JP2020105170A - Fluorescence labeling agent, photodynamic therapeutic agent and phthalocyanine - Google Patents
Fluorescence labeling agent, photodynamic therapeutic agent and phthalocyanine Download PDFInfo
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- JP2020105170A JP2020105170A JP2019228640A JP2019228640A JP2020105170A JP 2020105170 A JP2020105170 A JP 2020105170A JP 2019228640 A JP2019228640 A JP 2019228640A JP 2019228640 A JP2019228640 A JP 2019228640A JP 2020105170 A JP2020105170 A JP 2020105170A
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- unsubstituted alkyl
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- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 title claims abstract description 121
- 239000007850 fluorescent dye Substances 0.000 title claims abstract description 25
- 238000001215 fluorescent labelling Methods 0.000 title claims abstract description 24
- 239000003795 chemical substances by application Substances 0.000 title claims abstract description 23
- 239000003814 drug Substances 0.000 title claims abstract description 21
- 229940124597 therapeutic agent Drugs 0.000 title claims abstract description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 44
- 229910052782 aluminium Inorganic materials 0.000 claims abstract description 24
- 229910052710 silicon Inorganic materials 0.000 claims abstract description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 120
- 125000003118 aryl group Chemical group 0.000 claims description 99
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 52
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 39
- 125000000623 heterocyclic group Chemical group 0.000 claims description 30
- 125000001424 substituent group Chemical group 0.000 claims description 27
- 125000004104 aryloxy group Chemical group 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 229910052749 magnesium Inorganic materials 0.000 claims description 8
- 229910052725 zinc Inorganic materials 0.000 claims description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims description 7
- 150000001340 alkali metals Chemical class 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 abstract description 17
- 229910052751 metal Inorganic materials 0.000 abstract description 4
- 239000002184 metal Substances 0.000 abstract description 4
- -1 2-ethylhexyl group Chemical group 0.000 description 54
- 238000004519 manufacturing process Methods 0.000 description 54
- XQZYPMVTSDWCCE-UHFFFAOYSA-N phthalonitrile Chemical class N#CC1=CC=CC=C1C#N XQZYPMVTSDWCCE-UHFFFAOYSA-N 0.000 description 33
- 239000006185 dispersion Substances 0.000 description 31
- 239000002243 precursor Substances 0.000 description 30
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- 239000000126 substance Substances 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 13
- 239000003960 organic solvent Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 10
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 238000011156 evaluation Methods 0.000 description 10
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- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
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- 238000002189 fluorescence spectrum Methods 0.000 description 6
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 description 6
- 229960004657 indocyanine green Drugs 0.000 description 6
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- 239000003504 photosensitizing agent Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- ZKSVYBRJSMBDMV-UHFFFAOYSA-N 1,3-diphenyl-2-benzofuran Chemical compound C1=CC=CC=C1C1=C2C=CC=CC2=C(C=2C=CC=CC=2)O1 ZKSVYBRJSMBDMV-UHFFFAOYSA-N 0.000 description 4
- VSEIDZLLWQQJGK-CHOZPQDDSA-N CCC1=C(C)C2=N\C\1=C/C1=C(C)C(C(O)=O)=C(N1)\C(CC(=O)N[C@@H](CC(O)=O)C(O)=O)=C1/N=C(/C=C3\N/C(=C\2)C(C=C)=C3C)[C@@H](C)[C@@H]1CCC(O)=O Chemical compound CCC1=C(C)C2=N\C\1=C/C1=C(C)C(C(O)=O)=C(N1)\C(CC(=O)N[C@@H](CC(O)=O)C(O)=O)=C1/N=C(/C=C3\N/C(=C\2)C(C=C)=C3C)[C@@H](C)[C@@H]1CCC(O)=O VSEIDZLLWQQJGK-CHOZPQDDSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical class CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 4
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
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- ASMQGLCHMVWBQR-UHFFFAOYSA-M diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)([O-])OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-M 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000463 material Substances 0.000 description 4
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- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- KRTNITDCKAVIFI-UHFFFAOYSA-N tridecyl benzenesulfonate Chemical compound CCCCCCCCCCCCCOS(=O)(=O)C1=CC=CC=C1 KRTNITDCKAVIFI-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
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- XQXWVKQIQQTRDJ-UHFFFAOYSA-N undecyl benzenesulfonate Chemical compound CCCCCCCCCCCOS(=O)(=O)C1=CC=CC=C1 XQXWVKQIQQTRDJ-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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- 239000001018 xanthene dye Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Description
本発明は、蛍光標識剤および光線力学治療剤と、それに用いられるフタロシアニンに関する。 The present invention relates to a fluorescent labeling agent, a photodynamic therapeutic agent, and a phthalocyanine used therein.
バイオイメージングは、タンパク質や細胞、組織等を可視化する技術であり、生体内分子・細胞機能の解明や創薬の研究等、生物学、医学の研究領域で幅広く活用されている。 中でも蛍光バイオイメージング法は、現象の動的な観察、多色観察、高感度観察が可能なイメージング法である。蛍光バイオイメージング法は、主に標的部位に吸着、あるいは、標的部位でのみ発光する蛍光標識材を用い、紫外〜近赤外領域の光をその蛍光標識材に照射した際に発する蛍光を検出することにより、標的を可視化する方法である。近年は、非侵襲で診断可能なイメージング法として注目されており、特に生体透過性に優れた近赤外領域の光(700〜1500nm)を用いた近赤外蛍光イメージングは、患者への負担が少ない画像診断や外科手術ナビゲーションツールとして臨床現場への応用が進められている。 Bioimaging is a technique for visualizing proteins, cells, tissues, etc., and is widely used in research fields of biology and medicine, such as elucidation of in vivo molecular/cell functions and research of drug discovery. Among them, the fluorescence bioimaging method is an imaging method that enables dynamic observation of phenomena, multicolor observation, and highly sensitive observation. The fluorescence bioimaging method mainly uses a fluorescent labeling material that is adsorbed to a target site or emits light only at the target site, and detects fluorescence emitted when the fluorescent labeling material is irradiated with light in the ultraviolet to near infrared region. This is a method of visualizing the target. In recent years, it has attracted attention as an imaging method that can be diagnosed non-invasively, and in particular, near-infrared fluorescence imaging using light in the near-infrared region (700 to 1500 nm), which is excellent in biological permeability, puts a burden on the patient. It is being applied to clinical practice as a small number of diagnostic imaging and surgical navigation tools.
蛍光標識剤は、細胞や生体成分、組織等を標識する機能を有する蛍光色素であり、高感度に標識するために、高い蛍光強度を有する必要がある。蛍光標識剤としては、水溶性の有機分子であるシアニン系色素やキサンテン系色素等が用いられるが、非特許文献1、2に記載されるように蛍光強度や耐光性等の光安定性の低さが課題であった。近年、近赤外領域のシアニン系色素であるインドシアニングリーン等を用いて、その蛍光強度を改善する手法が開発されているように(特許文献1)、より高い蛍光強度や光安定性を有する蛍光標識剤が求められている。 The fluorescent labeling agent is a fluorescent dye having a function of labeling cells, biological components, tissues and the like, and it is necessary to have high fluorescence intensity for highly sensitive labeling. As the fluorescent labeling agent, a water-soluble organic molecule such as a cyanine dye or a xanthene dye is used. However, as described in Non-Patent Documents 1 and 2, low fluorescence stability and light stability such as light resistance are low. Was the issue. In recent years, as a method for improving the fluorescence intensity by using indocyanine green which is a cyanine dye in the near infrared region has been developed (Patent Document 1), it has higher fluorescence intensity and photostability. There is a need for fluorescent labeling agents.
一方、光線力学療法(Photodynamic therapy;PDT)は、ポルフィリン等の光感受性物質が腫瘍組織や腫瘍血管に特異的に集積する特性を利用し、光感受性物質が集積した腫瘍組織に特定波長の光線を照射し、一重項酸素を発生させ腫瘍細胞を選択的に破壊する低侵襲のがん治療法である(非特許文献3)。光感受性物質としては、一重項酸素発生能が求められている。保険適用となったPDTの光感受性物質として、Porfimer sodium(商品名 Photofrin、ファイザー社)やTalaporfin sodium(商品名 Laserphyrin、Meiji Seikaファルマ社)がある。 On the other hand, photodynamic therapy (PDT) utilizes the characteristic that photosensitizers such as porphyrin specifically accumulate in tumor tissues and tumor blood vessels, and a specific wavelength of light is applied to tumor tissues where photosensitizers are accumulated. It is a minimally invasive cancer treatment method in which irradiation is performed to generate singlet oxygen to selectively destroy tumor cells (Non-Patent Document 3). As the photosensitizer, the ability to generate singlet oxygen is required. As a photosensitizer of PDT which has been applied to insurance, there are Porfimer sodium (trade name: Photofrin, Pfizer) and Talaporfin sodium (trade name: Laserphyrin, Meiji Seika Pharma).
