CN117384173A - 一类中介四苯基取代四苯并卟吩衍生物及在医药领域的应用 - Google Patents
一类中介四苯基取代四苯并卟吩衍生物及在医药领域的应用 Download PDFInfo
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- CN117384173A CN117384173A CN202311375181.1A CN202311375181A CN117384173A CN 117384173 A CN117384173 A CN 117384173A CN 202311375181 A CN202311375181 A CN 202311375181A CN 117384173 A CN117384173 A CN 117384173A
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- Prior art keywords
- tetrabenzoporphine
- phenyl
- tetrakis
- oxo
- iii
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- 239000003814 drug Substances 0.000 title claims abstract description 17
- 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 title abstract description 6
- -1 (substituted) phenyl tetraphenylporphine Chemical class 0.000 claims abstract description 86
- 150000001875 compounds Chemical class 0.000 claims abstract description 74
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 12
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 8
- 206010059313 Anogenital warts Diseases 0.000 claims abstract description 4
- 206010027145 Melanocytic naevus Diseases 0.000 claims abstract description 4
- 208000007256 Nevus Diseases 0.000 claims abstract description 4
- 208000009621 actinic keratosis Diseases 0.000 claims abstract description 4
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 4
- 208000002780 macular degeneration Diseases 0.000 claims abstract description 4
- GZEFZLXJPGMRSP-UHFFFAOYSA-N 37,38,39,40-tetrazanonacyclo[28.6.1.13,10.112,19.121,28.04,9.013,18.022,27.031,36]tetraconta-1(37),2,4,6,8,10,12(39),13,15,17,19,21,23,25,27,29,31,33,35-nonadecaene Chemical compound c1ccc2c3cc4[nH]c(cc5nc(cc6[nH]c(cc(n3)c2c1)c1ccccc61)c1ccccc51)c1ccccc41 GZEFZLXJPGMRSP-UHFFFAOYSA-N 0.000 claims description 242
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 125
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 31
- 239000007983 Tris buffer Substances 0.000 claims description 24
- 125000006309 butyl amino group Chemical group 0.000 claims description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 9
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 8
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 6
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000005233 alkylalcohol group Chemical group 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 5
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 claims description 5
- PLSXAKJQEDOMBH-UHFFFAOYSA-N zinc(1+) Chemical compound [Zn+] PLSXAKJQEDOMBH-UHFFFAOYSA-N 0.000 claims description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 4
- YFNONBGXNFCTMM-UHFFFAOYSA-N butoxybenzene Chemical group CCCCOC1=CC=CC=C1 YFNONBGXNFCTMM-UHFFFAOYSA-N 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- OOGOFUKAJDPHDJ-UHFFFAOYSA-N 3-fluoro-4-hydroxy-5-methoxybenzaldehyde Chemical group COC1=CC(C=O)=CC(F)=C1O OOGOFUKAJDPHDJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 230000001404 mediated effect Effects 0.000 claims description 3
- YWMAPNNZOCSAPF-UHFFFAOYSA-N Nickel(1+) Chemical compound [Ni+] YWMAPNNZOCSAPF-UHFFFAOYSA-N 0.000 claims description 2
- WTCRPVQWYABJEI-UHFFFAOYSA-N [Pt+] Chemical compound [Pt+] WTCRPVQWYABJEI-UHFFFAOYSA-N 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 229910052763 palladium Inorganic materials 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
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 abstract description 10
- 206010030155 Oesophageal carcinoma Diseases 0.000 abstract description 10
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- 238000010521 absorption reaction Methods 0.000 abstract description 9
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- 238000002428 photodynamic therapy Methods 0.000 abstract description 5
