CN114524822A - Novel intermediate diphenyl naphthoporphin derivative and application thereof in medical field - Google Patents
Novel intermediate diphenyl naphthoporphin derivative and application thereof in medical field Download PDFInfo
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- CN114524822A CN114524822A CN202210184531.5A CN202210184531A CN114524822A CN 114524822 A CN114524822 A CN 114524822A CN 202210184531 A CN202210184531 A CN 202210184531A CN 114524822 A CN114524822 A CN 114524822A
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- Prior art keywords
- bis
- naphthoporphin
- phenyl
- carbamoyl
- cooh
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- UTGBJVCNAGGHCY-UHFFFAOYSA-N C(C=C1C=C2N=C(C=C(C=CC3=CC(C=C4)=NC4=C4)N3C3=CC=CC=C3)C3=C2C=CC2=CC=CC=C32)=C4N1C1=CC=CC=C1 Chemical class C(C=C1C=C2N=C(C=C(C=CC3=CC(C=C4)=NC4=C4)N3C3=CC=CC=C3)C3=C2C=CC2=CC=CC=C32)=C4N1C1=CC=CC=C1 UTGBJVCNAGGHCY-UHFFFAOYSA-N 0.000 title claims abstract description 13
- -1 alkyl carboxylic acid Chemical class 0.000 claims abstract description 140
- 150000001875 compounds Chemical class 0.000 claims abstract description 54
- 239000003814 drug Substances 0.000 claims abstract description 30
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 24
- 238000002360 preparation method Methods 0.000 claims abstract description 15
- 238000011282 treatment Methods 0.000 claims abstract description 15
- 125000005233 alkylalcohol group Chemical group 0.000 claims abstract description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 10
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 208000002780 macular degeneration Diseases 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- 206010059313 Anogenital warts Diseases 0.000 claims abstract description 4
- 206010067193 Naevus flammeus Diseases 0.000 claims abstract description 4
- 208000006787 Port-Wine Stain Diseases 0.000 claims abstract description 4
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 4
- 208000002026 familial multiple nevi flammei Diseases 0.000 claims abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 4
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
- 239000002253 acid Substances 0.000 claims description 10
- 238000004220 aggregation Methods 0.000 claims description 9
- 230000002776 aggregation Effects 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- HMKMKLAEOLHRDT-UHFFFAOYSA-N N1C(C=C2C3=C4C=CC=CC4=CC=C3C(C=C3NC(=C4)C=C3)=N2)=CC=C1C=C1C=CC4=N1 Chemical class N1C(C=C2C3=C4C=CC=CC4=CC=C3C(C=C3NC(=C4)C=C3)=N2)=CC=C1C=C1C=CC4=N1 HMKMKLAEOLHRDT-UHFFFAOYSA-N 0.000 claims description 4
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- 238000003745 diagnosis Methods 0.000 claims description 4
- 208000009621 actinic keratosis Diseases 0.000 claims description 3
- HTTRLMDNPFPQPC-UHFFFAOYSA-N OC(CNC(C(C=C1)=CC=C1C1=C(C=C2N=C(C=C(C=C3)NC3=CC(C=C3)=NC3=C3)C4=C2C=CC2=CC=CC=C42)NC3=C1)=O)=O Chemical compound OC(CNC(C(C=C1)=CC=C1C1=C(C=C2N=C(C=C(C=C3)NC3=CC(C=C3)=NC3=C3)C4=C2C=CC2=CC=CC=C42)NC3=C1)=O)=O HTTRLMDNPFPQPC-UHFFFAOYSA-N 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 238000011338 personalized therapy Methods 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims 1
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- 239000012535 impurity Substances 0.000 abstract 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- 229940079593 drug Drugs 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 16
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 238000001308 synthesis method Methods 0.000 description 11
- 238000002428 photodynamic therapy Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- JUJWROOIHBZHMG-RALIUCGRSA-N pyridine-d5 Chemical compound [2H]C1=NC([2H])=C([2H])C([2H])=C1[2H] JUJWROOIHBZHMG-RALIUCGRSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
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- 201000004101 esophageal cancer Diseases 0.000 description 3
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- 150000003278 haem Chemical class 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- RKCAIXNGYQCCAL-UHFFFAOYSA-N porphin Chemical compound N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 RKCAIXNGYQCCAL-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- UZFPOOOQHWICKY-UHFFFAOYSA-N 3-[13-[1-[1-[8,12-bis(2-carboxyethyl)-17-(1-hydroxyethyl)-3,7,13,18-tetramethyl-21,24-dihydroporphyrin-2-yl]ethoxy]ethyl]-18-(2-carboxyethyl)-8-(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid Chemical compound N1C(C=C2C(=C(CCC(O)=O)C(C=C3C(=C(C)C(C=C4N5)=N3)CCC(O)=O)=N2)C)=C(C)C(C(C)O)=C1C=C5C(C)=C4C(C)OC(C)C1=C(N2)C=C(N3)C(C)=C(C(O)C)C3=CC(C(C)=C3CCC(O)=O)=NC3=CC(C(CCC(O)=O)=C3C)=NC3=CC2=C1C UZFPOOOQHWICKY-UHFFFAOYSA-N 0.000 description 2
- UJKPHYRXOLRVJJ-MLSVHJFASA-N CC(O)C1=C(C)/C2=C/C3=N/C(=C\C4=C(CCC(O)=O)C(C)=C(N4)/C=C4\N=C(\C=C\1/N\2)C(C)=C4C(C)O)/C(CCC(O)=O)=C3C Chemical class CC(O)C1=C(C)/C2=C/C3=N/C(=C\C4=C(CCC(O)=O)C(C)=C(N4)/C=C4\N=C(\C=C\1/N\2)C(C)=C4C(C)O)/C(CCC(O)=O)=C3C UJKPHYRXOLRVJJ-MLSVHJFASA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- LYPFDBRUNKHDGX-SOGSVHMOSA-N N1C2=CC=C1\C(=C1\C=CC(=N1)\C(=C1\C=C/C(/N1)=C(/C1=N/C(/CC1)=C2/C1=CC(O)=CC=C1)C1=CC(O)=CC=C1)\C1=CC(O)=CC=C1)C1=CC(O)=CC=C1 Chemical compound N1C2=CC=C1\C(=C1\C=CC(=N1)\C(=C1\C=C/C(/N1)=C(/C1=N/C(/CC1)=C2/C1=CC(O)=CC=C1)C1=CC(O)=CC=C1)\C1=CC(O)=CC=C1)C1=CC(O)=CC=C1 LYPFDBRUNKHDGX-SOGSVHMOSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 206010034972 Photosensitivity reaction Diseases 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
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- 238000011156 evaluation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 208000007578 phototoxic dermatitis Diseases 0.000 description 2
- 231100000018 phototoxicity Toxicity 0.000 description 2
- 229960004293 porfimer sodium Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
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- ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N verteporfin Chemical compound C=1C([C@@]2([C@H](C(=O)OC)C(=CC=C22)C(=O)OC)C)=NC2=CC(C(=C2C=C)C)=NC2=CC(C(=C2CCC(O)=O)C)=NC2=CC2=NC=1C(C)=C2CCC(=O)OC ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N 0.000 description 2
- 229960003895 verteporfin Drugs 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
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- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
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- 231100000002 MTT assay Toxicity 0.000 description 1
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- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
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- 239000001963 growth medium Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 229960003569 hematoporphyrin Drugs 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 125000004252 isoindol-1-yl group Chemical group [H]N1C([H])=C2C([H])=C([H])C([H])=C([H])C2=C1* 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
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- 239000012299 nitrogen atmosphere Substances 0.000 description 1
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- 230000002093 peripheral effect Effects 0.000 description 1
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- 230000000717 retained effect Effects 0.000 description 1
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- 238000000926 separation method Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- YNHJECZULSZAQK-UHFFFAOYSA-N tetraphenylporphyrin Chemical class C1=CC(C(=C2C=CC(N2)=C(C=2C=CC=CC=2)C=2C=CC(N=2)=C(C=2C=CC=CC=2)C2=CC=C3N2)C=2C=CC=CC=2)=NC1=C3C1=CC=CC=C1 YNHJECZULSZAQK-UHFFFAOYSA-N 0.000 description 1
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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
- A61K41/0076—PDT with expanded (metallo)porphyrins, i.e. having more than 20 ring atoms, e.g. texaphyrins, sapphyrins, hexaphyrins, pentaphyrins, porphocyanines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention relates to a novel intermediate diphenyl naphthoporphin derivative (formula I) and application thereof in the field of medicine. In the formula 
, A and Y are the same or different and are independently CH2, C is equal to O, C, N or O; R1 and R2 are the same or different and at least one of R1 and R2 contains polar groups (such as carboxyl, hydroxyl, ether or amino), and the other one can be independently hydrogen, alkyl carboxylic acid, alkyl alcohol, alkyl containing N impurities or O impurities, alkyl alcohol containing N impurities or O impurities, alkyl carboxylic acid containing N impurities or O impurities, alkyl or alkyl alcohol or alkyl carboxylic acid containing carbonyl, alkyl or alkyl alcohol or alkyl carboxylic acid containing amido bonds, or alkyl carboxylic acid containing carbonyl and amido bonds. The invention relates to a compound which has good stability, simple and convenient preparation process, good hydrophilicity, good photodynamic effect and small photo-toxic side effect and can be used for personalized treatment. A photosensitizer prepared by the invention can be used as a photodynamic medicine for diagnosing and treating diseases such as tumors, macular degeneration of retina, nevus flammeus, condyloma acuminatum and the like.