本発明が解決しようとする課題は、蛍光標識剤および光線力学治療剤に適した蛍光強度、耐光性、一重項酸素発生能に優れた特性を有するフタロシアニンを提供することである。 The problem to be solved by the present invention is to provide a phthalocyanine suitable for a fluorescent labeling agent and a photodynamic therapeutic agent and having excellent fluorescence intensity, light resistance, and singlet oxygen generating ability.
本発明者らは前記諸問題を解決するために鋭意研究を重ねた結果、上記課題を解決するための優れた特性を有するフタロシアニンを見出し、本発明をなしたものである。 すなわち本発明は、下記一般式(1)または一般式(2)で表されるフタロシアニンを含むことを特徴とする蛍光標識剤に関する。
As a result of intensive studies to solve the above problems, the present inventors have found a phthalocyanine having excellent properties for solving the above problems, and have made the present invention. That is, the present invention relates to a fluorescent labeling agent containing phthalocyanine represented by the following general formula (1) or general formula (2).
一般式(1)
General formula (1)
(式中、X1〜X8は、それぞれ独立に、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、−O−R21、−S−R22を表し、R21およびR22は、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基を表す。R1〜R20は、それぞれ独立に、水素原子、ハロゲン原子、水酸基、ニトロ基、ホルミル基、シアノ基、−COOM2、−SO3M2、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアルケニル基、置換もしくは無置換のアリール基、−O−R23、−S−R24を表し、M2は、水素原子、アルカリ金属を、R23およびR24は、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基を表す。R1〜R20は、隣接する基同士が互いに連結して環を形成してもよい。Y1〜Y4は、それぞれ独立に、N−H、N−R25、O、Sを表し、R25は、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基を表す。M1は、AlまたはSiを表し、Alの場合はnが1であり、Siの場合はnが2である。Z1は、水酸基、−OP(=O)R26R27、−OC(=O)R28、−OS(=O)2R29、−SiR30R31R32を表す。R26およびR27は、それぞれ独立に、水素原子、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換のアルコキシル基、置換もしくは無置換のアリールオキシ基を表す。R28は、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換の複素環基を表す。R29は、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換の複素環基を表す。R30〜R32は、それぞれ独立に、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基を表す。) (In the formula, X 1 to X 8 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —O—R 21 , or —S—R 22 , and R 21 And R 22 represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group, and R 1 to R 20 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a formyl group or a cyano group. , -COOM 2, -SO 3 M 2 , substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aryl group, -O-R 23, Represents —S—R 24 , M 2 represents a hydrogen atom or an alkali metal, R 23 and R 24 represent a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group. R< 1 > to R< 20 > may form a ring by connecting adjacent groups to each other, and Y< 1 > to Y< 4 > are each independently N-H, N-R< 25 > , O, S. R 25 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, M 1 represents Al or Si, and in the case of Al, n is In the case of Si, n is 2. Z 1 is a hydroxyl group, -OP(=O)R 26 R 27 , -OC(=O)R 28 , -OS(=O) 2 R 29 , -SiR 30 R 31 R 32. R 26 and R 27 are each independently a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkoxyl group, Represents a substituted or unsubstituted aryloxy group, R 28 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle .R 29 representing the group, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, .R 30 to R 32 to represent a substituted or unsubstituted heterocyclic group, each independently represent a substituted or It represents an unsubstituted alkyl group or a substituted or unsubstituted aryl group.)
