CN106565760B - 氟硼二吡咯衍生物及其制备方法和在医药上的应用 - Google Patents
氟硼二吡咯衍生物及其制备方法和在医药上的应用 Download PDFInfo
- Publication number
- CN106565760B CN106565760B CN201610995708.4A CN201610995708A CN106565760B CN 106565760 B CN106565760 B CN 106565760B CN 201610995708 A CN201610995708 A CN 201610995708A CN 106565760 B CN106565760 B CN 106565760B
- Authority
- CN
- China
- Prior art keywords
- compound
- cancer
- logical formula
- reaction
- medicine
- 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.)
- Active
Links
- 239000003814 drug Substances 0.000 title claims abstract description 37
- 150000007980 azole derivatives Chemical class 0.000 title abstract description 10
- 238000002360 preparation method Methods 0.000 title abstract description 9
- 229910052796 boron Inorganic materials 0.000 title description 9
- 229910052731 fluorine Inorganic materials 0.000 title description 9
- 239000011737 fluorine Substances 0.000 title description 9
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 36
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 26
- 201000011510 cancer Diseases 0.000 claims abstract description 21
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Natural products C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 51
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- 229940079593 drug Drugs 0.000 claims description 16
- -1 (dimethylamino) carbon hexafluorophosphates Chemical class 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 9
- 206010006187 Breast cancer Diseases 0.000 claims description 8
- 208000026310 Breast neoplasm Diseases 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 201000009030 Carcinoma Diseases 0.000 claims description 4
- 208000017897 Carcinoma of esophagus Diseases 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- 208000024519 eye neoplasm Diseases 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 201000001275 rectum cancer Diseases 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 206010046766 uterine cancer Diseases 0.000 claims description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 3
- 239000012190 activator Substances 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- GFAUNYMRSKVDJL-UHFFFAOYSA-N formyl chloride Chemical compound ClC=O GFAUNYMRSKVDJL-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical class C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 2
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims 1
- XXYNZSATHOXXBJ-UHFFFAOYSA-N 4-hydroxyisoindole-1,3-dione Chemical compound OC1=CC=CC2=C1C(=O)NC2=O XXYNZSATHOXXBJ-UHFFFAOYSA-N 0.000 claims 1
- 206010005003 Bladder cancer Diseases 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims 1
- 206010033128 Ovarian cancer Diseases 0.000 claims 1
- 206010061535 Ovarian neoplasm Diseases 0.000 claims 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims 1
- 229940049706 benzodiazepine Drugs 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 238000006482 condensation reaction Methods 0.000 claims 1
