，并不用于限制本申请，尽管参照前述实施例对本申请进行了详细的说明，对于本领域的技术人员来说，其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换。凡在本申请的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本申请的保护范围之内。
Claims (8)
1.通式(I)所示的环庚烯并氮氧杂二萜衍生物或其药用盐，
其中，R2为O，a和b为双键时，R1选自-OH、-F、-Cl、-OC＝OCH2COOH、-NHR、-NR(R选自单取代芳基、C4-7的含杂原子环烷基)；R2为O，a，b为单键时，R4选自-OH、SH，R1为-OH；
R2为N时，R1选自-OH、-F、-OC＝OCH2COOH、-NHR、-NR(R选自单取代芳基、C4-7的含杂原子环烷基)，R1为-CHO时、R3选自F、Cl。
2.通式(II)所示的环庚烯并氮氧杂二萜衍生物或其药用盐，
其中，R选自-OH、-F、-Cl、-OC＝OCH2COOH、-NHR、-NR(R选自单取代芳基、C4-7的含杂原子环烷基)。
3.如权利要求1或2所述的通式(I)和(II)所示的环庚烯并氮氧杂二萜衍生物或其药用盐，其特征在于，所述的环庚烯并氮氧杂二萜衍生物包括但不限于下述结构式所示的化合物，
4.如权利要求1或2所述的通式(I)和(II)所示的环庚烯并氮氧杂二萜衍生物或其药用盐，其特征在于，所述的药用盐是指药学上可接受的盐，指与有机酸形成的盐，所述的有机酸包括但不限于酒石酸、柠檬酸、甲酸、乙酸、乙二酸、丁酸、草酸、马来酸、琥珀酸、己二酸、藻酸、天冬氨酸、苯磺酸、樟脑酸、樟脑磺酸、二葡糖酸、环戊烷丙酸、十二烷基硫酸、乙磺酸、葡庚糖酸、甘油磷酸、半硫酸、庚酸、己酸、延胡索酸、2-羟基乙磺酸、乳酸、甲磺酸、烟酸、2-萘磺酸、扑酸、果胶酯酸、3-苯基丙酸、苦味酸、新戊酸、丙酸、硫代氰酸、对甲苯磺酸盐、十一烷酸盐。
5.药物组合物，含有权利要求1或2所述的通式(I)和(II)所示的环庚烯并氮氧杂二萜衍生物任其一种或其任意组合及可药用载体。
6.权利要求1或2所述的通式(I)和(II)所示的环庚烯并氮氧杂二萜衍生物或其药用盐在制备抗肿瘤药物中的应用。
7.权利要求1或2所述的通式(I)和(II)所示的环庚烯并氮氧杂二萜衍生物或其药用盐在制备治疗或预防乳腺癌、肝癌、白血病、肺癌、结肠癌的药物中的应用。
8.权利要求1或2所述的通式(I)和(II)所示的环庚烯并氮氧杂二萜衍生物或其药用盐在制备Hsp90抑制剂中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210820079.7A CN115073355B (zh) | 2022-07-13 | 2022-07-13 | 环庚烯并氮氧杂二萜衍生物及其药物组合物和其在制药中的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210820079.7A CN115073355B (zh) | 2022-07-13 | 2022-07-13 | 环庚烯并氮氧杂二萜衍生物及其药物组合物和其在制药中的应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115073355A true CN115073355A (zh) | 2022-09-20 |
| CN115073355B CN115073355B (zh) | 2023-11-10 |
Family
ID=83260547
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210820079.7A Active CN115073355B (zh) | 2022-07-13 | 2022-07-13 | 环庚烯并氮氧杂二萜衍生物及其药物组合物和其在制药中的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115073355B (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010042489A2 (en) * | 2008-10-06 | 2010-04-15 | Emory University | Aminoquinoline derived heat shock protein 90 inhibitors, methods of preparing same, and methods for their use |
| CN103772176A (zh) * | 2014-02-26 | 2014-05-07 | 中国科学院昆明植物研究所 | Vibsane型二萜衍生物及其药物组合物和应用 |
| CN114195641A (zh) * | 2020-09-18 | 2022-03-18 | 沈阳药科大学 | 七元vibsane二萜类化合物及其制备和应用 |
-
2022