一般式(2)
General formula (2)
(式中、X9〜X16は、それぞれ独立に、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、−O−R41、−S−R42を表し、R41およびR42は、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基を表す。R33〜R40は、それぞれ独立に、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基を表す。M3は、H2、Mg、Zn、Al、Siを表し、M3が、H2、Mg、Znの場合はnが0であり、Alの場合はnが1であり、Siの場合はnが2である。Z2は、水酸基、−OP(=O)R43R44、−OC(=O)R45、−OS(=O)2R46、−SiR47R48R49を表す。R43およびR44は、それぞれ独立に、水素原子、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換のアルコキシル基、置換もしくは無置換のアリールオキシ基を表す。R45は、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基または置換基を有してもよい複素環基を表す。R46は、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換の複素環基を表す。R47〜R49は、それぞれ独立に、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基を表す。) (In the formula, X 9 to X 16 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —O—R 41 , or —S—R 42 , and R 41 And R 42 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, and R 33 to R 40 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyl group. Represents a cycloalkyl group or a substituted or unsubstituted aryl group, M 3 represents H 2 , Mg, Zn, Al or Si, and when M 3 is H 2 , Mg or Zn, n is 0, In the case of Al, n is 1. In the case of Si, n is 2. Z 2 is a hydroxyl group, -OP(=O)R 43 R 44 , -OC(=O)R 45 , -OS(= O) 2 R 46 , —SiR 47 R 48 R 49. R 43 and R 44 are each independently a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or R 45 represents an unsubstituted alkoxyl group, a substituted or unsubstituted aryloxy group, R 45 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group or a substituted represents a heterocyclic group which may have a group .R 46 represents a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, .R 47 to R representing a substituted or unsubstituted heterocyclic group 49 independently represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group.)
また、本発明は、下記一般式(1)または一般式(2)で表されるフタロシアニンを含むことを特徴とする光線力学治療剤に関する。 Further, the present invention relates to a photodynamic therapeutic agent containing a phthalocyanine represented by the following general formula (1) or general formula (2).
一般式(1)
General formula (1)
(式中、X1〜X8は、それぞれ独立に、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、−O−R21、−S−R22を表し、R21およびR22は、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基を表す。R1〜R20は、それぞれ独立に、水素原子、ハロゲン原子、水酸基、ニトロ基、ホルミル基、シアノ基、−COOM2、−SO3M2、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアルケニル基、置換もしくは無置換のアリール基、−O−R23、−S−R24を表し、M2は、水素原子、アルカリ金属を、R23およびR24は、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基を表す。R1〜R20は、隣接する基同士が互いに連結して環を形成してもよい。Y1〜Y4は、それぞれ独立に、N−H、N−R25、O、Sを表し、R25は、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基を表す。M1は、AlまたはSiを表し、Alの場合はnが1であり、Siの場合はnが2である。Z1は、水酸基、−OP(=O)R26R27、−OC(=O)R28、−OS(=O)2R29、−SiR30R31R32を表す。R26およびR27は、それぞれ独立に、水素原子、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換のアルコキシル基、置換もしくは無置換のアリールオキシ基を表す。R28は、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換の複素環基を表す。R29は、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換の複素環基を表す。R30〜R32は、それぞれ独立に、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基を表す。) (In the formula, X 1 to X 8 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —O—R 21 , or —S—R 22 , and R 21 And R 22 represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group, and R 1 to R 20 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a formyl group or a cyano group. , -COOM 2, -SO 3 M 2 , substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aryl group, -O-R 23, Represents —S—R 24 , M 2 represents a hydrogen atom or an alkali metal, R 23 and R 24 represent a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group. R< 1 > to R< 20 > may form a ring by connecting adjacent groups to each other, and Y< 1 > to Y< 4 > are each independently N-H, N-R< 25 > , O, S. R 25 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, M 1 represents Al or Si, and in the case of Al, n is In the case of Si, n is 2. Z 1 is a hydroxyl group, -OP(=O)R 26 R 27 , -OC(=O)R 28 , -OS(=O) 2 R 29 , -SiR 30 R 31 R 32. R 26 and R 27 are each independently a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkoxyl group, Represents a substituted or unsubstituted aryloxy group, R 28 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle .R 29 representing the group, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, .R 30 to R 32 to represent a substituted or unsubstituted heterocyclic group, each independently represent a substituted or It represents an unsubstituted alkyl group or a substituted or unsubstituted aryl group.)