- 230000009982 effect on human Effects 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 4
- 241000041303 Trigonostigma heteromorpha Species 0.000 abstract description 3
- 238000000034 method Methods 0.000 description 30
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- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 10
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
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- 239000007787 solid Substances 0.000 description 5
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 229910052802 copper Inorganic materials 0.000 description 4
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- 239000000203 mixture Substances 0.000 description 4
- JZRYQZJSTWVBBD-UHFFFAOYSA-N pentaporphyrin i Chemical compound N1C(C=C2NC(=CC3=NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 JZRYQZJSTWVBBD-UHFFFAOYSA-N 0.000 description 4
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- 150000003722 vitamin derivatives Chemical class 0.000 description 4
- 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 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
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- MHIITNFQDPFSES-UHFFFAOYSA-N 25,26,27,28-tetrazahexacyclo[16.6.1.13,6.18,11.113,16.019,24]octacosa-1(25),2,4,6,8(27),9,11,13,15,17,19,21,23-tridecaene Chemical compound N1C(C=C2C3=CC=CC=C3C(C=C3NC(=C4)C=C3)=N2)=CC=C1C=C1C=CC4=N1 MHIITNFQDPFSES-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-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
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 206010034960 Photophobia Diseases 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
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- JSHOAZBZHHEGHI-UHFFFAOYSA-N 4,5,6,7-tetrahydro-2h-isoindole Chemical compound C1CCCC2=CNC=C21 JSHOAZBZHHEGHI-UHFFFAOYSA-N 0.000 description 1
- 229950010481 5-aminolevulinic acid hydrochloride Drugs 0.000 description 1
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
- KSFOVUSSGSKXFI-GAQDCDSVSA-N CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O Chemical compound CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O KSFOVUSSGSKXFI-GAQDCDSVSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
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- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
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- 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
- 150000004035 chlorins Chemical class 0.000 description 1
- NWFNSTOSIVLCJA-UHFFFAOYSA-L copper;diacetate;hydrate Chemical compound O.[Cu+2].CC([O-])=O.CC([O-])=O NWFNSTOSIVLCJA-UHFFFAOYSA-L 0.000 description 1
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- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- FEIOASZZURHTHB-UHFFFAOYSA-N methyl 4-formylbenzoate Chemical compound COC(=O)C1=CC=C(C=O)C=C1 FEIOASZZURHTHB-UHFFFAOYSA-N 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 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 1
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- 229940055695 pancreatin Drugs 0.000 description 1
- SEVSMVUOKAMPDO-UHFFFAOYSA-N para-Acetoxybenzaldehyde Natural products CC(=O)OC1=CC=C(C=O)C=C1 SEVSMVUOKAMPDO-UHFFFAOYSA-N 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 230000036211 photosensitivity Effects 0.000 description 1
- 231100000760 phototoxic Toxicity 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 229950003776 protoporphyrin Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
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- 239000011701 zinc Substances 0.000 description 1
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