Description
Technical Field
The invention relates to the field of photosensitive drugs and photodynamic therapy, in particular to a novel intermediate diphenyl naphthoporphin derivative which has the advantages of good stability, simple and convenient preparation process, good hydrophilicity, difficult aggregation, excellent photodynamic effect and small phototoxic side effect and can be used for personalized treatment and an application thereof.
Background
Photodynamic therapy (PDT) is a new, promising approach to the diagnosis and treatment of tumors, which is being developed vigorously following traditional surgery, chemotherapy and radiotherapy. The principle is that after the photosensitizer is injected into human body intravenously, it can be selectively gathered or retained in the focus (such as malignant tumor), after the therapeutic concentration of the photosensitizer is reached, the focus position is irradiated by using light with specific wavelength, and the photosensitizer is excited to produce active oxygen (such as singlet oxygen) to kill tumor or other pathological tissues.
Photosensitizers, light of specific wavelengths and oxygen molecules are three essential elements essential for photodynamic therapy. Among them, photosensitizers play a dominant role in the overall PDT as the core of three elements of photodynamic therapy. Most of the current market uses porphin-like tetrapyrrole photosensitizers. The porphin photosensitizer mainly comprises a heme derivative (also called hematoporphyrin derivative) and a tetraphenylporphin derivative. Porfimer sodium (photosensitizer II) is used as a heme derivative, is the photodynamic drug which is applied to clinic at the earliest, has obvious treatment effect, but the drug is a mixture consisting of a plurality of isomers, the content of each component is difficult to control in the preparation process, and some components have long retention time in skin and poor tolerance (foreign medicines-synthetic medicines, biochemical medicines and preparation booklets, 1998,19, 32-34; world clinical medicines, 2018,39,285-288), so the clinical application of the drug is limited. The photosensitive drug Verteporfin (Verteporfin) approved by the United states FDA in 2000 for clinical treatment of tumor, macular degeneration and other diseases also belongs to a heme derivative, the maximum absorption wavelength of the photosensitizer can reach 689nm, the tissue penetrating capacity of the photosensitizer is twice that of porfimer sodium, and the photosensitizer can be rapidly eliminated from the body, but the synthesis process of the photosensitizer is complex, a plurality of isomers exist, the separation and purification are difficult, and the total yield is low (China New medicine journal, 2005,14,785 and 788; Aust.J.chem.,2008,61,741 and 754), so the clinical application of the photosensitizer is greatly limited. In addition, the photosensitizer Temoporfin (Temoporfin) marketed in 2001 is used for treating esophageal cancer and belongs to tetraphenyl porphin derivatives, but has the defects of easy oxidation of phenolic hydroxyl, poor stability, poor solubility in water, high price and the like (chem.Soc.Rev.,1995,24,19-33), and the clinical application of the photosensitizer is limited. The photosensitive drug paliporfin is approved to be used for treating prostatic cancer in 2018, but the molecular structure of the paliporfin contains heavy metal palladium, so that the paliporfin is high in toxicity. Therefore, the discovery of efficient novel photosensitizers remains a great challenge for scientists all over the world, and has important scientific significance and clinical application value.
The intermediate diphenyl naphthoporphin is a porphin compound with a novel structure, has more excellent optical properties compared with the traditional porphin compound, and has more potential to be developed into photodynamic medicaments.
Currently, only individual scholars have conducted research on the synthesis of intermediate diphenylnaphthoporphins. The Cheprakov group first reported in 2009 the synthesis of 5, 15-bis [ (3, 5-di-tert-butyl) phenyl ] naphthoporphin (Compound 1) (macromolecules, 2009,2,198-205) which had poor solubility and could not be tested for NMR carbon spectra.
The naphthoporphin is easier to generate self-aggregation or self-assembly phenomena than the traditional porphin compounds (such as hematoporphyrin compounds and intermediate tetraphenyl porphin compounds), so that the solubility of the compound is greatly reduced, the compound is difficult to dissolve in various solvents, and the optical performance and the pharmaceutical performance can be exerted only by remarkably improving the solubility of the compound through the structural modification of peripheral groups, thereby being used for clinical photodynamic therapy.
In order to find a novel photosensitive drug with novel structure, good optical performance and drug-forming property, a novel intermediate diphenyl naphthoporphin compound (series I) is designed and synthesized, and the solubility of the compound is obviously improved; pharmacological activity studies show that the photodynamic activities of the compounds are significantly higher than those of a control compound 1 and a positive control drug, i.e., the amporfin. Research shows that the new light-sensitive compound designed and synthesized by the team has high photodynamic pharmacological activity, small skin photo-toxic side effect, stable structure, simple and easy preparation process, good hydrophilicity, difficult aggregation and the like; in addition, the new compound has a plurality of absorption peaks at the position of 450-800nm, and can select a laser light source with a proper wavelength according to the actual volume and the position of focuses such as tumors and the like to realize personalized photodynamic diagnosis and treatment, so that the photodynamic treatment drug can be developed into photodynamic treatment drugs for diseases such as tumors, macular degeneration of retina, actinic keratosis, nevus flammeus, condyloma acuminatum and the like.
Disclosure of Invention
In order to overcome the defects of complex composition, unstable structure, difficult preparation, higher cost, easy aggregation, poor water solubility, strong skin light toxic and side effects, difficult personalized treatment development and the like existing in the conventional photosensitive drugs, the invention introduces a polar group as a hydrophilic group into the phenyl group of the intermediate diphenyl naphthoporphin compound, improves the hydrophilicity of the compound and inhibits the aggregation of the compound. After a great deal of creative work, a series of intermediate diphenyl naphthoporphin and amino acid condensation derivatives thereof are synthesized, and the invention is completed.
The invention relates to a kind of intermediate diphenyl naphthoporphin compound with the advantages of high photodynamic activity, small skin phototoxic side effect, stable property, good hydrophilicity, difficult aggregation, easy preparation of injection, personalized treatment and the like, and application thereof.
The invention is summarized as follows:
a novel intermediate diphenyl naphthoporphin derivative which has good stability and hydrophilicity, is not easy to aggregate and can be used for personalized treatment is characterized in that: the photosensitizer is a 5, 15-diphenyl naphthoporphin derivative (I):
wherein:
a and Y are the same or different and are independently CH2C-O, C, N or O; r1And R2The same or different and at least one contains a polar group (e.g., carboxyl, hydroxyl, ether or amino), and the other can be independently hydrogen, alkyl, alkylcarboxylic acid, alkyl alcohol, N-or O-hetero-containing alkyl alcohol, N-or O-hetero-containing alkylcarboxylic acid, carbonyl-containing alkyl or alkyl alcohol or alkylcarboxylic acid, amide bond-containing alkyl or alkyl alcohol or alkylcarboxylic acid, or both carbonyl and amide bond-containing alkylcarboxylic acid.
A compound of formula (I), R according to claim 11And R2Identical or different and at least one contains a polar group (e.g., carboxyl, hydroxyl, ether or amino), wherein:
the nonpolar group being-H, - (CH)2)mCH3,-(CH2)mCH(CH3)2,-(CH2)mC(CH3)3,-(CH2)mN[(CH2)nCH3]2,-(CH2)mO(CH2)nCH3,-(CH2)mO(CH2)nCH(CH3)2,-(CH2)mO(CH2)nC(CH3)3,-(CH2)m(OCH2CH2)qCH3,-(CH2)mCO(CH2)nCH3,-(CH2)mCO(CH2)nCH(CH3)2,-(CH2)mCO(CH2)nC(CH3)3,-(CH2)mCONH(CH2)pCH3,-(CH2)mCONH(CH2)pCH(CH3)2Or- (CH)2)mCONH(CH2)pC(CH3)3,m＝0-7,n＝0–7,p＝1-7,q＝1-5；
The polar group is- (CH)2)mCOOH,-(CH2)mCH(CH3)COOH,-(CH2)mOH,-(CH2)mCH(CH3)OH,-(CH2)m(OCH2CH2)qOCH3,-(CH2)mC6H4OH,-(CH2)mN[(CH2)nCOOH]2,-(CH2)mN[(CH2)pOH]2,-(CH2)mO(CH2)nCOOH,-(CH2)mO(CH2)pOH,-(CH2)m(OCH2CH2)qOH,-(CH2)mCO(CH2)nCOOH,-(CH2)mCO(CH2)nOH or an amino acid derivative, m-1-7, n-1-7, p-2-7, q-1-5.
The amino acid derivative according to claim 2, which is: - (CH)2)mCONH(CH2)nCOOH,-(CH2)mCONHCH(CH3)COOH,-(CH2)mCONH(CH2)nCO(CH2)pCOOH,-(CH2)mCONHCH[CH(CH3)2]COOH,-(CH2)mCONHCH[CH2CH(CH3)2]COOH,-(CH2)mCONHCH[CH(CH3)CH2CH3]COOH,-(CH2)mCONHCH(CH2C6H5)COOH,-(CH2)mCON[(CH2)nCOOH]2,-(CH2)mCONHCH(COOH)CH2COOH,m＝1-7,n＝1-7,p＝1-4。
A novel class of intermediate diphenylnaphthoporphin compounds and their amino acid condensates (I) as claimed in claim 1, wherein said compounds include the following:
5, 15-bis [3, 5-bis (carboxymethoxy) phenyl]Naphthoporphin (I)1)；
5, 15-bis [3, 5-bis (carboxypropoxy) phenyl]Naphthoporphin (I)2)；
5, 15-bis [3, 5-bis (carboxybutoxy) phenyl]Naphthoporphin (I)3)；
5, 15-bis [3, 5-bis (carboxypentyloxy) phenyl]Naphthoporphin (I)4)；
5, 15-bis [3, 5-bis (carboxyhexyloxy) phenyl]Naphthoporphin (I)5)；
5, 15-bis [3, 5-bis (2-hydroxyethoxy) phenyl]Naphthoporphin (I)6)；
5, 15-bis [3, 5-bis (2- (2-hydroxyethoxy) ethoxy) phenyl]Naphthoporphin (I)7)；
5, 15-bis [3, 5-bis (2- (2- (2-hydroxyethoxy) ethoxy) phenyl]Naphthoporphin (I)8)；
5, 15-bis [3, 5-bis (2- (2- (2-hydroxyethoxy) ethoxy) phenyl]Naphthoporphin (I)9)；
5, 15-bis [3, 5-bis (2-methoxyethoxy) phenyl]Naphthoporphin (I)10)；
5, 15-bis [3, 5-bis (2- (2-methoxyethoxy) ethoxy) phenyl]Naphthoporphin (I)11)；
5, 15-bis [3, 5-bis (2- (2- (2-methoxyethoxy) ethoxy) phenyl]Naphthoporphin (I)12)；
5, 15-bis [3, 5-bis (2- (2- (2-methoxyethoxy) ethoxy) phenyl]Naphthoporphin (I)13)；
5, 15-bis [3, 5-bis (methoxy) -4-carboxymethoxyphenyl]Naphthoporphin (I)14)；
5, 15-bis [3, 5-bis (methoxy) -4-carboxypropoxyphenyl]Naphthoporphin (I)15)；
5, 15-bis [3, 5-bis (methoxy) -4-carboxybutoxyphenyl]Naphthoporphin (I)16)；
5, 15-bis [3, 5-bis (methoxy) -4-carboxypentyloxyphenyl]Naphthoporphin (I)17)；
5, 15-bis [3, 5-di (ethoxy) -4-carboxymethoxyphenyl]Naphthoporphin (I)18)；
5, 15-bis [3, 5-bis (ethoxy) -4-carboxypropoxyphenyl]Naphthoporphin (I)19)；
5, 15-bis [3, 5-bis (ethoxy) -4-carboxybutoxyphenyl]Naphthoporphin (I)20)；
5, 15-bis [3, 5-di (ethoxy) -4-carboxypentyloxyphenyl]Naphthoporphin (I)21)；
5, 15-bis [3, 5-bis (propoxy) -4-carboxymethoxyphenyl]Naphthoporphin (I)22)；
5, 15-bis [3, 5-bis (propoxy) -4-carboxypropoxyphenyl]Naphthoporphin (I)23)；
5, 15-bis [3, 5-bis (propoxy) -4-carboxybutoxyphenyl]Naphthoporphin (I)24)；
5, 15-bis [3, 5-di (propoxy) -4-carboxypentyloxyphenyl]Naphthoporphin (I)25)；
5, 15-bis [3, 5-di (tert-butyl) -4-carboxymethoxyphenyl]Naphthoporphin (I)26)；
5, 15-bis [3, 5-di (tert-butyl) -4-carboxypropoxyphenyl]Naphthoporphin (I)27)；
5, 15-bis [3, 5-di (tert-butyl) -4-carboxybutoxyphenyl]Naphthoporphin (I)28)；
5, 15-bis [3, 5-di (tert-butyl) -4-carboxypentyloxyphenyl]Naphthoporphin (I)29)；
5, 15-bis [3, 5-bis (methoxy) -4- (2-hydroxyethoxy) phenyl]Naphthoporphin (I)30)；
5, 15-bis [3, 5-bis (methoxy) -4- (2- (2-hydroxyethoxy) ethoxy) phenyl]Naphthoporphin (I)31)；
5, 15-bis [3, 5-bis (methoxy) -4- (2- (2- (2-hydroxyethoxy) ethoxy) phenyl]Naphthoporphin (I)32)；
5, 15-bis [3, 5-bis (methoxy) -4- (2-methoxyethoxy) phenyl]Naphthoporphin (I)33)；
5, 15-bis [3, 5-bis (methoxy) -4- (2- (2-methoxyethoxy)Radical) ethoxy) phenyl]Naphthoporphin (I)34)；
5, 15-bis [3, 5-bis (methoxy) -4- (2- (2- (2-methoxyethoxy) ethoxy) phenyl]Naphthoporphin (I)35)；
5, 15-bis [4- ((carboxymethyl) carbamoyl) phenyl]Naphthoporphin (I)36)；
5, 15-bis [4- ((1-carboxyethyl) carbamoyl) phenyl]Naphthoporphin (I)37)；
5, 15-bis [4- ((2-carboxyethyl) carbamoyl) phenyl]Naphthoporphin (I)38)；
5, 15-bis [4- ((3-carboxypropyl) carbamoyl) phenyl]Naphthoporphin (I)39)；
5, 15-bis [4- ((4-carboxybutyl) carbamoyl) phenyl]Naphthoporphin (I)40)；
5, 15-bis [4- ((5-carboxypentyl) carbamoyl) phenyl]Naphthoporphin (I)41)；
5, 15-bis [4- (((dicarboxy) methyl) carbamoyl) phenyl]Naphthoporphin (I)42)；
5, 15-bis [4- ((N- (1-carboxy-2-phenyl) ethyl) carbamoyl) phenyl]Naphthoporphin (I)43)；
5, 15-bis [4- ((N- (1, 2-dicarboxy) ethyl) carbamoyl) phenyl]Naphthoporphin (I)44)；
5, 15-bis [4- ((N- (1, 3-dicarboxy) propyl) carbamoyl) phenyl]Naphthoporphin (I)45)；
5, 15-bis [4- ((N- (1-carboxy-2-hydroxy) ethyl) carbamoyl) phenyl]Naphthoporphin (I)46)；
5, 15-bis [ N, N-bis (carboxymethyl) carbamoyl) phenyl]Naphthoporphin (I)47)；
5, 15-bis [ N, N-bis (2-carboxyethyl) carbamoyl) phenyl]Naphthoporphin (I)48)；
5, 15-bis [ N, N-bis (3-carboxypropyl) carbamoyl) phenyl]Naphthoporphin (I)49)；
5, 15-bis [ N, N-bis (4-carboxybutyl) carbamoyl) phenyl]Naphthoporphin (I)50)；
5, 15-bis [ N, N-Bis (5-carboxypentyl) carbamoyl) phenyl]Naphthoporphin (I)51)。
The invention prepares the novel intermediate diphenyl naphthoporphin derivative (I) for the first time, and has novelty.
The intermediate diphenyl naphthoporphin derivative (I) has the advantages of high photodynamic activity, small skin phototoxic side effect, stable property, good hydrophilicity, difficult aggregation and easy preparation of an injection, and also has the advantages of strong absorption of multiple wavelengths of light in multiple wave bands so as to develop personalized treatment of diseases such as tumors and the like, overcomes the defects of complex composition, unstable structure, difficult preparation, high cost, easy aggregation, poor hydrophilicity, large skin phototoxic side effect, difficult development of personalized treatment and the like in the conventional photosensitive compound and photosensitive medicine, and has substantial progress and creativity.
The intermediate diphenyl naphthoporphin derivative (I) has obvious photodynamic activity and small skin toxic and side effects, can be used as a personalized photodynamic diagnosis and treatment medicine for diseases such as tumors, macular degeneration of retina, actinic keratosis, port nevus flammeus, condyloma acuminatum and the like, and has practicability.
The specific preparation scheme is as follows:
the invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.
The general preparation method comprises the following steps:
R3and R4R is an ester-or acetyl-containing protecting group1And R2And (3) derivatives.
In the step (i), the compound II and bis [4, 9-dihydro-2H-benzo [ f ] isoindol-1-yl ] methane are dissolved in dichloromethane, a catalytic amount of trifluoroacetic acid is dropwise added under the protection of nitrogen, the mixture is stirred and reacted at room temperature, TLC monitors the disappearance of the raw materials to generate products, dichlorodicyano benzoquinone and triethylamine are added, the reaction is continuously stirred, and TLC monitors the complete oxidation. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography to give a dark green powder (III).
In step (ii), the compound (III) is dissolved in a mixed solution of tetrahydrofuran and methanol, an aqueous solution of potassium hydroxide is added, and the reaction mixture is refluxed and stirred under a nitrogen atmosphere. The reaction solution was cooled to room temperature, the organic solvent was evaporated under reduced pressure, and the residue was diluted with water and adjusted to pH 5-6 with dilute hydrochloric acid. The filter cake was collected by filtration under reduced pressure and dried under vacuum to give a dark green solid (I).
[ example 1]
5, 15-bis [3, 5-bis (carboxymethoxy) phenyl]Naphthoporphin (I)1)
II (0.31g,1.71mmol) and bis (4, 9-dihydro-2H-benzo [ f)]Isoindol-1-yl) methane (0.6g,1.71mmol) was dissolved in dichloromethane (150mL), trifluoroacetic acid (39.0mg,0.34mmol) was added dropwise under nitrogen, and the reaction was stirred at room temperature for 1 hour. DDQ (0.582g,2.57mmol) was added, the reaction was stirred for 1 hour, concentrated to dryness and then refluxed with toluene (30mL) and DDQ (0.77g,3.42mmol) for 0.5 hour. The solvent was evaporated under reduced pressure and the resulting residue was purified by column chromatography (eluent dichloromethane) to give blackish green powder iii (0.71g, 64.8%).1H NMR(600MHz,CDCl3)δ:10.82(s,2H),9.79(s,2H),8.78-8.11(m,8H),7.71(s,12H),7.46(d,J＝2.3Hz,4H),4.81(s,8H),4.08(q,J＝7.3Hz,8H),1.07(t,J＝7.1Hz,12H).HRMS(MALDI-TOF):(m/z)calced for C80H62N4O121270.4359；found,1270.4410.
Naphthoporphin III (0.3g,0.023mmol) was dissolved in THF/MeOH (20mL, V)THF/VMeOH1/1), followed by addition of KOH solution (4mol/L,8mL) and heating of the reaction mixture under reflux for 3 h under nitrogen atmosphereWhen the reaction was complete, TLC monitored the completion of the reaction, the organic solvent was removed under reduced pressure, water (30mL) was added and the pH was adjusted to 5-6 with dilute hydrochloric acid solution (2 mol/L). Filtering, collecting filter cake, and vacuum drying the filter cake to obtain dark green solid I1(0.263g，96.2％)。
1H NMR(600MHz,Pyridine-d5)δ:11.55(s,2H),10.53(s,4H),8.56(s,8H),8.23(s,2H),8.15(s,4H),7.79(s,4H),7.62(s,4H),5.35(s,8H),-0.11(s,2H).HRMS(MALDI-TOF):(m/z)calced for C72H46N4O121158.3107；found,1158.3150.
[ example 2]
5, 15-bis [3, 5-bis (carboxypropoxy) phenyl]Naphthoporphin (I)2)
Reference Compound I1The synthesis method of (1) prepares the compound I2。
1H NMR(600MHz,DMSO-d6)δ:8.63(d,J＝7.9Hz,8H),8.03(s,8H),7.89-7.77(m,8H),7.71-7.54(m,16H),4.45(t,J＝3.8Hz,8H),3.64(t,J＝6.4Hz,8H),2.10-1.99(m,8H),1.87–1.76(m,8H).13C NMR(151MHz,DMSO-d6)δ:161.34,141.58,137.25,132.64,132.41,130.86,129.55,128.05,123.90,116.62,112.75,68.75,61.16,55.44,29.69,26.13.HRMS(MALDI-TOF):(m/z)calced for C92H78N4O81366.5814；found,1366.5791.