- 2022-07-13 CN CN202210820079.7A patent/CN115073355B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010042489A2 (en) * | 2008-10-06 | 2010-04-15 | Emory University | Aminoquinoline derived heat shock protein 90 inhibitors, methods of preparing same, and methods for their use |
| CN103772176A (zh) * | 2014-02-26 | 2014-05-07 | 中国科学院昆明植物研究所 | Vibsane型二萜衍生物及其药物组合物和应用 |
| CN114195641A (zh) * | 2020-09-18 | 2022-03-18 | 沈阳药科大学 | 七元vibsane二萜类化合物及其制备和应用 |
Non-Patent Citations (1)
| Title |
|---|
| LI, SHI-FANG: "Vibsane-type diterpenoids from Viburnum odoratissimum and their cytotoxic activities", BIOORGANIC CHEMISTRY, pages 1 - 11 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115073355B (zh) | 2023-11-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5817840A (en) | Water soluble taxol derivatives | |
| US5519155A (en) | Platinum complexes | |
| CN103739616B (zh) | 含噻唑基雷帕霉素类衍生物及其应用 | |
| CN114736214B (zh) | 一种倍半萜衍生物、其药物组合物及其制备方法和用途 | |
| KR100351952B1 (ko) | 캠프토테신,그제조방법및항종양제 | |
| CN110437285B (zh) | 青蒿素钌金属配合物及其制备方法和医药用途 | |
| CN110981881B (zh) | 白屈菜碱一氧化氮供体衍生物及其制备方法和用途 | |
| CA2484816C (en) | Halo-alkyl esters of camptothecins and methods of treating cancer using these compounds | |
| CN110143995B (zh) | 氮杂环取代18β-甘草次酸衍生物及其制备和应用 | |
| CN111253411A (zh) | 一种小檗碱亚油酸缀合物及其制备方法和用途 | |
| JPH035494A (ja) | 二量体エピポドフィロトキシングルコシド誘導体 | |
| CN115073355A (zh) | 环庚烯并氮氧杂二萜衍生物及其药物组合物和其在制药中的应用 | |
| CN115385875B (zh) | 一类紫杉醇衍生物及其制备方法和用途 | |
| CA1212670A (en) | Water-soluble rifampicin derivatives | |
| RU2259363C2 (ru) | Полусинтетические таксаны и фармацевтические композиции на их основе | |
| CN113024557B (zh) | 一种Peganumine A生物碱结构简化物及其应用 | |
| CN112225730A (zh) | 一种稠环化合物的晶型、其组合物、制备方法及其应用 | |
| EP3081560A1 (en) | Taxanes compounds, preparation method therefor, and uses thereof | |
| CN107129497B (zh) | 一类含氮芥的槐定碱类衍生物及其制备方法和用途 | |
| CA2429539A1 (en) | Dibenzosberanyl piperazine derivatives and drug-resistance overcoming agents containing the derivatives | |
| CN111689979A (zh) | 一种9-位哌嗪磺酰胺-10-羟基喜树碱类化合物及其制备方法和在抗肿瘤中的用途 | |
| CN116120254B (zh) | 13,14-双一氧化氮供体-β-榄香烯衍生物及其制备和应用 | |
| EP0047358B1 (en) | Indol acetic derivatives, process for producing the same and pharmaceutical compositions comprising the same | |
| CN115819424B (zh) | 吲唑并喹喔啉衍生物及其合成方法和应用 | |
| CN115232140B (zh) | 一种四氢喹啉并色满多环化合物及其制备方法与应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |