WO2022218092A1 - Deep infrared porphycene derivative, preparation method, anti-tumor drug, and application - Google Patents
Deep infrared porphycene derivative, preparation method, anti-tumor drug, and application Download PDFInfo
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- WO2022218092A1 WO2022218092A1 PCT/CN2022/081457 CN2022081457W WO2022218092A1 WO 2022218092 A1 WO2022218092 A1 WO 2022218092A1 CN 2022081457 W CN2022081457 W CN 2022081457W WO 2022218092 A1 WO2022218092 A1 WO 2022218092A1
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- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- pharmaceutically acceptable
- formula
- halogenated
- infrared
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 239000002246 antineoplastic agent Substances 0.000 title abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 title abstract description 5
- HMSMOZAIMDNRBW-UHFFFAOYSA-N 100572-96-1 Chemical class C1=CC2=NC1=CC=C(N1)C=CC1=C(N1)C=CC1=CC=C1C=CC2=N1 HMSMOZAIMDNRBW-UHFFFAOYSA-N 0.000 title abstract 3
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 29
- 239000003814 drug Substances 0.000 claims abstract description 7
- 229940079593 drug Drugs 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 100
- 150000001875 compounds Chemical class 0.000 claims description 90
- 150000004033 porphyrin derivatives Chemical class 0.000 claims description 80
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 69
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 150000004696 coordination complex Chemical class 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 206010028980 Neoplasm Diseases 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 239000003504 photosensitizing agent Substances 0.000 claims description 13
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical group ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 claims description 8
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 238000006396 nitration reaction Methods 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 230000009467 reduction Effects 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 6
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 4
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 claims description 4
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims description 4
- 206010061534 Oesophageal squamous cell carcinoma Diseases 0.000 claims description 4
- 208000036765 Squamous cell carcinoma of the esophagus Diseases 0.000 claims description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 4
- 230000009435 amidation Effects 0.000 claims description 4
- 238000007112 amidation reaction Methods 0.000 claims description 4
- 150000001450 anions Chemical class 0.000 claims description 4
- 201000010881 cervical cancer Diseases 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 208000007276 esophageal squamous cell carcinoma Diseases 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 201000011216 nasopharynx carcinoma Diseases 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 125000004969 haloethyl group Chemical group 0.000 claims description 2
- 125000004970 halomethyl group Chemical group 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 230000002165 photosensitisation Effects 0.000 claims description 2
- 239000001119 stannous chloride Substances 0.000 claims description 2
- 235000011150 stannous chloride Nutrition 0.000 claims description 2
- 239000003560 cancer drug Substances 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical group [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 22
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 20
- 239000001301 oxygen Substances 0.000 abstract description 20
- 231100000419 toxicity Toxicity 0.000 abstract description 17
- 230000001988 toxicity Effects 0.000 abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 14
- 210000005260 human cell Anatomy 0.000 abstract 1
- 208000017983 photosensitivity disease Diseases 0.000 abstract 1
- 231100000434 photosensitization Toxicity 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 49
- 239000012043 crude product Substances 0.000 description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 238000005481 NMR spectroscopy Methods 0.000 description 26
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 25
- 239000000243 solution Substances 0.000 description 23
- 239000012074 organic phase Substances 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000004237 preparative chromatography Methods 0.000 description 18
- 206010021143 Hypoxia Diseases 0.000 description 17
- 239000000203 mixture Substances 0.000 description 13
- 238000002474 experimental method Methods 0.000 description 12
- 230000001146 hypoxic effect Effects 0.000 description 11
- 101000669528 Homo sapiens Tachykinin-4 Proteins 0.000 description 10
- 206010034972 Photosensitivity reaction Diseases 0.000 description 10
- 102100039365 Tachykinin-4 Human genes 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- 208000007578 phototoxic dermatitis Diseases 0.000 description 9
- 231100000018 phototoxicity Toxicity 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- -1 organic acid ion Chemical class 0.000 description 8
- 230000035515 penetration Effects 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 238000002428 photodynamic therapy Methods 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
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- 238000010521 absorption reaction Methods 0.000 description 6
- 230000007954 hypoxia Effects 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 238000012258 culturing Methods 0.000 description 5
- 238000010586 diagram Methods 0.000 description 5
- CSMWJXBSXGUPGY-UHFFFAOYSA-L sodium dithionate Chemical group [Na+].[Na+].[O-]S(=O)(=O)S([O-])(=O)=O CSMWJXBSXGUPGY-UHFFFAOYSA-L 0.000 description 5
- 229940075931 sodium dithionate Drugs 0.000 description 5
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 4
- 239000012346 acetyl chloride Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 230000035899 viability Effects 0.000 description 4
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
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- 125000000753 cycloalkyl group Chemical group 0.000 description 3
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 229940014800 succinic anhydride Drugs 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 2
- GIAFURWZWWWBQT-UHFFFAOYSA-N 2-(2-aminoethoxy)ethanol Chemical compound NCCOCCO GIAFURWZWWWBQT-UHFFFAOYSA-N 0.000 description 2
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 2
- RLTPXEAFDJVHSN-UHFFFAOYSA-N 4-(trifluoromethyl)benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(C(F)(F)F)C=C1 RLTPXEAFDJVHSN-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 229940077388 benzenesulfonate Drugs 0.000 description 2
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- 238000001816 cooling Methods 0.000 description 2
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- 238000001212 derivatisation Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
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- 239000011777 magnesium Substances 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
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- 125000002950 monocyclic group Chemical group 0.000 description 2
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- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
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- 231100000820 toxicity test Toxicity 0.000 description 2
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
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- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- REAYFGLASQTHKB-UHFFFAOYSA-N [2-[3-(1H-pyrazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound N1N=CC(=C1)C=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 REAYFGLASQTHKB-UHFFFAOYSA-N 0.000 description 1
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
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- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 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
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([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
- 238000001514 detection method Methods 0.000 description 1
- BSLHUYXJLLINSM-UHFFFAOYSA-N dichloromethane;n-methylformamide Chemical compound ClCCl.CNC=O BSLHUYXJLLINSM-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000001973 epigenetic effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- ABCGFHPGHXSVKI-UHFFFAOYSA-O meso-tetrakis(n-methyl-4-pyridyl)porphine(4+) Chemical compound C1=C[N+](C)=CC=C1C(C1=CC=C(N1)C(C=1C=C[N+](C)=CC=1)=C1C=CC(=N1)C(C=1C=C[N+](C)=CC=1)=C1C=CC(N1)=C1C=2C=C[N+](C)=CC=2)=C2N=C1C=C2 ABCGFHPGHXSVKI-UHFFFAOYSA-O 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000000825 pharmaceutical preparation 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
- 230000036211 photosensitivity Effects 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
-
- 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
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention belongs to the technical field of photodynamic drugs and photosensitivity, and in particular relates to a deep-infrared porphyrin derivative, a preparation method, an antitumor drug and an application.
- Photodynamic therapy generally consists of three elements: a photosensitizer with a specific absorption wavelength, a light source with a specific wavelength, and oxygen within the tissue.
- the therapeutic effect of PDT depends largely on the properties of the light used to activate the photosensitizer.
- the penetration of light into tissue is a complex process that depends on the optical properties of the tissue at the wavelength of the light used. Significant heterogeneity exists between tissues and even within tissues, with many molecules affecting the scattering and absorption of light.
- the penetration depth of long-wave near-infrared (NIR) light is higher than that of short-wave UV-visible ( UV-Vis) light (spectrum) more than twice as large (range 400–700 nm).
- NIR near-infrared
- UV-Vis UV-visible
- efficacy may be limited due to absorption by endogenous chromophores such as hemoglobin, while at longer wavelengths water absorbs light. This limits the wavelength range to optimally penetrate tissues between 600 nm and 1200 nm, while light with wavelengths greater than 800 nm cannot provide enough energy to activate PS to triplet state and generate singlet oxygen.
- the "therapeutic window" for most PDT applications is located in the red region of the 620 to 800 nm spectrum for optimal tissue penetration and PS activation.
- PS is usually excited by short-wave UV-Vis light, so its poor tissue penetration has become an Achilles' heel in the treatment of deep subcutaneous tumors.
- near-infrared light is located in the "phototherapeutic window" of biological tissue, which promises deeper penetration and lower attenuation during tissue propagation.
- Hypoxia is a well-known feature of the solid tumor microenvironment and is often attributed to rapid tumor growth and insufficient oxygen supply.
- Hypoxic tumor tissue has protein-level, gene-level, and epigenetic variations, and such tumor tissue is often resistant to radiation therapy and chemotherapy.
- photodynamic therapy hypoxia is also a key factor affecting the therapeutic effect.
- photodynamic therapy in order to overcome tumor hypoxia, some methods have been adopted: inhaling high-purity oxygen to the patient to increase the oxygen content in the patient's blood to increase the oxygen content of the patient's tumor tissue; using nanoparticles to release oxygen; using bioreductive substances to destroy hypoxic environment.
- Patent CN110483531A discloses the preparation of a new water-soluble porphyrin derivative (formula IV) and its anti-tumor application, which can better kill cancer cells under low oxygen conditions.
- the light source used is 640 nm, which is also limited. application of compounds.
- the compound obtained by structural modification of the compound of formula IV has absorption in long-wave near-infrared (NIR), so that it can not only kill cancer cells under hypoxic conditions, but also extend the wavelength of the light source to 725 nm.
- NIR near-infrared
- the photosensitizer developed by the invention can play a role under low oxygen conditions, and can use long-wave near-infrared (NIR) light to have a good killing effect on various cancer cells, and has important anti-tumor application value.
- NIR near-infrared
- the present invention provides a deep-infrared porphyrin derivative, a preparation method, an antitumor drug and an application.
- the deep-infrared porphyrin derivative of the present invention has absorption in the long-wave near-infrared (NIR), so that it can not only kill cancer cells under hypoxic conditions, but also extend the wavelength of the light source to 725 nm, which can penetrate deeper tissues cells, has a good killing effect on a variety of cancer cells.
- NIR long-wave near-infrared
- the present invention is realized like this, a kind of deep infrared porphyrin derivative, it has the structure shown in formula I:
- R is selected from -NO 2 , -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-CO-R';
- Each R 1 is independently selected from: H, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-8 cycloalkyl, Halogen, CN, COOH, hydroxyl, amino, NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , C 1-6 alkoxy, halogenated C 1-6 alkoxy;
- A is selected from H, C 1-6 alkyl, halogenated C 1-6 alkyl; preferably H, C 1-3 alkyl, halogenated C 1-3 alkyl; most preferably H, CH 3 or CH 2 CH 3 ;
- B is selected from:
- R 2 is selected from H, C 1-6 Alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl-, C 3-8 cycloalkyl, C 2-8 heterocycloalkyl, C 6-10 aryl base, C 5-10 heteroaryl; each X is independently selected from O, S, NH;
- R 3 and R 4 are selected from H, halogen, Hydroxyl, -SH, -COOH, -COO C 1-6 alkyl, -CONH 2 , -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl) 2 , amino, NH(C 1 -6 alkyl), N(C 1-6 alkyl) 2 , C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 alkyl, halogenated C 1-6 alkyl , C 1-6 alkoxy-C 1-6 alkyl-, C 3-8 cycloalkyl, C 2-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl; or , R 3 and R 4 are selected from Wherein, R 5 , R 6 and R
- R' is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) w -COOH, -(CH 2 ) w -COOC 1-6 alkyl, -(CH 2 ) w - NH 2 , -(CH 2 ) w -NH(C 1-6 alkyl), -(CH 2 ) w -N(C 1-6 alkyl) 2 , -(CH 2 ) w -OH; wherein 0 ⁇ w ⁇ 7, specifically 0, 1, 2, 3, 4, 5, 6, 7.
- the compound of formula I has the structure shown in formula I-1, formula I-2 or formula I-3;
- each R 1 is independently selected from: H, C 1-6 alkyl, halogenated C 1-6 alkyl, halogen, CN, COOH, hydroxyl, amino, NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , C 1-6 alkoxy, halogenated C 1-6 alkoxy.
- each R 1 is independently selected from: C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy.
- each R 1 is independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl; further preferably propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl; most preferably tert-butyl-C( CH3 ) 3 .
- B is -(CH 2 CH 2 O) n -CH 2 CH 2 -OR 2 , -(CH 2 CH 2 S) n -CH 2 CH 2 -SR 2 , - (CH 2 CH 2 NH) n -CH 2 CH 2 -NHR 2 , -(CH 2 CH 2 O) n -CH 2 CH 2 -SR 2 , -(CH 2 CH 2 S) n -CH 2 CH 2 - OR 2 , -(CH 2 CH 2 O) n -CH 2 CH 2 -NHR 2 , -(CH 2 CH 2 S) n -CH 2 CH 2 -NHR 2 , -(CH 2 O) n -(CH 2 ) m -OR 2 , -(CH 2 S) n -(CH 2 ) m -SR 2 , -(CH 2 O) n -(CH 2 ) m -SR 2 , -(CH 2
- R 2 is preferably H, C 1-3 alkyl, halogenated C 1-3 alkyl;
- R 3 and R 4 are preferably H, halogen, hydroxyl, -SH, -COOH, -COOC 1-3 alkyl, -CONH 2 , -CONH(C 1-2 alkyl), -CON(C 1- 2 alkyl) 2 , amino, NH(C 1-2 alkyl), N(C 1-2 alkyl) 2 , C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1- 3 alkyl, halogenated C 1-3 alkyl, or, R 3 and R 4 are selected from R 5 , R 6 and R 7 are independently selected from C 1-3 alkyl, halogenated C 1-3 alkyl, preferably methyl, ethyl and propyl;
- Y- is preferably F - , Cl - , Br - , I - or an organic acid ion, the organic acid ion is preferably formate, acetate, trifluoroacetate, methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, p-trifluoromethylbenzenesulfonate, maleate.
- the pharmaceutically acceptable metal complex refers to the complex formed by the compound of formula I and Zn 2+ , Cu 2+ , Ni + , Fe 2+ , Co 2+ .
- B is selected from the following groups:
- B is selected from the following groups:
- R' is preferably C 1-4 alkyl, halogenated C 1-4 alkyl, -(CH 2 ) w -COOH, -(CH 2 ) w -COOC 1-6 Alkyl, -(CH 2 ) w -NH 2 , -(CH 2 ) w -NH(C 1-6 alkyl), -(CH 2 ) w -N(C 1-6 alkyl) 2 , -( CH 2 ) w -OH; wherein 0 ⁇ w ⁇ 3, specifically 0, 1, 2, and 3.
- R' is selected from methyl, ethyl, propyl , isopropyl , -CH2COOH , -CH2CH2COOH , -CH2NH2 , -CH2CH2NH2 , -CH2- OH, -CH2CH2 - OH, -CH2CH2CH2 - OH, halomethyl, haloethyl, halopropyl , haloisopropyl .
- the deep infrared porphyrin derivative has the following structure:
- the deep infrared porphyrin derivative has the following structure:
- the deep infrared porphyrin derivative is selected from the following compounds:
- Another object of the present invention is to provide a kind of preparation method of deep infrared porphyrin derivative, the preparation method of described deep infrared porphyrin derivative comprises the following steps:
- the first step the nitration of the compound of formula IV';
- it also includes the second step, the reduction of the compound of formula I-1;
- the preparation method of the deep infrared porphyrin derivative comprises the steps:
- the first step the nitration of the compound of formula IV;
- A, B, R 1 have the same meanings as A, B, R 1 in formula I.
- the organic solvent is selected from 1,2-dichloroethane, dichloromethane, ethanol, acetonitrile, and methanol;
- a reducing agent is added for reduction;
- the reducing agent is sodium dithionate, stannous chloride, stannous chloride dihydrate, Fe/HCl, Zn /HCl
- the organic solvent is selected from 1,2-dichloroethane, dichloromethane, ethanol, acetonitrile, methanol;
- acid anhydride or acid chloride is added to an organic solvent for condensation reaction;
- the organic solvent is selected from 1,2-dichloroethane, dichloromethane, tetrahydrofuran, ethanol, acetonitrile, methanol ;
- Another object of the present invention is to provide an application of a deep-infrared porphyrin derivative in the preparation of photodynamic drugs, photosensitizing drugs or drugs for treating cancer.
- the cancer is cervical cancer, esophageal squamous cell carcinoma, nasopharyngeal carcinoma and melanoma.
- Another object of the present invention is to provide a pharmaceutical composition, comprising the deep infrared porphyrin derivative of the present invention, and pharmaceutically acceptable excipients and/or carriers.
- Another object of the present invention is to provide a clinically acceptable pharmaceutical preparation prepared from the pharmaceutical composition.
- Another object of the present invention is to provide an antitumor drug comprising the deep infrared porphyrin derivative.
- Alkyl refers to a straight or branched chain saturated alkane containing from 1 to 12 carbon atoms.
- C1-6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl , neopentyl and isohexyl.
- Alkoxy refers to a straight or branched chain saturated alkane containing 1 to 12 carbon atoms containing a terminal "O" in the chain, eg, -O(alkyl). C 1-6 alkoxy is preferred. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.
- Halogen or halo refers to fluorine, chlorine, bromine or iodine.
- Aryl refers to a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl.
- Heteroaryl means a monovalent monocyclic aromatic or polycyclic aromatic group of 5 to 24 ring atoms containing one or more selected from the group consisting of Ring heteroatoms of N, O and S, the remaining ring atoms are C. Heteroaryl as defined herein is preferably a C5-10 heteroaryl, wherein the heteroatom is selected from N, O and S.
- Examples include, but are not limited to, furanyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophene -2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole.
- Cycloalkyl means a monocyclic or polycyclic saturated carbocyclic ring containing 3-10 carbon atoms.
- Examples of preferred C3-8 cycloalkyl, cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
- Heterocycloalkyl means that one or more carbon atoms in a “cycloalkyl” is replaced by a heteroatom, which is O, S, N. Preference is given to C2-8 heterocycloalkyl such as oxetanyl, oxetanyl, azetidinyl.