- 230000036632 reaction speed Effects 0.000 claims 1
- 201000005112 urinary bladder cancer Diseases 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 21
- 230000000694 effects Effects 0.000 abstract description 16
- 210000004881 tumor cell Anatomy 0.000 abstract description 13
- 230000001235 sensitizing effect Effects 0.000 abstract description 11
- 230000007062 hydrolysis Effects 0.000 abstract description 5
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 5
- 239000003504 photosensitizing agent Substances 0.000 abstract description 5
- LIQLLTGUOSHGKY-UHFFFAOYSA-N [B].[F] Chemical compound [B].[F] LIQLLTGUOSHGKY-UHFFFAOYSA-N 0.000 abstract description 4
- 150000003233 pyrroles Chemical class 0.000 abstract description 2
- 125000001424 substituent group Chemical group 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- 238000002560 therapeutic procedure Methods 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 238000012360 testing method Methods 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- 238000001819 mass spectrum Methods 0.000 description 7
- 230000003287 optical effect Effects 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical group [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 238000002428 photodynamic therapy Methods 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UJKPHYRXOLRVJJ-MLSVHJFASA-N CC(O)C1=C(C)/C2=C/C3=N/C(=C\C4=C(CCC(O)=O)C(C)=C(N4)/C=C4\N=C(\C=C\1/N\2)C(C)=C4C(C)O)/C(CCC(O)=O)=C3C Chemical compound CC(O)C1=C(C)/C2=C/C3=N/C(=C\C4=C(CCC(O)=O)C(C)=C(N4)/C=C4\N=C(\C=C\1/N\2)C(C)=C4C(C)O)/C(CCC(O)=O)=C3C UJKPHYRXOLRVJJ-MLSVHJFASA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001412 amines Chemical group 0.000 description 3
- 201000001531 bladder carcinoma Diseases 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000002270 dispersing agent Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- RKCAIXNGYQCCAL-UHFFFAOYSA-N porphin Chemical group N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 RKCAIXNGYQCCAL-UHFFFAOYSA-N 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229960000074 biopharmaceutical Drugs 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000004040 coloring Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 150000002240 furans Chemical class 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 229960003569 hematoporphyrin Drugs 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 210000003712 lysosome Anatomy 0.000 description 2
- 230000001868 lysosomic effect Effects 0.000 description 2
- 229960003511 macrogol Drugs 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- TXXHDPDFNKHHGW-UHFFFAOYSA-N muconic acid Chemical compound OC(=O)C=CC=CC(O)=O TXXHDPDFNKHHGW-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- JACPFCQFVIAGDN-UHFFFAOYSA-M sipc iv Chemical compound [OH-].[Si+4].CN(C)CCC[Si](C)(C)[O-].C=1C=CC=C(C(N=C2[N-]C(C3=CC=CC=C32)=N2)=N3)C=1C3=CC([C]1C=CC=CC1=1)=NC=1N=C1[C]3C=CC=CC3=C2[N-]1 JACPFCQFVIAGDN-UHFFFAOYSA-M 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- OBSLWIKITOYASJ-AZEWMMITSA-N (2r,3s,4s,5r,6s)-6-(hydroxymethyl)-3-(methylamino)oxane-2,4,5-triol Chemical compound CN[C@@H]1[C@H](O)O[C@@H](CO)[C@H](O)[C@H]1O OBSLWIKITOYASJ-AZEWMMITSA-N 0.000 description 1
