CN113831351B - 一类新型四吡咯衍生物及其应用 - Google Patents
一类新型四吡咯衍生物及其应用 Download PDFInfo
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- CN113831351B CN113831351B CN202111169329.7A CN202111169329A CN113831351B CN 113831351 B CN113831351 B CN 113831351B CN 202111169329 A CN202111169329 A CN 202111169329A CN 113831351 B CN113831351 B CN 113831351B
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- Prior art keywords
- phenyl
- bis
- dibromoporphine
- methoxy
- cooh
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- 150000001875 compounds Chemical class 0.000 claims abstract description 84
- -1 (disubstituted) phenyl dihalogenated porphine Chemical class 0.000 claims abstract description 72
- 239000003814 drug Substances 0.000 claims abstract description 28
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 22
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 6
- 208000002780 macular degeneration Diseases 0.000 claims abstract description 6
- 206010059313 Anogenital warts Diseases 0.000 claims abstract description 4
- 208000009621 actinic keratosis Diseases 0.000 claims abstract description 4
- 238000003745 diagnosis Methods 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 246
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 26
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
- 125000006309 butyl amino group Chemical group 0.000 claims description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 18
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 8
- 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
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 230000001404 mediated effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 23
- 125000000217 alkyl group Chemical group 0.000 abstract description 21
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- 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 8
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- 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 8
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- 101001018064 Homo sapiens Lysosomal-trafficking regulator Proteins 0.000 description 7
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 125000006267 biphenyl group Chemical group 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- JZRYQZJSTWVBBD-UHFFFAOYSA-N pentaporphyrin i Chemical group N1C(C=C2NC(=CC3=NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 JZRYQZJSTWVBBD-UHFFFAOYSA-N 0.000 description 6
- 206010034972 Photosensitivity reaction Diseases 0.000 description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- 208000007578 phototoxic dermatitis Diseases 0.000 description 5
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
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- OVTCUIZCVUGJHS-UHFFFAOYSA-N dipyrrin Chemical compound C=1C=CNC=1C=C1C=CC=N1 OVTCUIZCVUGJHS-UHFFFAOYSA-N 0.000 description 3
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- 229910052708 sodium Inorganic materials 0.000 description 3
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- 238000001291 vacuum drying Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000001028 anti-proliverative effect Effects 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
- 230000003197 catalytic effect Effects 0.000 description 2
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- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 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 2
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- KJLHJQGDBJNMPU-UHFFFAOYSA-L xf73 Chemical compound [Cl-].[Cl-].C1=CC(OCCC[N+](C)(C)C)=CC=C1C(C1=CC=C(N1)C=C1C=CC(=N1)C(C=1C=CC(OCCC[N+](C)(C)C)=CC=1)=C1C=CC(N1)=C1)=C2N=C1C=C2 KJLHJQGDBJNMPU-UHFFFAOYSA-L 0.000 description 2
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- 238000012449 Kunming mouse Methods 0.000 description 1
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- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 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
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- SVYWLZTVBMJCGG-UHFFFAOYSA-N ethyl 2-(4-formyl-2-methoxyphenoxy)acetate Chemical compound CCOC(=O)COC1=CC=C(C=O)C=C1OC SVYWLZTVBMJCGG-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
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- 239000001963 growth medium Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
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- 229960003569 hematoporphyrin Drugs 0.000 description 1