- the "anion" of the present invention is preferably F - , Cl - , Br - , I - or an organic acid ion.
- the organic acid ions are preferably formate, acetate, trifluoroacetate, methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, p-trifluoromethylbenzenesulfonate, and maleate.
- the porphyrin derivative of the present invention obtains a series of novel porphyrin derivative compounds through nitration, reduction and amide condensation of the compound of formula IV.
- the porphyrin derivatives have excellent water solubility and photodynamic activity, and at the same time, under the tested concentration (1-2000nM), they have no dark toxicity to human normal cells.
- the porphyrin derivative compared with the compound of formula IV, has an absorption wavelength >700 nm, can penetrate deeper tissue cells, and is a potential photodynamic therapy photosensitizer.
- Fig. 1 is the wavelength absorption of the porphyrin derivatives provided in the embodiment of the present invention.
- FIG. 2 is a schematic diagram of the phototoxicity of porphyrin derivative 14 and compound 8 provided in the embodiment of the present invention to human cervical cancer HeLa cells;
- FIG. 3 is a schematic diagram of the phototoxicity of porphyrin derivatives 14 and 8 provided in the embodiment of the present invention to human esophageal squamous cell carcinoma KYSE70 cells;
- FIG. 4 is a schematic diagram of the phototoxicity of porphyrin derivatives 14 and 8 provided in the embodiment of the present invention to human nasopharyngeal carcinoma HK-1 cells;
- FIG. 5 is a schematic diagram of the dark toxicity test results of porphyrin derivatives 14 and 8 provided in the embodiment of the present invention to human normal embryonic lung fibroblast MRC-5 cells.
- FIG. 6 is a schematic diagram of the dark toxicity test results of porphyrin derivatives 14 and 8 provided in the embodiment of the present invention to human normal hepatocyte L02 cells.
- reagents, instruments and methods involved in the following examples include:
- Reagent compound of formula IV (compound 1-6) was synthesized according to the synthesis method of patent CN110483531A; silver nitrate was purchased from Sigma-Aldrich company; stannous chloride hydrate was purchased from ACROS company; titanium tetrachloride (TiCl 4 ), zinc powder , n-butyl lithium (n-BuLi), tert-butyl cuprous chloride (CuCl), copper chloride (CuCl 2 ), magnesium (Mg) and 2,2,6,6-tetramethylpiperidine (TMPP), 2-(2-aminoethoxy)ethan-1-ol, benzenesulfonyl chloride and aluminum chloride (AlCl 3 ) were purchased from Shanghai TCI Company; calcium hydride (CaH2), dry tetrahydrofuran (THF), dichloromethane Methylformamide (DMF) and pyridine were purchased from DUKSAN. Chlorosulfonic acid, dich
- the compound of formula (1) (100 mg, 0.14 mmol) and sodium dithionate (340 mg, 1.4 mmol) were dissolved in dichloromethane (10 ml) and 10% aqueous sodium hydroxide solution (4 ml) and heated to reflux for 1 hour. The reaction solution was cooled and separated, the organic phase was washed with water once, and the organic phase was dried and concentrated to obtain a crude product. The crude product was separated and purified by preparative chromatography to obtain the compound of formula (7) (76 mg, yield 80%).
- the compound of formula (2) (100 mg, 0.15 mmol) and sodium dithionate (340 mg, 1.4 mmol) were dissolved in dichloromethane (10 ml) and 10% aqueous sodium hydroxide solution (4 ml) and heated to reflux for 1 hour. The reaction solution was cooled and separated, the organic phase was washed with water once, and the organic phase was dried and concentrated to obtain a crude product. The crude product was separated and purified by preparative chromatography to obtain the compound of formula (8) (72 mg, yield 75%).
- the compound of formula (3) (100 mg, 0.14 mmol) and sodium dithionate (340 mg, 1.4 mmol) were dissolved in dichloromethane (10 ml) and 10% aqueous sodium hydroxide solution (4 ml) and heated to reflux for 1 hour. The reaction solution was cooled and separated, the organic phase was washed with water once, and the organic phase was dried and concentrated to obtain a crude product. The crude product was separated and purified by preparative chromatography column to obtain the compound of formula (9) (81 mg, yield 85%).
- the compound of formula (4) (100 mg, 0.14 mmol) and sodium dithionate (340 mg, 1.4 mmol) were dissolved in dichloromethane (10 ml) and 10% aqueous sodium hydroxide solution (4 ml) and heated to reflux for 1 hour. The reaction solution was cooled and separated, the organic phase was washed with water once, and the organic phase was dried and concentrated to obtain a crude product. The crude product was separated and purified by preparative chromatography column to obtain the compound of formula (10) (76 mg, yield 80%).
- the compound of formula (5) (376 mg, 0.5 mmol) and stannous chloride dihydrate (900 mg, 4 mmol) were dissolved in pyridine (50 ml) and heated to reflux for 1 hour. After cooling, the reaction solution was directly concentrated to obtain the crude product. The crude product was separated and purified by preparative chromatography column to obtain the compound of formula (11) (162 mg, yield 45%).
- the compound of formula (6) (100 mg, 0.13 mmol) and stannous chloride dihydrate (225 mg, 1 mmol) were dissolved in pyridine (15 ml) and heated to reflux for 1 hour. After cooling, the reaction solution was directly concentrated to obtain the crude product. The crude product was separated and purified by preparative chromatography column to obtain the compound of formula (12) (43 mg, yield 45%).
- the compound of formula (7) (100 mg, 0.15 mmol) was dissolved in dichloromethane (15 ml), triethylamine (30 mg, 0.3 mmol) was added, and the temperature was lowered to 0°C; acetyl chloride (18 mg, 0.23 mmol) was added dropwise. After the addition was completed, the mixture was returned to room temperature and stirred for 2 hours. The system was concentrated to obtain crude product. The crude product was separated and purified by preparative chromatography column to obtain the compound of formula (13) (98 mg, yield 94.5%).
- the compound of formula (8) (100mg, 0.15mmol) was dissolved in tetrahydrofuran (10ml), 8% aqueous sodium bicarbonate solution (5ml) was added, the system was cooled to 0°C; acetic anhydride (30mg, 0.3mmol) was added. After the addition was completed, the mixture was returned to room temperature and stirred for 2 hours. The system was extracted with ethyl acetate, the organic phase was washed with saturated aqueous sodium bicarbonate solution, and the organic phase was dried and concentrated to obtain the crude product. The crude product was separated and purified by preparative chromatography column to obtain the compound of formula (14) (95 mg, yield 90%).
- the compound of formula (9) (100 mg, 0.15 mmol) was dissolved in dichloromethane (15 ml), triethylamine (30 mg, 0.3 mmol) was added, and the temperature was lowered to 0°C; acetyl chloride (18 mg, 0.23 mmol) was added dropwise. After the addition was completed, the mixture was returned to room temperature and stirred for 2 hours. The system was concentrated to obtain crude product. The crude product was separated and purified by preparative chromatography column to obtain the compound of formula (15) (91 mg, yield 86%).
- the compound of formula (10) (100 mg, 0.15 mmol) was dissolved in tetrahydrofuran (10 ml), 8% aqueous sodium bicarbonate solution (5 ml) was added, the system was cooled to 0 °C; acetic anhydride (30 mg, 0.3 mmol) was added. After the addition was completed, the mixture was returned to room temperature and stirred for 2 hours. The system was extracted with ethyl acetate, the organic phase was washed with saturated aqueous sodium bicarbonate solution, and the organic phase was dried and concentrated to obtain the crude product. The crude product was separated and purified by preparative chromatography column to obtain the compound of formula (16) (79 mg, yield 76%).
- the compound of formula (11) (100 mg, 0.139 mmol) was dissolved in dichloromethane (15 ml), triethylamine (28 mg, 0.28 mmol) was added, and the temperature was lowered to 0°C; acetyl chloride (18 mg, 0.23 mmol) was added dropwise. After the addition was completed, the mixture was returned to room temperature and stirred for 2 hours. The system was concentrated to obtain crude product. The crude product was separated and purified by preparative chromatography column to obtain the compound of formula (17) (82 mg, yield 76%).
- the compound of formula (12) (100 mg, 0.139 mmol) was dissolved in dichloromethane (15 ml), triethylamine (28 mg, 0.28 mmol) was added, and the temperature was lowered to 0°C; acetyl chloride (18 mg, 0.23 mmol) was added dropwise. After the addition was completed, the mixture was returned to room temperature and stirred for 2 hours. The crude product was separated and purified by preparative chromatography column to obtain the compound of formula (18) (69 mg, yield 68%).
- the compound of formula (7) (100 mg, 0.148 mmol) was dissolved in dichloromethane (15 ml), triethylamine (30 mg, 0.3 mmol) was added, and the temperature was lowered to 0 °C; succinic anhydride (48 mg, 0.22 mmol) was added dropwise. After the addition was completed, the mixture was returned to room temperature and stirred for 2 hours. The system was concentrated to obtain a crude product, which was separated and purified by a preparative chromatography column to obtain the compound of formula (19) (54 mg, yield 45%).
- the compound of formula (8) (100 mg, 0.152 mmol) was dissolved in dichloromethane (15 ml), triethylamine (61 mg, 0.6 mmol) was added, and the temperature was lowered to 0 °C; , 0.46 mmol). After the addition was completed, the mixture was returned to room temperature and stirred for 2 hours. The system was washed once with 1N HCl and saturated brine, and 10 ml of 30% sodium hydroxide solution was added to the organic phase and stirred at room temperature for 2 hours.
- the compound of formula (9) (90 mg, 0.134 mmol) was dissolved in dichloromethane (15 ml), triethylamine (30 mg, 0.3 mmol) was added, and the temperature was lowered to 0°C; succinic anhydride (48 mg, 0.22 mmol) was added dropwise. After the addition was completed, the mixture was returned to room temperature and stirred for 2 hours. The system was concentrated to obtain a crude product, which was separated and purified by a preparative chromatography column to obtain the compound of formula (19) (84 mg, yield 81%).
- the compound of formula (10) (100 mg, 0.152 mmol) was dissolved in 15 ml of tetrahydrofuran: water (1:1), 50% sodium hydroxide (2 ml) was added, and the temperature was lowered to 0 °C; succinic anhydride (48 mg, 0.22 mmol) was added dropwise. ) in tetrahydrofuran. After the addition was completed, the mixture was returned to room temperature and stirred for 2 hours. The pH of the system was adjusted to 2-3, extracted with 15 ml of ethyl acetate, the organic phase was washed with saturated brine, and the layers were separated. The organic phase was dried and concentrated to obtain a crude product, which was separated and purified by a preparative chromatographic column to obtain the compound of formula (22) (88 mg, yield 75%).
- the compound of formula (17) (50 mg, 0.065 mmol) and 0.5 ml of triethylamine were dissolved in acetonitrile (10 ml), heated to 80° C. to react for 5 hours, and the reaction was monitored by TLC. After the reaction was completed, the temperature was lowered to 0° C. and stirred for 2 hours. A solid was precipitated, which was filtered and dried to obtain the compound of formula (23) (45 mg, yield 81%).
- the compound of formula (18) (100 mg, 0.131 mmol) and 1 ml of triethylamine were dissolved in acetonitrile (15 ml), heated to 80° C. to react for 5 hours, and the reaction was monitored by TLC. After the reaction was completed, the temperature was lowered to 0° C. and stirred for 2 hours, and a solid was precipitated, which was filtered and dried to obtain the compound of formula (24) (904 mg, yield 85%).
- MTT thiazolyl blue assay was used to evaluate the photodynamic activity of porphyrin derivatives 8 and 14. First, the effect of illumination alone on the viability of HeLa cells was examined. Then, the cells were seeded in a 96-well culture plate at a concentration of 1 ⁇ 10 4 HeLa cells per well, and after culturing for 24 hours, culture solutions containing porphyrin derivatives 14 and 8 with different concentrations were added.
- the culture was continued for 24 h, 10 ⁇ L of MTT (5 mg/mL) was added to each well, and the incubation was continued for 4 h in the dark.
- a dark contrast test was also carried out. Discard the medium, add 100 ⁇ L DMSO to each well, and mix by shaking. At 490nm wavelength, the absorbance value was measured by a multi-function microplate reader, and the cell viability was calculated.
- the light conditions used in this experiment basically did not cause damage to HeLa cells, excluding the influence of light on this experiment.
- Both porphyrin derivatives 14 and 8 significantly inhibited the proliferation of HeLa cells and had strong phototoxicity.
- MTT (thiazolyl blue) assay was used to evaluate the photodynamic activities of porphyrin derivatives 14 and 8. First, the effect of illumination alone on the viability of KYSE70 cells was examined. Then, the cells were seeded in a 96-well culture plate at a concentration of 1 ⁇ 10 4 KYSE70 cells per well, and after culturing for 24 hours, culture solutions containing different concentrations of porphyrin derivatives 1 and 2 were added.
- the light conditions used in this experiment basically did not cause damage to KYSE70 cells, excluding the influence of light on this experiment.
- porphyrin derivatization Both compounds 14 and 8 significantly inhibited the proliferation of KYSE70 cells and had strong phototoxicity.
- MTT thiazolyl blue assay was used to evaluate the photodynamic activities of porphyrin derivatives 14 and 8. First, the effect of illumination alone on the viability of HK-1 cells was examined. Then, A375 cells were seeded in a 96-well culture plate at a concentration of 1 ⁇ 10 4 A375 cells per well, and after culturing for 24 hours, culture solutions containing porphyrin derivatives 14 and 8 at different concentrations were added.
- the light conditions used in this experiment basically did not cause damage to HK-1 cells, excluding the influence of light on this experiment.
- porphyrin derivatization Both compounds 14 and 8 significantly inhibited the proliferation of HK-1 cells and had strong phototoxicity.
- the present application also investigated the dark toxicity of porphyrin derivatives 14 and 8 to human normal hepatocyte L02 cells.
- MTT thiazolyl blue
- the inhibition rate of MRC-5 cell proliferation was 7.8%, with weak dark toxicity. It can be seen that the porphyrin derivatives of the present invention have great advantages as photosensitizers.
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Abstract
The present invention relates to the technical field of photodynamic drugs and photosensitization, and relates to a deep infrared porphycene derivative, a preparation method, an anti-tumor drug, and an application. The porphycene derivative of the present invention has excellent water solubility and photodynamic activity, has photodynamic activity in a low oxygen state, and has no dark toxicity to normal human cells.
Description
本发明属于光动力药物及光敏技术领域，尤其涉及一种深红外卟啉烯衍生物、制备方法、抗肿瘤药物和应用。The invention belongs to the technical field of photodynamic drugs and photosensitivity, and in particular relates to a deep-infrared porphyrin derivative, a preparation method, an antitumor drug and an application.
光动力治疗通常包含三个要素：具有特定吸收波长的光敏剂，特定波长的光源以及组织内的氧气。PDT的治疗效果很大一方面取决于用于激活光敏剂的光的属性。光在组织中的渗透是一个复杂的过程，这取决于在所用光的波长下组织的光学特性。组织之间甚至组织内部都存在明显的异质性，其中许多分子会影响光的散射和吸收。通过比较大多数组织(例如，皮肤，粘液组织等)内光的穿透深度和波长，可以发现长波近红外(NIR)光的穿透深度(光谱范围为700-1100nm)比短波长紫外可见(UV-Vis)光(光谱)大两倍以上(范围在400–700nm之间)。在较短的可见波长下，由于内源性发色团(例如血红蛋白)的吸收，功效可能受到限制，而在较长的波长下，水会吸收光。这限制了波长范围以最佳地穿透600nm至1200nm之间的组织，而波长大于800nm的光不能提供将PS激活到三重态并产生单重态氧所需的足够能量。因此，大多数PDT应用的“治疗窗口”位于620至800nm光谱的红色区域，可实现最佳的组织穿透和PS激活。但是，在传统的PDT中，PS通常会被短波UV-Vis光激发，因此其不良的组织穿透力已成为治疗皮肤以下深层肿瘤的致命弱点。幸运的是，近红外光位于生物组织的“光学治疗窗口”中，这有望在组织传播过程中实现更深的穿透力和更低的衰减。Photodynamic therapy generally consists of three elements: a photosensitizer with a specific absorption wavelength, a light source with a specific wavelength, and oxygen within the tissue. The therapeutic effect of PDT depends largely on the properties of the light used to activate the photosensitizer. The penetration of light into tissue is a complex process that depends on the optical properties of the tissue at the wavelength of the light used. Significant heterogeneity exists between tissues and even within tissues, with many molecules affecting the scattering and absorption of light. By comparing the penetration depth and wavelength of light in most tissues (eg, skin, mucous tissue, etc.), it can be found that the penetration depth of long-wave near-infrared (NIR) light (spectral range 700-1100 nm) is higher than that of short-wave UV-visible ( UV-Vis) light (spectrum) more than twice as large (range 400–700 nm). At shorter visible wavelengths, efficacy may be limited due to absorption by endogenous chromophores such as hemoglobin, while at longer wavelengths water absorbs light. This limits the wavelength range to optimally penetrate tissues between 600 nm and 1200 nm, while light with wavelengths greater than 800 nm cannot provide enough energy to activate PS to triplet state and generate singlet oxygen. Therefore, the "therapeutic window" for most PDT applications is located in the red region of the 620 to 800 nm spectrum for optimal tissue penetration and PS activation. However, in conventional PDT, PS is usually excited by short-wave UV-Vis light, so its poor tissue penetration has become an Achilles' heel in the treatment of deep subcutaneous tumors. Fortunately, near-infrared light is located in the "phototherapeutic window" of biological tissue, which promises deeper penetration and lower attenuation during tissue propagation.
低氧是实体瘤微环境的一个众所周知的特征，通常归因于肿瘤快速生长和供氧不足。低氧的肿瘤组织存在着蛋白质水平，基因水平以及表观遗传上的变异，同时这样的肿瘤组织通常对放射治疗和化学疗法耐受。在光动力治疗中，低氧也是一个影响治疗效果的关键因素。在光动力治疗中，为了克服肿瘤低氧采取了一些方法：给病人吸入高纯度氧气增加病人血液中氧含量以此来提高病人肿瘤组织的氧含量；利用纳米颗粒释放氧气；利用生物还原物质破坏低氧环境。Hypoxia is a well-known feature of the solid tumor microenvironment and is often attributed to rapid tumor growth and insufficient oxygen supply. Hypoxic tumor tissue has protein-level, gene-level, and epigenetic variations, and such tumor tissue is often resistant to radiation therapy and chemotherapy. In photodynamic therapy, hypoxia is also a key factor affecting the therapeutic effect. In photodynamic therapy, in order to overcome tumor hypoxia, some methods have been adopted: inhaling high-purity oxygen to the patient to increase the oxygen content in the patient's blood to increase the oxygen content of the patient's tumor tissue; using nanoparticles to release oxygen; using bioreductive substances to destroy hypoxic environment.
目前临床常用的大多数光敏剂如表1所示，使用的光源波长绝大多数<700nm，组织穿透力弱。Most of the commonly used photosensitizers in clinical practice are shown in Table 1. Most of the light source wavelengths used are less than 700 nm, and the tissue penetration is weak.
表1 获准上市或正在临床应用的光敏剂Table 1 Photosensitizers approved for marketing or in clinical use
专利CN110483531A公开了一种新型水溶性卟啉烯衍生物(式Ⅳ)的制备以及抗肿瘤的应用，能够在低氧条件下较好的杀死癌细胞，其使用的光源在640nm，同样限制的化合物的应用。Patent CN110483531A discloses the preparation of a new water-soluble porphyrin derivative (formula IV) and its anti-tumor application, which can better kill cancer cells under low oxygen conditions. The light source used is 640 nm, which is also limited. application of compounds.
综上，现有技术存在的问题包括：目前临床常用的大多数光敏剂以及文献报道的光敏剂，多数使用的光源波长<700nm，组织穿透力弱；此外，人肿瘤组织的氧含量较低大大限制目前的大多数光敏剂的使用。To sum up, the problems existing in the prior art include: most of the photosensitizers commonly used in clinical practice and those reported in the literature mostly use light sources with wavelengths <700 nm and weak tissue penetration; in addition, the oxygen content of human tumor tissue is low It greatly limits the use of most current photosensitizers.
本发明通过对式Ⅳ化合物进行结构修饰获得的化合物，在长波近红外(NIR)有吸收，使其不仅能在低氧条下杀死癌细胞，而且使得光源的波长延长到725nm。In the present invention, the compound obtained by structural modification of the compound of formula IV has absorption in long-wave near-infrared (NIR), so that it can not only kill cancer cells under hypoxic conditions, but also extend the wavelength of the light source to 725 nm.
本发明开发的光敏剂能够在低氧条件下发挥作用，并且可用长波近红外(NIR)光，对多种癌细胞具有很好的杀伤效果，具有重要的抗肿瘤应用价值。The photosensitizer developed by the invention can play a role under low oxygen conditions, and can use long-wave near-infrared (NIR) light to have a good killing effect on various cancer cells, and has important anti-tumor application value.
发明内容SUMMARY OF THE INVENTION
针对现有技术存在的问题，本发明提供了一种深红外卟啉烯衍生物、制备方法、抗肿瘤 药物和应用。本发明的深红外卟啉烯衍生物，在长波近红外(NIR)有吸收，使其不仅能在低氧条下杀死癌细胞，而且使得光源的波长延长到725nm，能够穿透更深的组织细胞，对多种癌细胞具有很好的杀伤效果。Aiming at the problems existing in the prior art, the present invention provides a deep-infrared porphyrin derivative, a preparation method, an antitumor drug and an application. The deep-infrared porphyrin derivative of the present invention has absorption in the long-wave near-infrared (NIR), so that it can not only kill cancer cells under hypoxic conditions, but also extend the wavelength of the light source to 725 nm, which can penetrate deeper tissues cells, has a good killing effect on a variety of cancer cells.
本发明是这样实现的，一种深红外卟啉烯衍生物，其具有式I所示结构：The present invention is realized like this, a kind of deep infrared porphyrin derivative, it has the structure shown in formula I:
或其药学上可接受的盐，或其药学上可接受的金属配合物；or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable metal complex thereof;
其中，in,
R选自-NO
2、-NH
2、-NH(C
1-6烷基)、-N(C
1-6烷基)
2、-NH-CO-R’；
R is selected from -NO 2 , -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-CO-R';
每个R
1独立地选自：H、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基-C
1-6烷基、C
3-8环烷基、卤素、CN、COOH、羟基、氨基、NH(C
1-6烷基)、N(C
1-6烷基)
2、C
1-6烷氧基、卤代C
1-6烷氧基；
Each R 1 is independently selected from: H, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-8 cycloalkyl, Halogen, CN, COOH, hydroxyl, amino, NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , C 1-6 alkoxy, halogenated C 1-6 alkoxy;
A选自H，C
1-6烷基、卤代C
1-6烷基；优选H，C
1-3烷基、卤代C
1-3烷基；最优选H、CH
3或者CH
2CH
3；
A is selected from H, C 1-6 alkyl, halogenated C 1-6 alkyl; preferably H, C 1-3 alkyl, halogenated C 1-3 alkyl; most preferably H, CH 3 or CH 2 CH 3 ;
B选自：B is selected from:
1)-(CH
2CH
2X)
n-(CH
2)
m-XR
2或-(CH
2X)
n-(CH
2)
m-XR
2；其中，R
2选自H、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基-C
1-6烷基-、C
3-8环烷基、C
2-8杂环烷基、C
6-10芳基、C
5-10杂芳基；每个X独立地选自O、S、NH；
1)-(CH 2 CH 2 X) n -(CH 2 ) m -XR 2 or -(CH 2 X) n -(CH 2 ) m -XR 2 ; wherein, R 2 is selected from H, C 1-6 Alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl-, C 3-8 cycloalkyl, C 2-8 heterocycloalkyl, C 6-10 aryl base, C 5-10 heteroaryl; each X is independently selected from O, S, NH;
2)-(CH
2)
n-CH
2-R
3或-(CH
2CH
2X)
n-(CH
2)
m-CH
2-R
4；其中，R
3、R
4选自H、卤素、羟基、-SH、-COOH、-COO C
1-6烷基、-CONH
2、-CONH(C
1-6烷基)、-CON(C
1-6烷基)
2、氨基、NH(C
1-6 烷基)、N(C
1-6烷基)
2、C
1-6烷氧基、卤代C
1-6烷氧基、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基-C
1-6烷基-、C
3-8环烷基、C
2-8杂环烷基、C
6-10芳基、C
5-10杂芳基；或者，R
3、R
4选自
其中，R
5、R
6、R
7独立的选自：C
1-6烷基、卤代C
1-6烷基；Y-为阴离子；其中当n≧2时，-(CH
2)
n-CH
2-R
3中一个或多个CH
2可替换为O、S、NH；每个X独立地选自O、S、NH；且0≤n≤14，0≤m≤14，具体为0、1、2、3、4、5、6、7、8、9、10、11、12、13、14；优选0≤n≤7，0≤m≤7；
2)-(CH 2 ) n -CH 2 -R 3 or -(CH 2 CH 2 X) n -(CH 2 ) m -CH 2 -R 4 ; wherein R 3 and R 4 are selected from H, halogen, Hydroxyl, -SH, -COOH, -COO C 1-6 alkyl, -CONH 2 , -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl) 2 , amino, NH(C 1 -6 alkyl), N(C 1-6 alkyl) 2 , C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 alkyl, halogenated C 1-6 alkyl , C 1-6 alkoxy-C 1-6 alkyl-, C 3-8 cycloalkyl, C 2-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl; or , R 3 and R 4 are selected from Wherein, R 5 , R 6 and R 7 are independently selected from: C 1-6 alkyl, halogenated C 1-6 alkyl; Y- is an anion; wherein when n≧2, -(CH 2 ) n - One or more CH 2 in CH 2 -R 3 can be replaced by O, S, NH; each X is independently selected from O, S, NH; and 0≤n≤14, 0≤m≤14, specifically 0 , 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14; preferably 0≤n≤7, 0≤m≤7;
R’选自C
1-6烷基、卤代C
1-6烷基、-(CH
2)
w-COOH、-(CH
2)
w-COOC
1-6烷基、-(CH
2)
w-NH
2、-(CH
2)
w-NH(C
1-6烷基)、-(CH
2)
w-N(C
1-6烷基)
2、-(CH
2)
w-OH；其中0≤w≤7，具体为0、1、2、3、4、5、6、7。
R' is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) w -COOH, -(CH 2 ) w -COOC 1-6 alkyl, -(CH 2 ) w - NH 2 , -(CH 2 ) w -NH(C 1-6 alkyl), -(CH 2 ) w -N(C 1-6 alkyl) 2 , -(CH 2 ) w -OH; wherein 0≤ w≤7, specifically 0, 1, 2, 3, 4, 5, 6, 7.
作为优选的方案，所述式I化合物具有式I-1、式I-2或式I-3所示的结构；As a preferred solution, the compound of formula I has the structure shown in formula I-1, formula I-2 or formula I-3;
作为优选，每个R
1独立地选自：H、C
1-6烷基、卤代C
1-6烷基、卤素、CN、COOH、羟基、氨基、NH(C
1-6烷基)、N(C
1-6烷基)
2、C
1-6烷氧基、卤代C
1-6烷氧基。
Preferably, each R 1 is independently selected from: H, C 1-6 alkyl, halogenated C 1-6 alkyl, halogen, CN, COOH, hydroxyl, amino, NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , C 1-6 alkoxy, halogenated C 1-6 alkoxy.
进一步地，每个R
1独立地选自：C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基。
Further, each R 1 is independently selected from: C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy.
作为优选的方案，每个R
1独立地选自甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、戊基；进一步优选丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基；最优选叔丁基-C(CH
3)
3。
As a preferred solution, each R 1 is independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl; further preferably propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl; most preferably tert-butyl-C( CH3 ) 3 .
在发明的一个优选实施方案中，其中，B为-(CH
2CH
2O)
n-CH
2CH
2-OR
2、-(CH
2CH
2S)
n-CH
2CH
2-SR
2、-(CH
2CH
2NH)
n-CH
2CH
2-NHR
2、-(CH
2CH
2O)
n-CH
2CH
2-SR
2、-(CH
2CH
2S)
n-CH
2CH
2-OR
2、-(CH
2CH
2O)
n-CH
2CH
2-NHR
2、-(CH
2CH
2S)
n-CH
2CH
2-NHR
2、-(CH
2O)
n-(CH
2)
m-OR
2、-(CH
2S)
n-(CH
2)
m-SR
2、-(CH
2O)
n-(CH
2)
m-SR
2、-(CH
2S)
n-(CH
2)
m-OR
2、-(CH
2)
5-R
3、-(CH
2CH
2X)
n-(CH
2)
m-CH
2-R
4；且0≤n≤7，0≤m≤7，优选m、n为0、1、2、3、4；
In a preferred embodiment of the invention, wherein B is -(CH 2 CH 2 O) n -CH 2 CH 2 -OR 2 , -(CH 2 CH 2 S) n -CH 2 CH 2 -SR 2 , - (CH 2 CH 2 NH) n -CH 2 CH 2 -NHR 2 , -(CH 2 CH 2 O) n -CH 2 CH 2 -SR 2 , -(CH 2 CH 2 S) n -CH 2 CH 2 - OR 2 , -(CH 2 CH 2 O) n -CH 2 CH 2 -NHR 2 , -(CH 2 CH 2 S) n -CH 2 CH 2 -NHR 2 , -(CH 2 O) n -(CH 2 ) m -OR 2 , -(CH 2 S) n -(CH 2 ) m -SR 2 , -(CH 2 O) n -(CH 2 ) m -SR 2 , -(CH 2 S) n -(CH ) 2 ) m -OR 2 , -(CH 2 ) 5 -R 3 , -(CH 2 CH 2 X) n -(CH 2 ) m -CH 2 -R 4 ; and 0≤n≤7, 0≤m≤ 7, preferably m, n are 0, 1, 2, 3, 4;
在发明的一个实施方案中，R
2优选H、C
1-3烷基、卤代C
1-3烷基；
In one embodiment of the invention, R 2 is preferably H, C 1-3 alkyl, halogenated C 1-3 alkyl;
进一步的，R
3、R
4优选H、卤素、羟基、-SH、-COOH、-COOC
1-3烷基、-CONH
2、 -CONH(C
1-2烷基)、-CON(C
1-2烷基)
2、氨基、NH(C
1-2烷基)、N(C
1-2烷基)
2、C
1-3烷氧基、卤代C
1-3烷氧基、C
1-3烷基、卤代C
1-3烷基、或者，R
3、R
4选自
R
5、R
6、R
7独立的选自C
1-3烷基、卤代C
1-3烷基，优选甲基、乙基、丙基；
Further, R 3 and R 4 are preferably H, halogen, hydroxyl, -SH, -COOH, -COOC 1-3 alkyl, -CONH 2 , -CONH(C 1-2 alkyl), -CON(C 1- 2 alkyl) 2 , amino, NH(C 1-2 alkyl), N(C 1-2 alkyl) 2 , C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1- 3 alkyl, halogenated C 1-3 alkyl, or, R 3 and R 4 are selected from R 5 , R 6 and R 7 are independently selected from C 1-3 alkyl, halogenated C 1-3 alkyl, preferably methyl, ethyl and propyl;
Y-优选F
-、Cl
-、Br
-、I
-或有机酸根离子，所述有机酸根离子优选甲酸根、乙酸根、三氟乙酸根、甲磺酸根、三氟甲磺酸根、苯磺酸根、对甲苯磺酸根、对三氟甲基苯磺酸根、马来酸根。
Y- is preferably F - , Cl - , Br - , I - or an organic acid ion, the organic acid ion is preferably formate, acetate, trifluoroacetate, methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, p-trifluoromethylbenzenesulfonate, maleate.
所述药学上可接受的金属配合物是指式I化合物与Zn
2+、Cu
2+、Ni
+、Fe
2+、Co
2+形成的配合物。
The pharmaceutically acceptable metal complex refers to the complex formed by the compound of formula I and Zn 2+ , Cu 2+ , Ni + , Fe 2+ , Co 2+ .
在发明的一个优选实施方案中，其中，B选自如下基团：In a preferred embodiment of the invention, wherein, B is selected from the following groups:
在发明的一个优选实施方案中，其中，B选自如下基团：In a preferred embodiment of the invention, wherein, B is selected from the following groups:
在发明的一个优选实施方案中，其中，R’优选C
1-4烷基、卤代C
1-4烷基、-(CH
2)
w-COOH、-(CH
2)
w-COOC
1-6烷基、-(CH
2)
w-NH
2、-(CH
2)
w-NH(C
1-6烷基)、-(CH
2)
w-N(C
1-6烷基)
2、-(CH
2)
w-OH；其中0≤w≤3，具体为0、1、2、3。
In a preferred embodiment of the invention, wherein, R' is preferably C 1-4 alkyl, halogenated C 1-4 alkyl, -(CH 2 ) w -COOH, -(CH 2 ) w -COOC 1-6 Alkyl, -(CH 2 ) w -NH 2 , -(CH 2 ) w -NH(C 1-6 alkyl), -(CH 2 ) w -N(C 1-6 alkyl) 2 , -( CH 2 ) w -OH; wherein 0≤w≤3, specifically 0, 1, 2, and 3.
进一步地，R’选自甲基、乙基、丙基、异丙基、-CH
2COOH、-CH
2CH
2COOH、-CH
2NH
2、-CH
2CH
2NH
2、-CH
2-OH、-CH
2CH
2-OH、-CH
2CH
2CH
2-OH、卤代甲基、卤代乙基、卤代丙基、卤代异丙基。
Further, R' is selected from methyl, ethyl, propyl , isopropyl , -CH2COOH , -CH2CH2COOH , -CH2NH2 , -CH2CH2NH2 , -CH2- OH, -CH2CH2 - OH, -CH2CH2CH2 - OH, halomethyl, haloethyl, halopropyl , haloisopropyl .
作为发明优选的方案，所述深红外卟啉烯衍生物具有如下结构：As a preferred solution of the invention, the deep infrared porphyrin derivative has the following structure:
作为发明优选的方案，所述深红外卟啉烯衍生物具有如下结构：As a preferred solution of the invention, the deep infrared porphyrin derivative has the following structure:
作为最优选的方案，所述深红外卟啉烯衍生物选自如下化合物：As the most preferred scheme, the deep infrared porphyrin derivative is selected from the following compounds:
本发明的另一目的在于提供一种深红外卟啉烯衍生物的制备方法，所述深红外卟啉烯衍生物的制备方法包括如下步骤：Another object of the present invention is to provide a kind of preparation method of deep infrared porphyrin derivative, the preparation method of described deep infrared porphyrin derivative comprises the following steps:
第一步，式IV’化合物的硝化；The first step, the nitration of the compound of formula IV';
根据需要，还包括第二步，式I-1化合物的还原；According to needs, it also includes the second step, the reduction of the compound of formula I-1;
根据需要，还包括第三步，式I-2化合物的酰胺化；According to needs, also includes the third step, the amidation of the compound of formula I-2;
进一步地，在一个优选的实施方案中，所述深红外卟啉烯衍生物的制备方法包括如下步骤：Further, in a preferred embodiment, the preparation method of the deep infrared porphyrin derivative comprises the steps:
第一步，式IV化合物的硝化；The first step, the nitration of the compound of formula IV;
根据需要，还包括Also includes as needed
第二步，式1化合物的还原；The second step, the reduction of the compound of formula 1;
第三步，式2化合物的酰胺化；The third step, amidation of the compound of formula 2;
在式IV’和式IV中，A、B、R
1的含义与式I中的A、B、R
1的含义相同。
In formula IV' and formula IV, A, B, R 1 have the same meanings as A, B, R 1 in formula I.