[ example 3]
5, 15-bis [3, 5-bis (2-hydroxyethoxy) phenyl]Naphthoporphin (I)6)
Reference Compound V1The synthesis method of (1) prepares the compound I6。1H NMR(600MHz,DMSO-d6)δ:9.23-7.62(d,J＝542.1Hz,23H),7.55(d,J＝20.2Hz,8H),4.30(t,J＝5.0Hz,8H),3.84(t,J＝5.0Hz,8H).13CNMR(151MHz,DMSO-d6)δ:161.41,133.72,129.11,129.02,128.85,126.46,123.87,121.83,111.95,103.04,75.26,60.80.HRMS(MALDI-TOF):(m/z)calced for C72H54N4O81102.3936；found,1102.3950.
[ example 4]
5, 15-bis [3, 5-bis (2- (2-hydroxyethoxy) ethoxy) phenyl]Naphthoporphin (I)7)
Reference Compound V1The synthesis method of (1) prepares the compound I7。1H NMR(600MHz,DMSO-d6)δ:8.48(s,12H),7.76(s,12H),7.52(d,J＝19.2Hz,8H),4.42(t,J＝6.2Hz,8H),3.87(t,J＝4.6Hz,8H),3.52(s,16H).13C NMR(151MHz,DMSO-d6)δ:161.43,133.79,129.16,129.15,128.88,126.50,124.00,122.03,112.15,103.04,73.17,69.59,68.62,60.85.HRMS(MALDI-TOF):(m/z)calced for C80H70N4O121278.4985；found,1278.5006.
[ example 5]
5, 15-bis [3, 5-bis (2- (2-methoxyethoxy) ethoxy) phenyl]Naphthoporphin (I)11)
Reference Compound V1The synthesis method of (1) prepares the compound I11。1H NMR(600MHz,CDCl3)δ:10.81(s,2H),9.80(s,4H),8.38(s,8H),7.78(s,12H),7.46(s,6H),7.26(s,overlap with CDCl3,2H)4.37(s,8H),3.94(s,8H),3.71(t,J＝4.4Hz,8H),3.54(t,J＝4.4Hz,8H),3.31(s,12H).13C NMR(151MHz,CDCl3)δ:161.38,140.32,139.71,139.48,133.55,133.19,130.88,130.03,129.85,129.01,128.01,127.45,126.51,123.24,113.69,112,98,104.34,89.69,71.69,70.41,69.56,67.96,58.76.HRMS(MALDI-TOF):(m/z)calced for C84H78N4O121334.5611；found,1334.5603.
[ example 6]
5, 15-bis [3, 5-bis (2- (2- (2-methoxyethoxy) ethoxy) phenyl]Naphthoporphin (I)12)
Reference Compound V1The synthesis method of (1) prepares the compound I12。
1H NMR(600MHz,CDCl3)δ:10.71(s,2H overlap with TFA),9.84(s,4H),8.63-8.48(m,4H),8.49-8.29(m,4H),8.23-8.05(m,4H),7.97-7.68(m,13H),7.38(s,2H),4.38(s,8H),3.98(s,8H),3.78(s,8H),3.68(s,8H),3.65(s,8H),3.59(s,9H),3.38(s,12H).13C NMR(151MHz,CDCl3)δ:161.31,140.43,140.18,139.65,133.58,133.21,130.87,130.10,129.80,129.01,128.09,127.52,126.54,123.33,113.84,112.92,104.25,89.51,71.50,70.52,70.16,69.80,69.55,67.73,58.52.HRMS(MALDI-TOF):(m/z)calced for C92H94N4O161510.6659；found,1510.6708.
[ example 7]
5, 15-bis [3, 5-bis (methoxy) -4-carboxypropoxyphenyl]Naphthoporphin (I)15)
Reference Compound I1The synthesis method of (1) prepares the compound I15。
1H NMR(600MHz,CDCl3)δ:10.82(s,2H),9.81(s,4H),8.52(d,J＝8.2Hz,4H),8.32(s,4H),8.08(d,J＝8.3Hz,4H),7.86(t,J＝7.4Hz,4H),7.82-7.75(m,8H),4.63(t,J＝5.8Hz,4H),3.93(s,12H),3.09(t,J＝7.3Hz,4H),2.53-2.41(m,4H)，1.47(s,4H).13C NMR(151MHz,CDCl3)δ:180.05,155.11,140.13,139.53,138.93,134.65,133.67,133.34,130.84,130.00,129.14,128.28,127.82,126.35,123.46,113.87,111.36,89.73,73.08,56.66,30.65,25.23.HRMS(MALDI-TOF):(m/z)calced for C76H58N4O101186.4147；found,1186.4199.
[ example 8]
5, 15-bis [3, 5-bis (methoxy) -4-carboxybutoxyphenyl]Naphthoporphin (I)16)
Reference Compound I1Synthetic method of (2) preparation of Compound I16。
1H NMR(600MHz,CDCl3)δ:10.83(s,2H),9.82(s,4H),8.53(d,J＝8.2Hz,4H),8.33(s,4H),8.08(d,J＝8.2Hz,4H),7.87(t,J＝7.2Hz,4H),7.80(s,8H),4.60(d,J＝5.7Hz,4H),3.93(s,12H),2.84–2.73(m,4H),2.28–2.19(m,8H),1.44(s,4H).13C NMR(151MHz,CDCl3)δ:180.67,155.28,140.33,139.70,139.26,134.75,133.84,133.51,130.98,130.16,129.30,128.45,127.96,126.56,123.63,111.36,56.84,33.84,29.61,21.64.HRMS(MALDI-TOF):(m/z)calced for C78H62N4O101214.4461；found,1214.4460.
[ example 9]
5, 15-bis [3, 5-di (tert-butyl) -4-carboxypropoxyphenyl]Naphthoporphin (I)27)
Reference Compound I1The synthesis method of (1) prepares the compound I27。
1H NMR(600MHz,CDCl3)δ:10.84(s,2H),9.81(s,4H),8.54(s,4H),8.42(s,4H),8.23(m,4H),7.89(d,J＝26.4Hz,8H),7.77(s,4H),4.41(t,J＝7.1Hz,4H),2.76(t,J＝7.3Hz,4H),2.31(m,4H),2.15(m,4H),1.61(s,36H).13C NMR(151MHz,CDCl3)δ:176.02,151.27,139.86,139.35,138.72,136.37,134.63,133.24,130.94,130.00,129.54,129.07,128.49,127.12,124.94,114.91,112.36,90.12,72.95,57.86,35.52,30.65,29.87,25.23.HRMS(MALDI-TOF):(m/z)calced for C88H82N4O61290.6170；found,1290.6229.
[ example 10]
5, 15-bis [3, 5-bis (methoxy) -4- (2- (2-hydroxyethoxy) ethoxy) phenyl]Naphthoporphin (I)31)
Reference Compound V1The synthesis method of (1) prepares the compound I31。
1H NMR(600MHz,CDCl3)δ:10.82(s,2H),9.82(s,4H),8.54(d,J＝8.3Hz,4H),8.31(s,4H),8.09(d,J＝8.3Hz,4H),7.87(t,J＝7.3Hz,4H),7.80(d,J＝8.5Hz,8H),4.77–4.72(m,4H),4.28–4.23(m,4H),4.09–4.05(m,4H),4.02–3.98(m,4H),3.94(s,12H).13C NMR(151MHz,CDCl3)δ:154.81,140.12,139.41,139.00,134.72,133.41,131.69,130.79,130.02,129.13,129.07,128.17,127.71,126.20,123.35,113.85,111.49,89.70.HRMS(MALDI-TOF):(m/z)calced for C76H62N4O101190.4460；found,1190.4464.