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- 230000005764 inhibitory process Effects 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
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0036—Porphyrins
-
- 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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Virology (AREA)
- Ophthalmology & Optometry (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一类中介二(二取代)苯基二卤代卟吩类四吡咯光敏化合物及其制备方法与应用,该化合物具有下述结构(I)和(II):其中:X为Cl,Br或I;A和Y相同或不同且独立地为CH2或O;当R1为烷基、含N或O原子的烷基、含羰基烷基或含酰胺键的烷基时,R2为烷基羧酸、烷基醇、含N或O原子的烷基羧酸、含N或O原子的烷基醇、含羰基烷基羧酸、含羰基烷基醇、含有酰胺键的烷基羧酸或同时含有羰基和酰胺键的烷基羧酸;或当R1为烷基羧酸、烷基醇、含N或O原子的烷基羧酸、含N或O原子的烷基醇、含羰基烷基羧酸、含羰基烷基醇、含有酰胺键的烷基羧酸或同时含有羰基和酰胺键的烷基羧酸时,R2为烷基、含N或O原子的烷基、含羰基烷基或含酰胺键的烷基;R3和R4相同或不同且至少有一个含有极性基团,且独立地为烷基、含N或O原子的烷基、含羰基烷基或含酰胺键的烷基、烷基羧酸、烷基醇、含N或O原子的烷基羧酸、含N或O原子的烷基醇、含羰基烷基羧酸、含羰基烷基醇、含有酰胺键的烷基羧酸或同时含有羰基和酰胺键的烷基羧酸。本发明制备的中介二卤代二苯基卟吩光敏剂具有显著的光动力活性,可作为光动力诊治肿瘤、视网膜黄斑变性、光化性角化病、鲜红斑痣、尖锐湿疣等疾病的药物。
Description
技术领域
本发明涉及光敏药物与光动力疗法领域,具体涉及一类稳定性好、制备工艺简便、亲水性好、不易聚集、光动力效果好、皮肤光毒副作用小的新型中介二(二取代)苯基二卤代卟吩类四吡咯衍生物及其应用。
背景技术
光动力疗法(PDT)是继传统的外科手术疗法、化学疗法、放射疗法后,一个正在蓬勃兴起、对肿瘤的诊断和治疗极具前景的新手段。其原理是光敏剂静脉注入人体后,可在病灶(如恶性肿瘤)内选择性地聚集或潴留,待光敏剂浓度达到一定程度后,采用特定波长的光进行定向照射,光敏剂受激发可产生光化学反应,最终产生活性氧(如单线态氧)杀伤肿瘤或其他病理性增生组织。
光敏剂、特定波长的光和氧分子是光动力治疗不可或缺的三个要素,其中,光敏剂作为光动力治疗三个主要成分的核心,在整个PDT中起着主导作用。目前市场上使用的大部分都是卟吩类四吡咯光敏剂。卟吩类光敏剂主要包括血红素衍生物(也称血卟啉衍生物)和四苯基卟吩衍生物。卟吩姆钠(光敏素II)作为血红素衍生物,是最早应用于临床的光敏药物,取得了显著的治疗效果,但该药物是由多个化合物组成的混合物,制备过程中各成分的含量较难控制,有些成分在皮肤中滞留时间长,需避光4周以上,病人难以耐受(国外医药-合成药、生化药、制剂分册,1998,19,32-34;世界临床药物,2018,39,285-288),限制了其在医学上的应用;2000年被美国FDA批准用于临床治疗肿瘤和视网膜黄斑变性等疾病的光敏药物维替泊芬(Verteporfin)也属于血红素衍生物,其最大吸收波长能达到689nm,穿透组织厚度是卟吩姆钠的两倍,能迅速的从细胞中清除,但其合成原料来自天然产物原卟啉,属于半合成的产物,合成过程复杂,有多个异构体,分离纯化困难,总收率低(中国新药杂志,2005,14,785-788;Aust.J.Chem.,2008,61,741-754),极大的限制其临床应用。此外,已上市的光敏剂替莫泊芬(Temoporfin)属于四苯基卟吩衍生物,它存在易被氧化、稳定性差、在水中溶解度较弱、价格昂贵等缺点(Chem.Soc.Rev.,1995,24,19-33),临床应用也受到限制。发现高效新型光敏剂是国内外科学工作者面临的巨大挑战,具有重要的科学意义与应用价值。
中介二苯基卟吩是一类结构新颖的四吡咯化合物,只有少量学者对其开展了初步研究。Arno Wiehe等合成的5,15-二(3-羟基苯基)卟吩(化合物1)具有较好的光动力作用,但由于周边苯环结构上有两个酚羟基,结构不稳定,易被氧化(J.Porphyr.Phthalocya.,2001,5,758-761)。马金石等以5,15-二(4-羧基苯基)卟吩(化合物2)作为中间体合成二芳基二氢卟吩衍生物,但并未对化合物2开展光动力治疗作用研究(CN 1382493A)。英国Destiny Pharma制药公司研发了光敏剂XF-73(Exeporfinium Chloride,化合物3),具有抗金黄色葡萄球菌感染作用,可作为光活化抗菌消毒剂,但不适用于肿瘤、视网膜黄斑变性等疾病的治疗(Antimicrob.Agents Chemother.,2005,49,1542-1552;CN 101389631A)。Yamada等制备了5,15-二(4-叔丁基苯基)-10,20-二溴卟吩(化合物4),将其作为中间体用于制备双肽链相连的多卟吩化合物,未对其行光动力活性评价(J.Am.Chem.Soc.,2014,136,6505-6509)。Kazuya等制备了5,15-二(4-甲酰乙酯苯基)-10,20-二溴卟吩(化合物5),将其作为中间体用于制备多卟吩共轭超分子化合物,未对其进行光动力活性评价(J.Porphyr.Phthalocya.,2007,11,359-367)。Christina等制备了5,15-二(4-羧基苯基)-10,20-二溴卟吩锌(化合物6),该化合物在电池中具有一定的光电转化效率,具有成为太阳能电池的光电材料的潜力(Eur.J.Inorg.Chem.,2013,1275-1286),但未开展光动力治疗作用研究。Wu等制备了5,15-二[(4-乙酰乙酯甲氧基)苯基]-10,20-二溴卟吩(化合物7)和5,15-二(4-乙羧基苯基)-10,20-二溴卟吩(化合物8),将其作为中间体用于制备乙炔桥接的三联卟吩化合物(Bioconjug.Chem.,2005,16,542-550),也未对其进行光动力活性研究。Julia等人制备了5,15-二(3,5-二叔丁基苯基)-10,20-二溴卟吩(化合物9),将其作为中间体用于制备双卟吩化合物,并未对进行光动力活性评价(Chem.Commun.,2020,56,14179)。Takuji等制备了5,15-二(3,5-二羟基苯基)-10,20-二溴卟吩锌(化合物10),将其作为中间体用于制备卟吩超分子化合物(JP 2004063421),也未对其进行光动力活性研究。
四吡咯大环化合物易出现自聚集或自组装现象,从而造成化合物溶解度大幅下降,难溶于各种溶剂,难以配成制剂使用,此外还可影响光动力活性,从而严重影响其成药性及在光动力治疗中的应用(Acta.Pharm.Sin.B.,2018,8,137-146)。
为发现结构新颖、光学性能好、成药性好的光敏新药,我们设计并制备了新型中介二苯基二卤代卟吩类四吡咯化合物。活性评价研究表明,与对照化合物1、化合物2、化合物3、化合物4、化合物5、化合物6、化合物7、化合物8、化合物9和化合物10相比,本团队设计合成的光敏剂光动力药理活性更高、皮肤光毒副作用更小,且具有结构稳定、制备工艺简单易行、亲水性好、可防止聚集等优点,可发展为肿瘤、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治疗药物。
发明内容
为克服现有光敏药物中存在的组成复杂、结构不稳定、制备困难、成本较高、易聚集、水溶性差、皮肤光毒副作用强等缺陷,本发明在中介二苯基二卤代卟吩化合物的苯基引入极性基团作为亲水基团,引入烷基作为疏水基团,提高化合物亲水性、抑制化合物的聚集能力;此外还在化合物中介位引入卤素,提高活性自由基的生成能力及光动力生物活性,所制备的新化合物结构稳定、亲水性好、不易聚集、制备工艺简单、生产成本低、光动力用强、皮肤光毒副作用小,在付出大量创造性劳动后合成了一系列中介二苯基二卤代卟吩及其氨基酸缩合物衍生物,完成本发明。
本发明涉及一类具有光动力活性高、皮肤光毒副作用小、性质稳定、亲水性好、不易聚集、易于配成注射剂等成药性优点的中介二苯基二卤代卟吩类四吡咯化合物及其应用。
本发明概述如下:
一类稳定性好、亲水性好、不易聚集的新型中介二(二取代)苯基二卤代卟吩衍生物,其特征在于:所述光敏剂即中介二[3,4-二取代]苯基二卤代卟吩衍生物(I)和中介二(3,5-二取代)苯基二卤代卟吩衍生物(II):
其中:
X为Cl,Br或I;
A和Y相同或不同且独立地为CH2或O;
当R1为烷基、含N或O原子的烷基、含羰基烷基或含酰胺键的烷基时,R2为烷基羧酸、烷基醇、含N或O原子的烷基羧酸、含N或O原子的烷基醇、含羰基烷基羧酸、含羰基烷基醇、含有酰胺键的烷基羧酸或同时含有羰基和酰胺键的烷基羧酸;
或当R1为烷基羧酸、烷基醇、含N或O原子的烷基羧酸、含N或O原子的烷基醇、含羰基烷基羧酸、含羰基烷基醇、含有酰胺键的烷基羧酸或同时含有羰基和酰胺键的烷基羧酸时,R2为烷基、含N或O原子的烷基、含羰基烷基或含酰胺键的烷基;
R3和R4相同或不同且至少有一个含有极性基团(如:羧基、醇或氨基)且独立地为烷基、含N或O原子的烷基、含羰基烷基或含酰胺键的烷基、烷基羧酸、烷基醇、含N或O原子的烷基羧酸、含N或O原子的烷基醇、含羰基烷基羧酸、含羰基烷基醇、含有酰胺键的烷基羧酸或同时含有羰基和酰胺键的烷基羧酸。
根据本发明中所述的中介二[3,4-二取代]苯基二卤代卟吩衍生物(I),其中
当R1为-(CH2)mCH3,-(CH2)mCH(CH3)2,-(CH2)mC(CH3)3,-(CH2)mN[(CH2)mCH3]2,
-(CH2)mO(CH2)mCH3,-(CH2)mO(CH2)mCH(CH3)2,-(CH2)mO(CH2)mC(CH3)3,
-(CH2)m(OCH2CH2)pCH3,-(CH2)mCO(CH2)mCH3,-(CH2)mCO(CH2)mCH(CH3)2,
-(CH2)mCO(CH2)mC(CH3)3,-(CH2)mCONH(CH2)nCH3,-(CH2)mCONH(CH2)nCH(CH3)2,
-(CH2)mCONH(CH2)nC(CH3)3,m=0-7,n=1-7,p=1-3时,