- 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 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- UPHOPMSGKZNELG-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=C(O)C=CC2=C1 UPHOPMSGKZNELG-UHFFFAOYSA-N 0.000 description 1
- UZFPOOOQHWICKY-UHFFFAOYSA-N 3-[13-[1-[1-[8,12-bis(2-carboxyethyl)-17-(1-hydroxyethyl)-3,7,13,18-tetramethyl-21,24-dihydroporphyrin-2-yl]ethoxy]ethyl]-18-(2-carboxyethyl)-8-(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid Chemical compound N1C(C=C2C(=C(CCC(O)=O)C(C=C3C(=C(C)C(C=C4N5)=N3)CCC(O)=O)=N2)C)=C(C)C(C(C)O)=C1C=C5C(C)=C4C(C)OC(C)C1=C(N2)C=C(N3)C(C)=C(C(O)C)C3=CC(C(C)=C3CCC(O)=O)=NC3=CC(C(CCC(O)=O)=C3C)=NC3=CC2=C1C UZFPOOOQHWICKY-UHFFFAOYSA-N 0.000 description 1
- KFKRXESVMDBTNQ-UHFFFAOYSA-N 3-[18-(2-carboxylatoethyl)-8,13-bis(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-21,24-diium-2-yl]propanoate Chemical compound N1C2=C(C)C(C(C)O)=C1C=C(N1)C(C)=C(C(O)C)C1=CC(C(C)=C1CCC(O)=O)=NC1=CC(C(CCC(O)=O)=C1C)=NC1=C2 KFKRXESVMDBTNQ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 238000007445 Chromatographic isolation Methods 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- TXXHDPDFNKHHGW-CCAGOZQPSA-N Muconic acid Natural products OC(=O)\C=C/C=C\C(O)=O TXXHDPDFNKHHGW-CCAGOZQPSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 1
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 1
- DDFGTVSLZJLQEV-UHFFFAOYSA-N [C](C1CCCCC1)C1CCCCC1 Chemical compound [C](C1CCCCC1)C1CCCCC1 DDFGTVSLZJLQEV-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- REDXJYDRNCIFBQ-UHFFFAOYSA-N aluminium(3+) Chemical compound [Al+3] REDXJYDRNCIFBQ-UHFFFAOYSA-N 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000003914 blood derivative Substances 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000000205 computational method Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000000413 hydrolysate Substances 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000006552 photochemical reaction Methods 0.000 description 1
- 238000005950 photosensitized reaction Methods 0.000 description 1
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229960004293 porfimer sodium Drugs 0.000 description 1
- 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 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- RDRCCJPEJDWSRJ-UHFFFAOYSA-N pyridine;1h-pyrrole Chemical compound C=1C=CNC=1.C1=CC=NC=C1 RDRCCJPEJDWSRJ-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 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 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/022—Boron compounds without C-boron linkages
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及pH敏感的缩酮连接的胆固醇‑氟硼二吡咯衍生物及其制备方法和在医药上的应用。特别地,本发明涉及通式(I)所示的胆固醇‑氟硼二吡咯衍生物、其制备方法及含有该配合物的药物组合物,以及其作为光敏剂的用途,特别是在治疗癌症中的用途,其中通式(I)中的各取代基与说明书中的定义相同。由于胆固醇基团的存在,该系列配合物很难被肿瘤细胞和正常细胞摄取,但在肿瘤组织细胞外微酸环境下,缩酮键发生水解反应,氟硼二吡咯的水解衍生物能很容易被癌细胞摄取,并展现极高的光敏活性,它们可制备成肿瘤细胞外微酸环境靶向光敏药物。