[ example 11]
5, 15-bis [3, 5-bis (methoxy) -4- (2- (2-methoxyethoxy) ethoxy) phenyl]Naphthoporphin (I)34)
Reference Compound V1The synthesis method of (1) prepares the compound I34。
1H NMR(600MHz,CDCl3)δ:10.83(s,2H),9.81(s,4H),8.52(s,4H),8.32(s,4H),8.07(s,4H),7.77(s,12H),4.74(t,J＝4.9Hz,4H),4.24(t,J＝4.9Hz,4H),4.03–3.98(m,4H),3.93(s,12H),3.81–3.76(m,4H),3.50(s,6H).13C NMR(151MHz,CDCl3)δ:155.17,140.27,139.63,139.46,134.75,133.74,133.39,131.05,130.20,129.21,128.26,127.80,126.47,125.62,123.44,114.09,111.50,89.86,72.14,70.89,70.69,59.08,56.81.HRMS(MALDI-TOF):(m/z)calced for C78H66N4O101218.4773；found,1218.4738.
[ example 12]
5, 15-bis [4- ((3-carboxypropyl) carbamoyl) phenyl]Naphthoporphin (I)39)
Reference Compound I1Synthetic method of (2) preparation of Compound I39。
1HNMR(600MHz,Pyridine-d5)δ:10.77-10.54(m,2H),10.02(d,J＝4.9Hz,4H),8.97-8.91(m,4H),8.52(d,J＝9.0Hz,4H),8.18(d,J＝8.7Hz,3H),7.99(s,4H),7.96(s,8H),7.78(t,J＝7.7Hz,4H),7.65(d,J＝7.3Hz,4H),4.29-4.04(m,4H),2.94(t,J＝7.9Hz,4H),2.53(t,J＝7.6Hz,4H),-1.11(s,2H).HRMS(MALDI-TOF):(m/z)calced for C74H52N6O61120.3948；found,1120.39467.
[ example 13]
5, 15-bis [4- ((N- (1, 3-dicarboxy) propyl) carbamoyl) phenyl]Naphthoporphin (I)45)
Reference Compound I1The synthesis method of (1) prepares the compound I45。1H NMR(600MHz,Pyridine-d5)δ:10.20(d,J＝8.0Hz,2H),10.10(s,2H),9.78(s,4H),8.72(s,4H),8.55(d,J＝8.2Hz,4H),8.03(d,J＝8.2Hz,4H),7.89(d,J＝4.5Hz,4H),7.86(s,4H),7.84(s,2H),7.72(t,J＝7.3Hz,4H),5.87(td,J＝8.7,5.2Hz,2H),3.27(t,J＝7.4Hz,4H),3.14(dt,J＝12.9,7.2Hz,2H),2.94(dq,J＝14.1,7.6Hz,2H),1.75(s,2H).13C NMR(151MHz,Pyridine-d5)δ:175.79,175.35,168.19,144.41,140.47,138.79,136.70,136.22,134.13,132.86,132.54,132.10,130.14,128.99,126.52,126.27,123.60,122.94,120.26,113.25,91.00,54.07,32.00,28.18.HRMS(MALDI-TOF):(m/z)calced for C76H52N6O101208.3745；found,1208.3738.
[ example 14]
5, 15-bis [ N, N-bis (carboxymethyl) carbamoyl) phenyl]Naphthoporphin (I)47)
Reference Compound I1Synthetic method of (2) preparation of Compound I47.
1H NMR(600MHz,CDCl3)δ:10.81(s,2H),9.80(s,4H),8.69(d,J＝7.6Hz,4H),8.51(d,J＝8.1Hz,4H),8.22(d,J＝7.5Hz,4H),8.08(s,4H),7.98(d,J＝8.4Hz,4H),7.86(s,4H),7.77(d,J＝8.8Hz,4H),4.77(s,4H),4.70(s,5H).13C NMR(125MHz,CDCl3)δ:175.99,150.26,141.81,133.09,132.78,132.05,131.65,130.99,129.44,128.96,128.14,126.82,125.09,124.63,121.18,120.25,118.64,114.00,94.19,48.81,31.03,21.06.HRMS(MALDI-TOF):(m/z)calced for C74H48N6O101180.3432；found,1180.3461.
[ example 15]
5, 15-bis [ N, N-bis (3-carboxypropyl) carbamoyl) phenyl]Naphthoporphin (I)49)
Reference Compound I1The synthesis method of (1) prepares the compound I49。
1H NMR(600MHz,CDCl3)δ:10.56(s,2H),9.77(s,2H),8.65-8.42(m,6H),8.13(d,J＝10.3Hz,2H),8.07-7.78(m,15H),7.74(t,J＝7.4Hz,3H),7.58(t,J＝8.0Hz,2H),7.32(t,J＝7.2Hz,2H),7.21(d,J＝7.3Hz,2H),7.00(d,J＝8.0Hz,2H),3.95(t,J＝6.5Hz,8H),2.67(t,J＝6.1Hz,8H),2.32-2.25(m,8H).HRMS(MALDI-TOF):(m/z)calced for C80H64N6O81236.4786；found,1236.4771.
[ example 16]
Measurement of ultraviolet-visible light absorption spectrum
Representative Compounds I1Dissolving in dimethyl sulfoxide (DMSO) to prepare a solution to be detected, placing 3mL of the solution to be detected in a quartz cuvette, and detecting the absorption spectrum of 300-800nm under an ultraviolet-visible spectrophotometer. The experimental results show that the compound I1Has absorption peaks at 417nm, 445nm, 475nm, 655nm, 713nm and 730nm, and corresponding molar absorptivity epsilon of 8.84, 10.35, 20.31, 2.47, 18.07 and 11.70 × 104L·mol-1·cm-1Compared with the hymporfin, the maximum absorption wavelength is red-shifted by nearly 100nm and the absorption intensity is enhanced, which shows that the light source with the wavelength corresponding to the absorption peak of the newly synthesized intermediate diphenyl naphthoporphin derivative can penetrate deeper tissues and is beneficial to better exerting the photodynamic treatment effect; and the newly synthesized compound has a plurality of absorption peaks at the position of 450-800nm, and a laser light source with proper wavelength can be selected for photodynamic therapy according to the actual volume size and the position of focuses such as tumors and the like, so that personalized therapy is realized.
[ example 17]
Experiment for measuring anti-tumor proliferation of photosensitizer by MTT method
Test cells:
human esophageal cancer cell Eca-109.
Light source:
XD-730AB laser; model SD2490 laser power measuring instrument.
Test compounds:
5, 15-bis [3, 5-bis (carboxymethoxy) phenyl]Naphthoporphin (I)1) 5, 15-bis [3, 5-bis (carboxypropoxy) phenyl]Naphthoporphin (I)2) 5, 15-bis [3, 5-bis (2-hydroxyethoxy) phenyl]Naphthoporphin (I)6) 5, 15-bis [3, 5-bis (2- (2-methoxyethoxy) ethoxy) phenyl]Naphthoporphin (I)11) 5, 15-two[3, 5-bis (methoxy) -4-carboxypropoxyphenyl]Naphthoporphin (I)15) 5, 15-bis [3, 5-bis (methoxy) -4-carboxybutoxyphenyl]Naphthoporphin (I)16) 5, 15-bis [3, 5-bis (methoxy) -4- (2- (2-methoxyethoxy) ethoxy) phenyl]Naphthoporphin (I)34) 5, 15-bis [4- ((3-carboxypropyl) carbamoyl) phenyl]Naphthoporphin (I)39) 5, 15-bis [4- ((N- (1, 3-dicarboxy) propyl) carbamoyl) phenyl]Naphthoporphin (I)45) 5, 15-bis [ N, N-bis (carboxymethyl) carbamoyl) phenyl]Naphthoporphin (I)47) 5, 15-bis [ N, N-bis (3-carboxypropyl) carbamoyl) phenyl]Naphthoporphin (I)49) (ii) a And 5, 15-bis [ (3, 5-di-tert-butyl) phenyl ] s]Naphthoporphin (control compound 1), and promoporphine (control drug).