R2为-(CH2)mCOOH,-(CH2)mCH(CH3)COOH,-(CH2)mOH,-(CH2)mCH(CH3)OH,
-(CH2)mC6H4OH,-(CH2)mN[(CH2)mCOOH]2,-(CH2)mN[(CH2)nOH]2,-(CH2)mO(CH2)mCOOH,
-(CH2)mO(CH2)nOH,-(CH2)m(OCH2CH2)pOH,-(CH2)mCO(CH2)mCOOH,-(CH2)mCO(CH2)mOH或氨基酸衍生物,m=1-7,n=2-7,p=1-3;
当R1为-(CH2)mCOOH,-(CH2)mCH(CH3)COOH,-(CH2)mOH,-(CH2)mCH(CH3)OH,
-(CH2)mC6H4OH,-(CH2)mN[(CH2)mCOOH]2,-(CH2)mN[(CH2)nOH]2,-(CH2)mO(CH2)mCOOH,
-(CH2)mO(CH2)nOH,-(CH2)m(OCH2CH2)pOH,-(CH2)mCO(CH2)mCOOH,-(CH2)mCO(CH2)mOH或氨基酸衍生物,m=1-7,n=2-7,p=1-3时,
R2为-(CH2)mCH3,-(CH2)mCH(CH3)2,-(CH2)mC(CH3)3,-(CH2)mN[(CH2)mCH3]2,
-(CH2)mO(CH2)mCH3,-(CH2)mO(CH2)mCH(CH3)2,-(CH2)mO(CH2)mC(CH3)3,
-(CH2)m(OCH2CH2)pCH3,-(CH2)mCO(CH2)mCH3,-(CH2)mCO(CH2)mCH(CH3)2,
-(CH2)mCO(CH2)mC(CH3)3,-(CH2)mCONH(CH2)nCH3,-(CH2)mCONH(CH2)nCH(CH3)2,
-(CH2)mCONH(CH2)nC(CH3)3,m=0-7,n=1-7,p=1-3。
根据本发明中所述的中介二(3,5-二取代)苯基二卤代卟吩衍生物(II),R3和R4相同或不同且至少有一个含有极性基团(如:羧基、醇或氨基),其中
非极性基团为-(CH2)mCH3,-(CH2)mCH(CH3)2,-(CH2)mC(CH3)3,-(CH2)mN[(CH2)mCH3]2,
-(CH2)mO(CH2)mCH3,-(CH2)mO(CH2)mCH(CH3)2,-(CH2)mO(CH2)mC(CH3)3,
-(CH2)m(OCH2CH2)pCH3,-(CH2)mCO(CH2)mCH3,-(CH2)mCO(CH2)mCH(CH3)2,
-(CH2)mCO(CH2)mC(CH3)3,-(CH2)mCONH(CH2)nCH3,-(CH2)mCONH(CH2)nCH(CH3)2或-(CH2)mCONH(CH2)nC(CH3)3,m=0-7,n=1-7,p=1-3;
极性基团为(CH2)mCOOH,-(CH2)mCH(CH3)COOH,-(CH2)mOH,-(CH2)mCH(CH3)OH,
-(CH2)mC6H4OH,-(CH2)mN[(CH2)mCOOH]2,-(CH2)mN[(CH2)nOH]2,-(CH2)mO(CH2)mCOOH,
-(CH2)mO(CH2)nOH,-(CH2)m(OCH2CH2)pOH,-(CH2)mCO(CH2)mCOOH,-(CH2)mCO(CH2)mOH或氨基酸衍生物,m=1-7,n=2-7,p=1-3。
根据本发明中提及的氨基酸衍生物,其中
-(CH2)mCONH(CH2)mCOOH,-(CH2)mCONHCH(CH3)COOH,
-(CH2)mCONH(CH2)mCO(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)mCOOH]2,
-(CH2)mCONHCH(COOH)CH2COOH,m=1-7,p=1-3。
根据本发明中所述的一类新型中介二(3,4-二取代)苯基二卤代卟吩化合物及其氨基酸缩合物(I),其特征在于该类化合物中包括如下化合物:
5,15-二[(3-甲氧基-4-羧甲氧基)苯基]-10,20-二氯卟吩(I1);
5,15-二[(3-羧甲氧基-4-甲氧基)苯基]-10,20-二氯卟吩(I2);
5,15-二[(3-乙氧基-4-羧甲氧基)苯基]-10,20-二氯卟吩(I3);
5,15-二[(3-羧甲氧基-4-乙氧基)苯基]-10,20-二氯卟吩(I4);
5,15-二[(3-丙氧基-4-羧甲氧基)苯基]-10,20-二氯卟吩(I5);
5,15-二[(3-羧甲氧基-4-丙氧基)苯基]-10,20-二氯卟吩(I6);
5,15-二[(3-甲氧基-4-羧丁氧基)苯基]-10,20-二氯卟吩(I7);
5,15-二[(3-羧丁氧基-4-甲氧基)苯基]-10,20-二氯卟吩(I8);
5,15-二[(3-乙氧基-4-羧丁氧基)苯基]-10,20-二氯卟吩(I9);
5,15-二[(3-羧丁氧基-4-乙氧基)苯基]-10,20-二氯卟吩(I10);
5,15-二[(3-丙氧基-4-羧丁氧基)苯基]-10,20-二氯卟吩(I11);
5,15-二[(3-羧丁氧基-4-丙氧基)苯基]-10,20-二氯卟吩(I12);
5,15-二[(3-甲氧基-4-羟乙氧基)苯基]-10,20-二氯卟吩(I13);
5,15-二[(3-羟乙氧基-4-甲氧基)苯基]-10,20-二氯卟吩(I14);
5,15-二[(3-乙氧基-4-羟乙氧基)苯基]-10,20-二氯卟吩(I15);
5,15-二[(3-羟乙氧基-4-乙氧基)苯基]-10,20-二氯卟吩(I16);
5,15-二[(3-丙氧基-4-羟乙氧基)苯基]-10,20-二氯卟吩(I17);
5,15-二[(3-羟乙氧基-4-丙氧基)苯基]-10,20-二氯卟吩(I18);
5,15-二[(3-甲氧基-4-羟丙氧基)苯基]-10,20-二氯卟吩(I19);
5,15-二[(3-羟丙氧基-4-甲氧基)苯基]-10,20-二氯卟吩(I20);
5,15-二[(3-乙氧基-4-羟丙氧基)苯基]-10,20-二氯卟吩(I21);
5,15-二[(3-羟丙氧基-4-乙氧基)苯基]-10,20-二氯卟吩(I22);
5,15-二[(3-丙氧基-4-羟丙氧基)苯基]-10,20-二氯卟吩(I23);
5,15-二[(3-羟丙氧基-4-丙氧基)苯基]-10,20-二氯卟吩(I24);
5,15-二[[3-甲氧基-4-(2-氧代-2-羧甲氨基)乙氧基]苯基]-10,20-二氯卟吩(I25);
5,15-二[[3-甲氧基-4-[2-氧代-2-(2-氧代-4-羧基)丁氨基]乙氧基]苯基]-10,20-二氯卟吩(I26);
5,15-二[[3-甲氧基-4-[2-氧代-2-(N,N-二羧甲基)氨基]乙氧基]苯基]-10,20-二氯卟吩(I27);
5,15-二[(3-甲氧基-4-羧甲氧基)苯基]-10,20-二溴卟吩(I28);
5,15-二[(3-羧甲氧基-4-甲氧基)苯基]-10,20-二溴卟吩(I29);
5,15-二[(3-乙氧基-4-羧甲氧基)苯基]-10,20-二溴卟吩(I30);
5,15-二[(3-羧甲氧基-4-乙氧基)苯基]-10,20-二溴卟吩(I31);
5,15-二[(3-丙氧基-4-羧甲氧基)苯基]-10,20-二溴卟吩(I32);
5,15-二[(3-羧甲氧基-4-丙氧基)苯基]-10,20-二溴卟吩(I33);
5,15-二[(3-甲氧基-4-羧丁氧基)苯基]-10,20-二溴卟吩(I34);
5,15-二[(3-羧丁氧基-4-甲氧基)苯基]-10,20-二溴卟吩(I35);
5,15-二[(3-乙氧基-4-羧丁氧基)苯基]-10,20-二溴卟吩(I36);
5,15-二[(3-羧丁氧基-4-乙氧基)苯基]-10,20-二溴卟吩(I37);
5,15-二[(3-丙氧基-4-羧丁氧基)苯基]-10,20-二溴卟吩(I38);
5,15-二[(3-羧丁氧基-4-丙氧基)苯基]-10,20-二溴卟吩(I39);
5,15-二[(3-甲氧基-4-羟乙氧基)苯基]-10,20-二溴卟吩(I40);
5,15-二[(3-羟乙氧基-4-甲氧基)苯基]-10,20-二溴卟吩(I41);
5,15-二[(3-乙氧基-4-羟乙氧基)苯基]-10,20-二溴卟吩(I42);
5,15-二[(3-羟乙氧基-4-乙氧基)苯基]-10,20-二溴卟吩(I43);
5,15-二[(3-丙氧基-4-羟乙氧基)苯基]-10,20-二溴卟吩(I44);
5,15-二[(3-羟乙氧基-4-丙氧基)苯基]-10,20-二溴卟吩(I45);
5,15-二[(3-甲氧基-4-羟丙氧基)苯基]-10,20-二溴卟吩(I46);
5,15-二[(3-羟丙氧基-4-甲氧基)苯基]-10,20-二溴卟吩(I47);
5,15-二[(3-乙氧基-4-羟丙氧基)苯基]-10,20-二溴卟吩(I48);
5,15-二[(3-羟丙氧基-4-乙氧基)苯基]-10,20-二溴卟吩(I49);
5,15-二[(3-丙氧基-4-羟丙氧基)苯基]-10,20-二溴卟吩(I50);
5,15-二[(3-羟丙氧基-4-丙氧基)苯基]-10,20-二溴卟吩(I51);
5,15-二[[3-甲氧基-4-(2-氧代-2-羧甲氨基)乙氧基]苯基]-10,20-二溴卟吩(I52);
5,15-二[[3-甲氧基-4-[2-氧代-2-(2-氧代-4-羧基)丁氨基]乙氧基]苯基]-10,20-二溴卟吩(I53);
5,15-二[[3-甲氧基-4-[2-氧代-2-(N,N-二羧甲基)氨基]乙氧基]苯基]-10,20-二溴卟吩(I54)。
根据本发明中所述的一类新型亲水性、不易聚集的中介二(3,5-二取代)苯基二卤代卟吩衍生物(I),其特征在于该类化合物中包括如下化合物:
5,15-二[(3-叔丁基-5-羧基)苯基]-10,20-二氯卟吩(II1);
5,15-二[(3-叔丁基-5-羧甲基)苯基]-10,20-二氯卟吩(II2);
5,15-二[(3-叔丁基-5-羧甲氧基)苯基]-10,20-二氯卟吩(II3);
5,15-二[(3-叔丁基-5-羧丙氧基)苯基]-10,20-二氯卟吩(II4);
5,15-二[(3-甲氧基-5-羟乙氧基)苯基]-10,20-二氯卟吩(II5);
5,15-二[(3-甲氧基-5-羟丙氧基)苯基]-10,20-二氯卟吩(II6);
5,15-二[(3,5-二羟乙氧基)苯基]-10,20-二氯卟吩(II7);
5,15-二[(3,5-二羟丙氧基)苯基]-10,20-二氯卟吩(II8);
5,15-二[[3-叔丁基-5-(羧甲氨基)甲酰基]苯基]-10,20-二氯卟吩(II9);
5,15-二[[3-叔丁基-5-[(2-氧代-4-羧基)丁氨基]甲酰基]苯基]-10,20-二氯卟吩(II10);