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/18—Metal complexes
- C09K2211/185—Metal complexes of the platinum group, i.e. Os, Ir, Pt, Ru, Rh or Pd
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/18—Metal complexes
- C09K2211/187—Metal complexes of the iron group metals, i.e. Fe, Co or Ni
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/18—Metal complexes
- C09K2211/188—Metal complexes of other metals not provided for in one of the previous groups
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Ophthalmology & Optometry (AREA)
- Epidemiology (AREA)
- Biotechnology (AREA)
- Materials Engineering (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Dermatology (AREA)
Abstract
本发明涉及一类中介四苯基取代四苯并卟吩衍生物,其特征在于所述光敏剂5,10,15,20‑四(取代)苯基四苯并卟吩衍生物(I)和(II),和5‑(取代)苯基‑10,15,20‑三(取代)苯基四苯并卟吩衍生物(III):
Description
技术领域
本发明属于光敏药物与光动力疗法领域,特别涉及一类中介四苯基取代四苯并卟吩衍生物及其在医药领域的应用。
背景技术
光动力疗法是指处于基态的光敏剂接受相应波长的光源照射时,吸收光子能量,从基态变成单重激发态。处于单重激发态的光敏剂很不稳定,会迅速经过物理退激或化学退激释放能量而返回基态,产生活性氧自由基杀死肿瘤细胞(J. Photoch. Photobio. B., 1990, 6, 343)并破坏照射区域血管,阻断肿瘤细胞营养和氧供给(Jpn. J. Cancer Res. 2000, 91, 560)。
光敏剂是影响光动力治疗效能最为关键的因素。光敏素Ⅱ为第一个上市的光敏剂,已获多国政府的药监部门批准应用于临床,疗效显著,它是由多种血卟啉衍生物组成的混合物, 在体内滞留的时间长,避光时间需4周以上,限制了临床应用。维替泊芬为苯并卟吩单酸衍生物,最大吸收波长较为689 nm,穿透组织的能力约为光敏素Ⅱ的两倍,但其含有同分异构体,难以制备与分离纯化,影响其在光动力疗法中的应用。替莫泊芬属于二氢卟吩类衍生物,最大吸收波长为652 nm, 但其结构不稳定,需要在-20 oC保存。艾拉(5-氨基酮戊酸盐酸盐)在细胞内可以转化为原卟啉(IX)而起到光敏作用,但艾拉容易吸潮,不易存储。本团队研制的血卟啉单甲醚(海姆泊芬)是一对异构体的混合物,光敏周期短,但化合物不够稳定,在600-800 nm吸收弱,需要进一步改善。由于目前上市光敏药物尚存在一些缺点,因此需开发结构单一、稳定性好、不易自聚集(自组装)、在600-800 nm范围有较强吸收、溶解性较好、光动力活性高的光敏新药。
Neya等合成了卟吩(化合物A),其主要吸收波长在450-500 nm,作为光敏剂需要进一步改善(J. Heterocyclic Chem., 1993, 30, 549)。Vicente等合成了四苯并卟吩(化合物B),其结构特征是在卟吩的四个吡咯的β位并入四个苯环,该化合物在630-700 nm有较强的吸收光谱,与卟吩相比发生了明显红移,但因其结构规整,容易发生自聚集(自组装),溶解性差(Tetrahedron Lett., 1997, 38, 3639);Vinogradov等制备了5,10,15,20-四苯基四苯并卟吩(化合物C), 只对其进行了简单的光学测试,并未进行进一步的光动力作用研究(US 6362175)。Florian等制备了5,10,15,20-四[4-羧基苯基]四苯并卟吩(化合物D),该化合物仅被作为中间体用于合成含有氨基的产物,并未对该化合物D进行光动力性能的评价(Bioorg. Med. Chem. 2009, 17, 7647)。Ruppel等制备了5,10,15,20-四[4-取代基苯基]四苯并卟吩(化合物E),将其用于材料领域研究,该化合物含有酚羟基,结构不稳定(Chem. Eur. J. 2020, 26, 3287)。Giraud等制备了5-[(4-羧基)苯基]-10,15,20-三苯基四苯并卟吩 (化合物F),未对其光动力性能进行评价 (Heterocycles 2003, 61, 417)。
基于此,我们对化合物D、E和F进行了研究,发现D化合物极性太大、亲水性太强、光动力抗肿瘤活性低;化合物E结构不稳定;化合物F光动力抗肿瘤活性低。为克服化合物D、E和F的缺点,我们分别以化合物D、E和F为先导化合物,对其进行了结构修饰与改造,制备了三个系列新的中介位苯环上含取代基的四苯并卟吩衍生物(I、II、III)。
研究表明:经改造后的新的系列I化合物对人食管癌细胞均有光动力抑制作用,且显著优于对照化合物D;新的系列II化合物稳定性好,对人食管癌细胞均有光动力抑制作用且显著优于对照化合物E;新的系列III化合物对人食管癌细胞均有光动力抑制作用,且显著优于对照化合物F。新化合物的皮肤光毒性低于光敏素II处理组和对照化合物D、E和F处理组。与上市药物相比,新化合物结构单一且稳定、制备工艺较为简便,在450-760 nm之间有显著的多波长吸收,可用于不同体积或不同深度的肿瘤的治疗,从而实现治疗的个性化与精准化。因此,新研制的化合物具有发展为肿瘤、视网膜黄斑变性、光化性角化病、鲜红斑痣、尖锐湿疣等疾病的光动力药物前景。
发明内容
为克服现有光敏药物或光敏剂中存在的不同缺点,如组成复杂、结构不够稳定、制备困难、成本较高、在红光区吸收弱、有皮肤光毒作用等,本发明分别以化合物D、E和F为先导化合物,对其进行了结构修饰与改造,制备了三个系列新的中介位苯环上含取代基的四苯并卟吩衍生物(化合物系列 I、系列II、系列III)。研究表明这些新化合物结构单一且稳定、制备工艺较为简便、溶解性好、在450-750 nm之间有显著多波长吸收、光动力活性高、皮肤光毒作用弱。
本发明概述如下:
一类中介四苯基取代四苯并卟吩衍生物,其特征在于所述光敏剂5,10,15,20-四(取代)苯基四苯并卟吩衍生物 (I) 、 (II) 和5-(取代)苯基-10,15,20-三(取代)苯基四苯并卟吩衍生物 (III):
其中:
M为2H、Ni、Cu、Zn、Pd、Pt;
X、Y和Z相同或不同且独立地为CH2、C=O、O、NH、C(CH3)2;
R1为极性基团,R3和R4相同或不同且至少有一个含有极性基团, 极性基团如:羧基、羟基或氨基、烷基羧酸、烷基醇、含N或O原子的烷基醇或烷基羧酸、含羰基的烷基醇或烷基羧酸、含酰胺键的烷基醇或烷基羧酸,或同时含有羰基和酰胺键的烷基羧酸;
非极性基团为:氢、烷基、含N或O原子的烷基、含羰基的烷基、或含酰胺键的烷基;
R2为H、(CH2)nMe、O(CH2)nMe、F、Cl、Br、I、CF3、n = 0- 6;
R5为H、(CH2)nMe、O(CH2)nMe、F、Cl、Br、I、CF3、n = 0- 6。
式(I - III)中:
极性基团为:-(CH2)mCOOH, -(CH2)mCH(CH3)COOH, -(CH2)mOH, -(CH2)mCH(CH3)OH,-(CH2)m(OCH2CH2)pOH, -(CH2)mC6H4OH, -(CH2)mN[(CH2)nCOOH]2, -(CH2)mN[(CH2)qOH]2, -(CH2)mO(CH2)nCOOH, -(CH2)mO(CH2)qOH, -(CH2)mCO(CH2)nCOOH, -(CH2)mCO(CH2)nOH或氨基酸衍生物, m = 1 - 7, n = 1 - 7, p = 1 - 5, q = 2 – 7;
氨基酸衍生物为:-(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;