Photodynamic anti-tumor cell proliferation effect experiment:
collecting cells in logarithmic growth phase, resuspending into cell suspension with complete medium, inoculating into 96-well plate, 100 μ L per well, placing at 37 deg.C with 5% CO2Culturing in an incubator, and adding a test compound after 24 hours; after further culturing for 24 hours, light treatment was carried out (wavelength: 730nm, light dose: 8J/cm)2) Adding culture medium for continuous culture; MTT assay was performed after 24 hours. Adding 20 μ L of 5mg/mL MTT into each well 4 hr before detection, removing culture solution 4 hr later, adding 150 μ L DMSO into each well, and detecting OD with microplate reader570. The experiment was repeated three times. The experimental results are shown in table 1, and the results show that the tested intermediate diphenyl naphthoporphin compound has antiproliferative effect on human esophageal cancer cells, and the photodynamic activity of the compound is obviously superior to that of the control compound 1 and the control drug, i.e. the hamporfin.
TABLE 1 inhibition of Eca-109 human esophageal carcinoma cell proliferation by novel compounds
P <0.05, P <0.01, P <0.001, compared to the control drug, hamporfin;
in comparison with the control compound 1, the compound of formula I,ΔP<0.05，ΔΔP<0.01，ΔΔΔP<0.001。
[ example 18]
Evaluation experiment of phototoxicity of photosensitizer to mouse skin
The test animals were: kunming mice, 5 weeks old (22. + -.2 g).
Light source: 230 V.E 27/ES Oseland simulated solar light; YK-PDT-300 type power density meter.
The tested medicine is as follows:
5, 15-bis [3, 5-bis (carboxymethoxy) phenyl]Naphthoporphin (I)1) 5, 15-bis [3, 5-bis (carboxypropoxy) phenyl]Naphthoporphin (I)2) 5, 15-bis [3, 5-bis (2-hydroxyethoxy) phenyl]Naphthoporphin (I)6) 5, 15-bis [3, 5-bis (methoxy) -4- (2- (2-methoxyethoxy) ethoxy) phenyl]Naphthoporphin (I)34) 5, 15-bis [4- ((3-carboxypropyl) carbamoyl) phenyl]Naphthoporphin (I)39) 5, 15-bis [4- ((N- (1, 3-dicarboxy) propyl) carbamoyl) phenyl]Naphthoporphin (I)45) 5, 15-bis [ N, N-bis (carboxymethyl) carbamoyl) phenyl]Naphthoporphin (I)47) 5, 15-bis [ N, N-bis (3-carboxypropyl) carbamoyl) phenyl]Naphthoporphin (I)49) (ii) a And photosensitizer II, promoporphine (control drug).
Mouse model skin phototoxicity evaluation experiment:
mice were randomly grouped into groups of 6 mice, each half male and female, and the back hair of the mice was shaved 24 hours before the experiment. The mice were anesthetized by intraperitoneal injection with 5% chloral hydrate and fixed in the prone position, the test drugs were administered to each group for 1 time of tail vein, the injection dose was 10mg/kg, and 4 hours after administration, the mice were irradiated by simulated sunlight at 45cm position under the light source for 10 minutes, and the illumination intensity was 10mW/cm2. Mice were strictly protected from light after irradiation, and the physiological condition of the animals was observed and recorded after irradiation. After 24 hours, the mice were sacrificed by cervical dislocation, and the back skin was taken with an 8 mm punch, weighed with an electronic analytical balance, and the back skin index was calculated, wherein the back skin index is back skin weight (mg)/body weight (g) × 100. The smaller difference between the index of the back skin of the test drug group and the index of the back skin of the control group indicates that the skin is less phototoxic. The results are shown in Table 2 and show that mice treated with naphthoporphyrin compounds were dorsalThe skin indexes are all significantly lower than those of the photosensitizer II and the hamporfin treatment group, which shows that the tested compounds have lower phototoxic side effect.
Table 2 calculation table of dorsal cortex index of compound to mouse back illumination zone
P <0.05, P <0.01, P <0.001 compared to the blank;
compared with the control drug of the photosensitizer II,ΔP<0.05，ΔΔP<0.01，ΔΔΔP<0.001；
compared with the reference drug, the hamporfin,#P<0.05，##P<0.01，###P<0.001。
Claims (5)
1. a novel intermediate diphenyl-substituted naphthoporphin derivative, characterized in that the photosensitizer is a 5, 15-di (substituted phenyl) naphthoporphin derivative (I):
wherein:
a and Y are the same or different and are independently CH2C-O, C, N or O; r1And R2The same or different and at least one contains a polar group (e.g., carboxyl, hydroxyl, ether or amino), and the other can be independently hydrogen, alkyl, alkylcarboxylic acid, alkyl alcohol, N-or O-hetero-containing alkyl alcohol, N-or O-hetero-containing alkylcarboxylic acid, carbonyl-containing alkyl or alkyl alcohol or alkylcarboxylic acid, amide bond-containing alkyl or alkyl alcohol or alkylcarboxylic acid, or both carbonyl and amide bond-containing alkylcarboxylic acid.
2. A compound of formula (I), R according to claim 11And R2Identical or different and at least one contains polar groups (e.g. carboxyl, hydroxyl)An alkyl, ether or amino group), wherein:
the nonpolar group being-H, - (CH)2)mCH3,-(CH2)mCH(CH3)2,-(CH2)mC(CH3)3,-(CH2)mN[(CH2)nCH3]2,-(CH2)mO(CH2)nCH3,-(CH2)mO(CH2)nCH(CH3)2,-(CH2)mO(CH2)nC(CH3)3,-(CH2)m(OCH2CH2)qCH3,-(CH2)mCO(CH2)nCH3,-(CH2)mCO(CH2)nCH(CH3)2,-(CH2)mCO(CH2)nC(CH3)3,-(CH2)mCONH(CH2)pCH3,-(CH2)mCONH(CH2)pCH(CH3)2Or- (CH)2)mCONH(CH2)pC(CH3)3,m＝0-7,n＝0-7,p＝1-7,q＝1-5；
The polar group is- (CH)2)mCOOH,-(CH2)mCH(CH3)COOH,-(CH2)mOH,-(CH2)nCH(CH3)OH,-(CH2)m(OCH2CH2)qOCH3,-(CH2)mC6H4OH,-(CH2)mN[(CH2)nCOOH]2,-(CH2)mN[(CH2)pOH]2,-(CH2)mO(CH2)nCOOH,-(CH2)mO(CH2)pOH,-(CH2)m(OCH2CH2)qOH,-(CH2)mCO(CH2)nCOOH,-(CH2)mCO(CH2)nOH or an amino acid derivative, m-1-7, n-1-7, p-2-7, q-1-5.