5,15-二[[3-叔丁基-5-[(N,N-二羧甲基)氨基]甲酰基]苯基]-10,20-二氯卟吩(II11);
5,15-二[(3-叔丁基-5-羧基)苯基]-10,20-二溴卟吩(II12);
5,15-二[(3-叔丁基-5-羧甲基)苯基]-10,20-二溴卟吩(II13);
5,15-二[(3-叔丁基-5-羧甲氧基)苯基]-10,20-二溴卟吩(II14);
5,15-二[(3-叔丁基-5-羧丙氧基)苯基]-10,20-二溴卟吩(II15);
5,15-二[(3-甲氧基-5-羟乙氧基)苯基]-10,20-二溴卟吩(II16);
5,15-二[(3-甲氧基-5-羟丙氧基)苯基]-10,20-二溴卟吩(II17);
5,15-二[(3,5-二羟乙氧基)苯基]-10,20-二溴卟吩(II18);
5,15-二[(3,5-二羟丙氧基)苯基]-10,20-二溴卟吩(II19);
5,15-二[[3-叔丁基-5-(羧甲氨基)甲酰基]苯基]-10,20-二溴卟吩(II20);
5,15-二[[3-叔丁基-5-[(2-氧代-4-羧基)丁氨基]甲酰基]苯基]-10,20-二溴卟吩(II21);
5,15-二[[3-叔丁基-5-[(N,N-二羧甲基)氨基]甲酰基]苯基]-10,20-二溴卟吩(II22)。
本发明首次制备了所述的中介二(二取代)苯基二卤代卟吩衍生物(I)和(II),具有新颖性。
本发明所述的中介二(二取代)苯基二卤代卟吩衍生物(I)和(II),具有光动力活性高、皮肤光毒副作用小、性质稳定、亲水性好、不易聚集、易于配成注射剂等优点,克服了现有光敏化合物与光敏药物中存在的组成复杂、结构不稳定、制备困难、成本较高,易聚集、亲水性较差、皮肤光毒副作用强等缺陷,具有实质性的进步,具有创造性。
本发明所述的中介二(二取代)苯基二卤代卟吩衍生物(I)和(II)具有显著的光动力活性、皮肤光毒副作用小,可作为光动力诊治肿瘤、视网膜黄斑变性、光化性角化病、鲜红斑痣、尖锐湿疣等疾病的药物,具有实用性。
具体制备方案
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发明所限定的范围。
一般方案1
R5和R6为含酯基或乙酰基保护基的R1和R2。
步骤(i)中,将化合物(III)与二吡咯甲烷溶于二氯甲烷,氮气保护下逐滴滴加催化量的三氟乙酸,室温搅拌反应,薄层层析色谱(TLC)监测原料消失产物生成,加入二氯二氰基苯醌和三乙胺,继续搅拌反应,TLC监测氧化完全。减压蒸除溶剂,所得残留物柱层析分离纯化得到紫红色粉末(IV)。
步骤(ii)中,将化合物(IV)溶于二氯甲烷和甲醇混合溶剂中,逐滴滴加卤代试剂[如:N-氯代丁酰亚胺(NCS),或N-溴代丁酰亚胺(NBS),或者N-溴代丁酰亚胺(NIS)]的甲醇溶液,反应混合物在0℃下搅拌,TLC监测原料消失产物生成,加入丙酮淬灭反应。减压蒸除溶剂后用二氯甲烷和甲醇重结晶得到紫红色粉末(V)。
步骤(ii)中,将化合物(V)溶于四氢呋喃中,加入氢氧化钾水溶液,反应混合物在氮气气氛下回流搅拌。反应液冷却至室温,减压蒸除有机溶剂后,残留物用水稀释,用稀盐酸调节pH至5-6。减压过滤收集滤饼,对滤饼进行真空干燥得到紫红色固体(I)。
一般方案2
R7和R8为含酯基或乙酰基保护基的R3和R4。
步骤(iv)中,将化合物(VI)与二吡咯甲烷溶于二氯甲烷,氮气保护下逐滴滴加催化量的三氟乙酸,室温搅拌反应,TLC监测原料消失产物生成,加入二氯二氰基苯醌和三乙胺,继续搅拌反应,TLC监测氧化完全。减压蒸除溶剂,所得残留物柱层析分离纯化得到紫红色粉末(VII)。
步骤(v)中,将化合物(VII)溶于二氯甲烷和甲醇混合溶剂中,逐滴滴加卤代试剂[如:N-氯代丁酰亚胺(NCS),或N-溴代丁酰亚胺(NBS),或者N-溴代丁酰亚胺(NIS)]的甲醇溶液,反应混合物在0℃下搅拌,TLC监测原料消失产物生成,加入丙酮淬灭反应。减压蒸除溶剂后用二氯甲烷和甲醇重结晶得到紫红色固体(VIII)。
步骤(vi)中,将化合物(VIII)溶于四氢呋喃中,加入氢氧化钾水溶液,反应混合物在氮气气氛下回流搅拌。反应液冷却至室温,减压蒸除有机溶剂后,残留物用水稀释,用稀盐酸调节pH至5-6。减压过滤收集滤饼,对滤饼进行真空干燥得到紫红色固体(II)。
[实施例1]
5,15-二[(3-甲氧基-4-羧甲氧基)苯基]-10,20-二氯卟吩(I1)
2-(4-甲酰基-2-甲氧基苯氧基)乙酸乙酯(643mg,2.7mmol)和二吡咯甲烷(392mg,2.7mmol)溶于DCM(500mL),氮气保护下逐滴滴加三氟乙酸(0.12mL,1.7mmol),室温搅拌反应12小时。加入二氯二氰基苯醌DDQ(0.735g,3.24mmol)和三乙胺(4mL),继续搅拌反应1小时。减压蒸除溶剂,所得残留物柱层析分离(洗脱剂为二氯甲烷)纯化得到紫红色粉末IV1(434.4mg,44.3%)。1H NMR(400MHz,CDCl3):δppm 10.32(s,2H),9.41(d,J=4.6Hz,4H),9.15(d,J=4.6Hz,4H),7.89(d,J=2.0Hz,2H),7.80(dd,J=8.0,2.1Hz,2H),7.29(s,2H),5.05(s,4H),4.48(q,J=7.1Hz,4H),4.06(s,6H),1.47(t,J=7.1Hz,6H),-3.06(s,2H).MS(MALDI-TOF):m/z=727.3[M+H]+。
5,15-二[(3-甲氧基-4-乙氧羰甲氧基)苯基]卟吩(600mg,0.82mmol)溶于DCM/MeOH(200mL,VDCM/VMeOH=9/1)中,逐滴加NCS(309mg,1.73mmol)的甲醇溶液,反应混合物在0℃下搅拌5小时,TLC监测原料消失产物生成,加入丙酮(5mL)淬灭反应。减压移除溶剂后用DCM和MeOH重结晶得到紫红色粉末V1(698mg,96%)。1H NMR(400MHz,CDCl3):δppm 9.63(d,J=4.3Hz,4H),8.91(brs,4H),7.76(s,2H),7.69(d,J=8.1Hz,2H),7.22(d,J=8.1Hz,2H),5.04(s,4H),4.48-4.43(m,4H),4.04(s,6H),1.48-1.43(m,6H),-2.72(s,2H).
5,15-二[(3-甲氧基-4-乙氧羰甲氧基)苯基]-10,20-二氯卟吩(400mg,0.45mmol)溶解于THF/MeOH(200mL,VTHF/VMeOH=1/1),然后加入KOH溶液(2mol/L,50mL),反应混合物在氮气气氛下加热回流搅拌6小时,TLC监测反应完全,减压移除有机溶剂,加入水(30mL),用稀盐酸溶液(2mol/L)调节pH至5-6。抽滤,收集滤饼,真空干燥滤饼得到紫红色固体I1(352mg,94%)。1H NMR(400MHz,DMSO-d6):δppm 12.45(s,2H),8.96(brs,4H),8.62(brs,4H),7.70(s,2H),7.63(s,2H),7.18(s,2H),4.36(s,4H),3.92(s,6H),-2.73(s,2H).13CNMR(101MHz,DMSO-d6):δppm 171.80,152.24,150.67,145.65,145.44,145.01,144.71,144.40,143.71,140.60,132.93,132.08,131.14,130.53,129.62,124.20,122.05,120.78,118.74,115.36,114.82,114.13,109.39,66.21,56.83.HRMS(MALDI-TOF):calculated forC38H28Cl2N4O8[M+H]+:738.13;found 739.0918。
[实施例2]
5,15-二[(3-甲氧基-4-羟乙氧基)苯基]-10,20-二氯卟吩(I13)
参照化合物I1的合成方法制备了化合物I13。1H NMR(400MHz,DMSO-d6):δppm 8.86(brs,4H),8.15(d,J=7.9Hz,4H),7.96(d,J=8.0Hz,2H),7.74(d,J=7.5Hz,2H),7.43(d,J=7.8Hz,2H),4.97(t,J=5.6Hz,2H),4.25(d,J=5.2Hz,4H),3.97(s,6H),3.75-3.70(m,4H),-2.73(s,2H).13C NMR(101MHz,DMSO-d6):δppm 151.12,150.91,145.65,145.44,145.01,144.71,144.40,143.71,140.60,132.93,131.96,131.14,130.53,130.00,124.20,122.05,120.78,118.74,115.34,114.86,114.13,109.39,70.25,60.89,56.83.HRMS(MALDI-TOF):calculated for C38H32Cl2N4O6[M+H]+,710.17;found 711.3284。
[实施例3]
5,15-二[[3-甲氧基-4-[2-氧代-2-(2-氧代-4-羧基)丁氨基]乙氧基]苯基]-10,20-二氯卟吩(I26)
参照化合物I1的合成方法制备了化合物I26。1H NMR(400MHz,DMSO-d6):δppm 12.55(s,2H),10.25(s,2H),9.58(d,J=4.5Hz,4H),8.99(brs,4H),7.73(s,2H),7.69(s,2H),7.20(d,J=7.3Hz,2H),4.85(s,4H),4.28(d,J=4.6Hz,4H),3.85(s,6H),2.82-2.71(m,8H),-2.73(s,2H).13C NMR(101MHz,DMSO-d6):δppm 204.48,175.89,169.81,152.24,150.67,145.65,145.01,144.71,144.40,143.71,140.60,132.93(s),131.14,130.53,129.62,124.20,122.05,120.78,118.74,115.36,114.82,114.13,109.39,68.20,56.83,47.38,37.95,31.19.HRMS(MALDI-TOF):calculated for C48H42Cl2N6O12[M+H]+,965.79;found 966.1093。
[实施例4]
5,15-二[(3-甲氧基-4-羧甲氧基)苯基]-10,20-二溴卟吩(I28)