非极性基团为:-H, -(CH2)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)PCH3, -(CH2)mCO(CH2)nCH3, -(CH2)mCO(CH2)nCH(CH3)2, -(CH2)mCO(CH2)nC(CH3)3, -(CH2)mCONH(CH2)qCH3, -(CH2)mCONH(CH2)qCH(CH3)2或-(CH2)mCONH(CH2)qC(CH3)3,m = 0 - 7, n = 0 - 7, p = 1 - 5, q =0 -7。
所述的一类中介四苯基取代四苯并卟吩衍生物(I) 和 (II),其特征在于该类化合物中包括如下代表性化合物:
5,10,15,20-四[(4-羧甲基)苯基]四苯并卟吩 (I1);
5,10,15,20-四[(4-羧甲氧基)苯基]四苯并卟吩 (I2);
5,10,15,20-四[(4-羧丙氧基)苯基]四苯并卟吩 (I3);
5,10,15,20-四[(4-羧丁氧基)苯基]四苯并卟吩 (I4);
5,10,15,20-四[(4-羧戊氧基)苯基]四苯并卟吩 (I5);
5,10,15,20-四[(4-羧己氧基)苯基]四苯并卟吩 (I6);
5,10,15,20-四[(3-羧甲基)苯基]四苯并卟吩 (I7);
5,10,15,20-四[(3-羧甲氧基)苯基]四苯并卟吩 (I8);
5,10,15,20-四[(3-羧丙氧基)苯基]四苯并卟吩 (I9);
5,10,15,20-四[(3-羧丁氧基)苯基]四苯并卟吩 (I10);
5,10,15,20-四[(3-羧戊氧基)苯基]四苯并卟吩 (I11);
5,10,15,20-四[(3-羧己氧基)苯基]四苯并卟吩 (I12);
5,10,15,20-四[(2-羧甲氧基)苯基]四苯并卟吩 (I13);
5,10,15,20-四[(2-羧丙氧基)苯基]四苯并卟吩 (I14);
5,10,15,20-四[(4-羧甲氧基)苯基]四苯并卟吩铜 (I15);
5,10,15,20-四[(4-羧甲氧基)苯基]四苯并卟吩镍 (I16);
5,10,15,20-四[(4-羧甲氧基)苯基]四苯并卟吩锌 (I17);
5,10,15,20-四[(4-羧甲氧基)苯基]四苯并卟吩钯 (I18);
5,10,15,20-四[(4-羧甲氧基)苯基]四苯并卟吩铂 (I19);
5,10,15,20-四[4-(2-氧代-2-羧甲氨基)乙基苯基]四苯并卟吩 (I20);
5,10,15,20-四[4-[2-氧代-2-(2-氧代-4-羧基)丁氨基]乙基苯基]四苯并卟吩(I21);
5,10,15,20-四[4-[2-氧代-2-(N,N-二羧甲基)亚氨基]乙基苯基]四苯并卟吩(I22);
5,10,15,20-四[4-[2-氧代-2-(N,N-二羧乙基)亚氨基]乙基苯基]四苯并卟吩(I23);
5,10,15,20-四[4-[2-氧代-2-(2-氧代-4-羧基)丁氨基]乙氧基苯基]四苯并卟吩(I24);
5,10,15,20-四[4-[2-氧代-2-(2-氧代-4-羧基)丁氨基]丁氧基苯基]四苯并卟吩(I25);
5,10,15,20-四[3-(2-氧代-2-羧甲氨基)乙基苯基]四苯并卟吩 (I26);
5,10,15,20-四[3-[2-氧代-2-(2-氧代-4-羧基)丁氨基]乙基苯基]四苯并卟吩(I27);
5,10,15,20-四[3-[2-氧代-2-(N,N-二羧甲基)亚氨基]乙基苯基]四苯并卟吩(I28);
5,10,15,20-四[3-[2-氧代-2-(N,N-二羧乙基)亚氨基]乙基苯基]四苯并卟吩(I29);
5,10,15,20-四[3-[2-氧代-2-(2-氧代-4-羧基)丁氨基]乙氧基苯基]四苯并卟吩(I30);
5,10,15,20-四[3-[2-氧代-2-(2-氧代-4-羧基)丁氨基]丁氧基苯基]四苯并卟吩(I31);
5,10,15,20-四[(4-羟乙氧基)苯基]四苯并卟吩 (I32);
5,10,15,20-四[(4-羟丙氧基)苯基]四苯并卟吩 (I33);
5,10,15,20-四[(3,5-二氟-4-羧甲氧基)苯]四苯并卟吩 (I34);
5,10,15,20-四[(3,5-二氟-4-羧丙氧基)苯基]四苯并卟吩 (I35);
5,10,15,20-四[(3,5-二氟-4-羧丁氧基)苯基]四苯并卟吩 (I36);
5,10,15,20-四[(3,5-二氟-4-羧戊氧基)苯基]四苯并卟吩 (I37);
5,10,15,20-四[(3,5-二氟-4-羧己氧基)苯基]四苯并卟吩 (I38);
5,10,15,20-四[(3,5-二氟-4-羟乙氧基)苯]四苯并卟吩 (I39);
5,10,15,20-四[(3,5-二氟-4-羟丙氧基)苯基]四苯并卟吩 (I40);
5,10,15,20-四[(3,5-二氯-4-羧甲氧基)苯基]四苯并卟吩 (I41);
5,10,15,20-四[(3,5-二氯-4-羟乙氧基)苯基]四苯并卟吩 (I42);
5,10,15,20-四[(3,5-二溴-4-羧甲氧基)苯基]四苯并卟吩 (I43);
5,10,15,20-四[(3,5-二溴-4-羟乙氧基)苯基]四苯并卟吩 (I44);
5,10,15,20-四[(3,5-二甲氧基-4-羧甲氧基)苯基]四苯并卟吩 (I45);
5,10,15,20-四[(3,5-二甲氧基-4-羟乙氧基)苯基]四苯并卟吩 (I46);
5,10,15,20-四[(3-甲氧基-4-羟基)苯基]四苯并卟吩 (II1);
5,10,15,20-四[(3-硝基-4-羟基)苯基]四苯并卟吩 (II2);
5,10,15,20-四[(3-氟-4-羟基)苯基]四苯并卟吩 (II3);
5,10,15,20-四[(3-氯-4-羟基)苯基]四苯并卟吩 (II4);
5,10,15,20-四[(3-溴-4-羟基)苯基]四苯并卟吩 (II5);
5,10,15,20-四[(3-甲氧基-4-羧甲氧基)苯基]四苯并卟吩 (II6);
5,10,15,20-四[(3-甲氧基-4-羧丙氧基)苯基]四苯并卟吩 (II7);
5,10,15,20-四[(3-甲氧基-4-羟乙氧基)苯基]四苯并卟吩 (II8);
5,10,15,20-四[(3-甲氧基-4-羟丙氧基)苯基]四苯并卟吩 (II9);
5,10,15,20-四[(4-甲氧基-3-羟基)苯基]四苯并卟吩 (II10)。
所述的一类5-(取代)苯基-10,15,20-三(取代)苯基四苯并卟吩衍生物 (III),其特征在于该类化合物中包括如下代表性化合物:
5-[(4-羧甲氧基)苯基]-10,15,20-三苯基四苯并卟吩 (III1);
5-[(4-羧丙氧基)苯基)]-10,15,20-三苯基四苯并卟吩 (III2);
5-[(4-羧丁氧基)苯基)]-10,15,20-三苯基四苯并卟吩 (III3);
5-[(4-羧戊氧基)苯基]-10,15,20-三苯基四苯并卟吩 (III4);
5-[4-羧苯基]-10,15,20-三[4-氯苯基]四苯并卟吩 (III5);
5-[4-羧苯基]-10,15,20-三[4-三氟甲基苯基]四苯并卟吩 (III6);
5-[4-羧苯基]-10,15,20-三[4-氟苯基]四苯并卟吩 (III7);
5-[4-羧苯基]-10,15,20-三[4-甲氧基苯基]四苯并卟吩 (III8);
5-[4-羧苯基]-10,15,20-三[4-甲基苯基]四苯并卟吩 (III9);
5-[(3,5-二氟-4-羧甲氧基)苯基]-10,15,20-三[4-甲氧基苯基]四苯并卟吩(III10);
5-[(3,5-二氟-4-羧甲氧基)苯基]-10,15,20-三[4-三氟甲基苯基]四苯并卟吩(III11);
5-[(3,5-二甲氧基-4-(N,N-二羧乙基)氨基甲酰氧基)苯基]-10,15,20-三[4-三氟甲基苯基]四苯并卟吩 (III12)。
所述的一类5, 10, 15, 20-(取代)苯基四苯并卟吩衍生物 (I) 和 (II)和5-(取代)苯基-10, 15, 20-三(取代)苯基四苯并卟吩衍生物 (III) ,具有显著的光动力活性,可作为治疗肿瘤、视网膜黄斑变性、光化性角化病、鲜红斑痣、尖锐湿疣等疾病的光动力药物,以及作为光电材料与试剂。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解,在阅读了本发明讲授的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
[实施例1]
5,10,15,20-四[(4-羧甲基)苯基]四苯并卟吩 (I1) 的制备