3. The amino acid derivative according to claim 2, which is:
-(CH2)mCONH(CH2)nCOOH,-(CH2)mCONHCH(CH3)COOH,
-(CH2)mCONH(CH2)nCO(CH2)pCOOH,-(CH2)mCONHCH[CH(CH3)2]COOH,
-(CH2)mCONHCH[CH2CH(CH3)2]COOH,-(CH2)mCONHCH[CH(CH3)CH2CH3]COOH,
-(CH2)mCONHCH(CH2C6H5)COOH,-(CH2)mCON[(CH2)nCOOH]2,
-(CH2)mCONHCH(COOH)CH2COOH,m＝1-7,n＝1＝7,p＝1-4。
4. the novel class of mesodiphenyl-substituted naphthoporphin compounds and their amino acid condensates as claimed in claim 1, wherein said compounds include the following:
5, 15-bis [3, 5-bis (carboxymethoxy) phenyl]Naphthoporphin (I)1)；
5, 15-bis [3, 5-bis (carboxypropoxy) phenyl]Naphthoporphin (I)2)；
5, 15-bis [3, 5-bis (carboxybutoxy) phenyl]Naphthoporphin (I)3)；
5, 15-bis [3, 5-bis (carboxypentyloxy) phenyl]Naphthoporphin (I)4)；
5, 15-bis [3, 5-bis (carboxyhexyloxy) phenyl]Naphthoporphin (I)5)；
5, 15-bis [3, 5-bis (2-hydroxyethoxy) phenyl]Naphthoporphin (I)6)；
5, 15-bis [3, 5-bis (2- (2-hydroxy) s)Ethoxy) phenyl]Naphthoporphin (I)7)；
5, 15-bis [3, 5-bis (2- (2- (2-hydroxyethoxy) ethoxy) phenyl]Naphthoporphin (I)8)；
5, 15-bis [3, 5-bis (2- (2- (2-hydroxyethoxy) ethoxy) phenyl]Naphthoporphin (I)9)；
5, 15-bis [3, 5-bis (2-methoxyethoxy) phenyl]Naphthoporphin (I)10)；
5, 15-bis [3, 5-bis (2- (2-methoxyethoxy) ethoxy) phenyl]Naphthoporphin (I)11)；
5, 15-bis [3, 5-bis (2- (2- (2-methoxyethoxy) ethoxy) phenyl]Naphthoporphin (I)12)；
5, 15-bis [3, 5-bis (2- (2- (2-methoxyethoxy) ethoxy) phenyl]Naphthoporphin (I)13)；
5, 15-bis [3, 5-bis (methoxy) -4-carboxymethoxyphenyl]Naphthoporphin (I)14)；
5, 15-bis [3, 5-bis (methoxy) -4-carboxypropoxyphenyl]Naphthoporphin (I)15)；
5, 15-bis [3, 5-bis (methoxy) -4-carboxybutoxyphenyl]Naphthoporphin (I)16)；
5, 15-bis [3, 5-bis (methoxy) -4-carboxypentyloxyphenyl]Naphthoporphin (I)17)；
5, 15-bis [3, 5-di (ethoxy) -4-carboxymethoxyphenyl]Naphthoporphin (I)18)；
5, 15-bis [3, 5-bis (ethoxy) -4-carboxypropoxyphenyl]Naphthoporphin (I)19)；
5, 15-bis [3, 5-bis (ethoxy) -4-carboxybutoxyphenyl]Naphthoporphin (I)20)；
5, 15-bis [3, 5-di (ethoxy) -4-carboxypentyloxyphenyl]Naphthoporphin (I)21)；
5, 15-bis [3, 5-bis (propoxy) -4-carboxymethoxyphenyl]Naphthoporphin (I)22)；
5, 15-bis [3, 5-bis (propoxy) -4-carboxypropoxyphenyl]Naphthoporphin (I)23)；
5, 15-bis [3, 5-bis (propoxy) -4-carboxybutoxyPhenyl radical]Naphthoporphin (I)24)；
5, 15-bis [3, 5-di (propoxy) -4-carboxypentyloxyphenyl]Naphthoporphin (I)25)；
5, 15-bis [3, 5-di (tert-butyl) -4-carboxymethoxyphenyl]Naphthoporphin (I)26)；
5, 15-bis [3, 5-di (tert-butyl) -4-carboxypropoxyphenyl]Naphthoporphin (I)27)；
5, 15-bis [3, 5-di (tert-butyl) -4-carboxybutoxyphenyl]Naphthoporphin (I)28)；
5, 15-bis [3, 5-di (tert-butyl) -4-carboxypentyloxyphenyl]Naphthoporphin (I)29)；
5, 15-bis [3, 5-bis (methoxy) -4- (2-hydroxyethoxy) phenyl]Naphthoporphin (I)30)；
5, 15-bis [3, 5-bis (methoxy) -4- (2- (2-hydroxyethoxy) ethoxy) phenyl]Naphthoporphin (I)31)；
5, 15-bis [3, 5-bis (methoxy) -4- (2- (2- (2-hydroxyethoxy) ethoxy) phenyl]Naphthoporphin (I)32)；
5, 15-bis [3, 5-bis (methoxy) -4- (2-methoxyethoxy) phenyl]Naphthoporphin (I)33)；
5, 15-bis [3, 5-bis (methoxy) -4- (2- (2-methoxyethoxy) ethoxy) phenyl]Naphthoporphin (I)34)；
5, 15-bis [3, 5-bis (methoxy) -4- (2- (2- (2-methoxyethoxy) ethoxy) phenyl]Naphthoporphin (I)35)；
5, 15-bis [4- ((carboxymethyl) carbamoyl) phenyl]Naphthoporphin (I)36)；
5, 15-bis [4- ((1-carboxyethyl) carbamoyl) phenyl]Naphthoporphin (I)37)；
5, 15-bis [4- ((2-carboxyethyl) carbamoyl) phenyl]Naphthoporphin (I)38)；
5, 15-bis [4- ((3-carboxypropyl) carbamoyl) phenyl]Naphthoporphin (I)39)；
5, 15-bis [4- ((4-carboxybutyl) carbamoyl) phenyl]Naphthoporphin (I)40)；
5, 15-bis [4- ((5-carboxypentyl) carbamoyl) phenyl]Naphthoporphin (I)41)；
5, 15-bis [4- (((dicarboxy) methyl) carbamoyl) phenyl]Naphthoporphin (I)42)；
5, 15-bis [4- ((N- (1-carboxy-2-phenyl) ethyl) carbamoyl) phenyl]Naphthoporphin (I)43)；
5, 15-bis [4- ((N- (1, 2-dicarboxy) ethyl) carbamoyl) phenyl]Naphthoporphin (I)44)；
5, 15-bis [4- ((N- (1, 3-dicarboxy) propyl) carbamoyl) phenyl]Naphthoporphin (I)45)；
5, 15-bis [4- ((N- (1-carboxy-2-hydroxy) ethyl) carbamoyl) phenyl]Naphthoporphin (I)46)；
5, 15-bis [ N, N-bis (carboxymethyl) carbamoyl) phenyl]Naphthoporphin (I)47)；
5, 15-bis [ N, N-bis (2-carboxyethyl) carbamoyl) phenyl]Naphthoporphin (I)48)；
5, 15-bis [ N, N-bis (3-carboxypropyl) carbamoyl) phenyl]Naphthoporphin (I)49)；
5, 15-bis [ N, N-bis (4-carboxybutyl) carbamoyl) phenyl]Naphthoporphin (I)50)；
5, 15-bis [ N, N-bis (5-carboxypentyl) carbamoyl) phenyl]Naphthoporphin (I)51)。
5. The use of the novel intermediate diphenyl naphthoporphine and its amino acid condensate (I) according to claim 1, which are highly hydrophilic, less prone to aggregation and amenable to personalized therapy, in the preparation of photodynamic medicaments for the diagnosis and treatment of tumors, macular degeneration, actinic keratosis, nevus flammeus, condyloma acuminatum, etc.
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