优选地，第一步反应，在有机溶剂中，加入硝酸银和醋酸进行硝化；优选地所述有机溶剂选自1,2-二氯乙烷、二氯甲烷、乙醇、乙腈、甲醇；Preferably, in the first step reaction, in an organic solvent, silver nitrate and acetic acid are added for nitration; preferably, the organic solvent is selected from 1,2-dichloroethane, dichloromethane, ethanol, acetonitrile, and methanol;
优选地，第二步反应，在有机溶剂中，加入还原剂进行还原；优选地，所述还原剂为连二硫酸钠、氯化亚锡、氯化亚锡二水合物、Fe/HCl、Zn/HCl，有机溶剂选自1,2-二氯乙烷、二氯甲烷、乙醇、乙腈、甲醇；Preferably, in the second step reaction, in an organic solvent, a reducing agent is added for reduction; preferably, the reducing agent is sodium dithionate, stannous chloride, stannous chloride dihydrate, Fe/HCl, Zn /HCl, the organic solvent is selected from 1,2-dichloroethane, dichloromethane, ethanol, acetonitrile, methanol;
优选地，第三步反应，在有机溶剂中，加入酸酐或酰氯进行缩合反应；优选地，所述有机溶剂选自1,2-二氯乙烷、二氯甲烷、四氢呋喃、乙醇、乙腈、甲醇；Preferably, in the third step of the reaction, acid anhydride or acid chloride is added to an organic solvent for condensation reaction; preferably, the organic solvent is selected from 1,2-dichloroethane, dichloromethane, tetrahydrofuran, ethanol, acetonitrile, methanol ;
本发明的另一目的在于提供一种深红外卟啉烯衍生物在制备光动力药物、光敏药物或治疗癌症药物中的应用。Another object of the present invention is to provide an application of a deep-infrared porphyrin derivative in the preparation of photodynamic drugs, photosensitizing drugs or drugs for treating cancer.
进一步，所述癌症为***、食管鳞癌、鼻咽癌和黑色素瘤。Further, the cancer is cervical cancer, esophageal squamous cell carcinoma, nasopharyngeal carcinoma and melanoma.
本发明的另一目的在于提供一种药物组合物，包括本发明所述的深红外卟啉烯衍生物，以及药学上可接受的辅料和/或载体。Another object of the present invention is to provide a pharmaceutical composition, comprising the deep infrared porphyrin derivative of the present invention, and pharmaceutically acceptable excipients and/or carriers.
本发明的另一目的在于提供一种由所述药物组合物制备的临床可接受的药物制剂。Another object of the present invention is to provide a clinically acceptable pharmaceutical preparation prepared from the pharmaceutical composition.
本发明的另一目的在于提供一种包含所述深红外卟啉烯衍生物的抗肿瘤药物。Another object of the present invention is to provide an antitumor drug comprising the deep infrared porphyrin derivative.
本申请中的术语定义：Definitions of terms in this application:
“烷基”是指含有1-12个碳原子的直链或支链饱和烷烃。C
1-6烷基基团的例子包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、新戊基和异己基。
"Alkyl" refers to a straight or branched chain saturated alkane containing from 1 to 12 carbon atoms. Examples of C1-6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl , neopentyl and isohexyl.
“烷氧基”是指在链中含有末端“O”的包含1-12个碳原子的直链或支链饱和烷烃，例如-O(烷基)。优选C
1-6烷氧基。烷氧基基团的例子包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、叔丁氧基或戊氧基基团。
"Alkoxy" refers to a straight or branched chain saturated alkane containing 1 to 12 carbon atoms containing a terminal "O" in the chain, eg, -O(alkyl). C 1-6 alkoxy is preferred. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.
“卤素”或“卤代”是指氟、氯、溴或碘。"Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.
“芳基”是指具有1至3个芳香族环的环状芳香族烃基团，包括单环或二环基团，如苯基、联苯或萘基。"Aryl" refers to a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl.
“杂芳基”意指5至24个环原子的单价单环芳香族基团或多环芳香族基团，这些单环芳香族基团或多环芳香族基团含有一个或多个选自N、O和S的环杂原子，其余的环原子是C。如本文所定义的杂芳基优选C
5-10杂芳基，其中杂原子选自N、O和S。例子包括但不限于呋喃基、噻吩基、吡咯基、吡啶基、吡唑基、嘧啶基、咪唑基、异噁唑基、噁唑基、噁二唑基、吡嗪基、吲哚基、噻吩-2-基、喹啉基、苯并吡喃基、异噻唑基、噻唑基、噻二唑、吲唑。
"Heteroaryl" means a monovalent monocyclic aromatic or polycyclic aromatic group of 5 to 24 ring atoms containing one or more selected from the group consisting of Ring heteroatoms of N, O and S, the remaining ring atoms are C. Heteroaryl as defined herein is preferably a C5-10 heteroaryl, wherein the heteroatom is selected from N, O and S. Examples include, but are not limited to, furanyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophene -2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole.
“环烷基”意指含有3-10个碳原子的单环或多环饱和碳环。优选C
3-8环烷基、环烷基基团 的例子包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、
"Cycloalkyl" means a monocyclic or polycyclic saturated carbocyclic ring containing 3-10 carbon atoms. Examples of preferred C3-8 cycloalkyl, cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
“杂环烷基”是指“环烷基”中的一个或多个碳原子被杂原子取代，所述杂原子为O、S、N。优先C
2-8杂环烷基，如氧杂环丙基、氧杂环丁基、氮杂环丁基。
"Heterocycloalkyl" means that one or more carbon atoms in a "cycloalkyl" is replaced by a heteroatom, which is O, S, N. Preference is given to C2-8 heterocycloalkyl such as oxetanyl, oxetanyl, azetidinyl.
本发明的“阴离子”优选F
-、Cl
-、Br
-、I
-或有机酸根离子。
The "anion" of the present invention is preferably F - , Cl - , Br - , I - or an organic acid ion.
所述有机酸根离子优选甲酸根、乙酸根、三氟乙酸根、甲磺酸根、三氟甲磺酸根、苯磺酸根、对甲苯磺酸根、对三氟甲基苯磺酸根、马来酸根。The organic acid ions are preferably formate, acetate, trifluoroacetate, methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, p-trifluoromethylbenzenesulfonate, and maleate.
本发明的优点及积极效果为：本发明的卟啉烯衍生物通过对式IV化合物的硝化，还原，酰胺缩合得到一系列新型卟啉烯衍生化合物。卟啉烯衍生物具有优异的水溶性和光动力活性，同时，在测试浓度(1～2000nM)下，对人正常细胞没有暗毒性。同时，对比式IV化合物，卟啉烯衍生物的吸收波长>700nm,能够穿透更深的组织细胞，是一种潜在的光动力治疗光敏剂。The advantages and positive effects of the present invention are as follows: the porphyrin derivative of the present invention obtains a series of novel porphyrin derivative compounds through nitration, reduction and amide condensation of the compound of formula IV. The porphyrin derivatives have excellent water solubility and photodynamic activity, and at the same time, under the tested concentration (1-2000nM), they have no dark toxicity to human normal cells. Meanwhile, compared with the compound of formula IV, the porphyrin derivative has an absorption wavelength >700 nm, can penetrate deeper tissue cells, and is a potential photodynamic therapy photosensitizer.
图1是本发明实施例提供的卟啉烯衍生物的波长吸收。Fig. 1 is the wavelength absorption of the porphyrin derivatives provided in the embodiment of the present invention.
图2是本发明实施例提供的卟啉烯衍生物14和化合物8对人***HeLa细胞的光毒性示意图；2 is a schematic diagram of the phototoxicity of porphyrin derivative 14 and compound 8 provided in the embodiment of the present invention to human cervical cancer HeLa cells;
图中：(a)光照条件(λ＝680±15nm，λ＝725±15nm，照射总剂量为6J/cm
2)下，HeLa细胞的存活率；(b)在常规氧和低氧条件下，黑暗和光照(λ＝680±15nm，照射总剂量为6J/cm
2)，卟啉烯衍生物14对HeLa细胞活性的影响；(c)在常规氧和低氧条件下，光照(λ＝725±15nm，照射总剂量为6J/cm
2)，卟啉烯衍生物8对HeLa细胞活性的影响。
In the figure: (a) The survival rate of HeLa cells under light conditions (λ=680±15nm, λ=725±15nm, and the total irradiation dose is 6J/cm 2 ); (b) Under conventional oxygen and hypoxia conditions, Dark and light (λ=680±15nm, total irradiation dose of 6J/cm 2 ), the effect of porphyrin derivative 14 on the viability of HeLa cells; (c) Under normal oxygen and hypoxic conditions, light (λ=725 ±15nm, the total irradiation dose is 6J/cm 2 ), the effect of porphyrin derivative 8 on the activity of HeLa cells.
图3是本发明实施例提供的卟啉烯衍生物14和8对人食管鳞癌KYSE70细胞的光毒性示意图；3 is a schematic diagram of the phototoxicity of porphyrin derivatives 14 and 8 provided in the embodiment of the present invention to human esophageal squamous cell carcinoma KYSE70 cells;
图中：(a)光照条件(λ＝680±15nm，λ＝725±15nm，照射总剂量为6J/cm
2)下，HK-1细胞的存活率；(b)在常规氧和低氧条件下，黑暗和光照(λ＝680±15nm，照射总剂量为6J/cm
2)，卟啉烯衍生物14对HK-1细胞活性的影响；(c)黑暗和光照条件(λ＝725±15nm，照射总剂量为6J/cm
2)下，卟啉烯衍生物8对KYSE70细胞活性的影响。
In the figure: (a) the survival rate of HK-1 cells under light conditions (λ=680±15nm, λ=725±15nm, the total irradiation dose is 6J/cm 2 ); (b) under normal oxygen and hypoxia conditions Under dark and light conditions (λ=680±15nm, the total irradiation dose was 6J/cm 2 ), the effect of porphyrin derivative 14 on the activity of HK-1 cells; (c) dark and light conditions (λ=725±15nm) , under the total irradiation dose of 6J/cm 2 ), the effect of porphyrin derivative 8 on the activity of KYSE70 cells.
图4是本发明实施例提供的卟啉烯衍生物14和8对人鼻咽癌HK-1细胞的光毒性示意图；4 is a schematic diagram of the phototoxicity of porphyrin derivatives 14 and 8 provided in the embodiment of the present invention to human nasopharyngeal carcinoma HK-1 cells;
图中：(a)光照条件(λ＝680±15nm，λ＝725±15nm，照射总剂量为6J/cm
2)下，HK-1细胞的存活率；(b)在常规氧和低氧条件下，黑暗和光照(λ＝680±15nm，照射总剂量为6J/cm
2)，卟啉烯衍生物14对HK-1细胞活性的影响；(c)黑暗和光照条件(λ＝725±15nm，照射总剂量为6J/cm
2)下，卟啉烯衍生物8对HK-1细胞活性的影响。
In the figure: (a) the survival rate of HK-1 cells under light conditions (λ=680±15nm, λ=725±15nm, the total irradiation dose is 6J/cm 2 ); (b) under normal oxygen and hypoxia conditions Under dark and light conditions (λ=680±15nm, the total irradiation dose was 6J/cm 2 ), the effect of porphyrin derivative 14 on the activity of HK-1 cells; (c) dark and light conditions (λ=725±15nm) , under the total irradiation dose of 6J/cm 2 ), the effect of porphyrin derivative 8 on the activity of HK-1 cells.
图5是本发明实施例提供的卟啉烯衍生物14和8对人正常胚肺成纤维细胞MRC-5细胞的暗毒性实验结果示意图。FIG. 5 is a schematic diagram of the dark toxicity test results of porphyrin derivatives 14 and 8 provided in the embodiment of the present invention to human normal embryonic lung fibroblast MRC-5 cells.
图6是本发明实施例提供的卟啉烯衍生物14和8对人正常肝细胞L02细胞的暗毒性实验结果示意图。FIG. 6 is a schematic diagram of the dark toxicity test results of porphyrin derivatives 14 and 8 provided in the embodiment of the present invention to human normal hepatocyte L02 cells.
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention, but not to limit the present invention.
以下实施例中涉及的试剂、仪器及方法包括：The reagents, instruments and methods involved in the following examples include:
试剂：式Ⅳ化合物(化合物1-6)根据专利CN110483531A的合成方法合成；硝酸银购买于Sigma-Aldrich公司；氯化亚锡水合物购买于ACROS公司；四氯化钛(TiCl
4)，锌粉，正丁基锂(n-BuLi)，氯化叔丁基氯化亚铜(CuCl)、氯化铜(CuCl
2)，镁(Mg)和2,2,6,6-四甲基哌啶(TMPP)，2-(2-氨基乙氧基)乙-1-醇、苯磺酰氯和氯化铝(AlCl
3)购自于上海TCI公司；氢化钙(CaH2)干燥四氢呋喃(THF)、二甲基甲酰胺(DMF)和吡啶购自于DUKSAN公司。氯磺酸，二氯甲烷，碳酸氢钠，无水硫酸钠，二甘醇胺，三氯氧磷等试剂，均为国产分析纯试剂。
Reagent: compound of formula IV (compound 1-6) was synthesized according to the synthesis method of patent CN110483531A; silver nitrate was purchased from Sigma-Aldrich company; stannous chloride hydrate was purchased from ACROS company; titanium tetrachloride (TiCl 4 ), zinc powder , n-butyl lithium (n-BuLi), tert-butyl cuprous chloride (CuCl), copper chloride (CuCl 2 ), magnesium (Mg) and 2,2,6,6-tetramethylpiperidine (TMPP), 2-(2-aminoethoxy)ethan-1-ol, benzenesulfonyl chloride and aluminum chloride (AlCl 3 ) were purchased from Shanghai TCI Company; calcium hydride (CaH2), dry tetrahydrofuran (THF), dichloromethane Methylformamide (DMF) and pyridine were purchased from DUKSAN. Chlorosulfonic acid, dichloromethane, sodium bicarbonate, anhydrous sodium sulfate, diethylene glycol amine, phosphorus oxychloride and other reagents are all domestic analytical reagents.
仪器和方法：核磁共振仪(Bruker NMR 400MHz)和质谱仪(Bruker Autoflex MALDI-TOF)。Apparatus and methods: Nuclear Magnetic Resonance (Bruker NMR 400 MHz) and Mass Spectrometer (Bruker Autoflex MALDI-TOF).
实施例1：式(1)化合物Example 1: Compound of formula (1)
化合物1(1g，1.5mmol)溶于醋酸(50ml)和1,2-二氯乙烷(50ml)搅拌溶解，加硝酸银(0.53g，32mmol)后加热至80℃反应4小时。反应体系冷却至室温，体系用水(50ml)洗涤两次。有机相用硫酸钠干燥后浓缩得到粗品。粗品用二氯甲烷和正庚烷重结晶得到深绿色粉末(0.85g，收率80％)。Compound 1 (1 g, 1.5 mmol) was dissolved in acetic acid (50 ml) and 1,2-dichloroethane (50 ml) with stirring, and silver nitrate (0.53 g, 32 mmol) was added and heated to 80°C for 4 hours. The reaction system was cooled to room temperature, and the system was washed twice with water (50 ml). The organic phase was dried over sodium sulfate and concentrated to give the crude product. The crude product was recrystallized from dichloromethane and n-heptane to give a dark green powder (0.85 g, 80% yield).
1H NMR(400MHz,CDCl
3)δ10.77(s,1H),9.90(m,3H),9.24(d,1H),9.17(d,1H),9.07(s,1H), 6.0(s,1H),3.67(m,2H),3.5(m,4H),3.31(s,H),2.95(m,2H),2.18(s,9H),2.17(s,9H),2.15(s,9H).HRMS(MALDI-TOF)Found:705.3350(M+H)。
1 H NMR (400MHz, CDCl 3 ) δ 10.77(s, 1H), 9.90(m, 3H), 9.24(d, 1H), 9.17(d, 1H), 9.07(s, 1H), 6.0(s, 1H), 3.67(m, 2H), 3.5(m, 4H), 3.31(s, H), 2.95(m, 2H), 2.18(s, 9H), 2.17(s, 9H), 2.15(s, 9H) ).HRMS (MALDI-TOF) Found: 705.3350 (M+H).
实施例2：式(2)化合物Example 2: Compound of formula (2)
化合物2(1g，1.6mmol)溶于醋酸(50ml)和1,2-二氯乙烷(50ml)搅拌溶解，加硝酸银(0.53g，32mmol)后加热至80℃反应4小时。反应体系冷却至室温，体系用水(50ml)洗涤两次。有机相用硫酸钠干燥后浓缩得到粗品。粗品用二氯甲烷和正庚烷重结晶得到绿色粉末(0.8g，收率75％)。Compound 2 (1 g, 1.6 mmol) was dissolved in acetic acid (50 ml) and 1,2-dichloroethane (50 ml) with stirring, and silver nitrate (0.53 g, 32 mmol) was added and heated to 80°C for 4 hours. The reaction system was cooled to room temperature, and the system was washed twice with water (50 ml). The organic phase was dried over sodium sulfate and concentrated to give the crude product. The crude product was recrystallized from dichloromethane and n-heptane to give a green powder (0.8 g, 75% yield).
1H NMR(400MHz,CDCl
3)δ10.67(s,1H),9.85(m,3H),9.14(d,1H),9.07(d,1H),9.02(s,1H),6.0(s,1H),3.97(m,2H),3.65(m,2H),3.58(m,2H),2.95(m,2H),2.18(s,9H),2.17(s,9H),2.15(s,9H),1.9(s,1H).HRMS(MALDI-TOF)Found:691.3207(M+H)。
1 H NMR (400MHz, CDCl 3 ) δ 10.67(s, 1H), 9.85(m, 3H), 9.14(d, 1H), 9.07(d, 1H), 9.02(s, 1H), 6.0(s, 1H), 3.97(m, 2H), 3.65(m, 2H), 3.58(m, 2H), 2.95(m, 2H), 2.18(s, 9H), 2.17(s, 9H), 2.15(s, 9H) ), 1.9(s,1H).HRMS(MALDI-TOF)Found:691.3207(M+H).