一般式(2)
General formula (2)
(式中、X9〜X16は、それぞれ独立に、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、−O−R41、−S−R42を表し、R41およびR42は、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基を表す。R33〜R40は、それぞれ独立に、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基を表す。M3は、H2、Mg、Zn、Al、Siを表し、M3が、H2、Mg、Znの場合はnが0であり、Alの場合はnが1であり、Siの場合はnが2である。Z2は、水酸基、−OP(=O)R43R44、−OC(=O)R45、−OS(=O)2R46、−SiR47R48R49を表す。R43およびR44は、それぞれ独立に、水素原子、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換のアルコキシル基、置換もしくは無置換のアリールオキシ基を表す。R45は、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基または置換基を有してもよい複素環基を表す。R46は、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換の複素環基を表す。R47〜R49は、それぞれ独立に、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基を表す。) (In the formula, X 9 to X 16 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —O—R 41 , or —S—R 42 , and R 41 And R 42 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, and R 33 to R 40 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyl group. Represents a cycloalkyl group or a substituted or unsubstituted aryl group, M 3 represents H 2 , Mg, Zn, Al or Si, and when M 3 is H 2 , Mg or Zn, n is 0, In the case of Al, n is 1. In the case of Si, n is 2. Z 2 is a hydroxyl group, -OP(=O)R 43 R 44 , -OC(=O)R 45 , -OS(= O) 2 R 46 , —SiR 47 R 48 R 49. R 43 and R 44 are each independently a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or R 45 represents an unsubstituted alkoxyl group, a substituted or unsubstituted aryloxy group, R 45 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group or a substituted represents a heterocyclic group which may have a group .R 46 represents a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, .R 47 to R representing a substituted or unsubstituted heterocyclic group 49 independently represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group.)
また、本発明は、下記一般式(1)で表されるフタロシアニンに関する。 The present invention also relates to phthalocyanine represented by the following general formula (1).
一般式(1)
General formula (1)
(式中、X1〜X8は、それぞれ独立に、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、−O−R21、−S−R22を表し、R21およびR22は、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基を表す。R1〜R20は、それぞれ独立に、水素原子、ハロゲン原子、水酸基、ニトロ基、ホルミル基、シアノ基、−COOM2、−SO3M2、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアルケニル基、置換もしくは無置換のアリール基、−O−R23、−S−R24を表し、M2は、水素原子、アルカリ金属を、R23およびR24は、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基を表す。R1〜R20は、隣接する基同士が互いに連結して環を形成してもよい。Y1〜Y4は、それぞれ独立に、N−H、N−R25、O、Sを表し、R25は、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基を表す。M1は、AlまたはSiを表し、Alの場合はnが1であり、Siの場合はnが2である。Z1は、水酸基、−OP(=O)R26R27、−OC(=O)R28、−OS(=O)2R29、−SiR30R31R32を表す。R26およびR27は、それぞれ独立に、水素原子、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換のアルコキシル基、置換もしくは無置換のアリールオキシ基を表す。R28は、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換の複素環基を表す。R29は、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換の複素環基を表す。R30〜R32は、それぞれ独立に、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基を表す。) (In the formula, X 1 to X 8 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —O—R 21 , or —S—R 22 , and R 21 And R 22 represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group, and R 1 to R 20 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a formyl group or a cyano group. , -COOM 2, -SO 3 M 2 , substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aryl group, -O-R 23, Represents —S—R 24 , M 2 represents a hydrogen atom or an alkali metal, R 23 and R 24 represent a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group. R< 1 > to R< 20 > may form a ring by connecting adjacent groups to each other, and Y< 1 > to Y< 4 > are each independently N-H, N-R< 25 > , O, S. R 25 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, M 1 represents Al or Si, and in the case of Al, n is In the case of Si, n is 2. Z 1 is a hydroxyl group, -OP(=O)R 26 R 27 , -OC(=O)R 28 , -OS(=O) 2 R 29 , -SiR 30 R 31 R 32. R 26 and R 27 are each independently a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkoxyl group, Represents a substituted or unsubstituted aryloxy group, R 28 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle .R 29 representing the group, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, .R 30 to R 32 to represent a substituted or unsubstituted heterocyclic group, each independently represent a substituted or It represents an unsubstituted alkyl group or a substituted or unsubstituted aryl group.)
また、本発明は、下記一般式(3)で表されるフタロシアニンに関する。 The present invention also relates to phthalocyanine represented by the following general formula (3).