将4,5,6,7-四氢异吲哚1(1.9 g, 15.68 mmol)、4-甲酰基苯甲酸甲酯(2.79 g,15.68 mmol)溶解在干燥的DCM(500 mL)中,在氩气保护及避光条件下逐滴加入三氟化硼乙醚溶液(0.4 mL),室温反应2 h。然后加入DDQ(4.27 g,18.81 mmol),继续反应12 h。TLC监测反应结束,浓缩,利用柱层析分离纯化(VDCM/VTHF = 30/1)所得残留物,得到绿色固体5,10,15,20-四[(4-甲氧羰甲基)苯基]四环己烯并卟吩III1。取5,10,15,20-四[(4-甲氧羰甲基)苯基]四环己烯并卟吩III1(1 g, 0.893 mmol),完全溶解在DMF(50 mL)中,然后加入一水合醋酸铜(0.71 g, 3.57 mmol),氩气保护下,在100 ℃反应20 - 30 min,冷却后,加入水(100 mL),抽滤,真空干燥得到暗红色固体5,10,15,20-四[(4-甲氧羰甲基)苯基]四环己烯并卟吩铜IV1。取5,10,15,20-四[(4-甲氧羰甲基)苯基]四环己烯并卟吩铜IV1(0.5 g,0.423 mmol)完全溶解在干燥的THF(50 mL)中,然后加入DDQ(0.961 g, 3.84 mmol),氩气保护下室温反应30 min,减压除去THF,并用DCM溶解残留物,依次用水(100 mL*3)、10%Na2SO3溶液(100 mL*3)、饱和的NaCl溶液(100 mL*3)洗涤,无水Na2SO4干燥后过滤,浓缩,对所得粗产物进行柱层析分离纯化(DCM),得到绿色固体5,10,15,20-四[(4-甲氧羰甲基)苯基]四苯并卟吩铜V1。取5,10,15,20-四[(4-甲氧羰甲基)苯基]四苯并卟吩铜V1(0.2 g,0.172 mmol),于冰浴下完全溶解在三氟乙酸(2 mL)中,然后缓慢滴加浓硫酸(0.5 mL),继续反应20 min,TLC监测反应结束,将其转移到冰水(20 mL)中,并用饱和的NaHCO3溶液将pH调至中性,并用DCM(100 mL*3)萃取,合并有机相,依次用水(100 mL*3)、饱和的NaCl溶液(100 mL*3)洗涤,无水Na2SO4干燥后抽滤,浓缩,得到绿色固体5,10,15,20-四[(4-甲氧羰甲基)苯基]四苯并卟吩VI1。取5,10,15,20-四[(4-甲氧羰甲基)苯基]四苯并卟吩VI1(0.12 g,0.109 mmol),溶解于THF(20 mL)中,然后加入2 mol/L KOH溶液(10 mL),加热回流2 - 3h。TLC监测反应结束,冷却至室温,减压除去THF,然后用2 mol/L HCl溶液将pH调节至5 -6,抽滤,真空干燥后得到绿色固体5,10,15,20-四[(4-羧甲基)苯基]四苯并卟吩I1(0.102g),5步反应收率20.5 %。1H NMR (400 MHz, DMSO-d 6 ): δ ppm 12.75 (s, 4H), 8.54 (s,8H), 7.89 (s, 8H), 7.45 - 7.26 (m, 16H), 4.06 (s, 8H), -1.93 (s, 2H). 13C NMR(151 MHz, DMSO-d 6 -TFA): δ ppm 173.02, 141.25, 138.79, 137.46, 136.28, 131.08,130.80, 130.63, 129.86, 123.91, 118.44, 116.52, 114.61, 114.34, 112.70,41.24. HRMS (MALDI-TOF): m/z calcd for C68H46N4O8 [M+H]+, 1047.3316; found,1047.3392。
[实施例2]
5,10,15,20-四[(4-羧甲氧基)苯基]四苯并卟吩(I2)的制备
采用化合物I1的合成方法制备了化合物I2。1H NMR (600 MHz, DMSO-d 6 ): δ ppm12.61 (s, 4H), 8.19 (d, J = 8.1 Hz, 16H), 7.49 (d, J = 8.4 Hz, 16H), 5.05 (s,8H), -1.12 (s, 2H). 13C NMR (151 MHz, DMSO-d 6 ): δ ppm 170.68, 159.27, 135.67,115.73, 115.34, 65.60. HRMS (MALDI-TOF): m/z calcd for C68H46N4O12 [M+H]+,1111.3112; found, 1111.3140。
[实施例3]
5,10,15,20-四[(4-羧丙氧基)苯基]四苯并卟吩(I3)的制备
采用化合物I1的合成方法制备了化合物I3。1H NMR (600 MHz, DMSO-d 6 ): δ ppm12.39 (s, 4H), 8.18 (d, J = 8.2 Hz, 16H), 7.49 (d, J = 8.4 Hz, 16H), 4.35 (d,J = 4.7 Hz, 8H), 2.60 (s, 8H), 2.20 (s, 8H), -1.07 (s, 2H). 13C NMR (151 MHz,DMSO-d 6 ): δ ppm 174.81, 135.86, 115.59, 67.59, 33.04, 26.80. HRMS (MALDI-TOF): m/z calcd for C76H62N4O12 [M+H]+, 1223.4364; found, 1223.4782。
[实施例4]
5,10,15,20-四[(4-羧丁氧基)苯基]四苯并卟吩(I4)的制备
采用化合物I1的合成方法制备了化合物I4。1H NMR (400 MHz, DMSO-d 6 ): δ ppm12.48 (s, 4H), 8.24 (m, 16H), 7.45 (t, J = 14.4 Hz, 16H), 4.34 (s, 8H), 1.96(s, 8H), 1.89 (d, J = 7.0 Hz, 8H), 1.36 (s, 8H), -1.08 (s, 2H). 13C NMR (151MHz, DMSO-d 6 -TFA): δ ppm 174.91, 141.66, 138.05, 132.05, 130.66, 130.16,123.53, 118.40, 116.49, 116.08, 114.58, 114.16, 112.67, 68.33, 33.90, 28.72,21.85. HRMS (MALDI-TOF): m/z calcd for C80H70N4O12 [M+H]+, 1279.4990; found,1279.5003。
[实施例5]
5,10,15,20-四[(4-羧戊氧基)苯基]四苯并卟吩(I5)的制备
采用化合物I1的合成方法制备了化合物I5。1H NMR (400 MHz, DMSO-d 6 ): δ ppm12.65 (s, 4H), 8.24 (m, 16H), 7.45 (t, J = 14.4 Hz, 16H), 4.13 (d, J = 7.2Hz, 8H), 1.96 (s, 8H), 1.89 (d, J = 7.0 Hz, 8H), 1.72 (t, J = 7.4 Hz, 8H),1.36-1.32 (m, 8H), -1.08 (s, 2H). 13C NMR (151 MHz, DMSO-d 6 -TFA): δ ppm174.97, 161.60, 141.70, 138.07, 130.65, 123.53, 118.37, 116.46, 114.55,112.64, 68.52, 34.17, 29.04, 25.80, 24.90. HRMS (MALDI-TOF): m/z calcd forC84H78N4O12 [M+H]+, 1335.5616; found, 1335.5669。
[实施例6]
5,10,15,20-四[(3-羧甲氧基)苯基]四苯并卟吩(I8)的制备
采用化合物I1的合成方法制备了化合物I8。1H NMR (600 MHz, DMSO-d 6 ): δ ppm12.65 (s, 4H), 7.94 - 7.80 (m, 16H), 7.44 - 7.14 (m, 16H), 4.84 (d, J =18.3Hz, 8H), -1.20 (m, 2H). 13C NMR (151 MHz, DMSO-d 6 ): δ ppm 171.80, 159.58,157.27, 151.14, 142.28, 142.01, 139.31, 138.71, 136.65, 131.32, 129.32,128.41, 128.14, 126.39, 124.70, 124.45, 123.61, 122.94, 120.87, 120.46,120.14, 118.88, 66.03. HRMS (MALDI-TOF): m/z calcd for C68H46N4O12 [M+H]+,1111.3112; found, 1111.3157。
[实施例7]