实施例3：式(3)化合物Example 3: Compound of formula (3)
化合物3(1g，1.5mmol)溶于醋酸(50ml)和1,2-二氯乙烷(50ml)搅拌溶解，加硝酸银(0.53g，32mmol)后加热至80℃反应4小时。反应体系冷却至室温，体系用水(50ml)洗涤两次。有机相用硫酸钠干燥后浓缩得到粗品。粗品用二氯甲烷和正庚烷重结晶得到绿色粉末(0.85g，收率80％)。
1H NMR(400MHz,CDCl
3)δ10.73(s,1H),9.86(m,3H),9.21(d,1H),9.13(d,1H),9.03(s,1H),6.0(s,1H),3.57(m,2H),3.30(s,H),2.95(m,2H),2.17(s,9H),2.16(s,9H),2.14(s,9H),1.60(m,6H).HRMS(MALDI-TOF)Found:703.3566(M+H)。
Compound 3 (1 g, 1.5 mmol) was dissolved in acetic acid (50 ml) and 1,2-dichloroethane (50 ml) with stirring, and silver nitrate (0.53 g, 32 mmol) was added and heated to 80°C for 4 hours. The reaction system was cooled to room temperature, and the system was washed twice with water (50 ml). The organic phase was dried over sodium sulfate and concentrated to give the crude product. The crude product was recrystallized from dichloromethane and n-heptane to give a green powder (0.85 g, 80% yield). 1 H NMR (400MHz, CDCl 3 ) δ 10.73(s, 1H), 9.86(m, 3H), 9.21(d, 1H), 9.13(d, 1H), 9.03(s, 1H), 6.0(s, 1H), 3.57(m, 2H), 3.30(s, H), 2.95(m, 2H), 2.17(s, 9H), 2.16(s, 9H), 2.14(s, 9H), 1.60(m, 6H ).HRMS(MALDI-TOF) Found: 703.3566(M+H).
实施例4：式(4)化合物Example 4: Compound of formula (4)
化合物4(1g，1.6mmol)溶于醋酸(50ml)和1,2-二氯乙烷(50ml)搅拌溶解，加硝酸银(0.53g，32mmol)后加热至80℃反应4小时。反应体系冷却至室温，体系用水(50ml)洗涤两次。有机相用硫酸钠干燥后浓缩得到粗品，将粗品经过制备色谱柱分离纯化得到式(4)化合物(0.65g，收率59％)。
1H NMR(400MHz,CDCl
3)δ10.75(s,1H),9.87(m,3H),9.21(d,1H),9.16(d,1H),9.06(s,1H),6.0(s,1H),3.65(s,1H),3.47(t,2H),2.90(t,2H),2.18(s,9H),2.17(s,9H),2.15(s,9H),1.9(m,6H).HRMS(MALDI-TOF)Found:689.3402(M+H)。
Compound 4 (1 g, 1.6 mmol) was dissolved in acetic acid (50 ml) and 1,2-dichloroethane (50 ml) with stirring to dissolve, silver nitrate (0.53 g, 32 mmol) was added, and the reaction was heated to 80° C. for 4 hours. The reaction system was cooled to room temperature, and the system was washed twice with water (50 ml). The organic phase was dried over sodium sulfate and concentrated to obtain a crude product, which was separated and purified by a preparative chromatography column to obtain the compound of formula (4) (0.65 g, yield 59%). 1 H NMR (400MHz, CDCl 3 ) δ 10.75(s, 1H), 9.87(m, 3H), 9.21(d, 1H), 9.16(d, 1H), 9.06(s, 1H), 6.0(s, 1H), 3.65(s, 1H), 3.47(t, 2H), 2.90(t, 2H), 2.18(s, 9H), 2.17(s, 9H), 2.15(s, 9H), 1.9(m, 6H ).HRMS(MALDI-TOF) Found: 689.3402(M+H).
实施例5：式(5)化合物Example 5: Compound of formula (5)
化合物5(1g，1.4mmol)溶于醋酸(50ml)和1,2-二氯乙烷(50ml)搅拌溶解，加硝酸银(0.53g，32mmol)后加热至80℃反应4小时。反应体系冷却至室温，体系用水(50ml)洗涤两次。有机相用硫酸钠干燥后浓缩得粗品，将粗品经过制备色谱柱分离纯化得到式(5)化合物(0.65g，收率61％)。
1H NMR(400MHz,CDCl
3)δ10.70(s,1H),9.83(m,3H),9.17(d,1H),9.12(d,1H),9.01(s,1H),6.0(s,1H),4.10(m,6H),3.10(t,2H),2.18(s,9H),2.17(s,9H),2.15(s,9H).HRMS(MALDI-TOF)Found:753.2350(M+H)。
Compound 5 (1 g, 1.4 mmol) was dissolved in acetic acid (50 ml) and 1,2-dichloroethane (50 ml) with stirring, and silver nitrate (0.53 g, 32 mmol) was added and heated to 80°C for 4 hours. The reaction system was cooled to room temperature, and the system was washed twice with water (50 ml). The organic phase was dried over sodium sulfate and concentrated to obtain a crude product, which was separated and purified by a preparative chromatography column to obtain the compound of formula (5) (0.65 g, yield 61%). 1 H NMR (400MHz, CDCl 3 ) δ 10.70(s, 1H), 9.83(m, 3H), 9.17(d, 1H), 9.12(d, 1H), 9.01(s, 1H), 6.0(s, 1H),4.10(m,6H),3.10(t,2H),2.18(s,9H),2.17(s,9H),2.15(s,9H).HRMS(MALDI-TOF)Found:753.2350(M+ H).
实施例6：式(6)化合物Example 6: Compound of formula (6)
化合物6(1g，1.4mmol)溶于醋酸(50ml)和1,2-二氯乙烷(50ml)搅拌溶解，加硝酸银(0.53g，32mmol)后加热至80℃反应4小时。反应体系冷却至室温，体系用水(50ml)洗涤两次。有机相用硫酸钠干燥后浓缩得粗品，将粗品经过制备色谱柱分离纯化得到式(6)化合物(0.64g，收率62％)。
1H NMR(400MHz,CDCl
3)δ10.73(s,1H),9.86(m,3H),9.20(d,1H),9.14(d,1H),9.03(s,1H),6.0(s,1H),3.8(t,2H),3.1(t,2H),2.18(s,9H),2.17(s,9H),2.15(s,9H),1.4(m,6H).HRMS(MALDI-TOF)Found:751.2556(M+H)。
Compound 6 (1 g, 1.4 mmol) was dissolved in acetic acid (50 ml) and 1,2-dichloroethane (50 ml) with stirring, and silver nitrate (0.53 g, 32 mmol) was added and heated to 80°C for 4 hours. The reaction system was cooled to room temperature, and the system was washed twice with water (50 ml). The organic phase was dried with sodium sulfate and concentrated to obtain a crude product, which was separated and purified by a preparative chromatography column to obtain the compound of formula (6) (0.64 g, yield 62%). 1 H NMR (400MHz, CDCl 3 ) δ 10.73(s, 1H), 9.86(m, 3H), 9.20(d, 1H), 9.14(d, 1H), 9.03(s, 1H), 6.0(s, 1H), 3.8(t, 2H), 3.1(t, 2H), 2.18(s, 9H), 2.17(s, 9H), 2.15(s, 9H), 1.4(m, 6H).HRMS(MALDI-TOF )Found: 751.2556(M+H).
实施例7：式(7)化合物Example 7: Compound of formula (7)
将式(1)化合物(100mg，0.14mmol)和连二硫酸钠(340mg，1.4mmol)溶于二氯甲烷(10ml)和10％氢氧化钠水溶液(4ml)中，加热回流1小时。冷却反应液，分液，有机相用水洗涤一次，有机相干燥浓缩得到粗品。将粗品经过制备色谱柱分离纯化得到式(7)化合物(76mg，收率80％)。The compound of formula (1) (100 mg, 0.14 mmol) and sodium dithionate (340 mg, 1.4 mmol) were dissolved in dichloromethane (10 ml) and 10% aqueous sodium hydroxide solution (4 ml) and heated to reflux for 1 hour. The reaction solution was cooled and separated, the organic phase was washed with water once, and the organic phase was dried and concentrated to obtain a crude product. The crude product was separated and purified by preparative chromatography to obtain the compound of formula (7) (76 mg, yield 80%).
1H NMR(400MHz,CDCl
3)δ9.82(s,1H),9.78(d,1H),9.45(d,1H),9.09(m,2H),9.03(d,1H),8.3(s,1H),6.95(t,2H),6.20(s,1H),3.67(m,2H),3.5(m,4H),3.31(s,H),2.95(m,2H),2.18(s,9H),2.17(s,9H),2.15(s,9H).HRMS(MALDI-TOF)Found:675.3610(M+H)。
1 H NMR (400MHz, CDCl 3 ) δ 9.82(s, 1H), 9.78(d, 1H), 9.45(d, 1H), 9.09(m, 2H), 9.03(d, 1H), 8.3(s, 1H), 6.95(t, 2H), 6.20(s, 1H), 3.67(m, 2H), 3.5(m, 4H), 3.31(s, H), 2.95(m, 2H), 2.18(s, 9H) ), 2.17(s, 9H), 2.15(s, 9H).HRMS(MALDI-TOF) Found: 675.3610(M+H).
实施例8：式(8)化合物Example 8: Compound of formula (8)
将式(2)化合物(100mg，0.15mmol)和连二硫酸钠(340mg，1.4mmol)溶于二氯甲烷(10ml)和10％氢氧化钠水溶液(4ml)中，加热回流1小时。冷却反应液，分液，有机相用水洗涤一次，有机相干燥浓缩得到粗品。将粗品经过制备色谱柱分离纯化得到式(8)化合物(72mg，收率75％)。
1H NMR(400MHz,CDCl
3)δ9.72(s,1H),9.68(d,1H),9.35(d,1H),9.01(m,2H),9.03(d,1H),8.23(s,1H),6.85(t,2H),6.15(s,1H),3.97(m,2H),3.65(m,2H),3.58(m,2H),2.95(m,2H),2.18(s,9H),2.17(s,9H),2.15(s,9H).HRMS(MALDI-TOF)Found:665.3451(M+H)。
The compound of formula (2) (100 mg, 0.15 mmol) and sodium dithionate (340 mg, 1.4 mmol) were dissolved in dichloromethane (10 ml) and 10% aqueous sodium hydroxide solution (4 ml) and heated to reflux for 1 hour. The reaction solution was cooled and separated, the organic phase was washed with water once, and the organic phase was dried and concentrated to obtain a crude product. The crude product was separated and purified by preparative chromatography to obtain the compound of formula (8) (72 mg, yield 75%). 1 H NMR (400MHz, CDCl 3 ) δ 9.72(s, 1H), 9.68(d, 1H), 9.35(d, 1H), 9.01(m, 2H), 9.03(d, 1H), 8.23(s, 1H), 6.85(t, 2H), 6.15(s, 1H), 3.97(m, 2H), 3.65(m, 2H), 3.58(m, 2H), 2.95(m, 2H), 2.18(s, 9H ), 2.17(s, 9H), 2.15(s, 9H).HRMS(MALDI-TOF) Found: 665.3451(M+H).
实施例9：式(9)化合物Example 9: Compound of formula (9)
将式(3)化合物(100mg，0.14mmol)和连二硫酸钠(340mg，1.4mmol)溶于二氯甲烷(10ml)和10％氢氧化钠水溶液(4ml)中，加热回流1小时。冷却反应液，分液，有机相用水洗涤一次，有机相干燥浓缩得到粗品。将粗品经过制备色谱柱分离纯化得到式(9)化合物(81mg，收率85％)。
1H NMR(400MHz,CDCl
3)δ9.90(s,1H),9.85(d,1H),9.54(d,1H),9.16(m,2H),9.10(d,1H),8.38(s,1H),6.99(t,2H),6.28(s,1H),3.57(m,2H),3.30(s,H),2.95(m,2H),2.17(s,9H),2.16(s,9H),2.14(s,9H),1.60(m,6H).HRMS(MALDI-TOF)Found:673.3818(M+H)。
The compound of formula (3) (100 mg, 0.14 mmol) and sodium dithionate (340 mg, 1.4 mmol) were dissolved in dichloromethane (10 ml) and 10% aqueous sodium hydroxide solution (4 ml) and heated to reflux for 1 hour. The reaction solution was cooled and separated, the organic phase was washed with water once, and the organic phase was dried and concentrated to obtain a crude product. The crude product was separated and purified by preparative chromatography column to obtain the compound of formula (9) (81 mg, yield 85%). 1 H NMR (400MHz, CDCl 3 ) δ 9.90(s, 1H), 9.85(d, 1H), 9.54(d, 1H), 9.16(m, 2H), 9.10(d, 1H), 8.38(s, 1H), 6.99(t, 2H), 6.28(s, 1H), 3.57(m, 2H), 3.30(s, H), 2.95(m, 2H), 2.17(s, 9H), 2.16(s, 9H) ), 2.14(s, 9H), 1.60(m, 6H). HRMS(MALDI-TOF) Found: 673.3818(M+H).
实施例10：式(10)化合物Example 10: Compound of formula (10)
将式(4)化合物(100mg，0.14mmol)和连二硫酸钠(340mg，1.4mmol)溶于二氯甲烷(10ml)和10％氢氧化钠水溶液(4ml)中，加热回流1小时。冷却反应液，分液，有机相用水洗涤一次，有机相干燥浓缩得到粗品。将粗品经过制备色谱柱分离纯化得到式(10)化合物(76mg，收率80％)。
1H NMR(400MHz,CDCl
3)δ9.87(s,1H),9.83(d,1H),9.52(d,1H),9.13(m,2H),9.10(d,1H),8.35(s,1H),6.99(t,2H),6.23(s,1H),3.65(s,1H),3.47(t,2H),2.90(t,2H),2.18(s,9H),2.17(s,9H),2.15(s,9H),1.9(m,6H).HRMS(MALDI-TOF)Found:659.3661(M+H)。
The compound of formula (4) (100 mg, 0.14 mmol) and sodium dithionate (340 mg, 1.4 mmol) were dissolved in dichloromethane (10 ml) and 10% aqueous sodium hydroxide solution (4 ml) and heated to reflux for 1 hour. The reaction solution was cooled and separated, the organic phase was washed with water once, and the organic phase was dried and concentrated to obtain a crude product. The crude product was separated and purified by preparative chromatography column to obtain the compound of formula (10) (76 mg, yield 80%). 1 H NMR (400MHz, CDCl 3 ) δ 9.87(s, 1H), 9.83(d, 1H), 9.52(d, 1H), 9.13(m, 2H), 9.10(d, 1H), 8.35(s, 1H), 6.99(t, 2H), 6.23(s, 1H), 3.65(s, 1H), 3.47(t, 2H), 2.90(t, 2H), 2.18(s, 9H), 2.17(s, 9H) ), 2.15(s, 9H), 1.9(m, 6H). HRMS(MALDI-TOF) Found: 659.3661(M+H).
实施例11：式(11)化合物Example 11: Compound of formula (11)
将式(5)化合物(376mg，0.5mmol)和氯化亚锡二水合物(900mg，4mmol)溶于吡啶(50ml)中，加热回流1小时。冷却，反应液直接浓缩得到粗品。将粗品经过制备色谱柱分离纯化得到式(11)化合物(162mg，收率45％)。
1H NMR(400MHz,CDCl
3)δ9.89(s,1H),9.84(d,1H),9.49(d,1H),9.14(m,2H),9.09(d,1H),8.36(s,1H),6.99(t,2H),6.26(s,1H),4.10(m,6H),3.10(t,2H),2.18(s,9H),2.17(s,9H),2.15(s,9H).HRMS(MALDI-TOF)Found:723.2609(M+H)。
The compound of formula (5) (376 mg, 0.5 mmol) and stannous chloride dihydrate (900 mg, 4 mmol) were dissolved in pyridine (50 ml) and heated to reflux for 1 hour. After cooling, the reaction solution was directly concentrated to obtain the crude product. The crude product was separated and purified by preparative chromatography column to obtain the compound of formula (11) (162 mg, yield 45%). 1 H NMR (400MHz, CDCl 3 ) δ 9.89(s, 1H), 9.84(d, 1H), 9.49(d, 1H), 9.14(m, 2H), 9.09(d, 1H), 8.36(s, 1H), 6.99(t, 2H), 6.26(s, 1H), 4.10(m, 6H), 3.10(t, 2H), 2.18(s, 9H), 2.17(s, 9H), 2.15(s, 9H) ).HRMS(MALDI-TOF) Found: 723.2609(M+H).
实施例12：式(12)化合物Example 12: Compound of formula (12)
将式(6)化合物(100mg，0.13mmol)和氯化亚锡二水合物(225mg，1mmol)溶于吡啶(15ml)中，加热回流1小时。冷却，反应液直接浓缩得到粗品。将粗品经过制备色谱柱分离纯化得到式(12)化合物(43mg，收率45％)。
1H NMR(400MHz,CDCl
3)δ9.85(s,1H),9.81(d,1H),9.48(d,1H),9.12(m,2H),9.06(d,1H),8.33(s,1H),6.98(t,2H),6.24(s,1H),3.8(t,2H),3.1(t,2H),2.18(s,9H),2.17(s,9H),2.15(s,9H),1.4(m,6H).HRMS(MALDI-TOF)Found:721.2817(M+H)。
The compound of formula (6) (100 mg, 0.13 mmol) and stannous chloride dihydrate (225 mg, 1 mmol) were dissolved in pyridine (15 ml) and heated to reflux for 1 hour. After cooling, the reaction solution was directly concentrated to obtain the crude product. The crude product was separated and purified by preparative chromatography column to obtain the compound of formula (12) (43 mg, yield 45%). 1 H NMR (400MHz, CDCl 3 ) δ 9.85(s, 1H), 9.81(d, 1H), 9.48(d, 1H), 9.12(m, 2H), 9.06(d, 1H), 8.33(s, 1H), 6.98(t, 2H), 6.24(s, 1H), 3.8(t, 2H), 3.1(t, 2H), 2.18(s, 9H), 2.17(s, 9H), 2.15(s, 9H) ), 1.4(m,6H).HRMS(MALDI-TOF)Found:721.2817(M+H).