Description
技术领域
本发明属于医药领域,涉及氟硼二吡咯衍生物及其制备方法及其在医药上的应用,本发明公开了其作为光敏剂,用于治疗癌症的用途。
技术背景
光动力治疗(Photodynamic Therapy,简称PDT),又称光辐射疗法(Photoradiation Therapy,简称PRT)或称光化学疗法(Photochemotherapy),是一种基于特定化学物质的光化学反应原理的治疗方法。所用的化学物质称为肿瘤化学诊治药物(也称光敏剂,Photosensitizer,简称PS)。PDT疗法过程是通过静脉注射将光敏剂注入体内(对于皮肤也可以将其涂于患处),经过一定时间后用特定波长的光照射肿瘤组织,富集在肿瘤组织的光敏剂在光的激发下,产生一系列光物理化学反应,产生细胞毒性的活性氧,从而杀死癌细胞破坏肿瘤组织。
1996年被美国FDA批准用于临床,1997年FDA将其列入肿瘤治疗的五类基本方法(手术、放疗、化疗、光动力、生化免疫)之一。和传统的疗法相比,PDT疗法具有创伤很小、毒性低微、选择性好、适用性好、可重复治疗、可姑息治疗、可协同手术提高疗效、可消灭隐性癌病灶、可保护容貌及重要器官功能、治疗时间短等优势。
光动力疗法还可以有效地治疗细菌感染、口腔感染、黄斑变性眼病、动脉硬化、创伤感染以及皮肤病等非癌症疾病。光敏剂还可以用于光动力消毒,最主要的是用于血液和血液衍生物的灭菌消毒。同时,利用光敏剂的荧光性质进行光动力诊断,也是医用光敏剂的一个重要用途。
光动力治疗的关键在于光敏剂,光动力疗效取决于光敏剂的优劣。基于光动力治疗在治疗肿瘤和其他疾病方面的潜力,科学界普遍认为,光动力治疗将成为21世纪的重要医疗方法。现在临床主要应用的光敏剂为卟非姆纳(Porfimer sodium,Photofin),该药先后在荷兰、加拿大、日本、美国、法国、德国、英国等28个国家和地区上市。我国在光动力治疗(PDT)方面的研究较美国、日本等国起步较迟,但进步较快。20世纪80年代初至今,为发展光动力治疗做了大量工作,与国外报道的成果相比,其深度和广度并无太大差距。重庆华鼎现代生物制药有限责任公司研制、生产用以治疗肿瘤的血卟啉(Hematoporphyrin,喜泊分),已经由国家食品药品管理局(SFDA)正式批准生产、销售并应用于临床。喜泊分是我国唯一上市的抗癌光敏剂,是国外上市的卟非姆纳类似物,均是血卟啉衍生物,同属于第一代抗癌光敏药物。
尽管卟非姆纳和喜泊分在临床上取得了成功,但其组分复杂,各种成分在光动力损伤中的作用至今也未弄清,占药物总量20%以上的非活性成分不仅不能对病变的靶组织产生有效的光动力损伤作用,反而成为导致正常组织发生光敏反应的祸首。另外第一代光敏药物对肿瘤的靶向作用不强,研究高效、低毒的具有肿瘤靶向性的光敏药物是最近的研究热点。
肿瘤实体组织部位存在的缺氧微环境导致该部位肿瘤细胞外的pH值较低(在6.5左右),而正常组织细胞外pH值为7.4左右。肿瘤实体组织和正常组织之间的pH值差异为肿瘤靶向药物的设计提供了新的策略。本专利发明人近年报道了多个系列的pH敏感的光敏药物,比如轴向氨基衍生物取代硅酞菁,通过氨基在不同pH环境下的离子化程度不同影响光敏活性(Jiang,X.-J.et.al,Chem.Commun.,2010,46,3188–3190);轴向苯基衍生物取代硅酞菁,通过pH环境下酞菁分子的聚集程度不同影响光敏活性(Jiang,X.-J.et.al,Chem.Eur.J.,2010,16,4777–4783);通过pH敏感的缩酮键连接的氟硼二吡咯衍生物和二茂铁衍生物,由于二茂铁为荧光淬灭剂,可以通过光诱导电子转移(photoinduced electrontransfer,PET)过程淬灭氟硼二吡咯衍生物的光敏活性,但在微酸环境下,缩酮键断裂,二吡咯衍生物的光敏活性得到恢复(Jiang,X.-J.et.al,Chem.Eur.J.2016,22,8273–8281)。但这些化合物和目前报道的大多数pH敏感的药物均不是肿瘤细胞外微酸环境靶向药物,这是由于肿瘤细胞和正常细胞的亚细胞组织如线粒体、溶酶体等均显酸性,溶酶体的pH值更可以低至5。这些化合物在被肿瘤细胞和正常细胞摄取后,可以被亚细胞组织中的酸激发光敏活性,损伤肿瘤细胞和正常细胞。
发明内容
本发明公开了一系列肿瘤细胞外微酸环境靶向光敏药物。公开了一系列缩酮连接的胆固醇-氟硼二吡咯衍生物的结构、合成及应用。在氟硼二吡咯衍生物引入胆固醇基团,氟硼二吡咯衍生物和胆固醇之间用酸敏感的缩酮键连接,由于胆固醇的非极性特性和大位阻作用,胆固醇-氟硼二吡咯衍生物很难被癌细胞和正常细胞摄取,但在肿瘤实体组织癌细胞外的微酸环境下,缩酮键发生水解反应,胆固醇基团脱落,氟硼二吡咯水解衍生物能被癌细胞摄取并展现极高的光敏活性,它们是肿瘤细胞外微酸环境靶向光敏药物。
本发明提供的一种通式(I)所示的化合物:
或其药学上可接受的盐。
通式(I)所示的化合物在微酸环境下的水解反应化学式(1)
通式(I)的所示化合物的水解产物为通式(V)化合物的结构与已有文献报道的化合物结构相同和类似(Jiang,X.-J.et.al,Chem.Eur.J.2016,22,8273–8281),这些化合物在肿瘤细胞摄取率高,在很低的浓度下展现非常高的光敏活性。
本发明还提供一种制备通式(I)所示的化合物的方法,该方法包括:
第1步,所述溶剂选自N,N-二甲基甲酰胺、二甲基亚砜、二氯甲烷、三氯甲烷和四氢呋喃;所述反应在-5~80℃温度下进行;所述碱性条件由选自吡啶、三乙胺、氢化钠和4-N,N-二甲基吡啶等试剂提供;所述通式(II)化合物与胆固醇甲酰氯的摩尔比为1:0.2~2;
第2步,所述溶剂选自N,N-二甲基甲酰胺、二甲基亚砜、二氯甲烷、三氯甲烷和四氢呋喃;所述的催化剂选用三乙胺、吡啶、N,N-二甲基吡啶;所述缩合剂选用二环己基碳二亚胺、二异丙基碳二亚胺、1-(3-二甲胺基丙基)-3-乙基碳二亚胺、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、O-(7-氮杂苯并三氮唑-1-基)-二(二甲胺基)碳鎓六氟磷酸盐、O-(苯并三氮唑-1-基)-二(二甲胺基)碳鎓六氟磷酸盐、O-(苯并三氮唑-1-基)-二(二甲胺基)碳鎓四氟硼酸盐、O-(N-丁二酰亚胺基)-二(二甲胺基)碳鎓四氟硼酸盐中的至少一种;和/或所述缩合活化剂选用1-羟基苯并三氮唑、1-羟基-7-偶氮苯并三氮唑、N-羟基琥珀酰亚胺、N-羟基邻苯二甲酰亚胺中的一种;所述反应在-5~80℃温度下进行;所述通式(IV)化合物与通式(III)化合物的摩尔比为1:0.4~4;通式(IV)化合物与缩合剂的摩尔比为1:0.4~4。
如果有必要,通过本领域技术人员熟知的方法,如通过蒸馏、通过硅胶柱色谱法或者通过高效液相色谱法(HPLC)也可以纯化化合物。