参照化合物I1的合成方法制备了化合物I28。1H NMR(400MHz,DMSO-d6):δppm 12.58(s,2H),9.66(brs,4H),8.99(brs,4H),7.79(s,2H),7.64(s,2H),7.17(d,J=7.8Hz,2H),4.38(s,4H),3.91(s,6H),-2.83(s,2H).13C NMR(101MHz,DMSO-d6):δppm 170.72,158.51,136.02,133.55,121.67,113.71,103.50,79.76,79.43,79.10,65.43.HRMS(MALDI-TOF):calculated for C38H28Br2N4O8[M+H]+:826.03;found 827.2019。
[实施例5]
5,15-二[(3-羧甲氧基-4-甲氧基)苯基]-10,20-二溴卟吩(I29)
参照化合物I1的合成方法制备了化合物I29。1H NMR(400MHz,DMSO-d6):δppm 9.78(d,J=4.8Hz,4H),9.10(d,J=4.8Hz,4H),8.09(d,J=1.9Hz,2H),7.84(dd,J=8.1,1.9Hz,2H),7.38(d,J=8.2Hz,2H),5.18(s,4H),4.08(s,6H),-2.53(s,2H).13C NMR(101MHz,DMSO-d6):δppm 171.80,151.90,149.46,147.57,146.75,145.01,143.71,140.60,133.74,132.63,130.86,128.49,127.21,125.86,124.25,122.22,118.58,115.74,115.11,112.97,110.59,105.56,66.21,56.83.HRMS(MALDI-TOF):calculated for C38H28Br2N4O8[M+H]+:826.03;found 827.1175。
[实施例6]
5,15-二[(3-甲氧基-4-羧丁氧基)苯基]-10,20-二溴卟吩(I34)
参照化合物I1的合成方法制备了化合物I34。1H NMR(400MHz,Pyr):δppm 11.30(d,J=2.6Hz,4H),10.58(s,4H),9.43(s,2H),9.30(s,2H),8.91(d,J=8.3Hz,2H),5.94(s,4H),5.72(d,J=7.1Hz,4H),5.47(s,6H),3.97–3.92(m,4H),-0.95(s,2H)..13C NMR(101MHz,Pyr):δppm177.25,151.12,150.91,147.57,146.75,145.01,143.71,140.60,133.74,132.63,131.96,131.14,130.00,128.49,127.21,125.86,124.25,122.22,118.58,115.34,114.91,110.59,105.56,69.99,56.83,31.84,24.05.HRMS(MALDI-TOF):calculated for C42H36Br2N4O8[M+H]+:882.09;found883.3643。
[实施例7]
5,15-二[(3-羧丁氧基-4-甲氧基)苯基]-10,20-二溴卟吩(I35)
参照化合物I1的合成方法制备了化合物I35。1H NMR(400MHz,DMSO-d6):δppm 9.77(d,J=4.6Hz,4H),9.09(s,4H),8.09(s,2H),7.84(d,J=7.9Hz,2H),7.39(d,J=8.2Hz,2H),5.18(s,4H),4.17(d,J=7.1Hz,4H),4.09(s,4H),4.08(s,6H),-2.54(s,2H).13C NMR(101MHz,DMSO-d6):δppm 177.25,152.90,150.34,147.57,146.75,145.01,143.71,140.60,133.74,132.63,131.14,130.60,129.81,128.49,127.21,125.86,124.25,122.22,118.58,115.11,112.74,110.59,105.56,69.99,56.83,31.84,24.05.HRMS(MALDI-TOF):calculated for C42H36Br2N4O8[M+H]+:882.09;found,883.0923。
[实施例8]
5,15-二[[3-甲氧基-4-[2-氧代-2-(2-氧代-4-羧基)丁氨基]乙氧基]苯基]-10,20-二溴卟吩(I53)
参照化合物I1的合成方法制备了化合物I53。1H NMR(400MHz,DMSO-d6):δppm 12.64(s,2H),10.35(s,2H),9.62(d,J=4.5Hz,4H),8.96(brs,4H),7.83(s,2H),7.66(s,2H),7.20(d,J=7.5Hz,2H),4.82(s,4H),4.35(d,J=4.6Hz,4H),3.98(s,6H),2.82-2.60(m,8H),-2.75(s,2H).13C NMR(101MHz,DMSO-d6):δppm 204.48,175.89,171.66,147.57,145.01,143.14,136.36,132.63,131.14,128.49,125.86,124.25,119.28,118.50,115.11,105.56,55.23,47.38,44.50,37.95,31.19.HRMS(MALDI-TOF):calculated forC48H42Br2N6O12[M+H]+,1052.12;found 1053.1233。
[实施例9]
5,15-二[(3-叔丁基-5-羧基)苯基]-10,20-二氯卟吩(II1)
参照化合物I1的合成方法制备了化合物II1。1H NMR(400MHz,DMSO-d6):δppm12.43(s,2H),9.67(brs,4H),8.83(brs,4H),7.73(s,2H),7.57(s,2H),7.38(s,2H)1.58(s,9H),1.37(s,9H),-2.82(d,J=18.7Hz,2H).13C NMR(101MHz,DMSO-d6):δppm 167.64,152.62,145.65,145.44,145.01,144.70,144.40,141.13,140.27,132.93,132.04,131.39,130.53,130.20,124.20,122.05,120.78,118.82 114.82,114.13,109.39,35.51,31.36.HRMS(MALDI-TOF):calculated for C42H36Cl2N4O4[M+H]+,730.21;found,731.6385。
[实施例10]
5,15-二[(3-甲氧基-5-羟乙氧基)苯基]-10,20-二氯卟吩(II5)
参照化合物I1的合成方法制备了化合物II5。1H NMR(400MHz,DMSO-d6):δppm 8.84(brs,4H),8.18(d,J=7.9Hz,4H),7.99(d,J=8.1Hz,2H),7.74(d,J=7.9Hz,2H),7.43(d,J=7.5Hz,2H),4.97(t,J=5.5Hz,2H),4.23(d,J=5.2Hz,4H),3.97(s,6H),3.73-3.70(m,4H),-2.93(s,2H).13C NMR(101MHz,DMSO-d6):δppm 160.98,159.59,145.65,145.44,145.01,144.70,144.40,141.13,140.23,132.93,131.14,130.53,124.20,122.05,120.78,118.82,118.00,116.89,114.77,109.39,105.35,69.84,60.89,56.08.HRMS(MALDI-TOF):calculated for C38H32Cl2N4O6[M+H]+,710.17;found 711.2912。
[实施例11]
5,15-二[(3,5-二羟乙氧基)苯基]-10,20-二氯卟吩(II7)
参照化合物I1的合成方法制备了化合物II7。1H NMR(400MHz,DMSO-d6):δppm 8.94(brs,4H),8.21(d,J=6.9Hz,4H),7.87(d,J=8.5Hz,2H),7.71(d,J=7.7Hz,2H),7.53(d,J=7.4Hz,2H),4.99(s,4H),4.23(d,J=5.1Hz,8H),3.75-3.69(m,8H),-2.93(s,2H).13C NMR(101MHz,DMSO-d6):δppm 159.24,145.65,145.44,145.01,144.70,141.13,138.79,132.93,131.14,130.53,124.20,122.05,120.78,118.82,116.83(s),114.82,109.39,107.33,69.84,60.89.HRMS(MALDI-TOF):calculated for C40H36Cl2N4O8[M+H]+,770.19;found 771.2536。
[实施例12]
5,15-二[[3-叔丁基-5-[(2-氧代-4-羧基)丁氨基]甲酰基]苯基]-10,20-二氯卟吩(II10)
参照化合物I1的合成方法制备了化合物II10。1H NMR(400MHz,DMSO-d6):δppm12.58(s,2H),9.66(s,4H),8.85(s,4H),8.64(t,J=5.6Hz,2H),8.13(d,J=7.9Hz,2H),7.77(d,J=8.0Hz,2H),4.16(d,J=5.5Hz,4H),3.91(s,4H),2.76(t,J=6.5Hz,4H),1.61(s,18H),-2.95(s,2H).13CNMR(101MHz,DMSO-d6):δppm 204.48,175.89,166.93,152.81,145.65,145.44,144.70,141.06,138.35,134.21,132.93,131.13,130.53,129.96,124.20,122.05,120.78,118.82,118.00,114.82,114.13,109.39,49.27,37.95,35.51,31.28.HRMS(MALDI-TOF):calculated for C52H50Cl2N6O8[M+H]+,956.31;found 957.1026。
[实施例13]
5,15-二[[3-叔丁基-5-[(N,N-二羧甲基)氨基]甲酰基]苯基]-10,20-二氯卟吩(II11)