实施例13：式(13)化合物Example 13: Compound of formula (13)
将式(7)化合物(100mg，0.15mmol)溶于二氯甲烷(15ml)中，加三乙胺(30mg,0.3mmol)，降温至0℃；滴加乙酰氯(18mg,0.23mmol)。加毕，恢复室温搅拌2小时。体系浓缩得到粗品。将粗品经过制备色谱柱分离纯化得到式(13)化合物(98mg，收率94.5％)。The compound of formula (7) (100 mg, 0.15 mmol) was dissolved in dichloromethane (15 ml), triethylamine (30 mg, 0.3 mmol) was added, and the temperature was lowered to 0°C; acetyl chloride (18 mg, 0.23 mmol) was added dropwise. After the addition was completed, the mixture was returned to room temperature and stirred for 2 hours. The system was concentrated to obtain crude product. The crude product was separated and purified by preparative chromatography column to obtain the compound of formula (13) (98 mg, yield 94.5%).
1H NMR(400MHz,CDCl
3)δ11.25(s,1H),10.86(s,1H),10.07(s,1H),10.01(d,1H),9.85(d,1H),9.27(d,2H),9.14(s,1H),5.58(t,2H),5.18(s,1H),3.5(m,4H),3.31(s,3H),2.95(m,2H),2.18(s,9H),2.17(s,9H),2.15(s,9H),2.05(s,3H).HRMS(MALDI-TOF)Found:717.3623(M+H)。
1 H NMR (400MHz, CDCl 3 ) δ 11.25(s, 1H), 10.86(s, 1H), 10.07(s, 1H), 10.01(d, 1H), 9.85(d, 1H), 9.27(d, 2H), 9.14(s, 1H), 5.58(t, 2H), 5.18(s, 1H), 3.5(m, 4H), 3.31(s, 3H), 2.95(m, 2H), 2.18(s, 9H) ), 2.17(s, 9H), 2.15(s, 9H), 2.05(s, 3H). HRMS(MALDI-TOF) Found: 717.3623(M+H).
实施例14：式(14)化合物Example 14: Compound of formula (14)
将式(8)化合物(100mg，0.15mmol)溶于四氢呋喃(10ml)中，加8％碳酸氢钠水溶液(5ml)，体系降温至0℃；加乙酸酐(30mg,0.3mmol)。加毕，恢复室温搅拌2小时。体系加乙酸乙酯萃取，有机相用饱和碳酸氢钠水溶液洗涤，有机相干燥浓缩得到粗品。将粗品经过制备色谱柱分离纯化得到式(14)化合物(95mg，收率90％)。
1H NMR(400MHz,CDCl
3)δ11.21(s,1H),10.82(s,1H),10.05(s,1H),9.97(d,1H),9.82(d,1H),9.26(d,2H),9.11(s,1H),5.55(t,2H),5.16(s,1H),3.97(m,2H),3.65(m,2H),3.58(m,2H),2.95(m,2H),2.18(s,9H),2.17(s,9H),2.15(s,9H),2.05(s,3H).HRMS(MALDI-TOF)Found:703.3553(M+H)。
The compound of formula (8) (100mg, 0.15mmol) was dissolved in tetrahydrofuran (10ml), 8% aqueous sodium bicarbonate solution (5ml) was added, the system was cooled to 0°C; acetic anhydride (30mg, 0.3mmol) was added. After the addition was completed, the mixture was returned to room temperature and stirred for 2 hours. The system was extracted with ethyl acetate, the organic phase was washed with saturated aqueous sodium bicarbonate solution, and the organic phase was dried and concentrated to obtain the crude product. The crude product was separated and purified by preparative chromatography column to obtain the compound of formula (14) (95 mg, yield 90%). 1 H NMR (400MHz, CDCl 3 ) δ 11.21(s, 1H), 10.82(s, 1H), 10.05(s, 1H), 9.97(d, 1H), 9.82(d, 1H), 9.26(d, 2H), 9.11(s, 1H), 5.55(t, 2H), 5.16(s, 1H), 3.97(m, 2H), 3.65(m, 2H), 3.58(m, 2H), 2.95(m, 2H) ), 2.18(s, 9H), 2.17(s, 9H), 2.15(s, 9H), 2.05(s, 3H). HRMS(MALDI-TOF) Found: 703.3553(M+H).
实施例15：式(15)化合物Example 15: Compound of formula (15)
将式(9)化合物(100mg，0.15mmol)溶于二氯甲烷(15ml)中，加三乙胺(30mg,0.3mmol)，降温至0℃；滴加乙酰氯(18mg,0.23mmol)。加毕，恢复室温搅拌2小时。体系浓缩得到粗品。将粗品经过制备色谱柱分离纯化得到式(15)化合物(91mg，收率86％)。
1H NMR(400MHz,CDCl
3)δ11.25(s,1H),10.86(s,1H),10.07(s,1H),10.01(d,1H),9.85(d,1H),9.27(d,2H),9.14(s,1H),5.58(t,2H),5.18(s,1H),3.57(m,2H),3.30(s,H),2.95(m,2H),2.17(s,9H),2.16(s,9H),2.14(s,9H),2.04(s,3H),1.60(m,6H).HRMS(MALDI-TOF)Found:715.3932(M+H)。
The compound of formula (9) (100 mg, 0.15 mmol) was dissolved in dichloromethane (15 ml), triethylamine (30 mg, 0.3 mmol) was added, and the temperature was lowered to 0°C; acetyl chloride (18 mg, 0.23 mmol) was added dropwise. After the addition was completed, the mixture was returned to room temperature and stirred for 2 hours. The system was concentrated to obtain crude product. The crude product was separated and purified by preparative chromatography column to obtain the compound of formula (15) (91 mg, yield 86%). 1 H NMR (400MHz, CDCl 3 ) δ 11.25(s, 1H), 10.86(s, 1H), 10.07(s, 1H), 10.01(d, 1H), 9.85(d, 1H), 9.27(d, 2H), 9.14(s, 1H), 5.58(t, 2H), 5.18(s, 1H), 3.57(m, 2H), 3.30(s, H), 2.95(m, 2H), 2.17(s, 9H) ), 2.16(s, 9H), 2.14(s, 9H), 2.04(s, 3H), 1.60(m, 6H). HRMS(MALDI-TOF) Found: 715.3932(M+H).
实施例16：式(16)化合物Example 16: Compound of formula (16)
将式(10)化合物(100mg，0.15mmol)溶于四氢呋喃(10ml)中，加8％碳酸氢钠水溶液(5ml)，体系降温至0℃；加乙酸酐(30mg,0.3mmol)。加毕，恢复室温搅拌2小时。体系加乙酸乙酯萃取，有机相用饱和碳酸氢钠水溶液洗涤，有机相干燥浓缩得到粗品。将粗品经过制备色谱柱分离纯化得到式(16)化合物(79mg，收率76％)。
1H NMR(400MHz,CDCl
3)δ11.20(s,1H),10.81(s,1H),10.02(s,1H),9.96(d,1H),9.80(d,1H),9.22(d,2H),9.09(s,1H),5.52(t,2H),5.12(s,1H),3.65(s,1H),3.47(t,2H),2.90(t,2H),2.18(s,9H),2.17(s,9H),2.15(s,9H),2.06(s,3H),1.9(m,6H).HRMS(MALDI-TOF)Found:701.3765(M+H)。
The compound of formula (10) (100 mg, 0.15 mmol) was dissolved in tetrahydrofuran (10 ml), 8% aqueous sodium bicarbonate solution (5 ml) was added, the system was cooled to 0 °C; acetic anhydride (30 mg, 0.3 mmol) was added. After the addition was completed, the mixture was returned to room temperature and stirred for 2 hours. The system was extracted with ethyl acetate, the organic phase was washed with saturated aqueous sodium bicarbonate solution, and the organic phase was dried and concentrated to obtain the crude product. The crude product was separated and purified by preparative chromatography column to obtain the compound of formula (16) (79 mg, yield 76%). 1 H NMR (400MHz, CDCl 3 )δ11.20(s,1H), 10.81(s,1H), 10.02(s,1H), 9.96(d,1H), 9.80(d,1H), 9.22(d, 2H), 9.09(s, 1H), 5.52(t, 2H), 5.12(s, 1H), 3.65(s, 1H), 3.47(t, 2H), 2.90(t, 2H), 2.18(s, 9H ), 2.17(s, 9H), 2.15(s, 9H), 2.06(s, 3H), 1.9(m, 6H). HRMS(MALDI-TOF) Found: 701.3765(M+H).
实施例17：式(17)化合物Example 17: Compound of formula (17)
将式(11)化合物(100mg，0.139mmol)溶于二氯甲烷(15ml)中，加三乙胺(28mg,0.28mmol)，降温至0℃；滴加乙酰氯(18mg,0.23mmol)。加毕，恢复室温搅拌2小时。体系浓缩得到粗品。将粗品经过制备色谱柱分离纯化得到式(17)化合物(82mg，收率76％)。
1H NMR(400MHz,CDCl
3)δ11.15(s,1H),10.76(s,1H),9.07(s,1H),9.01(d,1H),9.75(d,1H),9.17(d,2H),9.04(s,1H),5.48(t,2H),5.08(s,1H),4.10(m,6H),3.10(t,2H),2.18(s,9H),2.17(s,9H),2.15(s,9H),2.04(s,3H).HRMS(MALDI-TOF)Found:765.2710(M+H)。
The compound of formula (11) (100 mg, 0.139 mmol) was dissolved in dichloromethane (15 ml), triethylamine (28 mg, 0.28 mmol) was added, and the temperature was lowered to 0°C; acetyl chloride (18 mg, 0.23 mmol) was added dropwise. After the addition was completed, the mixture was returned to room temperature and stirred for 2 hours. The system was concentrated to obtain crude product. The crude product was separated and purified by preparative chromatography column to obtain the compound of formula (17) (82 mg, yield 76%). 1 H NMR (400MHz, CDCl 3 )δ11.15(s,1H), 10.76(s,1H), 9.07(s,1H), 9.01(d,1H), 9.75(d,1H), 9.17(d, 2H), 9.04(s, 1H), 5.48(t, 2H), 5.08(s, 1H), 4.10(m, 6H), 3.10(t, 2H), 2.18(s, 9H), 2.17(s, 9H) ), 2.15(s, 9H), 2.04(s, 3H). HRMS(MALDI-TOF) Found: 765.2710(M+H).
实施例18：式(18)化合物Example 18: Compound of formula (18)
将式(12)化合物(100mg，0.139mmol)溶于二氯甲烷(15ml)中，加三乙胺(28mg,0.28mmol)，降温至0℃；滴加乙酰氯(18mg,0.23mmol)。加毕，恢复室温搅拌2小时。将粗品经过制备色谱柱分离纯化得到式(18)化合物(69mg，收率68％)。
1H NMR(400MHz,CDCl
3)δ11.18(s,1H),10.79(s,1H),9.99(s,1H),9.93(d,1H),9.78(d,1H),9.19(d,2H),9.06(s,1H),5.50(t,2H),5.10(s,1H),3.8(t,2H),3.1(t,2H),2.18(s,9H),2.17(s,9H),2.15(s,9H),2.04(s,3H),1.4(m,6H).HRMS(MALDI-TOF)Found:763.2921(M+H)。
The compound of formula (12) (100 mg, 0.139 mmol) was dissolved in dichloromethane (15 ml), triethylamine (28 mg, 0.28 mmol) was added, and the temperature was lowered to 0°C; acetyl chloride (18 mg, 0.23 mmol) was added dropwise. After the addition was completed, the mixture was returned to room temperature and stirred for 2 hours. The crude product was separated and purified by preparative chromatography column to obtain the compound of formula (18) (69 mg, yield 68%). 1 H NMR (400MHz, CDCl 3 )δ11.18(s,1H), 10.79(s,1H), 9.99(s,1H), 9.93(d,1H), 9.78(d,1H), 9.19(d, 2H), 9.06(s, 1H), 5.50(t, 2H), 5.10(s, 1H), 3.8(t, 2H), 3.1(t, 2H), 2.18(s, 9H), 2.17(s, 9H) ), 2.15(s, 9H), 2.04(s, 3H), 1.4(m, 6H). HRMS(MALDI-TOF) Found: 763.2921(M+H).
实施例19：式(19)化合物Example 19: Compound of formula (19)
将式(7)化合物(100mg，0.148mmol)溶于二氯甲烷(15ml)中，加三乙胺(30mg,0.3mmol)，降温至0℃；滴加丁二酸酐(48mg,0.22mmol)。加毕，恢复室温搅拌2小时。体系浓缩得到粗品，将粗品经过制备色谱柱分离纯化得到式(19)化合物(54mg，收率45％)。The compound of formula (7) (100 mg, 0.148 mmol) was dissolved in dichloromethane (15 ml), triethylamine (30 mg, 0.3 mmol) was added, and the temperature was lowered to 0 °C; succinic anhydride (48 mg, 0.22 mmol) was added dropwise. After the addition was completed, the mixture was returned to room temperature and stirred for 2 hours. The system was concentrated to obtain a crude product, which was separated and purified by a preparative chromatography column to obtain the compound of formula (19) (54 mg, yield 45%).
1H NMR(400MHz,CDCl
3)δ13.12(s,1H),11.23(s,1H),10.84(s,1H),10.05(s,1H),10.00(d,1H),9.83(d,1H),9.25(d,2H),9.12(s,1H),5.56(t,2H),5.16(s,1H),3.5(m,4H),3.31(s,3H),2.95(m,6H),2.18(s,9H),2.17(s,9H),2.15(s,9H).HRMS(MALDI-TOF)Found:775.3769(M+H)。
1 H NMR (400MHz, CDCl 3 ) δ 13.12(s, 1H), 11.23(s, 1H), 10.84(s, 1H), 10.05(s, 1H), 10.00(d, 1H), 9.83(d, 1H), 9.25(d, 2H), 9.12(s, 1H), 5.56(t, 2H), 5.16(s, 1H), 3.5(m, 4H), 3.31(s, 3H), 2.95(m, 6H) ), 2.18(s, 9H), 2.17(s, 9H), 2.15(s, 9H). HRMS(MALDI-TOF) Found: 775.3769(M+H).
实施例20：式(20)化合物Example 20: Compound of formula (20)
将式(8)化合物(100mg，0.152mmol)溶于二氯甲烷(15ml)中，加三乙胺(61mg,0.6mmol)，降温至0℃；滴加丁二酸单乙酯乙酰氯(75mg,0.46mmol)。加毕，恢复室温搅拌2小时。体系用1N HCl和饱和食盐水各洗涤一次，有机相加10ml30％氢氧化钠溶液室温搅拌2小时。反应完毕，分液，水相用10ml二氯甲烷洗涤一次，水相用3N盐酸调PH至2-3。二氯甲烷萃取，分液，有机相浓缩得到粗品，将粗品经过制备色谱柱分离纯化得到式(20)化合物(70mg，收率64％)。The compound of formula (8) (100 mg, 0.152 mmol) was dissolved in dichloromethane (15 ml), triethylamine (61 mg, 0.6 mmol) was added, and the temperature was lowered to 0 °C; , 0.46 mmol). After the addition was completed, the mixture was returned to room temperature and stirred for 2 hours. The system was washed once with 1N HCl and saturated brine, and 10 ml of 30% sodium hydroxide solution was added to the organic phase and stirred at room temperature for 2 hours. After the reaction was completed, the liquids were separated, the aqueous phase was washed once with 10 ml of dichloromethane, and the pH of the aqueous phase was adjusted to 2-3 with 3N hydrochloric acid. Extraction with dichloromethane, separation, and concentration of the organic phase to obtain a crude product, which was separated and purified by a preparative chromatography column to obtain the compound of formula (20) (70 mg, yield 64%).
1H NMR(400MHz,CDCl
3)δ13.10(s,1H),11.25(s,1H),10.86(s,1H),10.07(s,1H),10.01(d,1H),9.85(d,1H),9.27(d,2H),9.14(s,1H),5.58(t,2H),5.18(s,1H),3.97(m,2H),3.65(m,2H),3.58(m,2H),2.95(m,6H),2.18(s,9H),2.17(s,9H),2.15(s,9H).HRMS(MALDI-TOF)Found:761.3625(M+H)。
1 H NMR (400MHz, CDCl 3 ) δ 13.10(s, 1H), 11.25(s, 1H), 10.86(s, 1H), 10.07(s, 1H), 10.01(d, 1H), 9.85(d, 1H), 9.27(d, 2H), 9.14(s, 1H), 5.58(t, 2H), 5.18(s, 1H), 3.97(m, 2H), 3.65(m, 2H), 3.58(m, 2H) ), 2.95(m, 6H), 2.18(s, 9H), 2.17(s, 9H), 2.15(s, 9H). HRMS(MALDI-TOF) Found: 761.3625(M+H).
实施例21：式(21)化合物Example 21: Compound of formula (21)
将式(9)化合物(90mg，0.134mmol)溶于二氯甲烷(15ml)中，加三乙胺(30mg,0.3mmol)，降温至0℃；滴加丁二酸酐(48mg,0.22mmol)。加毕，恢复室温搅拌2小时。体系浓缩得到粗品，将粗品经过制备色谱柱分离纯化得到式(19)化合物(84mg，收率81％)。The compound of formula (9) (90 mg, 0.134 mmol) was dissolved in dichloromethane (15 ml), triethylamine (30 mg, 0.3 mmol) was added, and the temperature was lowered to 0°C; succinic anhydride (48 mg, 0.22 mmol) was added dropwise. After the addition was completed, the mixture was returned to room temperature and stirred for 2 hours. The system was concentrated to obtain a crude product, which was separated and purified by a preparative chromatography column to obtain the compound of formula (19) (84 mg, yield 81%).