本发明还提供一种药物组合物,其含有治疗有效量的通式(I)所示的化合物或或其药学上可接受的盐,以及药学上可接受的载体、稀释剂或赋形剂。
本发明还涉及通式(I)所示的化合物或其药学上可接受的盐,或包含其的药物组合物在制备光动力药物或光敏药物中的用途。
本发明还涉及通式(I)所示的化合物或其药学上可接受的盐,或包含其的药物组合物在制备治疗癌症的药物中的用途。其中所述的癌症选自其中所述的癌症选自肺癌、胃癌、食管癌、乳腺癌、膀胱癌、前列腺癌、胰腺癌、胆管癌、直肠癌、结肠癌、皮肤癌、头颈部癌症、眼肿瘤、子宫癌和卵巢癌,优乳腺癌。
本发明还涉及通式(I)所示的化合物或其药学上可接受的盐,或包含其的药物组合物,其用作光动力药物或光敏药物。
本发明还涉及通式(I)所示的化合物或其药学上可接受的盐,或包含其的药物组合物,其用于治疗癌症。其中所述的癌症选自肺癌、胃癌、食管癌、乳腺癌、膀胱癌、前列腺癌、胰腺癌、胆管癌、直肠癌、结肠癌、皮肤癌、头颈部癌症、眼肿瘤、子宫癌和卵巢癌,优选乳腺癌。
本发明还涉及一种治疗癌症的方法,其包括给予所需患者治疗有效量的通式(I)所示的化合物或其药学上可接受的盐,或包含其的药物组合物,然后用适宜的光源照射。所述适宜的光源可以由普通光源连接合适的滤光片来提供或由特定波长的激光来提供,光源的波长范围为550~900nm,优选620~720nm。
根据本发明的化合物可以被口服施用、舌下施用、肠胃外施用、皮下施用、肌内施用、静脉内施用、经皮施用、局部施用或直肠施用。
在本发明的药用化合物中,对于口服施用、舌下施用、肠胃外施用、皮下施用、肌内施用、静脉内施用、经皮施用、局部施用或直肠施用而言,活性成分可以与常规的药用载体混合在一起,以施用单位的形式施用于动物或人类。适合的施用单位形式包含口服形式如片剂、凝胶胶囊剂、粉剂、颗粒剂和口服的溶液剂或混悬剂,舌下或口腔施用形式,肠胃外、皮下、肌内、静脉内、鼻内或眼内施用形式和直肠施用形式。
当固体组合物被制备成片剂形式时,主要活性成分与药用载体如明胶、淀粉、乳糖、硬脂酸镁、滑石、阿拉伯胶等混合。片剂可以采用蔗糖或其他适合的材料包衣或者以如此的方式处理以至于其具有延长的或延迟的活性并且连续释放预定量的活性成分。
通过将活性成分与稀释剂混合并通过将获得的混合物倾倒入软质或硬质胶囊中来获得凝胶胶囊制剂。
糖浆剂或酊剂形式的制剂可以包含活性成分连同甜味剂、防腐剂以及芳香剂和适当的着色剂。
可分散于水中的粉剂或颗粒剂可以包含活性成分,其与分散剂、表面活性剂、润湿剂或悬浮剂以及与矫味剂或甜味剂混合在一起。其药物组合中含有聚氧乙烯蓖麻油及其衍生物、二甲亚砜、乙醇、甘油、N,N-二甲基甲酰胺、聚乙二醇300-3000、环糊精、葡萄糖、吐温、聚乙二醇单硬脂酸酯中的一种或几种。
栓剂用于直肠施用,其采用在直肠温度下熔化的粘合剂,例如,可可脂或聚乙二醇来制备。
水性混悬剂、等渗的生理盐水溶液剂或无菌的且可注射的溶液剂(其包含药理学上可兼容的分散剂和/或润湿剂)用于肠胃外、鼻内或眼内施用。其药物组合中含有聚氧乙烯蓖麻油及其衍生物、二甲亚砜、乙醇、甘油、N,N-二甲基甲酰胺、聚乙二醇300-3000、环糊精、葡萄糖、吐温、聚乙二醇单硬脂酸酯中的一种或几种。
活性成分(可能与一种或多种添加剂载体一起)也可以被配制成微囊剂。
本发明的化合物能够以介于0.01mg/天和5000mg/天之间的剂量来使用,以单一剂量/天的方式来提供或者以全天内若干剂量的方式来施用,例如,相同剂量每天两次。所施用的日剂量有利地介于0.1mg和200mg之间,甚至更有利地介于2.5mg和50mg之间。使用超出这些范围的剂量可能是需要的,本领域技术人员自身将会意识到这一点。
在本发明的一个特定实施方案中,药物组合物也可以被配制用于外部施用。它可以被引入到该施用类型的常用形式(即,特别是洗剂、泡沫剂、凝胶剂、分散剂、喷雾剂)中,所述常用形式具有赋形剂,所述赋形剂特别地能够穿透皮肤,以便于改善活性成分的性质和可接近性。除了根据本发明的组合物之外,这些组合物通常进一步包含生理上可接受的介质,所述介质通常包含水或溶剂,例如,醇、醚或乙二醇。所述组合物还可以包含表面活性剂、防腐剂、稳定剂、乳化剂、增稠剂、产生互补效果或可能的协同效果的其他活性成分、微量元素、精油、香料、着色剂、胶原蛋白、化学或矿物过滤剂。
定义
除非有相反陈述,否则下列用在说明书和权利要求书中的术语具有下述含义。
在本发明中,“药学上可接受的”被理解为是指其用于制备药物组合物,所述组合物一般是安全的,无毒的,在生物学或其他方面满足需要并且所述组合物可以被接受用于兽类和人类药物用途。
在本发明中,化合物的“药学上可接受的盐”被理解为指代下列盐,其是药学上可接受的(如本文所定义的)盐并且其具备预期的母体化合物的药理活性。这种盐包括:
(1)与无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等形成的酸加成盐,或与有机酸如乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、乙醇酸、羟萘酸、2-羟基乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘康酸、2-萘磺酸、丙酸、水杨酸、琥珀酸、二苯甲酰基-L-酒石酸、酒石酸、对甲苯磺酸、三甲基乙酸、三氟乙酸等形成的酸加成盐;和
(2)当母体化合物中存在的酸质子被金属离子,例如,碱金属离子(例如,Na+、K+或Li+),碱土金属离子(如Ca2+或Mg2+)或铝离子代替;或者与有机碱或无机碱配位时形成的盐。可接受的有机碱包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、氨丁三醇等。可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠和氢氧化钠。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
“Ts”为对甲基苯磺酸基。
具体实施方式
通过阅读下列实施例,本领域技术人员将会更好地理解本发明。这些实施例仅用于解释本发明。
本发明实施例中未注明具体条件的实验方法,通常按照常规条件,或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂,为市场购买的常规试剂。式(IV)化合物参考文献方法合成得到(Jiang,X.-J.et.al,Chem.Eur.J.2016,22,8273–8281)。
核磁共振仪:Bruker ARX-400型高分辨高分辨核磁共振仪。
质谱:QSTAR Elite串联四级杆飞行时间质谱仪。
MTT检测仪器:Thermo Scientific Multiskan GO全波长酶标仪
PBS缓冲液:磷酸盐缓冲液
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR化学位移(δ)以10-6(ppm)的单位给出。测定溶剂为氘代三氯甲烷(CD3Cl),内标为四甲基硅烷(TMS)。使用下列缩写:s为单峰,bs为宽单峰,d为二重峰,t为三重峰,qdt为四重峰,m为多重峰或大量峰,dd为双二重峰等。