参照化合物I1的合成方法制备了化合物II11。1H NMR(400MHz,DMSO-d6):δppm12.61(s,4H),9.63(d,J=3.7Hz,4H),8.97(brs,4H),7.79(d,J=7.2Hz,2H),7.62(d,J=7.9Hz,4H),4.38(s,4H),4.22(s,4H),1.61(s,18H),-2.87(s,2H).13C NMR(101MHz,DMSO-d6):δppm 172.28,153.54,145.65,145.44,145.01,144.70,144.40,141.13,140.07,138.72,133.22,132.93,131.65,131.14,130.53,129.34,124.20,122.05,120.78,118.82,118.00,114.82,114.13,109.39,47.56,35.51,31.36.HRMS(MALDI-TOF):calculated forC50H46Cl2N6O10[M+H]+,960.27;found961.1324。
[实施例14]
5,15-二[(3-叔丁基-5-羧基)苯基]-10,20-二溴卟吩(II12)
参照化合物I1的合成方法制备了化合物II12。1H NMR(400MHz,DMSO-d6):δppm12.52(s,2H),9.70(brs,4H),8.84(brs,4H),8.66(s,2H),8.48(s,2H),8.38(s,2H)1.55(s,9H),1.36(s,9H),-2.90(d,J=18.7Hz,2H).13C NMR(101MHz,DMSO-d6):δppm 172.82,157.76,142.71,128.09,127.74,123.74,122.71,121.66,121.45,114.81,103.89,67.38,60.20,41.89,41.00,31.12,29.79,28.93.24.98,14.05.HRMS(MALDI-TOF):calculatedfor C42H36Br2N4O4[M+H]+,818.11;found,819.6385。
[实施例15]
5,15-二[(3-甲氧基-5-羟乙氧基)苯基]-10,20-二溴卟吩(II16)
参照化合物I1的合成方法制备了化合物II16。1H NMR(400MHz,DMSO-d6):δppm 8.88(brs,4H),8.07(d,J=8.4Hz,4H),7.93(s,2H),7.78(d,J=7.5Hz,2H),7.49(d,J=7.2Hz,2H),4.98(t,J=5.1Hz,2H),4.23(d,J=4.8Hz,4H),4.01(s,6H),3.75-3.70(m,4H),-2.82(s,2H).13C NMR(101MHz,DMSO-d6):δppm 160.98,159.59,147.57,146.75,145.01,144.70,141.13,140.23,133.74,132.63,131.14,128.49,127.21,125.86,124.25,122.22,118.50,116.89,115.11,114.73,110.59,105.56,105.35,69.84,60.89,56.08.HRMS(MALDI-TOF):calculated for C38H32Br2N4O6[M+H]+,798.07;found 799.3214。
[实施例16]
5,15-二[(3,5-二羟乙氧基)苯基]-10,20-二溴卟吩(II18)
参照化合物I1的合成方法制备了化合物II18。1H NMR(400MHz,DMSO-d6):δppm 8.93(brs,4H),8.12(d,J=8.5Hz,4H),7.87(s,2H),7.65(d,J=7.2Hz,2H),7.44(d,J=7.1Hz,2H),4.93(S,4H),4.23(d,J=4.8Hz,8H),3.71-3.63(m,8H),-2.82(s,2H).13C NMR(101MHz,DMSO-d6):δppm 159.24,147.57,146.75,145.01,144.70,141.13,138.79,133.74,132.63,131.14,128.49,127.21,125.86,124.25,122.22,118.50,118.00,116.83,115.11,110.59,107.33,105.56,69.84,60.89.HRMS(MALDI-TOF):calculated for C40H36Br2N4O8[M+H]+,858.09;found859.0256。
[实施例17]
5,15-二[[3-叔丁基-5-[(2-氧代-4-羧基)丁氨基]甲酰基]苯基]-10,20-二溴卟吩(II21)
参照化合物I1的合成方法制备了化合物II21。1H NMR(400MHz,DMSO-d6):δppm12.24(s,2H),9.54(s,4H),8.82(s,4H),8.56(s,2H),8.13(d,J=6.4Hz,2H),7.96(s,2H),4.11(d,J=4.9Hz,4H),2.72(t,J=6.1Hz,4H),2.47(t,J=6.0Hz,4H),1.68(s,18H),-3.20(s,2H).13C NMR(101MHz,DMSO-d6):δppm 204.48,175.89,166.93,152.81,147.57,146.75,145.01,144.70,141.06,138.35,134.21,133.74,132.63,131.13,129.96,128.49,127.21,125.86,124.25,122.22,118.50,115.11,110.59,105.56,49.27,37.95,35.51,31.28.HRMS(MALDI-TOF):calculated for C50H46Br2N6O10[M+H]+,1044.21;found 1045.0122。
[实施例18]
5,15-二[[3-叔丁基-5-[(N,N-二羧甲基)氨基]甲酰基]苯基]-10,20-二溴卟吩(II22)
参照化合物I1的合成方法制备了化合物II22。1H NMR(400MHz,DMSO-d6):δppm12.59(s,4H),9.64(d,J=3.7Hz,4H),8.85(brs,4H),8.10(d,J=7.9Hz,4H),7.67(d,J=8.0Hz,2H),4.34(s,4H),4.11(s,4H),1.58(s,9H),1.53(s,9H),-3.00(s,2H).13C NMR(101MHz,DMSO-d6):δppm 172.28,153.54,147.57,146.75,145.01,144.70,141.13,140.07,138.72,133.74,133.22,132.63,131.14,129.34,128.49,127.21,125.86,124.25,122.22,118.50,118.00,115.11,110.59,105.56,47.56,35.51,31.36.HRMS(MALDI-TOF):calculated for C50H46Br2N6O10[M+H]+,1048.16;found 1049.1078。
[实施例19]
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:
XD-650AB型激光器;SD2490型激光功率测量仪。
受试药物:
5,15-二[(3-甲氧基-4-羧甲氧基)苯基]-10,20-二氯卟吩(I1);5,15-二[(3-羧甲氧基-4-甲氧基)苯基]-10,20-二氯卟吩(I2);5,15-二[(3-乙氧基-4-羧甲氧基)苯基]-10,20-二氯卟吩(I3);5,15-二[(3-丙氧基-4-羧甲氧基)苯基]-10,20-二氯卟吩(I5);5,15-二[(3-甲氧基-4-羧丁氧基)苯基]-10,20-二氯卟吩(I7);5,15-二[(3-甲氧基-4-羟乙氧基)苯基]-10,20-二氯卟吩(I13);5,15-二[(3-甲氧基-4-羟丙氧基)苯基]-10,20-二氯卟吩(I19);5,15-二[[3-甲氧基-4-(2-氧代-2-羧甲氨基)乙氧基]苯基]-10,20-二氯卟吩(I25);5,15-二[[3-甲氧基-4-[2-氧代-2-(2-氧代-4-羧基)丁氨基]乙氧基]苯基]-10,20-二氯卟吩(I26);5,15-二[[3-甲氧基-4-[2-氧代-2-(N,N-二羧甲基)氨基]乙氧基]苯基]-10,20-二氯卟吩(I27);5,15-二[(3-甲氧基-4-羧甲氧基)苯基]-10,20-二溴卟吩(I28);5,15-二[(3-羧甲氧基-4-甲氧基)苯基]-10,20-二溴卟吩(I29);5,15-二[(3-乙氧基-4-羧甲氧基)苯基]-10,20-二溴卟吩(I30);5,15-二[(3-丙氧基-4-羧甲氧基)苯基]-10,20-二溴卟吩(I32);5,15-二[(3-甲氧基-4-羧丁氧基)苯基]-10,20-二溴卟吩(I34);5,15-二[(3-甲氧基-4-羟乙氧基)苯基]-10,20-二溴卟吩(I40);5,15-二[(3-甲氧基-4-羟丙氧基)苯基]-10,20-二溴卟吩(I46);5,15-二[[3-甲氧基-4-(2-氧代-2-羧甲氨基)乙氧基]苯基]-10,20-二溴卟吩(I52);5,15-二[[3-甲氧基-4-[2-氧代-2-(2-氧代-4-羧基)丁氨基]乙氧基]
苯基]-10,20-二溴卟吩(I53);5,15-二[[3-甲氧基-4-[2-氧代-2-(N,N-二羧甲基)氨基]乙氧基]
苯基]-10,20-二溴卟吩(I54);5,15-二[(3-叔丁基-5-羧基)苯基]-10,20-二氯卟吩(II1);5,15-二[(3-叔丁基-5-羧甲基)苯基]-10,20-二氯卟吩(II2);5,15-二[(3-叔丁基-5-羧甲氧基)苯基]-10,20-二氯卟吩(II3);5,15-二[(3-叔丁基-5-羧丙氧基)苯基]-10,20-二氯卟吩(II4);5,15-二[(3-甲氧基-5-羟乙氧基)苯基]-10,20-二氯卟吩(II5);5,15-二[(3-甲氧基-5-羟丙氧基)苯基]-10,20-二氯卟吩(II6);5,15-二[(3,5-二羟乙氧基)苯基]-10,20-二氯卟吩(II7);5,15-二[(3,5-二羟丙氧基)苯基]-10,20-二氯卟吩(II8);5,15-二[[3-叔丁基-5-(羧甲氨基)甲酰基]苯基]-10,20-二氯卟吩(II9);5,15-二[[3-叔丁基-5-[(2-氧代-4-羧基)丁氨基]甲酰基]