1H NMR(400MHz,CDCl
3)δ13.20(s,1H),11.35(s,1H),10.93(s,1H),10.20(s,1H),10.13(d,1H),9.95(d,1H),9.47(d,2H),9.24(s,1H),5.68(t,2H),5.38(s,1H),3.57(m,2H),3.30(s,3H),2.95(m,6H),2.17(s,9H),2.16(s,9H),2.14(s,9H),2.04(s,3H),1.60(m,6H).HRMS(MALDI-TOF)Found:773.3870(M+H)。
1 H NMR (400MHz, CDCl 3 ) δ 13.20(s, 1H), 11.35(s, 1H), 10.93(s, 1H), 10.20(s, 1H), 10.13(d, 1H), 9.95(d, 1H), 9.47(d, 2H), 9.24(s, 1H), 5.68(t, 2H), 5.38(s, 1H), 3.57(m, 2H), 3.30(s, 3H), 2.95(m, 6H) ),2.17(s,9H),2.16(s,9H),2.14(s,9H),2.04(s,3H),1.60(m,6H).HRMS(MALDI-TOF)Found:773.3870(M+H ).
实施例22：式(22)化合物Example 22: Compound of formula (22)
将式(10)化合物(100mg，0.152mmol)溶于15ml四氢呋喃：水(1:1)中，加50％氢氧化钠(2ml)，降温至0℃；滴加丁二酸酐(48mg,0.22mmol)的四氢呋喃溶液。加毕，恢复室温搅拌2小时。体系调PH至2-3，15ml乙酸乙酯萃取，有机相用饱和食盐水洗涤，分液，有机相干燥后浓缩得到粗品，将粗品经过制备色谱柱分离纯化得到式(22)化合物(88mg，收率75％)。The compound of formula (10) (100 mg, 0.152 mmol) was dissolved in 15 ml of tetrahydrofuran: water (1:1), 50% sodium hydroxide (2 ml) was added, and the temperature was lowered to 0 °C; succinic anhydride (48 mg, 0.22 mmol) was added dropwise. ) in tetrahydrofuran. After the addition was completed, the mixture was returned to room temperature and stirred for 2 hours. The pH of the system was adjusted to 2-3, extracted with 15 ml of ethyl acetate, the organic phase was washed with saturated brine, and the layers were separated. The organic phase was dried and concentrated to obtain a crude product, which was separated and purified by a preparative chromatographic column to obtain the compound of formula (22) (88 mg, yield 75%).
1H NMR(400MHz,CDCl
3)δ13.26(s,1H),11.15(s,1H),10.73(s,1H),10.00(s,1H),9.93(d,1H),9.95(d,1H),9.27(d,2H),9.04(s,1H),5.48(t,2H),5.18(s,1H),3.65(s,1H),3.47(t,2H),2.90(t,6H),2.18(s,9H),2.17(s,9H),2.15(s,9H),1.9(m,6H).HRMS(MALDI-TOF)Found:759.3821(M+H)。
1 H NMR (400MHz, CDCl 3 ) δ 13.26(s, 1H), 11.15(s, 1H), 10.73(s, 1H), 10.00(s, 1H), 9.93(d, 1H), 9.95(d, 1H), 9.27(d, 2H), 9.04(s, 1H), 5.48(t, 2H), 5.18(s, 1H), 3.65(s, 1H), 3.47(t, 2H), 2.90(t, 6H) ), 2.18(s, 9H), 2.17(s, 9H), 2.15(s, 9H), 1.9(m, 6H). HRMS(MALDI-TOF) Found: 759.3821(M+H).
实施例23：式(23)化合物Example 23: Compound of formula (23)
将式(17)化合物(50mg，0.065mmol)和0.5ml三乙胺溶于乙腈(10ml)中，加热至80℃反应5小时，TLC监控反应。反应完毕，降至0℃搅拌2小时，有固体析出，过滤，干燥得到式(23)化合物(45mg，收率81％)。The compound of formula (17) (50 mg, 0.065 mmol) and 0.5 ml of triethylamine were dissolved in acetonitrile (10 ml), heated to 80° C. to react for 5 hours, and the reaction was monitored by TLC. After the reaction was completed, the temperature was lowered to 0° C. and stirred for 2 hours. A solid was precipitated, which was filtered and dried to obtain the compound of formula (23) (45 mg, yield 81%).
1H NMR(400MHz,CDCl
3)δ11.25(s,1H),10.86(s,1H),10.07(s,1H),10.01(d,1H),9.85(d,1H),9.27(d,2H),9.14(s,1H),5.58(t,2H),5.18(s,1H),4.10(m,6H),3.10(t,2H),2.85(m,6H)2.18(s,9H),2.17(s,9H),2.15(s,9H),2.04(s,3H),1.07(t,9H).HRMS(MALDI-TOF)Found:786.4728(M+)。
1 H NMR (400MHz, CDCl 3 ) δ 11.25(s, 1H), 10.86(s, 1H), 10.07(s, 1H), 10.01(d, 1H), 9.85(d, 1H), 9.27(d, 2H), 9.14(s, 1H), 5.58(t, 2H), 5.18(s, 1H), 4.10(m, 6H), 3.10(t, 2H), 2.85(m, 6H), 2.18(s, 9H) , 2.17(s, 9H), 2.15(s, 9H), 2.04(s, 3H), 1.07(t, 9H). HRMS(MALDI-TOF) Found: 786.4728(M+).
实施例24：式(24)化合物Example 24: Compound of formula (24)
将式(18)化合物(100mg，0.131mmol)和1ml三乙胺溶于乙腈(15ml)中，加热至80℃反应5小时，TLC监控反应。反应完毕，降至0℃搅拌2小时，有固体析出，过滤，干燥得到式(24)化合物(904mg，收率85％)。The compound of formula (18) (100 mg, 0.131 mmol) and 1 ml of triethylamine were dissolved in acetonitrile (15 ml), heated to 80° C. to react for 5 hours, and the reaction was monitored by TLC. After the reaction was completed, the temperature was lowered to 0° C. and stirred for 2 hours, and a solid was precipitated, which was filtered and dried to obtain the compound of formula (24) (904 mg, yield 85%).
1H NMR(400MHz,CDCl
3)δ11.22(s,1H),10.83(s,1H),10.05(s,1H),10.00(d,1H),9.81(d,1H),9.23(d,2H),9.12(s,1H),5.53(t,2H),5.15(s,1H),3.8(t,2H),3.1(m,8H),2.18(s,9H),2.17(s,9H),2.15(s,9H),2.04(s,3H),1.2(m,15H).HRMS(MALDI-TOF)Found:784.493(M+)。
1 H NMR (400MHz, CDCl 3 ) δ 11.22(s, 1H), 10.83(s, 1H), 10.05(s, 1H), 10.00(d, 1H), 9.81(d, 1H), 9.23(d, 2H), 9.12(s, 1H), 5.53(t, 2H), 5.15(s, 1H), 3.8(t, 2H), 3.1(m, 8H), 2.18(s, 9H), 2.17(s, 9H) ), 2.15(s, 9H), 2.04(s, 3H), 1.2(m, 15H). HRMS(MALDI-TOF) Found: 784.493(M+).
下面结合实验对本发明的技术效果作详细的描述。The technical effects of the present invention will be described in detail below in conjunction with experiments.
实验1 卟啉烯衍生物8和14对人***HeLa细胞的光毒性 Experiment 1 Phototoxicity of porphyrin derivatives 8 and 14 on human cervical cancer HeLa cells
MTT(噻唑蓝)实验被用来评价卟啉烯衍生物8和14的光动力活性。首先，检测了单独光照对HeLa细胞存活率的影响。然后，以每孔1×10
4HeLa细胞的浓度接种在96孔培养板中，培养24h后，加入含有不同浓度卟啉烯衍生物14和8的培养液。继续培养2h后(低氧条件下，先将96孔培养板置于含1％氧气的氮气条件下培养4小时)，采用LED灯(λ＝680±15nm光照用于卟啉烯衍生物14；725±15nm光照用于卟啉烯衍生物8，照射总剂量为6J/cm
2)照射细胞。照射后，继续培养24h，每孔加入10μL MTT(5mg/mL)，避光继续孵育4h。同时进行了黑暗对比试验。弃去培养基，每孔加入100μL DMSO，振荡混匀。在490nm波长下，利用多功能酶标仪测定吸光度值，并计算出细胞的活力。
MTT (thiazolyl blue) assay was used to evaluate the photodynamic activity of porphyrin derivatives 8 and 14. First, the effect of illumination alone on the viability of HeLa cells was examined. Then, the cells were seeded in a 96-well culture plate at a concentration of 1×10 4 HeLa cells per well, and after culturing for 24 hours, culture solutions containing porphyrin derivatives 14 and 8 with different concentrations were added. After continuing to culture for 2 hours (under hypoxic conditions, the 96-well culture plate was first placed in nitrogen containing 1% oxygen for 4 hours), and the LED light (λ=680±15 nm) was used for porphyrin derivative 14; 725±15 nm light was used for porphyrin derivative 8, and the total irradiation dose was 6 J/cm 2 ) to irradiate the cells. After irradiation, the culture was continued for 24 h, 10 μL of MTT (5 mg/mL) was added to each well, and the incubation was continued for 4 h in the dark. A dark contrast test was also carried out. Discard the medium, add 100 μL DMSO to each well, and mix by shaking. At 490nm wavelength, the absorbance value was measured by a multi-function microplate reader, and the cell viability was calculated.
如图2所示，本实验所采用的光照条件基本上不会对HeLa细胞造成损伤，排除了光照对本实验的影响。实验结果提示：卟啉烯衍生物14和8在测试浓度(1～500nM)下没有暗毒性。在常规氧和低氧条件下，光照条件(λ＝680±15nm光照用于卟啉烯衍生物14；725±15nm光照用于卟啉烯衍生物8，照射总剂量为6J/cm
2)，卟啉烯衍生物14和8均显著性抑制了HeLa细胞的增殖，具有很强的光毒性。
As shown in Figure 2, the light conditions used in this experiment basically did not cause damage to HeLa cells, excluding the influence of light on this experiment. The experimental results indicated that the porphyrin derivatives 14 and 8 had no dark toxicity at the tested concentrations (1-500 nM). Under normal oxygen and hypoxic conditions, light conditions (λ=680±15nm light for porphyrin derivative 14; 725±15nm light for porphyrin derivative 8, the total irradiation dose is 6J/cm 2 ), Both porphyrin derivatives 14 and 8 significantly inhibited the proliferation of HeLa cells and had strong phototoxicity.
实验2 卟啉烯衍生物14和8对人食管鳞癌KYSE70细胞的光毒性Experiment 2 Phototoxicity of porphyrin derivatives 14 and 8 on human esophageal squamous cell carcinoma KYSE70 cells
MTT(噻唑蓝)实验被用来评价卟啉烯衍生物14和8的光动力活性。首先，检测了单独光照对KYSE70细胞存活率的影响。然后，以每孔1×10
4KYSE70细胞的浓度接种在96孔培养板中，培养24h后，加入含有不同浓度卟啉烯衍生物1和2的培养液。继续培养2h后(低氧条件下，先将96孔培养板置于含1％氧气的氮气条件下培养4小时)，采用LED灯(λ＝680±15nm光照卟啉烯衍生物14；725±15nm光照卟啉烯衍生物8，照射总剂量为6J/cm
2)照射细胞。照射后，继续培养24h，每孔加入10μL MTT(5mg/mL)，避光继续孵育4h。同时进行了黑暗对比试验。弃去培养基，每孔加入100μL DMSO，振荡混匀。在490nm波长下，利用多功能酶标仪测定吸光度值，并计算出细胞的活力。
MTT (thiazolyl blue) assay was used to evaluate the photodynamic activities of porphyrin derivatives 14 and 8. First, the effect of illumination alone on the viability of KYSE70 cells was examined. Then, the cells were seeded in a 96-well culture plate at a concentration of 1×10 4 KYSE70 cells per well, and after culturing for 24 hours, culture solutions containing different concentrations of porphyrin derivatives 1 and 2 were added. After culturing for 2 hours (under hypoxic conditions, place the 96-well culture plate in nitrogen containing 1% oxygen for 4 hours), use LED light (λ=680±15nm to illuminate porphyrin derivative 14; 725± The cells were irradiated with 15 nm light on the porphyrin derivative 8, with a total irradiation dose of 6 J/cm 2 ). After irradiation, the culture was continued for 24 h, 10 μL of MTT (5 mg/mL) was added to each well, and the incubation was continued for 4 h in the dark. A dark contrast test was also carried out. Discard the medium, add 100 μL DMSO to each well, and mix by shaking. At 490nm wavelength, the absorbance value was measured by a multi-function microplate reader, and the cell viability was calculated.
如图3所示，本实验所采用的光照条件基本上不会对KYSE70细胞造成损伤，排除了光照对本实验的影响。实验结果提示：卟啉烯衍生物14和8在测试浓度(1～500nM)下没有暗毒性。在常规氧和低氧条件下，光照条件(λ＝680±15nm光照卟啉烯衍生物14；725±15nm光照卟啉烯衍生物8，照射总剂量为6J/cm
2)，卟啉烯衍生物14和8均显著性抑制了KYSE70细胞的增殖，具有很强的光毒性。
As shown in Figure 3, the light conditions used in this experiment basically did not cause damage to KYSE70 cells, excluding the influence of light on this experiment. The experimental results indicated that the porphyrin derivatives 14 and 8 had no dark toxicity at the tested concentrations (1-500 nM). Under normal oxygen and hypoxic conditions, light conditions (λ=680±15nm light on porphyrin derivative 14; 725±15nm light on porphyrin derivative 8, the total irradiation dose is 6J/cm 2 ), porphyrin derivatization Both compounds 14 and 8 significantly inhibited the proliferation of KYSE70 cells and had strong phototoxicity.
实验3 卟啉烯衍生物14和8对人鼻咽癌HK-1细胞的光毒性Experiment 3 Phototoxicity of porphyrin derivatives 14 and 8 on human nasopharyngeal carcinoma HK-1 cells
MTT(噻唑蓝)实验被用来评价卟啉烯衍生物14和8的光动力活性。首先，检测了单独光照对HK-1细胞存活率的影响。然后，以每孔1×10
4A375细胞的浓度接种在96孔培养板中，培养24h后，加入含有不同浓度卟啉烯衍生物14和8的培养液。继续培养2h后(低氧条件下，先将96孔培养板置于含1％氧气的氮气条件下培养4小时)，采用LED灯(λ＝680±15nm光照卟啉烯衍生物14；725±15nm光照卟啉烯衍生物8，照射总剂量为6J/cm
2)照射细胞。照射后，继续培养24h，每孔加入10μL MTT(5mg/mL)，避光继续孵育4h。同时进行了黑暗对比试验。弃去培养基，每孔加入100μL DMSO，振荡混匀。在490nm波长下，利用多功能酶标仪测定吸光度值，并计算出细胞的活力。
MTT (thiazolyl blue) assay was used to evaluate the photodynamic activities of porphyrin derivatives 14 and 8. First, the effect of illumination alone on the viability of HK-1 cells was examined. Then, A375 cells were seeded in a 96-well culture plate at a concentration of 1×10 4 A375 cells per well, and after culturing for 24 hours, culture solutions containing porphyrin derivatives 14 and 8 at different concentrations were added. After culturing for 2 hours (under hypoxic conditions, place the 96-well culture plate in nitrogen containing 1% oxygen for 4 hours), use LED light (λ=680±15nm to illuminate the porphyrin derivative 14; 725± The cells were irradiated with 15 nm light on the porphyrin derivative 8, with a total irradiation dose of 6 J/cm 2 ). After irradiation, the culture was continued for 24 h, 10 μL of MTT (5 mg/mL) was added to each well, and the incubation was continued for 4 h in the dark. A dark contrast test was also carried out. Discard the medium, add 100 μL DMSO to each well, and mix by shaking. At 490nm wavelength, the absorbance value was measured by a multi-function microplate reader, and the cell viability was calculated.
如图4所示，本实验所采用的光照条件基本上不会对HK-1细胞造成损伤，排除了光照对本实验的影响。实验结果提示：卟啉烯衍生物14和8在测试浓度(1～500nM)下没有暗毒性。在常规氧和低氧条件下，光照条件(λ＝680±15nm光照卟啉烯衍生物14；725±15nm光照卟啉烯衍生物8，照射总剂量为6J/cm
2)，卟啉烯衍生物14和8均显著性抑制了HK-1细胞的增殖，具有很强的光毒性。
As shown in Figure 4, the light conditions used in this experiment basically did not cause damage to HK-1 cells, excluding the influence of light on this experiment. The experimental results indicated that the porphyrin derivatives 14 and 8 had no dark toxicity at the tested concentrations (1-500 nM). Under normal oxygen and hypoxic conditions, light conditions (λ=680±15nm light on porphyrin derivative 14; 725±15nm light on porphyrin derivative 8, the total irradiation dose is 6J/cm 2 ), porphyrin derivatization Both compounds 14 and 8 significantly inhibited the proliferation of HK-1 cells and had strong phototoxicity.
实验5 卟啉烯衍生物14和8对人正常胚肺成纤维细胞MRC-5细胞的暗毒性检测对正常细胞的暗毒性大小也是评价光动力光敏剂的一项重要标准。暗毒性小或无暗毒性意味着光敏 剂对正常组织的损伤小，也就是毒副作用小、较为安全。因此，本申请还考察了卟啉烯衍生物14和8对人正常胚肺成纤维细胞MRC-5细胞的暗毒性。MTT(噻唑蓝)实验被用来评价卟啉烯衍生物14和8的暗毒性。实验结果提示：卟啉烯衍生物14在测试浓度(1～1000nM)，对MRC-5细胞增殖的抑制率是10.5％，具有较弱的暗毒性；而卟啉烯衍生物8在1000nM时，对MRC-5细胞增殖的抑制率是12.0％，具有较弱的暗毒性。Experiment 5 Detection of dark toxicity of porphyrin derivatives 14 and 8 to human normal embryonic lung fibroblast MRC-5 cells The magnitude of dark toxicity to normal cells is also an important criterion for evaluating photodynamic photosensitizers. Low or no dark toxicity means that the photosensitizer has little damage to normal tissues, that is, less toxic and side effects, and is relatively safe. Therefore, the present application also investigated the dark toxicity of porphyrin derivatives 14 and 8 to human normal embryonic lung fibroblast MRC-5 cells. MTT (thiazolyl blue) assay was used to evaluate the dark toxicity of porphyrin derivatives 14 and 8. The experimental results showed that: the porphyrin derivative 14 at the test concentration (1-1000nM), the inhibition rate of MRC-5 cell proliferation was 10.5%, and had weak dark toxicity; The inhibition rate of MRC-5 cell proliferation was 12.0% with weak dark toxicity.