薄层层析硅胶板使用青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.2mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
实施例中如无特殊说明,反应均在氩气氛或氮气氛下进行。
实施例中如无特殊说明,反应中的溶液是指水溶液。
实施例中如无特殊说明,反应的温度为室温。
实施例中的反应进程的监测采用薄层色谱法(TLC)。
实施例1 化合物1的合成
第1步;
在冰水浴中,把化合物1-1(1.62g,10mmol),氯甲酸胆固醇(2.2g,4.9mmol)和三乙胺(2g,20mmol)加入二氯甲烷(50mL),继续搅拌反应2小时,停止反应,向反应液中加入水(100mL),搅拌静置,收集有机相,有机相用无水硫酸钠干燥,减压蒸馏,粗产品用硅胶层析柱分离纯化,洗脱剂为三氯甲烷/甲醇(9:1),得到白色固体1-2(1.53g,55%)。MS(ESI):m/z=598[M+Na]+。
第2步
将化合物式(IV)(1.06g,1.0mmol)和化合物1-2(1.15g,2mmol)溶解在N,N-二甲基甲酰胺(20mL),溶液温度降至0℃搅拌0.5小时,慢慢加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC.HCL)(767mg,4mmol),4-N,N-二甲基吡啶(244mg,2mmol),反应液温度升到在60℃反应12小时。反应液冷却到室温,过滤,收率滤液,减压干燥去除溶剂,剩下固体用硅胶层析色谱分离纯化,解析剂为三氯甲烷/甲醇(9:1v/v)收集主要组份,减压干燥得到绿色固体粉末1(0.45g,20%)。1H NMR(400MHz,CDCl3):δ8.11(d,J=16.4Hz,2H,CH=CH),7.60(d,J=8.4Hz,4H,ArH),7.56(d,J=16.4Hz,2H,CH=CH),7.13(d,J=8.4Hz,2H,ArH),7.06(d,J=8.4Hz,2H,ArH),6.97(d,J=8.4Hz,4H,ArH),5.51-5.55(m,4H,chol-6-CH),4.53(s,4H,CH2),4.35-4.39(m,4H,chol-6-CH),3.92(t,J=4.4Hz,2H,CH2),3.76-3.78(m,2H,CH2),3.70-3.74(m,2H,CH2),3.66-3.68(m,2H,CH2),3.55-3.59(m,2H,CH2),3.42-3.52(m,14H,CH2),3.20-3.35(s,7H,CH2,CH3),1.73-2.32(m,16H,chol),0.86-1.56(m,82H,chol,CH3),0.68(s,6H,chol-18-CH3)。MS(ESI):m/z=2177[M+H]+。
实施例2 化合物2的合成
第1步
在冰水浴中,把化合物2-1(1.64g,10mmol),氯甲酸胆固醇(1.55g,3.5mmol)和吡啶(0.8g,10.1mmol)加入二氯甲烷(25mL),温度升到室温,继续搅拌反应2小时,停止反应,向反应液中加入水(100mL),搅拌静置,收集有机相,有机相用无水硫酸钠干燥,减压蒸馏,粗产品用硅胶层析柱分离纯化,洗脱剂为三氯甲烷/甲醇(15:1),得到白色固体2-2(1.02g,49%)。MS(ESI):m/z=599[M+Na]+。
第2步
将化合物式(IV)(1.06g,1mmol)和化合物2-2(1.15g,2mmol)溶解在四氢呋喃(30mL),溶液温度降至0℃搅拌0.5小时,慢慢加入二环己基碳二亚胺(DCC)(412mg,2mmol),1-羟基苯并三唑(270mg,2mmol),三乙胺(404mg,4mmol),反应液温度升到在60℃反应12小时。反应液冷却到室温,过滤,收率滤液,减压干燥去除溶剂,剩下固体用硅胶层析色谱分离纯化,解析剂为三氯甲烷/甲醇(9:1v/v)收集主要组份,减压干燥得到蓝色固体粉末2(0.29g,13%)。1HNMR(400MHz,CDCl3):δ8.10(d,J=16.4Hz,2H,CH=CH),7.61(d,J=8.4Hz,4H,ArH),7.58(d,J=16.4Hz,2H,CH=CH),7.15(d,J=8.4Hz,2H,ArH),7.05(d,J=8.4Hz,2H,ArH),6.96(d,J=8.4Hz,4H,ArH),5.32-5.35(m,2H,chol-6-CH),4.55(s,4H,CH2),4.35-4.40(m,2H,chol-3-CH),4.21-4.33(m,8H,CH2),3.93(t,J=4.4Hz,2H,CH2),3.77-3.79(m,2H,CH2),3.71-3.73(m,2H,CH2),3.67-3.69(m,2H,CH2),3.56-3.59(m,2H,CH2),3.40-3.53(m,10H,CH2),3.39(s,3H,CH3),1.70-2.29(m,16H,chol),0.88-1.58(m,82H,chol,CH3),0.68(s,6H,chol-18-CH3)。MS(ESI):m/z=2181[M+H]+。
测试例:体外抗肿瘤细胞光敏实验
供试品:本发明化合物2
阳性对照品:血卟啉注射液(英文名:Hematoporphyrin Injection;商品名:喜泊分,重庆市华鼎现代生物制药有限责任公司生产)。
测试细胞:人乳腺癌细胞MCF-7
主要试剂:1)RPMI-1640完全培养液:于500mL RPMI-1640液体培养液(GIBCO公司)中加入青霉素/链霉素10万U,胎牛血清56mL,混匀。2)MTT溶液(MTT:3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐,购于美国MP公司):将粉状MTT以5mg/mL的浓度溶于PBS溶液,过滤灭菌,现配现用。
实验方法:
1)供试品配制方法:将供试品用DMSO配成浓度为1mM的母液;实验时取100μL1mg/mL的母液,加入1.15mL 0.5%(w/w)聚氧乙烯蓖麻油pH 7.4PBS和pH 6.5PBS缓冲液,配制成80μg/mL药液,并用相对应的PBS缓冲液稀释成不同浓度的药液,稀释过程中保持药液pH值不变,药液配制后马上进行细胞加药培养。各药物和阴性对照组中DMSO的终浓度是≤1%。喜泊芬为5mL液体溶液含25mg制剂,浓度5mg/mL。取100μL 5mg/mL的制剂,加入4.90mL pH7.4PBS或pH 6.5PBS缓冲液,并用相对应的PBS缓冲液稀释成不同浓度的药液,稀释过程中保持药液pH值不变,药液配制后马上进行细胞加药培养。