5,10,15,20-四[(4-羧甲氧基)苯基]四苯并卟吩铜(I15)的制备
采用化合物I1的合成方法制备了化合物I15。HRMS (MALDI-TOF): m/z calcd forC68H44CuN4O12 [M+H]+, 1172.2252; found, 1172.2260。
[实施例8]
5,10,15,20-四[(4-羧甲氧基)苯基]四苯并卟吩锌(I17)的制备
采用化合物I1的合成方法制备了化合物I17。1H NMR (400 MHz, DMSO-d 6 ): δ ppm13.30 (s, 4H), 8.19 (d, J = 8.1 Hz, 4H), 8.12 (d, J = 8.1 Hz, 6H), 7.48 (d, J= 7.8 Hz, 10H), 7.25 (d, J = 41.7 Hz, 12H), 5.04 (d, J = 5.2 Hz, 8H). 13C NMR(151 MHz, DMSO-d 6 ): δ ppm 170.78, 158.94, 143.56, 138.95, 136.41, 135.31,125.53, 124.40, 116.37, 115.53, 65.60. HRMS (MALDI-TOF): m/z calcd forC68H44N4O12Zn [M+H]+, 1172.2247; found, 1172.2280。
[实施例9]
5,10,15,20-四[4-[2-氧代-2-(2-氧代-4-羧基)丁氨基]乙基苯基]四苯并卟吩(I21)的制备
采用化合物I1的合成方法制备了化合物I21。1H NMR (400 MHz, DMSO-d 6 ): δ ppm13.25 (s, 4H), 8.18 (d, J = 8.0 Hz, 8H), 7.50-7.34 (m, 12H), 7.27 (d, J = 4.7Hz, 16H), 4.82 (s, 8H), 4.35 (d, J = 4.6 Hz, 8H), 2.82-2.60 (m, 16H), -2.75(s, 2H). 13C NMR (101 MHz, DMSO-d 6 ): δ ppm 204.48, 175.89, 171.66, 157.27,151.38, 142.01, 141.16, 139.31, 136.68, 136.31, 131.32, 128.41, 127.60,126.39, 124.74, 124.45, 122.94, 120.82, 120.46, 120.02, 47.38, 44.50, 37.95,31.19. HRMS (MALDI-TOF): m/z calcd for C88H74N8O16 [M+H]+, 1499.5223; found,1499.5278。
[实施例10]
5,10,15,20-四[(4-羟乙氧基)苯基]四苯并卟吩(I32)的制备
采用化合物I1的合成方法制备了化合物I32。1H NMR (600 MHz, DMSO-d 6 ) δ:8.62-8.60 (m, 8H), 7.60-7.55 (m, 16H), 7.47-7.45 (m, 8H), 5.33 (brs, 4H),4.38 (br. s, 8H), 3.97 (t, J = 6 HZ, 8H). 13C NMR (151 MHz, DMSO-d 6 ) δ:161.42, 141.99, 138.19, 132.35, 130.75, 129.59, 123.65, 113.67, 70.63, 60.16.HRMS (ESI): m/z calcd. for C68H54N4O8 [M+H]+ 1055.3942; found 1055.4006。
[实施例11]
5,10,15,20-四[(3-甲氧基-4-羟基)苯基]四苯并卟吩(II1)的制备
采用化合物I1的合成方法制备了化合物II1。1H NMR (400 MHz, DMSO-d 6 ): δ ppm9.81 (s, 4H), 8.06-8.00 (m, 8H), 7.60-7.50 (m, 20H), 4.14 (s, 12H). 13C NMR(101 MHz, DMSO-d 6 ): δ ppm 147.27, 142.01, 141.16, 139.31, 137.00, 136.65,131.36, 128.41, 126.39, 124.70, 124.45, 122.94, 120.82, 120.46, 120.02,114.50, 48.82. HRMS (MALDI-TOF): m/z calcd for C64H46N4O8 [M+H]+, 999.3316;found, 999.3386。
[实施例12]
5,10,15,20-四[(3-氟-4-羟基)苯基]四苯并卟吩(II3)的制备
采用化合物I1的合成方法制备了化合物II3。1H NMR (400 MHz, DMSO-d 6 ): δ ppm11.18 (s, 4H), 8.60-8.53 (m, 4H), 8.38-8.30 (m, 4H), 7.65-7.46 (m, 20H). 13CNMR (101 MHz, DMSO-d 6 ): δ ppm 153.61, 148.15, 147.51, 134.22, 132.01, 122.82,121.16, 119.41, 117.32, 112.64, 111.41. HRMS (MALDI-TOF): m/z calcd forC60H34F4N4O4 [M+H]+, 951.2516; found, 951.2569。
[实施例13]
5,10,15,20-四[(3-甲氧基-4-羟乙氧基)苯基]四苯并卟吩 (II8)的制备
采用化合物I1的合成方法制备了化合物II8。1H NMR (600 MHz, DMSO-d 6 ) δ:9.59 (s, 1H), 9.22 (s, 1H), 8.39-8.02 (m, 8H), 7.64-7.42 (m, 18H), 4.35 (s,4H), 4.10-3.89 (m, 28H). 13C NMR (101 MHz, DMSO-d 6 ): δ ppm 153.61, 148.15,147.51, 134.22, 132.01, 122.82, 121.16, 119.41, 117.32, 112.64, 111.41, 69.8,60.9, 56.1. HRMS (ESI):m/z calcd. for C72H62N4O12 [M]+ 1174.4364; found1174.4329。
[实施例14]
5-[4-羧苯基]-10,15,20-三[4-氟苯基]四苯并卟吩(III7)的制备
采用化合物I1的合成方法制备了化合物III7。1H NMR (400 MHz, DMSO-d 6 ): δppm 13.48 (s, 1H), 8.50-8.36 (m, 12H), 7.81-7.79 (m, 8H), 7.36-7.18 (m, 12H),-0.95 (s, 2H). 13C NMR (101 MHz, DMSO-d 6 ): δ ppm 164.43, 162.79, 138.03,136.67, 135.00, 130.53, 116.83, 116.69, 114.95. HRMS (MALDI-TOF): m/z calcdfor C61H35F3N4O2 [M+H]+, 913.2712; found, 913.2822。
[实施例15]
5-[4-羧苯基]-10,15,20-三[4-甲氧基苯基]四苯并卟吩(III8)的制备
采用化合物I1的合成方法制备了化合物III8。1H NMR (400 MHz, DMSO-d 6 ): δppm 13.61 (s, 1H), 8.72-8.69 (m, 5H), 8.11-8.01 (m, 3H), 7.99-7.76 (m, 4H)7.43-7.12 (m, 20H), 3.77 (s, 9H). 13C NMR (101 MHz, DMSO-d 6 ): δ ppm 169.31,164.65, 140.36, 137.72, 134.51, 134.22, 132.01, 122.82, 121.16, 119.41,117.32, 108.41, 55.8. HRMS (MALDI-TOF): m/z calcd for C64H44N4O5 [M+H]+,949.3312; found, 949.3567。
[实施例16]
5-[4-羧苯基]-10,15,20-三[4-甲基苯基]四苯并卟吩(III9)的制备