苯基]-10,20-二氯卟吩(II10);5,15-二[[3-叔丁基-5-[(N,N-二羧甲基)氨基]甲酰基]苯基]-10,20-二氯卟吩(II11);5,15-二[(3-叔丁基-5-羧基)苯基]-10,20-二溴卟吩(II12);5,15-二[(3-叔丁基-5-羧甲基)苯基]-10,20-二溴卟吩(II13);5,15-二[(3-叔丁基-5-羧甲氧基)苯基]-10,20-二溴卟吩(II14);5,15-二[(3-叔丁基-5-羧丙氧基)苯基]-10,20-二溴卟吩(II15);5,15-二[(3-甲氧基-5-羟乙氧基)苯基]-10,20-二溴卟吩(II16);5,15-二[(3-甲氧基-5-羟丙氧基)苯基]-10,20-二溴卟吩(II17);5,15-二[(3,5-二羟乙氧基)苯基]-10,20-二溴卟吩(II18);5,15-二[(3,5-二羟丙氧基)苯基]-10,20-二溴卟吩(II19);5,15-二[[3-叔丁基-5-(羧甲氨基)甲酰基]苯基]-10,20-二溴卟吩(II20);5,15-二[[3-叔丁基-5-[(2-氧代-4-羧基)丁氨基]甲酰基]苯基]-10,20-二溴卟吩(II21);5,15-二[[3-叔丁基-5-[(N,N-二羧甲基)氨基]甲酰基]苯基]-10,20-二溴卟吩(II22)。
对照化合物:
化合物1、化合物2、化合物3、化合物4、化合物5、化合物6、化合物7、化合物8、化合物9、化合物10。
对照药物:
海姆泊芬。
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,完全培养基重悬成细胞悬液,随之将其接种于96孔板,每孔100μL,置于37℃5% CO2培养箱培养,24小时后加入光敏剂;12小时后进行光照处理(功率18mW/cm2,波长650nm,光剂量4J/cm2)并加入培养基继续培养;24小时后进行MTT检测。培养终止前4小时加入20μL 5mg/mL的MTT,吸弃培养液后加150μL DMSO终止反应,酶标仪570nm检测OD值。实验重复三次。实验结果见表1,结果发现中介二苯基二卤代卟吩衍生物I1-3,I5,I7,I13,I19,I25-30,I32,I34,I40,I46,I52-54和II1-22对人食管癌细胞均有抗增殖作用,且光动力活性均显著优于对照化合物1-10和对照药物海姆泊芬。
表1新化合物对Eca-109人食管癌细胞增殖抑制作用
与对照化合物1-10中抗肿瘤效果最好的对照化合物8相比,ΔP<0.05,ΔΔP<0.01,ΔΔΔP<0.001;与对照药海姆泊芬相比,*P<0.05,**P<0.01,***P<0.001。
[实施例20]
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±2g)。
光源:
230V·E27/ES欧司朗模拟太阳光灯;YK-PDT-300型功率密度计。
受试药物:
5,15-二[(3-甲氧基-4-羧甲氧基)苯基]-10,20-二氯卟吩(I1);5,15-二[(3-羧甲氧基-4-甲氧基)苯基]-10,20-二氯卟吩(I2);5,15-二[(3-乙氧基-4-羧甲氧基)苯基]-10,20-二氯卟吩(I3);5,15-二[(3-丙氧基-4-羧甲氧基)苯基]-10,20-二氯卟吩(I5);5,15-二[(3-甲氧基-4-羧丁氧基)苯基]-10,20-二氯卟吩(I7);5,15-二[(3-甲氧基-4-羟乙氧基)苯基]-10,20-二氯卟吩(I13);5,15-二[(3-甲氧基-4-羟丙氧基)苯基]-10,20-二氯卟吩(I19);5,15-二[[3-甲氧基-4-(2-氧代-2-羧甲氨基)乙氧基]苯基]-10,20-二氯卟吩(I25);5,15-二[[3-甲氧基-4-[2-氧代-2-(2-氧代-4-羧基)丁氨基]乙氧基]苯基]-10,20-二氯卟吩(I26);5,15-二[[3-甲氧基-4-[2-氧代-2-(N,N-二羧甲基)氨基]乙氧基]苯基]-10,20-二氯卟吩(I27);5,15-二[(3-甲氧基-4-羧甲氧基)苯基]-10,20-二溴卟吩(I28);5,15-二[(3-羧甲氧基-4-甲氧基)苯基]-10,20-二溴卟吩(I29);5,15-二[(3-乙氧基-4-羧甲氧基)苯基]-10,20-二溴卟吩(I30);5,15-二[(3-丙氧基-4-羧甲氧基)苯基]-10,20-二溴卟吩(I32);5,15-二[(3-甲氧基-4-羧丁氧基)苯基]-10,20-二溴卟吩(I34);5,15-二[(3-甲氧基-4-羟乙氧基)苯基]-10,20-二溴卟吩(I40);5,15-二[(3-甲氧基-4-羟丙氧基)苯基]-10,20-二溴卟吩(I46);5,15-二[[3-甲氧基-4-(2-氧代-2-羧甲氨基)乙氧基]苯基]-10,20-二溴卟吩(I52);5,15-二[[3-甲氧基-4-[2-氧代-2-(2-氧代-4-羧基)丁氨基]乙氧基]苯基]-10,20-二溴卟吩(I53);5,15-二[[3-甲氧基-4-[2-氧代-2-(N,N-二羧甲基)氨基]乙氧基]苯基]-10,20-二溴卟吩(I54);5,15-二[(3-叔丁基-5-羧基)苯基]-10,20-二氯卟吩(II1);5,15-二[(3-叔丁基-5-羧甲基)苯基]-10,20-二氯卟吩(II2);5,15-二[(3-叔丁基-5-羧甲氧基)苯基]-10,20-二氯卟吩(II3);5,15-二[(3-叔丁基-5-羧丙氧基)苯基]-10,20-二氯卟吩(II4);5,15-二[(3-甲氧基-5-羟乙氧基)苯基]-10,20-二氯卟吩(II5);5,15-二[(3-甲氧基-5-羟丙氧基)苯基]-10,20-二氯卟吩(II6);5,15-二[(3,5-二羟乙氧基)苯基]-10,20-二氯卟吩(II7);5,15-二[(3,5-二羟丙氧基)苯基]-10,20-二氯卟吩(II8);5,15-二[[3-叔丁基-5-(羧甲氨基)甲酰基]苯基]-10,20-二氯卟吩(II9);5,15-二[[3-叔丁基-5-[(2-氧代-4-羧基)丁氨基]甲酰基]苯基]-10,20-二氯卟吩(II10);5,15-二[[3-叔丁基-5-[(N,N-二羧甲基)氨基]甲酰基]苯基]-10,20-二氯卟吩(II11);5,15-二[(3-叔丁基-5-羧基)苯基]-10,20-二溴卟吩(II12);5,15-二[(3-叔丁基-5-羧甲基)苯基]-10,20-二溴卟吩(II13);5,15-二[(3-叔丁基-5-羧甲氧基)苯基]-10,20-二溴卟吩(II14);5,15-二[(3-叔丁基-5-羧丙氧基)苯基]-10,20-二溴卟吩(II15);5,15-二[(3-甲氧基-5-羟乙氧基)苯基]-10,20-二溴卟吩(II16);5,15-二[(3-甲氧基-5-羟丙氧基)苯基]-10,20-二溴卟吩(II17);5,15-二[(3,5-二羟乙氧基)苯基]-10,20-二溴卟吩(II18);5,15-二[(3,5-二羟丙氧基)苯基]-10,20-二溴卟吩(II19);5,15-二[[3-叔丁基-5-(羧甲氨基)甲酰基]苯基]-10,20-二溴卟吩(II20);5,15-二[[3-叔丁基-5-[(2-氧代-4-羧基)丁氨基]甲酰基]苯基]-10,20-二溴卟吩(II21);5,15-二[[3-叔丁基-5-[(N,N-二羧甲基)氨基]甲酰基]苯基]-10,20-二溴卟吩(II22);
对照药物:
光敏素II。
小鼠模型皮肤光毒性评价实验:
将小鼠随机分组,8只为一组,雌雄各半,实验前24h将小鼠背部毛发剃除。各组给予受试药物1次性尾部静脉,注射剂量为10mg/kg,给药后4h接受模拟太阳光照射10min,光照强度为10mW/cm2。照光前需使用5%水合氯醛经腹腔注射麻醉小鼠,麻醉剂量为0.06mL/10g。将小鼠俯卧固定在自制固定器,小鼠在暗室内置于光源下45cm处照光。小鼠照光后需严格避光,照射后严密观察并记录动物的生理情况。模拟太阳光照射24h后将小鼠颈椎脱臼法处死,用8mm打孔器取背部皮肤,电子分析天平称重,计算背部皮指数,背部皮指数计算公式为背部皮指数=背部皮肤重量(mg)/体重(g)×100。受试药物组的背皮指数与对照组的背部皮指数差异越小表示皮肤光毒性越弱。实验结果见表2,结果发现经中介二苯基二卤代卟吩衍生物I1-3,I5,I7,I13,I19,I25,I27-30,I32,I34,I40,I46,I52,I54,II1,II3,II5-9,II11-19,II21-22处理的小鼠背部皮指数显著低于光敏素II处理组,表明上述受试化合物均具有较低的皮肤光毒副作用。
表2新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,ΔP<0.05,ΔΔP<0.01,ΔΔΔP<0.001。
Claims (4)
1.一类中介二(二取代)苯基二卤代卟吩类四吡咯光敏化合物,其特征在于:所述光敏化合物为中介二[3,4-二取代]苯基二卤代卟吩衍生物(I)和中介二(3,5-二取代)苯基二卤代卟吩衍生物(II):
其中:
X为Cl,Br或I;
A和Y相同或不同且独立地为CH2或O;
R1为-(CH2)mCH3,-(CH2)mCH(CH3)2,-(CH2)mC(CH3)3,-(CH2)mN[(CH2)mCH3]2,-(CH2)mO(CH2)mCH3,-(CH2)mO(CH2)mCH(CH3)2,-(CH2)mO(CH2)mC(CH3)3,-(CH2)m(OCH2CH2)pCH3,-(CH2)mCO(CH2)mCH3,-(CH2)mCO(CH2)mCH(CH3)2,-(CH2)mCO(CH2)mC(CH3)3,-(CH2)mCONH(CH2)nCH3,-(CH2)mCONH(CH2)nCH(CH3)2,-(CH2)mCONH(CH2)nC(CH3)3,m=0-7,n=1-7,p=1-3,
R2为-(CH2)mCOOH,-(CH2)mCH(CH3)COOH,-(CH2)mOH,-(CH2)mCH(CH3)OH,-(CH2)mC6H4OH,-(CH2)mN[(CH2)mCOOH]2,-(CH2)mN[(CH2)nOH]2,-(CH2)mO(CH2)mCOOH,-(CH2)mO(CH2)nOH,-(CH2)m(OCH2CH2)pOH,-(CH2)mCO(CH2)mCOOH,-(CH2)mCO(CH2)mOH或氨基酸衍生物,m=1-7,n=2-7,p=1-3;
或R1为-(CH2)mCOOH,-(CH2)mCH(CH3)COOH,-(CH2)mOH,-(CH2)mCH(CH3)OH,-(CH2)mC6H4OH,-(CH2)mN[(CH2)mCOOH]2,-(CH2)mN[(CH2)nOH]2,-(CH2)mO(CH2)mCOOH,-(CH2)mO(CH2)nOH,-(CH2)m(OCH2CH2)pOH,-(CH2)mCO(CH2)mCOOH,-(CH2)mCO(CH2)mOH或氨基酸衍生物,m=1-7,n=2-7,p=1-3,