2)选用对数生长期的贴壁肿瘤细胞,用胰酶消化后,用含10%胎牛血清的RPMIl640培养基配成适合浓度的细胞悬液,接种在96孔培养板中。每孔接种100μL,每加完一排将细胞悬液摇一下,加完细胞后轻轻水平转动培养板使细胞均匀地分散在皿孔表面,96孔板周围一圈孔加入无菌PBS,37℃,5%CO2培养24小时。然后分别加入不同浓度的受试药物、阳性药物、溶剂和培养液各100μL,每组3个平行孔。混匀后分为光照和避光两组,均在加药共培养2小时后,弃去培养基,重新加入不含供试品的培养基置37℃、5%CO2条件下继续培养24小时。24小时后,每孔加入5mg/mL MTT,20μL,37℃、5%CO2条件下孵育4小时后,仔细吸弃上清液,每孔加入200μL DMSO,振荡10分钟,使形成的甲臜颗粒充分溶解后,酶标仪检测吸光值,测定波长570nm,参考波长630nm。光源通过200W的卤素灯连接隔热水槽加大于610nm的滤光片提供,光剂量为48J cm-2。
3)药物对肿瘤细胞生长的抑制率的计算方法:肿瘤细胞生长抑制率(%)=[(阴性对照组OD均值-给药组OD均值)/阴性对照组OD均值]×100%。半数抑制浓度IC50的计算,采用logit回归法测定。
实验结果:
表1 化合物2和喜泊分在照光时人乳腺癌细胞MCF-7的IC50(ng/mL)值
实验结果显示,在避光环境下,所有测试的化合物在浓度高达5000ng/mL时,没有显示细胞毒性,但在照光情况下喜泊分在pH 6.5和pH 7.4时对人乳腺癌细胞MCF-7的半致死浓度IC50值相差不大,在3800-4100ng/mL之间。但化合物2在pH 7.4的药液培养细胞时,浓度高达8000ng/mL,在照光时完全没有光敏活性,但化合物2在pH 6.5的药液进行培养细胞时,展现非常高的光敏活性,IC50值为125ng/mL,展现非常明显的肿瘤细胞外微酸环境靶向性。
目前已知,几乎所有的实体肿瘤都存在微酸环境,如肺癌、胃癌、食管癌、乳腺癌、膀胱癌、前列腺癌、胰腺癌、胆管癌、直肠癌、结肠癌、皮肤癌、头颈部癌症、眼肿瘤、子宫癌和卵巢癌等实体肿瘤均存在微酸环境,本专利公开的化合物或其药学上可接受的盐,或包含其的药物组合物均可以制备成光敏药物治疗上述癌症。
以上所述仅为本发明的实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (7)
1.一种通式(I)所示的化合物:
其中:X=O或NH;
或其药学上可接受的盐。
2.一种制备根据权利要求1所述的通式(I)所示的化合物的方法,该方法包括:
第1步,在有机溶剂中,在碱性环境下,含有缩醛键的通式(II)化合物与胆固醇甲酰氯反应得到得到通式(III)化合物;
第2步,在有机溶剂中,在碱性条件下,化合物(IV)与通式(III)化合物在缩合剂和催化剂的作用下发生缩合反应,得到通式(I)化合物,为了加快反应速度,可以在此反应过程中加入缩合活化剂。
3.根据权利要求2所述的方法,其中:
第1步,所述溶剂选自N,N-二甲基甲酰胺、二甲基亚砜、二氯甲烷、三氯甲烷和四氢呋喃;所述反应在-5~80℃温度下进行;所述碱性条件由选自吡啶、三乙胺、氢化钠和4-N,N-二甲基吡啶中的一种试剂提供;所述通式(II)化合物与胆固醇甲酰氯的摩尔比为1:0.2~2;
第2步,所述溶剂选自N,N-二甲基甲酰胺、二甲基亚砜、二氯甲烷、三氯甲烷和四氢呋喃;所述的催化剂选用三乙胺、吡啶、N,N-二甲基吡啶;所述缩合剂选用二环己基碳二亚胺、二异丙基碳二亚胺、1-(3-二甲胺基丙基)-3-乙基碳二亚胺、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、O-(7-氮杂苯并三氮唑-1-基)-二(二甲胺基)碳鎓六氟磷酸盐、O-(苯并三氮唑-1-基)-二(二甲胺基)碳鎓六氟磷酸盐、O-(苯并三氮唑-1-基)-二(二甲胺基)碳鎓四氟硼酸盐、O-(N-丁二酰亚胺基)-二(二甲胺基)碳鎓四氟硼酸盐中的至少一种;和/或所述缩合活化剂选用1-羟基苯并三氮唑、1-羟基-7-偶氮苯并三氮唑、N-羟基琥珀酰亚胺、N-羟基邻苯二甲酰亚胺中的一种;所述反应在-5~80℃温度下进行;所述通式(IV)化合物与通式(III)化合物的摩尔比为1:0.4~4;通式(IV)化合物与缩合剂的摩尔比为1:0.4~4。
4.一种药物组合物,其含有治疗有效量的根据权利要求1所述的通式(I)所示的化合物以及药学上可接受的载体、稀释剂或赋形剂。
5.根据权利要求1所述的通式(I)所示的化合物或根据权利要求4所述的药物组合物在制备光动力药物或光敏药物中的用途。
6.根据权利要求1所述的通式(I)所示的化合物或根据权利要求4所述的药物组合物在制备治疗癌症的药物中的用途。
7.根据权利要求6所述的用途,其中所述的癌症选自肺癌、胃癌、食管癌、乳腺癌、膀胱癌、前列腺癌、胰腺癌、胆管癌、直肠癌、结肠癌、皮肤癌、头颈部癌症、眼肿瘤、子宫癌和卵巢癌。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610995708.4A CN106565760B (zh) | 2016-11-11 | 2016-11-11 | 氟硼二吡咯衍生物及其制备方法和在医药上的应用 |
PCT/CN2017/070300 WO2018086243A1 (zh) | 2016-11-11 | 2017-01-05 | 氟硼二吡咯衍生物及其制备方法和在医药上的应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610995708.4A CN106565760B (zh) | 2016-11-11 | 2016-11-11 | 氟硼二吡咯衍生物及其制备方法和在医药上的应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN106565760A CN106565760A (zh) | 2017-04-19 |
CN106565760B true CN106565760B (zh) | 2018-01-30 |
Family
ID=58542470
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610995708.4A Active CN106565760B (zh) | 2016-11-11 | 2016-11-11 | 氟硼二吡咯衍生物及其制备方法和在医药上的应用 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN106565760B (zh) |
WO (1) | WO2018086243A1 (zh) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107629063B (zh) * | 2017-09-25 | 2019-03-19 | 深圳市声光动力生物医药科技有限公司 | 酸敏感的酞菁锌-吉非替尼配合物及其制备方法和在医药上的应用 |
CN107629077B (zh) * | 2017-09-25 | 2019-03-19 | 深圳市声光动力生物医药科技有限公司 | 酸敏感的吉非替尼-氟硼二吡咯衍生物及其制备方法和在医药上的应用 |