采用化合物I1的合成方法制备了化合物III9。1H NMR (400 MHz, DMSO-d 6 ): δppm 13.41 (s, 1H), 8.52-8.49 (m, 5H), 8.21-8.19 (m, 3H), 7.79-7.68 (m, 4H)7.44-7.25 (m, 20H), 2.77 (s, 9H). 13C NMR (101 MHz, DMSO-d 6 ): δ ppm 169.31,164.65, 140.36, 137.72, 134.51, 134.22, 132.01, 122.82, 121.16, 119.41,117.32, 108.41, 21.21. HRMS (MALDI-TOF): m/z calcd for C64H44N4O2 [M+H]+,901.3464; found, 901.3537。
[实施例17]
光敏剂对人食管癌Eca-109细胞的光动力抗增殖实验
受试细胞:人食管癌细胞Eca-109。
光源:MDL-III-650 型激光器;SD2490型激光功率测量仪。
受试化合物:
5,10,15,20-四[(4-羧甲基)苯基]四苯并卟吩 (I1);5,10,15,20-四[(4-羧甲氧基)苯基]四苯并卟吩 (I2);5,10,15,20-四[(4-羧丙氧基)苯基]四苯并卟吩 (I3);5,10,15,20-四[(4-羧丁氧基)苯基]四苯并卟吩 (I4);5,10,15,20-四[(4-羧戊氧基)苯基]四苯并卟吩 (I5);5,10,15,20-四[(3-羧甲氧基)苯基]四苯并卟吩 (I8);5,10,15,20-四[(4-羧甲氧基)苯基]四苯并卟吩铜 (I15);5,10,15,20-四[(4-羧甲氧基)苯基]四苯并卟吩锌(I17);5,10,15,20-四[4-[2-氧代-2-(2-氧代-4-羧基)丁氨基]乙基苯基]四苯并卟吩(I21);5,10,15,20-四[(4-羟乙氧基)苯基]四苯并卟吩 (I32);5,10,15,20-四[(3-甲氧基-4-羟基)苯基]四苯并卟吩 (II1);5,10,15,20-四[(3-甲氧-4-羟基)苯基]四苯并卟吩(II8);5-[4-羧苯基]-10,15,20-三[4-氟苯基]四苯并卟吩 (III7);5-[4-羧苯基]-10,15,20-三[4-甲氧基苯基]四苯并卟吩 (III8);5,10,15,20-四[4-羧基苯基]苯并卟吩对照化合物D);5,10,15,20-四[4-取代基苯基]四苯并卟吩(对照化合物E); 5-[(4-羧基)苯基]-10,15,20-三苯基苯并卟吩 (对照化合物F);海姆泊芬(对照化合物)。
光动力抗肿瘤细胞增殖作用实验:
将处于对数生长期的细胞用胰酶消化后,用完全培养基重悬成细胞悬液,再将其接种于96 孔板,每孔100 μL,置于37 ℃ 5% CO2培养箱培养24 h。细胞贴壁后将每孔中的培养液替换为200 μL含受试化合物(5 μM)的培养液并孵育24 h;然后进行光照(功率20mW/cm2,波长650 nm,光剂量10 J/cm2);72 h时每孔加入20 μL 5 mg/mL的MTT溶液,孵育4 h后吸弃并加入150 μL 二甲基亚砜,酶标仪570 nm 检测OD 值。实验重复三次。实验结果见表1,结果表明:经改造后的新的系列I化合物对人食管癌细胞均有不同程度的光动力抑制作用,且优于对照化合物D;新的系列II化合物稳定性好,对人食管癌细胞均有不同程度的光动力抑制作用,且稳定性与生物活性优于对照化合物E;新的系列III化合物对人食管癌细胞均有不同程度的光动力抑制作用,且优于对照化合物F。其中化合物I2、I3、I4、I5、I8、I17和I21的光动力抗肿瘤活性显著优于对照药海姆泊芬。
表1 新化合物对Eca-109人食管癌细胞增殖抑制作用
与对照药海姆泊芬相比,*p <0.05,**p <0.01,***p <0.001;
与对照化合物D相比,△ p <0.05,△△ p <0.01,△△△ p <0.001;
与对照化合物E相比,# P <0.05,## P <0.01,### P <0.001;
与对照化合物F相比,& P <0.05,&& P <0.01,&&& P <0.001。
[实施例18]
光敏剂对小鼠皮肤光毒性评价实验
受试动物:昆明小鼠,5周龄(22 ± 2 g)。
光源:230V·E27/ES欧司朗模拟太阳光灯;YK-PDT-300型功率密度计。
受试化合物:
5,10,15,20-四[(4-羧甲基)苯基]苯并卟吩 (I1);5,10,15,20-四[(4-羧甲氧基)苯基]苯并卟吩 (I2);5,10,15,20-四[(4-羧丙氧基)苯基]苯并卟吩 (I3);5,10,15,20-四[(4-羧丁氧基)苯基]苯并卟吩 (I4);5,10,15,20-四[(4-羧戊氧基)苯基]苯并卟吩 (I5);5,10,15,20-四[(3-羧甲氧基)苯基]苯并卟吩 (I8);5,10,15,20-四[(4-羧甲氧基)苯基]苯并卟吩铜 (I15);5,10,15,20-四[(4-羧甲氧基)苯基]苯并卟吩锌(I17);5,10,15,20-四[4-[2-氧代-2-(2-氧代-4-羧基)丁氨基]乙基苯基]苯并卟吩 (I21);5,10,15,20-四[(4-羟乙氧基)苯基]苯并卟吩 (I32);5,10,15,20-四[(3-甲氧基-4-羟基)苯基]苯并卟吩 (II1);5,10,15,20-四[(3-甲氧-4-羟基)苯基]苯并卟吩 (II8);5-[4-羧苯基]-10,15,20-三[4-氟苯基]苯并卟吩 (III7);5-[4-羧苯基]-10,15,20-三[4-甲氧基苯基]苯并卟吩 (III8);5,10,15,20-四[4-羧基苯基]苯并卟吩 (对照化合物D);5,10,15,20-四[4-取代基苯基]四苯并卟吩(对照化合物E);5-[(4-羧基)苯基]-10,15,20-三苯基苯并卟吩(对照化合物F);光敏素II(对照化合物)。
小鼠模型皮肤光毒性评价实验:
将小鼠随机分组,6只为一组,雌雄各半,使用5%水合氯醛经腹腔注射麻醉小鼠并将其固定。各组给予含受试化合物的溶液尾部静脉注射,注射剂量为10 mg/kg,给药后4小时接受置于光源下45 cm 处经模拟太阳光照射10 分钟, 光照强度为10 mW/cm2。照光后的小鼠进行严格避光,观察并记录其生理情况。24小时后将小鼠颈椎脱臼法处死,用8 毫米打孔器取背部皮肤,电子分析天平称重,计算背部皮指数,其中背部皮指数=背部皮肤重量(mg) /体重(g) ×100。实验结果见表2,结果表明经中介四苯基取代的四苯并卟吩衍生物处理的小鼠背部皮指数均显著低于光敏素II处理组和对照化合物D、E和F处理组,表明上述受试化合物的皮肤光毒副作用均较弱。
表2 化合物对小鼠背部照光区背皮指数计算表
与空白对照相比,*p <0.05,**p <0.01,***p <0.001;
与对照药物光敏素II相比,△ p <0.05,△△ p <0.01,△△△ p <0.001;
与对照化合物D相比,# P <0.05,## P <0.01,### P <0.001;
与对照化合物E相比,& P <0.05,&& P <0.01,&&& P <0. 001;
与对照化合物F相比,^ P <0.05,^^ P <0.01,^^^ P <0. 001。
Claims (5)
1.一类中介四苯基取代四苯并卟吩衍生物,其特征在于所述光敏剂5,10,15,20-四(取代)苯基四苯并卟吩衍生物 (I) 和 (II), 和5-(取代)苯基-10,15,20-三(取代)苯基四苯并卟吩衍生物 (III):
其中:
M为2H、Ni、Cu、Zn、Pd、Pt;
X、Y和Z相同或不同且独立地为CH2、C=O、O、NH、C(CH3)2;
R1为极性基团;
R3和R4相同或不同且至少有一个含有极性基团。极性基团含羧基、羟基或氨基、烷基羧酸、烷基醇、含N或O原子的烷基醇或烷基羧酸、含羰基的烷基醇或烷基羧酸、含酰胺键的烷基醇或烷基羧酸、或同时含有羰基和酰胺键的烷基羧酸;非极性基团含氢、烷基、含N或O原子的烷基、含羰基的烷基、或含酰胺键的烷基;
R2为H、(CH2)nMe、O(CH2)nMe、F、Cl、Br、I、CF3、n = 0- 6;
R5为H、(CH2)nMe、O(CH2)nMe、F、Cl、Br、I、CF3、n = 0- 6。
2.根据权利要求1所述的中介四苯基取代四苯并卟吩衍生物I、II和III,其中:
极性基团为:-(CH2)mCOOH, -(CH2)mCH(CH3)COOH, -(CH2)mOH, -(CH2)mCH(CH3)OH, -(CH2)m(OCH2CH2)pOH, -(CH2)mC6H4OH, -(CH2)mN[(CH2)nCOOH]2, -(CH2)mN[(CH2)qOH]2, -(CH2)mO(CH2)nCOOH, -(CH2)mO(CH2)qOH, -(CH2)mCO(CH2)nCOOH, -(CH2)mCO(CH2)nOH或氨基酸衍生物, m = 1 - 7, n = 1 - 7, p = 1 - 5, q = 2 - 7;