实验6 卟啉烯衍生物14和8对人正常肝细胞L02细胞的暗毒性Experiment 6 Dark toxicity of porphyrin derivatives 14 and 8 to human normal hepatocyte L02 cells
本申请还考察了卟啉烯衍生物14和8对人正常肝细胞L02细胞的暗毒性。MTT(噻唑蓝)实验被用来评价卟啉烯衍生物14和8的暗毒性。实验结果提示：卟啉烯衍生物14在测试浓度(1～1000nM)时，对MRC-5细胞增殖的抑制率是6.5％，具有较弱的暗毒性；而卟啉烯衍生物2在1000nM时，对MRC-5细胞增殖的抑制率是7.8％，具有较弱的暗毒性。可见，本发明所述卟啉烯衍生物作为光敏剂之用，具有很大的优势。The present application also investigated the dark toxicity of porphyrin derivatives 14 and 8 to human normal hepatocyte L02 cells. MTT (thiazolyl blue) assay was used to evaluate the dark toxicity of porphyrin derivatives 14 and 8. The experimental results indicated that the inhibition rate of porphyrin derivative 14 on the proliferation of MRC-5 cells was 6.5% at the test concentration (1-1000 nM), and had weak dark toxicity; while the porphyrin derivative 2 was at 1000 nM. , the inhibition rate of MRC-5 cell proliferation was 7.8%, with weak dark toxicity. It can be seen that the porphyrin derivatives of the present invention have great advantages as photosensitizers.
以上所述仅为本发明的较佳实施例而已，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。The above descriptions are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements and improvements made within the spirit and principles of the present invention shall be included in the protection of the present invention. within the range.
Claims (15)
- 一种深红外卟啉烯衍生物，或其药学上可接受的盐，或其药学上可接受的金属配合物，所述卟啉烯衍生物具有式I所示的结构：A deep-infrared porphyrin derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable metal complex thereof, the porphyrin derivative having the structure shown in formula I:
其中，in,R选自-NO 2、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、-NH-CO-R’； R is selected from -NO 2 , -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-CO-R';每个R 1独立地选自：H、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基-C 1-6烷基、C 3-8环烷基、卤素、CN、COOH、羟基、氨基、NH(C 1-6烷基)、N(C 1-6烷基) 2、C 1-6烷氧基、卤代C 1-6烷氧基； Each R 1 is independently selected from: H, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-8 cycloalkyl, Halogen, CN, COOH, hydroxyl, amino, NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , C 1-6 alkoxy, halogenated C 1-6 alkoxy;A选自H，C 1-6烷基、卤代C 1-6烷基； A is selected from H, C 1-6 alkyl, halogenated C 1-6 alkyl;B选自：B is selected from:1)-(CH 2CH 2X) n-(CH 2) m-XR 2或-(CH 2X) n-(CH 2) m-XR 2；其中，R 2选自H、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基-C 1-6烷基-、C 3-8环烷基、C 2-8杂环烷基、C 6-10芳基、C 5-10杂芳基；每个X独立地选自O、S、NH； 1)-(CH 2 CH 2 X) n -(CH 2 ) m -XR 2 or -(CH 2 X) n -(CH 2 ) m -XR 2 ; wherein, R 2 is selected from H, C 1-6 Alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl-, C 3-8 cycloalkyl, C 2-8 heterocycloalkyl, C 6-10 aryl base, C 5-10 heteroaryl; each X is independently selected from O, S, NH;2)-(CH 2) n-CH 2-R 3或-(CH 2CH 2X) n-(CH 2) m-CH 2-R 4；其中，R 3、R 4选自H、卤素、羟基、-SH、-COOH、-COO C 1-6烷基、-CONH 2、-CONH(C 1-6烷基)、-CON(C 1-6烷基) 2、氨基、NH(C 1-6烷基)、N(C 1-6烷基) 2、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基-C 1-6烷基-、C 3-8环烷基、C 2-8杂环烷基、C 6-10芳基、C 5-10杂芳基；或者，R 3、R 4选自其中，R 5、R 6、R 7独立的选自C 1-6烷基、卤代C 1-6烷基；Y-为阴离子；其中当n≧2时， -(CH 2) n-CH 2-R 3中一个或多个CH 2可替换为O、S、NH；每个X独立地选自O、S、NH；且0≤n≤14，0≤m≤14，优选0≤n≤7，0≤m≤7； 2)-(CH 2 ) n -CH 2 -R 3 or -(CH 2 CH 2 X) n -(CH 2 ) m -CH 2 -R 4 ; wherein R 3 and R 4 are selected from H, halogen, Hydroxyl, -SH, -COOH, -COO C 1-6 alkyl, -CONH 2 , -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl) 2 , amino, NH(C 1 -6 alkyl), N(C 1-6 alkyl) 2 , C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 alkyl, halogenated C 1-6 alkyl , C 1-6 alkoxy-C 1-6 alkyl-, C 3-8 cycloalkyl, C 2-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl; or , R 3 and R 4 are selected from
Wherein, R 5 , R 6 , R 7 are independently selected from C 1-6 alkyl, halogenated C 1-6 alkyl; Y- is an anion; wherein when n≧2, -(CH 2 ) n -CH One or more CH 2 in 2 -R 3 can be replaced by O, S, NH; each X is independently selected from O, S, NH; and 0≤n≤14, 0≤m≤14, preferably 0≤n ≤7, 0≤m≤7;R’选自C 1-6烷基、卤代C 1-6烷基、-(CH 2) w-COOH、-(CH 2) w-COO C 1-6烷基、-(CH 2) w-NH 2、-(CH 2) w-NH(C 1-6烷基)、-(CH 2) w-N(C 1-6烷基) 2、-(CH 2) w-OH；其中0≤w≤7。 R' is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) w -COOH, -(CH 2 ) w -COO C 1-6 alkyl, -(CH 2 ) w -NH 2 , -(CH 2 ) w -NH(C 1-6 alkyl), -(CH 2 ) w -N(C 1-6 alkyl) 2 , -(CH 2 ) w -OH; wherein 0 ≤w≤7. - 根据权利要求1所述的深红外卟啉烯衍生物，或其药学上可接受的盐，或其药学上可接受的金属配合物，其特征在于，每个R 1独立地选自C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基；A选自H，C 1-3烷基、卤代C 1-3烷基。 The deep infrared porphyrin derivative according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable metal complex thereof, wherein each R 1 is independently selected from C 1- 6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy; A is selected from H, C 1-3 alkyl, halogenated C 1-3 alkyl base.
- 根据权利要求2所述的深红外卟啉烯衍生物，或其药学上可接受的盐，或其药学上可接受的金属配合物，其特征在于，每个R 1独立地选自甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、戊基；优选丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基。 The deep-infrared porphyrin derivative according to claim 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable metal complex thereof, wherein each R is independently selected from methyl, Ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl; preferably propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl.
- 根据权利要求1所述的深红外卟啉烯衍生物，或其药学上可接受的盐，或其药学上可接受的金属配合物，其特征在于具有如下结构式：The deep infrared porphyrin derivative according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable metal complex thereof, is characterized in that it has the following structural formula:
- 根据权利要求1-4任一项所述的深红外卟啉烯衍生物，或其药学上可接受的盐，或其药学上可接受的金属配合物，其特征在于：B选自-(CH 2CH 2O) n-CH 2CH 2-OR 2、-(CH 2CH 2S) n-CH 2CH 2-SR 2、-(CH 2CH 2NH) n-CH 2CH 2-NHR 2、-(CH 2CH 2O) n-CH 2CH 2-SR 2、-(CH 2CH 2S) n-CH 2CH 2-OR 2、-(CH 2CH 2O) n-CH 2CH 2-NHR 2、-(CH 2CH 2S) n-CH 2CH 2-NHR 2、-(CH 2O) n-(CH 2) m-OR 2、-(CH 2S) n-(CH 2) m-SR 2、-(CH 2O) n-(CH 2) m-SR 2、-(CH 2S) n-(CH 2) m-OR 2、-(CH 2) 5-R 3、-(CH 2CH 2X) n-(CH 2) m-CH 2-R 4；且0≤n≤7，0≤m≤7，优选m、n为0、1、2、3、4。 The deep-infrared porphyrin derivative according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable metal complex thereof, wherein B is selected from -(CH 2 CH 2 O) n -CH 2 CH 2 -OR 2 , -(CH 2 CH 2 S) n -CH 2 CH 2 -SR 2 , -(CH 2 CH 2 NH) n -CH 2 CH 2 -NHR 2 , -(CH 2 CH 2 O) n -CH 2 CH 2 -SR 2 , -(CH 2 CH 2 S) n -CH 2 CH 2 -OR 2 , -(CH 2 CH 2 O) n -CH 2 CH 2 -NHR 2 , -(CH 2 CH 2 S) n -CH 2 CH 2 -NHR 2 , -(CH 2 O) n -(CH 2 ) m -OR 2 , -(CH 2 S) n -(CH 2 ) m -SR 2 , -(CH 2 O) n -(CH 2 ) m -SR 2 , -(CH 2 S) n -(CH 2 ) m -OR 2 , -(CH 2 ) 5 -R 3 , -(CH 2 CH 2 X) n -(CH 2 ) m -CH 2 -R 4 ; and 0≤n≤7, 0≤m≤7, preferably m, n are 0, 1, 2, 3, 4 .
- 根据权利要求1-4任一项所述的深红外卟啉烯衍生物，或其药学上可接受的盐，或其药学上可接受的金属配合物，其特征在于：R 2选自H、C 1-3烷基、卤代C 1-3烷基； The deep-infrared porphyrin derivative according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable metal complex thereof, is characterized in that: R 2 is selected from H, C 1-3 alkyl, halogenated C 1-3 alkyl;R 3、R 4选自H、卤素、羟基、-SH、-COOH、-COO C 1-3烷基、-CONH 2、-CONH(C 1-2烷基)、-CON(C 1-2烷基) 2、氨基、NH(C 1-2烷基)、N(C 1-2烷基) 2、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3 烷基、卤代C 1-3烷基；或者，R 3、R 4选自R 5、R 6、R 7独立的选自C 1-3烷基、卤代C 1-3烷基；Y-为阴离子； R 3 , R 4 are selected from H, halogen, hydroxyl, -SH, -COOH, -COO C 1-3 alkyl, -CONH 2 , -CONH(C 1-2 alkyl), -CON(C 1-2 alkyl) 2 , amino, NH(C 1-2 alkyl), N(C 1-2 alkyl) 2 , C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 Alkyl, halogenated C 1-3 alkyl; or, R 3 , R 4 are selected from
R 5 , R 6 and R 7 are independently selected from C 1-3 alkyl, halogenated C 1-3 alkyl; Y- is an anion;R’选自C 1-4烷基、卤代C 1-4烷基、-(CH 2) w-COOH、-(CH 2) w-COOC 1-6烷基、-(CH 2) w-NH 2、-(CH 2) w-NH(C 1-6烷基)、-(CH 2) w-N(C 1-6烷基) 2、-(CH 2) w-OH；其中0≤w≤3，具体为0、1、2、3。 R' is selected from C 1-4 alkyl, halogenated C 1-4 alkyl, -(CH 2 ) w -COOH, -(CH 2 ) w -COOC 1-6 alkyl, -(CH 2 ) w - NH 2 , -(CH 2 ) w -NH(C 1-6 alkyl), -(CH 2 ) w -N(C 1-6 alkyl) 2 , -(CH 2 ) w -OH; wherein 0≤ w≤3, specifically 0, 1, 2, and 3. - 根据权利要求1-4任一项所述的深红外卟啉烯衍生物，或其药学上可接受的盐，或其药学上可接受的金属配合物，其特征在于：B选自下列取代基：The deep-infrared porphyrin derivative according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable metal complex thereof, characterized in that: B is selected from the following substituents :
- 根据权利要求1-4任一项所述的深红外卟啉烯衍生物，或其药学上可接受的盐，或其药学上可接受的金属配合物，其特征在于：R’选自甲基、乙基、丙基、异丙基、-CH 2COOH、-CH 2CH 2COOH、-CH 2NH 2、-CH 2CH 2NH 2、-CH 2-OH、-CH 2CH 2-OH、-CH 2CH 2CH 2-OH、卤代甲基、卤代乙基、卤代丙基、卤代异丙基。 The deep-infrared porphyrin derivative according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable metal complex thereof, characterized in that: R' is selected from methyl , ethyl, propyl , isopropyl, -CH2COOH , -CH2CH2COOH , -CH2NH2 , -CH2CH2NH2 , -CH2 - OH , -CH2CH2 - OH , -CH 2 CH 2 CH 2 -OH, halomethyl, haloethyl, halopropyl, haloisopropyl.
- 根据权利要求1-4任一项所述的深红外卟啉烯衍生物，或其药学上可接受的盐，或其药学上可接受的金属配合物，所述卟啉烯衍生物选自下列化合物：The deep-infrared porphyrin derivative according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable metal complex thereof, wherein the porphyrin derivative is selected from the following Compound:
- 权利要求1所述的深红外卟啉烯衍生物，或其药学上可接受的盐，或其药学上可接受的金属配合物的制备方法，其特征在于包括如下步骤：The deep-infrared porphyrin derivative of claim 1, or a pharmaceutically acceptable salt thereof, or a method for preparing a pharmaceutically acceptable metal complex thereof, is characterized in that comprising the steps:第一步，式IV’化合物的硝化；The first step, the nitration of the compound of formula IV';
根据需要，还包括第二步，式I-1化合物的还原；According to needs, it also includes the second step, the reduction of the compound of formula I-1;
根据需要，还包括第三步，式I-2化合物的酰胺化；According to needs, also includes the third step, the amidation of the compound of formula I-2;
- 根据权利要求10所述的深红外卟啉烯衍生物，或其药学上可接受的盐，或其药学上可接受的金属配合物的制备方法，其特征在于包括如下步骤：The deep-infrared porphyrin derivative according to claim 10, or a pharmaceutically acceptable salt thereof, or a method for preparing a pharmaceutically acceptable metal complex thereof, is characterized in that comprising the steps:第一步，式IV化合物的硝化；The first step, the nitration of the compound of formula IV;
根据需要，还包括第二步，式1化合物的还原；According to needs, it also includes the second step, the reduction of the compound of formula 1;
根据需要，还包括第三步，式2化合物的酰胺化；According to need, it also includes the third step, the amidation of the compound of formula 2;
- 根据权利要求10或11所述的深红外卟啉烯衍生物，或其药学上可接受的盐，或其药学上可接受的金属配合物的制备方法，其特征在于：The deep-infrared porphyrin derivative according to claim 10 or 11, or a pharmaceutically acceptable salt thereof, or a method for preparing a pharmaceutically acceptable metal complex thereof, is characterized in that:第一步反应，在有机溶剂中，加入硝酸银和醋酸进行硝化；所述有机溶剂选自1,2-二氯乙烷、二氯甲烷、乙醇、乙腈、甲醇；In the first step reaction, in an organic solvent, silver nitrate and acetic acid are added for nitration; the organic solvent is selected from 1,2-dichloroethane, dichloromethane, ethanol, acetonitrile, and methanol;第二步反应，在有机溶剂中，加入还原剂进行还原；所述还原剂为连二硫酸钠、氯化亚锡、氯化亚锡二水合物、Fe/HCl、Zn/HCl，有机溶剂选自1,2-二氯乙烷、二氯甲烷、乙醇、乙腈、甲醇；In the second step reaction, in an organic solvent, a reducing agent is added for reduction; the reducing agent is sodium hydrosulfate, stannous chloride, stannous chloride dihydrate, Fe/HCl, Zn/HCl, and the organic solvent is selected from From 1,2-dichloroethane, dichloromethane, ethanol, acetonitrile, methanol;第三步反应，在有机溶剂中，加入酸酐或酰氯进行缩合反应；所述有机溶剂选自1,2-二氯乙烷、二氯甲烷、四氢呋喃、乙醇、乙腈、甲醇。In the third step of the reaction, acid anhydride or acid chloride is added to an organic solvent for condensation reaction; the organic solvent is selected from 1,2-dichloroethane, dichloromethane, tetrahydrofuran, ethanol, acetonitrile, and methanol.
- 权利要求1-9任一项所述的深红外卟啉烯衍生物，或其药学上可接受的盐，或其药学上可接受的金属配合物在制备光动力药物、光敏药物或治疗癌症药物中的应用。Deep infrared porphyrin derivative described in any one of claim 1-9, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable metal complex in the preparation of photodynamic drug, photosensitizing drug or treating cancer drug applications in .
- 根据权利要求13所述的应用，其特征在于所述癌症为***、食管鳞癌、鼻咽癌和黑色素瘤。The application according to claim 13, wherein the cancer is cervical cancer, esophageal squamous cell carcinoma, nasopharyngeal carcinoma and melanoma.
- 药物组合物，包括治疗有效量的权利要求1-9任一项所述的深红外卟啉烯衍生物，或其药学上可接受的盐，或其药学上可接受的金属配合物，以及药学上可接受的辅料和/或载体。A pharmaceutical composition, comprising a therapeutically effective amount of the deep-infrared porphyrin derivative according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable metal complex thereof, and a pharmaceutical composition acceptable excipients and/or carriers.
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| CN110483531A (en) * | 2019-08-29 | 2019-11-22 | 李德芳 | A kind of water-soluble porphyrin ene derivative, preparation method, anti-tumor drug and application |
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