WO2019056376A1 (zh) * | 2017-09-25 | 2019-03-28 | 深圳市声光动力生物医药科技有限公司 | 酸敏感的吉非替尼-氟硼二吡咯衍生物及其制备方法和在医药上的应用 |
CN108373478A (zh) * | 2017-12-13 | 2018-08-07 | 湖北远大生命科学与技术有限责任公司 | 一类牛磺酸取代的氟硼荧荧光化合物及其制备方法和用途 |
KR102009601B1 (ko) * | 2018-04-30 | 2019-08-09 | 고려대학교 산학협력단 | 종양 표적화 광역학 치료제 |
WO2021169661A1 (zh) * | 2020-02-28 | 2021-09-02 | 复旦大学 | 4位阳离子双取代bodipy类化合物及其制备方法和用途 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103183697B (zh) * | 2013-02-26 | 2015-08-26 | 南京大学 | 基于二联杂环并吡咯基团的近红外氟硼二吡咯化合物及其制法和用途 |
CN103755753B (zh) * | 2014-01-25 | 2016-05-04 | 福州大学 | 一类糖基化氟硼二吡咯衍生物及其制备和应用 |
CN104387412B (zh) * | 2014-12-17 | 2016-01-06 | 福州大学 | 埃罗替尼修饰的氟硼二吡咯衍生物及其制备和应用 |
CN105833271B (zh) * | 2016-04-14 | 2019-02-15 | 江苏师范大学 | 一种金刚烷修饰的近红外氟硼二吡咯光敏剂及其制备方法 |
-
2016
- 2016-11-11 CN CN201610995708.4A patent/CN106565760B/zh active Active
-
2017
- 2017-01-05 WO PCT/CN2017/070300 patent/WO2018086243A1/zh active Application Filing
Also Published As
Publication number | Publication date |
---|---|
WO2018086243A1 (zh) | 2018-05-17 |
CN106565760A (zh) | 2017-04-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN106565760B (zh) | 氟硼二吡咯衍生物及其制备方法和在医药上的应用 | |
CN107629077B (zh) | 酸敏感的吉非替尼-氟硼二吡咯衍生物及其制备方法和在医药上的应用 | |
CN106565763B (zh) | pH敏感的轴向取代硅酞菁配合物及其制备方法和在医药上的应用 | |
CN106749478B (zh) | pH敏感的1,4‑二取代酞菁锌配合物及其制备方法和在医药上的应用 | |
CN104974182B (zh) | 酞菁硅配合物、其制备方法及其在医药上的应用 | |
CN106349148A (zh) | 具有抗肿瘤转移和抗炎活性的新型吲哚类化合物,其合成和应用 | |
KR102245556B1 (ko) | 신규 클로린 e6 유도체 및 이의 약학적으로 허용가능한 염, 이의 제조방법 및 응용 | |
CN107400142B (zh) | 一种硼酸和硼酸酯类化合物及其应用 | |
CN110256313A (zh) | 一种光敏剂前药化合物及其制备方法和应用 | |
CN106046008A (zh) | 二氢卟吩p6类氨基酸衍生物及其制备方法和用途 | |
CN107629063B (zh) | 酸敏感的酞菁锌-吉非替尼配合物及其制备方法和在医药上的应用 | |
CN110981865B (zh) | 一种用于治疗脑胶质瘤的药物及其制备方法 | |
CN107556335B (zh) | 酸敏感的硼亚酞菁-吉非替尼配合物及其制备方法和在医药上的应用 | |
CN107474065B (zh) | 酸敏感的吉非替尼轴向取代酞菁硅配合物及其制备方法和在医药上的应用 | |
WO2019056376A1 (zh) | 酸敏感的吉非替尼-氟硼二吡咯衍生物及其制备方法和在医药上的应用 | |
WO2019056375A1 (zh) | 酸敏感的吉非替尼轴向取代酞菁硅配合物及其制备方法和在医药上的应用 | |
Schurig et al. | Experimental antitumor activity of BMY-28090, a new antitumor antibiotic | |
CN106554356B (zh) | 1,4‑二取代酞菁锌配合物及其制备方法和在医药上的应用 | |
CN108640965A (zh) | 2-取代-18β-甘草次酸衍生物及其应用 | |
CN102504013B (zh) | 一种靶向抗癌转移化学药物padm及制备方法和用途 | |
WO2019056374A1 (zh) | 酸敏感的硼亚酞菁-吉非替尼配合物及其制备方法和在医药上的应用 | |
WO2020057605A2 (zh) | 一种葡萄糖类化合物、药物组合物及其应用 | |
CN110183471B (zh) | 一种哌嗪类衍生物及制备方法及应用 | |
WO2019056373A1 (zh) | 酸敏感的酞菁锌-吉非替尼配合物及其制备方法和在医药上的应用 | |
JPH11269065A (ja) | 癌細胞のアポトーシス耐性の克服剤 |
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 | ||
TR01 | Transfer of patent right |
Effective date of registration: 20231107 Address after: No. 101, No. 12 Beihuan North Third Lane, Guantian Community, Shiyan Street, Bao'an District, Shenzhen City, Guangdong Province, 518000 Patentee after: SHENZHEN DAVOOS SCIENCE AND TECHNOLOGY LTD. Address before: D703, 7th Floor, Silver Star Technology Building, No. 1301, Sightseeing Road, Dabuxiang Community, Guanlan Street, Longhua New District, Shenzhen City, Guangdong Province, 518000 Patentee before: SHENZHEN SONO-PHOTODYNAMIC BIO-MED TECHNOLOGY Ltd. |
|
TR01 | Transfer of patent right |