氨基酸衍生物为:-(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;
非极性基团为:-H, -(CH2)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)PCH3, -(CH2)mCO(CH2)nCH3, -(CH2)mCO(CH2)nCH(CH3)2, -(CH2)mCO(CH2)nC(CH3)3,-(CH2)mCONH(CH2)qCH3, -(CH2)mCONH(CH2)qCH(CH3)2或-(CH2)mCONH(CH2)qC(CH3)3, m = 0 -7, n = 0 - 7, p = 1 - 5, q =0 – 7。
3.根据权利要求1所述的一类中介四苯基取代四苯并卟吩衍生物(I) 和 (II),其特征在于该类化合物包括如下代表性化合物:
5,10,15,20-四[(4-羧甲基)苯基]四苯并卟吩 (I1);
5,10,15,20-四[(4-羧甲氧基)苯基]四苯并卟吩 (I2);
5,10,15,20-四[(4-羧丙氧基)苯基]四苯并卟吩 (I3);
5,10,15,20-四[(4-羧丁氧基)苯基]四苯并卟吩 (I4);
5,10,15,20-四[(4-羧戊氧基)苯基]四苯并卟吩 (I5);
5,10,15,20-四[(4-羧己氧基)苯基]四苯并卟吩 (I6);
5,10,15,20-四[(3-羧甲基)苯基]四苯并卟吩 (I7);
5,10,15,20-四[(3-羧甲氧基)苯基]四苯并卟吩 (I8);
5,10,15,20-四[(3-羧丙氧基)苯基]四苯并卟吩 (I9);
5,10,15,20-四[(3-羧丁氧基)苯基]四苯并卟吩 (I10);
5,10,15,20-四[(3-羧戊氧基)苯基]四苯并卟吩 (I11);
5,10,15,20-四[(3-羧己氧基)苯基]四苯并卟吩 (I12);
5,10,15,20-四[(2-羧甲氧基)苯基]四苯并卟吩 (I13);
5,10,15,20-四[(2-羧丙氧基)苯基]四苯并卟吩 (I14);
5,10,15,20-四[(4-羧甲氧基)苯基]四苯并卟吩铜 (I15);
5,10,15,20-四[(4-羧甲氧基)苯基]四苯并卟吩镍 (I16);
5,10,15,20-四[(4-羧甲氧基)苯基]四苯并卟吩锌 (I17);
5,10,15,20-四[(4-羧甲氧基)苯基]四苯并卟吩钯 (I18);
5,10,15,20-四[(4-羧甲氧基)苯基]四苯并卟吩铂 (I19);
5,10,15,20-四[4-(2-氧代-2-羧甲氨基)乙基苯基]四苯并卟吩 (I20);
5,10,15,20-四[4-[2-氧代-2-(2-氧代-4-羧基)丁氨基]乙基苯基]四苯并卟吩 (I21);
5,10,15,20-四[4-[2-氧代-2-(N,N-二羧甲基)亚氨基]乙基苯基]四苯并卟吩 (I22);
5,10,15,20-四[4-[2-氧代-2-(N,N-二羧乙基)亚氨基]乙基苯基]四苯并卟吩 (I23);
5,10,15,20-四[4-[2-氧代-2-(2-氧代-4-羧基)丁氨基]乙氧基苯基]四苯并卟吩(I24);
5,10,15,20-四[4-[2-氧代-2-(2-氧代-4-羧基)丁氨基]丁氧基苯基]四苯并卟吩(I25);
5,10,15,20-四[3-(2-氧代-2-羧甲氨基)乙基苯基]四苯并卟吩 (I26);
5,10,15,20-四[3-[2-氧代-2-(2-氧代-4-羧基)丁氨基]乙基苯基]四苯并卟吩 (I27);
5,10,15,20-四[3-[2-氧代-2-(N,N-二羧甲基)亚氨基]乙基苯基]四苯并卟吩 (I28);
5,10,15,20-四[3-[2-氧代-2-(N,N-二羧乙基)亚氨基]乙基苯基]四苯并卟吩 (I29);
5,10,15,20-四[3-[2-氧代-2-(2-氧代-4-羧基)丁氨基]乙氧基苯基]四苯并卟吩(I30);
5,10,15,20-四[3-[2-氧代-2-(2-氧代-4-羧基)丁氨基]丁氧基苯基]四苯并卟吩(I31);
5,10,15,20-四[(4-羟乙氧基)苯基]四苯并卟吩 (I32);
5,10,15,20-四[(4-羟丙氧基)苯基]四苯并卟吩 (I33);
5,10,15,20-四[(3,5-二氟-4-羧甲氧基)苯]四苯并卟吩 (I34);
5,10,15,20-四[(3,5-二氟-4-羧丙氧基)苯基]四苯并卟吩 (I35);
5,10,15,20-四[(3,5-二氟-4-羧丁氧基)苯基]四苯并卟吩 (I36);
5,10,15,20-四[(3,5-二氟-4-羧戊氧基)苯基]四苯并卟吩 (I37);
5,10,15,20-四[(3,5-二氟-4-羧己氧基)苯基]四苯并卟吩 (I38);
5,10,15,20-四[(3,5-二氟-4-羟乙氧基)苯]四苯并卟吩 (I39);
5,10,15,20-四[(3,5-二氟-4-羟丙氧基)苯基]四苯并卟吩 (I40);
5,10,15,20-四[(3,5-二氯-4-羧甲氧基)苯基]四苯并卟吩 (I41);
5,10,15,20-四[(3,5-二氯-4-羟乙氧基)苯基]四苯并卟吩 (I42);
5,10,15,20-四[(3,5-二溴-4-羧甲氧基)苯基]四苯并卟吩 (I43);
5,10,15,20-四[(3,5-二溴-4-羟乙氧基)苯基]四苯并卟吩 (I44);
5,10,15,20-四[(3,5-二甲氧基-4-羧甲氧基)苯基]四苯并卟吩 (I45);
5,10,15,20-四[(3,5-二甲氧基-4-羟乙氧基)苯基]四苯并卟吩 (I46);
5,10,15,20-四[(3-甲氧基-4-羟基)苯基]四苯并卟吩 (II1);
5,10,15,20-四[(3-硝基-4-羟基)苯基]四苯并卟吩 (II2);
5,10,15,20-四[(3-氟-4-羟基)苯基]四苯并卟吩 (II3);
5,10,15,20-四[(3-氯-4-羟基)苯基]四苯并卟吩 (II4);
5,10,15,20-四[(3-溴-4-羟基)苯基]四苯并卟吩 (II5);
5,10,15,20-四[(3-甲氧基-4-羧甲氧基)苯基]四苯并卟吩 (II6);
5,10,15,20-四[(3-甲氧基-4-羧丙氧基)苯基]四苯并卟吩 (II7);
5,10,15,20-四[(3-甲氧基-4-羟乙氧基)苯基]四苯并卟吩 (II8);
5,10,15,20-四[(3-甲氧基-4-羟丙氧基)苯基]四苯并卟吩 (II9);
5,10,15,20-四[(4-甲氧基-3-羟基)苯基]四苯并卟吩 (II10)。
4.根据权利要求1所述的一类5-(取代)苯基-10,15,20-三(取代)苯基四苯并卟吩衍生物 (III),其特征在于该类化合物包括如下代表性化合物:
5-[(4-羧甲氧基)苯基]-10,15,20-三苯基四苯并卟吩 (III1);
5-[(4-羧丙氧基)苯基)]-10,15,20-三苯基四苯并卟吩 (III2);
5-[(4-羧丁氧基)苯基)]-10,15,20-三苯基四苯并卟吩 (III3);
5-[(4-羧戊氧基)苯基]-10,15,20-三苯基四苯并卟吩 (III4);
5-[4-羧苯基]-10,15,20-三[4-氯苯基]四苯并卟吩 (III5);
5-[4-羧苯基]-10,15,20-三[4-三氟甲基苯基]四苯并卟吩(III6);
5-[4-羧苯基]-10,15,20-三[4-氟苯基]四苯并卟吩 (III7);
5-[4-羧苯基]-10,15,20-三[4-溴苯基]四苯并卟吩 (III8);
5-[4-羧苯基]-10,15,20-三[4-甲基苯基]四苯并卟吩 (III9);
5-[(3,5-二氟-4-羧甲氧基)苯基]-10,15,20-三[4-甲氧基苯基]四苯并卟吩 (III10);
5-[(3,5-二氟-4-羧甲氧基)苯基]-10,15,20-三[4-三氟甲基苯基]四苯并卟吩(III11);
5-[(3,5-二甲氧基-4-(N,N-二羧乙基)氨基甲酰氧基)苯基]-10,15,20-三[4-三氟甲基苯基]四苯并卟吩 (III12)。
5.根据权利要求1所述的一类5,10,15,20-四(取代)苯基四苯并卟吩衍生物 (I) 和(II)和5-(取代)苯基-10,15,20-三(取代)苯基四苯并卟吩衍生物 (III) ,具有显著的光动力活性,可作为治疗肿瘤、视网膜黄斑变性、光化性角化病、鲜红斑痣、尖锐湿疣等疾病的光动力药物,以及作为光电材料与试剂。
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