R2为-(CH2)mCH3,-(CH2)mCH(CH3)2,-(CH2)mC(CH3)3,-(CH2)mN[(CH2)mCH3]2,-(CH2)mO(CH2)mCH3,-(CH2)mO(CH2)mCH(CH3)2,-(CH2)mO(CH2)mC(CH3)3,-(CH2)m(OCH2CH2)pCH3,-(CH2)mCO(CH2)mCH3,-(CH2)mCO(CH2)mCH(CH3)2,-(CH2)mCO(CH2)mC(CH3)3,-(CH2)mCONH(CH2)nCH3,-(CH2)mCONH(CH2)nCH(CH3)2,-(CH2)mCONH(CH2)nC(CH3)3,m=0-7,n=1-7,p=1-3;
R3和R4相同或不同,为极性或非极性基团且至少有一个含有极性基团,其中:
非极性基团为-(CH2)mCH3,-(CH2)mCH(CH3)2,-(CH2)mC(CH3)3,-(CH2)mN[(CH2)mCH3]2,-(CH2)mO(CH2)mCH3,-(CH2)mO(CH2)mCH(CH3)2,-(CH2)mO(CH2)mC(CH3)3,-(CH2)m(OCH2CH2)pCH3,-(CH2)mCO(CH2)mCH3,-(CH2)mCO(CH2)mCH(CH3)2,-(CH2)mCO(CH2)mC(CH3)3,-(CH2)mCONH(CH2)nCH3,-(CH2)mCONH(CH2)nCH(CH3)2或-(CH2)mCONH(CH2)nC(CH3)3,m=0-7,n=1-7,p=1-3;
极性基团为(CH2)mCOOH,-(CH2)mCH(CH3)COOH,-(CH2)mOH,-(CH2)mCH(CH3)OH,-(CH2)mC6H4OH,-(CH2)mN[(CH2)mCOOH]2,-(CH2)mN[(CH2)nOH]2,-(CH2)mO(CH2)mCOOH,-(CH2)mO(CH2)nOH,-(CH2)m(OCH2CH2)pOH,-(CH2)mCO(CH2)mCOOH,-(CH2)mCO(CH2)mOH或氨基酸衍生物,m=1-7,n=2-7,p=1-3;
其中氨基酸衍生物为:
-(CH2)mCONH(CH2)mCOOH,-(CH2)mCONHCH(CH3)COOH,
-(CH2)mCONH(CH2)mCO(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)mCOOH]2,
-(CH2)mCONHCH(COOH)CH2COOH,m=1-7,p=1-3。
2.根据权利要求1所述的一类中介二(3,4-二取代)苯基二卤代卟吩衍生物(I),为如下化合物:5,15-二[(3-甲氧基-4-羧甲氧基)苯基]-10,20-二氯卟吩(I1);
5,15-二[(3-羧甲氧基-4-甲氧基)苯基]-10,20-二氯卟吩(I2);
5,15-二[(3-乙氧基-4-羧甲氧基)苯基]-10,20-二氯卟吩(I3);
5,15-二[(3-丙氧基-4-羧甲氧基)苯基]-10,20-二氯卟吩(I5);
5,15-二[(3-甲氧基-4-羧丁氧基)苯基]-10,20-二氯卟吩(I7);
5,15-二[(3-羧丁氧基-4-甲氧基)苯基]-10,20-二氯卟吩(I8);
5,15-二[(3-乙氧基-4-羧丁氧基)苯基]-10,20-二氯卟吩(I9);
5,15-二[(3-丙氧基-4-羧丁氧基)苯基]-10,20-二氯卟吩(I11);
5,15-二[(3-甲氧基-4-羟乙氧基)苯基]-10,20-二氯卟吩(I13);
5,15-二[(3-羟乙氧基-4-甲氧基)苯基]-10,20-二氯卟吩(I14);
5,15-二[(3-乙氧基-4-羟乙氧基)苯基]-10,20-二氯卟吩(I15);
5,15-二[(3-羟乙氧基-4-乙氧基)苯基]-10,20-二氯卟吩(I16);
5,15-二[(3-丙氧基-4-羟乙氧基)苯基]-10,20-二氯卟吩(I17);
5,15-二[(3-羟乙氧基-4-丙氧基)苯基]-10,20-二氯卟吩(I18);
5,15-二[(3-甲氧基-4-羟丙氧基)苯基]-10,20-二氯卟吩(I19);
5,15-二[(3-羟丙氧基-4-甲氧基)苯基]-10,20-二氯卟吩(I20);
5,15-二[(3-乙氧基-4-羟丙氧基)苯基]-10,20-二氯卟吩(I21);
5,15-二[(3-羟丙氧基-4-乙氧基)苯基]-10,20-二氯卟吩(I22);
5,15-二[(3-丙氧基-4-羟丙氧基)苯基]-10,20-二氯卟吩(I23);
5,15-二[(3-羟丙氧基-4-丙氧基)苯基]-10,20-二氯卟吩(I24);
5,15-二[[3-甲氧基-4-(2-氧代-2-羧甲氨基)乙氧基]苯基]-10,20-二氯卟吩(I25);
5,15-二[[3-甲氧基-4-[2-氧代-2-(2-氧代-4-羧基)丁氨基]乙氧基]苯基]-10,20-二氯卟吩(I26);
5,15-二[[3-甲氧基-4-[2-氧代-2-(N,N-二羧甲基)氨基]乙氧基]苯基]-10,20-二氯卟吩(I27);
5,15-二[(3-甲氧基-4-羧甲氧基)苯基]-10,20-二溴卟吩(I28);
5,15-二[(3-羧甲氧基-4-甲氧基)苯基]-10,20-二溴卟吩(I29);
5,15-二[(3-乙氧基-4-羧甲氧基)苯基]-10,20-二溴卟吩(I30);
5,15-二[(3-羧甲氧基-4-乙氧基)苯基]-10,20-二溴卟吩(I31);
5,15-二[(3-丙氧基-4-羧甲氧基)苯基]-10,20-二溴卟吩(I32);
5,15-二[(3-羧甲氧基-4-丙氧基)苯基]-10,20-二溴卟吩(I33);
5,15-二[(3-甲氧基-4-羧丁氧基)苯基]-10,20-二溴卟吩(I34);
5,15-二[(3-羧丁氧基-4-甲氧基)苯基]-10,20-二溴卟吩(I35);
5,15-二[(3-乙氧基-4-羧丁氧基)苯基]-10,20-二溴卟吩(I36);
5,15-二[(3-羧丁氧基-4-乙氧基)苯基]-10,20-二溴卟吩(I37);
5,15-二[(3-丙氧基-4-羧丁氧基)苯基]-10,20-二溴卟吩(I38);
5,15-二[(3-羧丁氧基-4-丙氧基)苯基]-10,20-二溴卟吩(I39);
5,15-二[(3-甲氧基-4-羟乙氧基)苯基]-10,20-二溴卟吩(I40);
5,15-二[(3-羟乙氧基-4-甲氧基)苯基]-10,20-二溴卟吩(I41);
5,15-二[(3-乙氧基-4-羟乙氧基)苯基]-10,20-二溴卟吩(I42);
5,15-二[(3-羟乙氧基-4-乙氧基)苯基]-10,20-二溴卟吩(I43);
5,15-二[(3-丙氧基-4-羟乙氧基)苯基]-10,20-二溴卟吩(I44);
5,15-二[(3-羟乙氧基-4-丙氧基)苯基]-10,20-二溴卟吩(I45);
5,15-二[(3-甲氧基-4-羟丙氧基)苯基]-10,20-二溴卟吩(I46);
5,15-二[(3-羟丙氧基-4-甲氧基)苯基]-10,20-二溴卟吩(I47);
5,15-二[(3-乙氧基-4-羟丙氧基)苯基]-10,20-二溴卟吩(I48);
5,15-二[(3-羟丙氧基-4-乙氧基)苯基]-10,20-二溴卟吩(I49);
5,15-二[(3-丙氧基-4-羟丙氧基)苯基]-10,20-二溴卟吩(I50);
5,15-二[(3-羟丙氧基-4-丙氧基)苯基]-10,20-二溴卟吩(I51);
5,15-二[[3-甲氧基-4-(2-氧代-2-羧甲氨基)乙氧基]苯基]-10,20-二溴卟吩(I52);
5,15-二[[3-甲氧基-4-[2-氧代-2-(2-氧代-4-羧基)丁氨基]乙氧基]苯基]-10,20-二溴卟吩(I53);
5,15-二[[3-甲氧基-4-[2-氧代-2-(N,N-二羧甲基)氨基]乙氧基]苯基]-10,20-二溴卟吩(I54)。
3.根据权利要求1所述的一类中介二(3,5-二取代)苯基二卤代卟吩衍生物(II),为如下化合物:
5,15-二[(3-叔丁基-5-羧基)苯基]-10,20-二氯卟吩(II1);
5,15-二[(3-叔丁基-5-羧甲基)苯基]-10,20-二氯卟吩(II2);
5,15-二[(3-叔丁基-5-羧甲氧基)苯基]-10,20-二氯卟吩(II3);
5,15-二[(3-叔丁基-5-羧丙氧基)苯基]-10,20-二氯卟吩(II4);
5,15-二[(3-甲氧基-5-羟乙氧基)苯基]-10,20-二氯卟吩(II5);
5,15-二[(3-甲氧基-5-羟丙氧基)苯基]-10,20-二氯卟吩(II6);
5,15-二[(3,5-二羟乙氧基)苯基]-10,20-二氯卟吩(II7);
5,15-二[(3,5-二羟丙氧基)苯基]-10,20-二氯卟吩(II8);
5,15-二[[3-叔丁基-5-(羧甲氨基)甲酰基]苯基]-10,20-二氯卟吩(II9);
5,15-二[[3-叔丁基-5-[(2-氧代-4-羧基)丁氨基]甲酰基]苯基]-10,20-二氯卟吩(II10);
5,15-二[[3-叔丁基-5-[(N,N-二羧甲基)氨基]甲酰基]苯基]-10,20-二氯卟吩(II11);
5,15-二[(3-叔丁基-5-羧基)苯基]-10,20-二溴卟吩(II12);
5,15-二[(3-叔丁基-5-羧甲基)苯基]-10,20-二溴卟吩(II13);
5,15-二[(3-叔丁基-5-羧甲氧基)苯基]-10,20-二溴卟吩(II14);
5,15-二[(3-叔丁基-5-羧丙氧基)苯基]-10,20-二溴卟吩(II15);
5,15-二[(3-甲氧基-5-羟乙氧基)苯基]-10,20-二溴卟吩(II16);
5,15-二[(3-甲氧基-5-羟丙氧基)苯基]-10,20-二溴卟吩(II17);
5,15-二[(3,5-二羟乙氧基)苯基]-10,20-二溴卟吩(II18);
5,15-二[(3,5-二羟丙氧基)苯基]-10,20-二溴卟吩(II19);
5,15-二[[3-叔丁基-5-(羧甲氨基)甲酰基]苯基]-10,20-二溴卟吩(II20);
5,15-二[[3-叔丁基-5-[(2-氧代-4-羧基)丁氨基]甲酰基]苯基]-10,20-二溴卟吩(II21);
5,15-二[[3-叔丁基-5-[(N,N-二羧甲基)氨基]甲酰基]苯基]-10,20-二溴卟吩(II22)。
4.根据权利要求1所述的一类中介二(二取代)苯基二卤代卟吩类四吡咯光敏化合物在制备诊断和治疗肿瘤、视网膜黄斑变性、光化性角化病、鲜红斑痣、尖锐湿疣疾病的光动力药物中的应用。
Priority Applications (1)
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