一般式(3)
General formula (3)
(式中、X17〜X24は、それぞれ独立に、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、−O−R58、−S−R59を表し、R58およびR59は、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基を表す。R50〜R57は、それぞれ独立に、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基を表す。M4は、Al、Siを表し、M4が、Alの場合はnが1であり、Siの場合はnが2である。Z3は、水酸基、−OP(=O)R60R61、−OC(=O)R62、−OS(=O)2R63、−SiR64R65R66を表す。R60およびR61は、それぞれ独立に、水素原子、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換のアルコキシル基、置換もしくは無置換のアリールオキシ基を表す。R62は、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換の複素環基を表す。R63は、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換の複素環基を表す。R64〜R66はそれぞれ独立に置換基を有してもよいアルキル基、置換もしくは無置換のアリール基を表す。) (In the formula, X 17 to X 24 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —O—R 58 , or —S—R 59 , and R 58 And R 59 represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group, and R 50 to R 57 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyl group. .M 4 representing an cycloalkyl group, a substituted or unsubstituted aryl groups, Al, represents Si, M 4 is in the case of Al and n is 1, .Z for Si is n is 2 3 Represents a hydroxyl group, -OP(=O)R 60 R 61 , -OC(=O)R 62 , -OS(=O) 2 R 63 , -SiR 64 R 65 R 66. R 60 and R 61 are each. Each independently represents a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkoxyl group, or a substituted or unsubstituted aryloxy group, and R 62 represents hydrogen. An atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, R 63 represents a hydroxyl group, a substituted or unsubstituted alkyl group Represents a group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, and R 64 to R 66 each independently represent an alkyl group which may have a substituent, a substituted or unsubstituted aryl group. .)
本発明によって、蛍光強度や耐光性に優れた蛍光標識剤および一重項酸素発生能に優れた光線力学治療剤を提供することが可能となった。 The present invention has made it possible to provide a fluorescent labeling agent having excellent fluorescence intensity and light resistance, and a photodynamic therapeutic agent having excellent singlet oxygen generating ability.
以下、本発明を詳細に説明する。本発明の蛍光標識剤や光線力学治療剤に用いられるフタロシアニンは、一般式(1)〜(3)で表される構造を有する。以下、一般式(1)〜(3)に共通する基について説明する。 Hereinafter, the present invention will be described in detail. The phthalocyanine used in the fluorescent labeling agent or photodynamic therapeutic agent of the present invention has a structure represented by the general formulas (1) to (3). The groups common to the general formulas (1) to (3) will be described below.
アルキル基としては、直鎖状または分岐鎖状のアルキル基が挙げられる。具体例としては、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基、ドデシル基、オクタデシル基、イソプロピル基、イソブチル基、イソペンチル基、2−エチルヘキシル基、sec−ブチル基、tert−ブチル基、sec−ペンチル基、tert−ペンチル基、tert−オクチル基、ネオペンチル基等を挙げることができる。アルキル基の炭素数は1〜30の範囲内であることが好ましい。 Examples of the alkyl group include linear or branched alkyl groups. As specific examples, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, dodecyl group, octadecyl group, isopropyl group, isobutyl group, isopentyl group, 2-ethylhexyl group, sec-butyl group, tert-butyl group, sec-pentyl group, tert-pentyl group, tert-octyl group, neopentyl group and the like can be mentioned. The alkyl group preferably has 1 to 30 carbon atoms.
上記アルキル基における置換基としては、フッ素、塩素、臭素等のハロゲン原子、水酸基、アミノ基、ニトロ基、ホルミル基、シアノ基、カルボキシル基等の他、後述するアリール基、シクロアルキル基、複素環基が挙げられる。また、構造の一部が、エステル結合(−COO−)やエーテル結合(−O−)で置換されたものも置換基として含めるものとする。 Examples of the substituent in the alkyl group include a halogen atom such as fluorine, chlorine and bromine, a hydroxyl group, an amino group, a nitro group, a formyl group, a cyano group and a carboxyl group, as well as an aryl group, a cycloalkyl group and a heterocycle described later. Groups. In addition, a part of the structure substituted with an ester bond (—COO—) or an ether bond (—O—) is also included as a substituent.
したがって、置換アルキル基としては、上記の置換基で置換されたアルキル基を意味する。一つ又は二つ以上の置換基で置換されたものであっても良い。例えば、ハロゲン原子で置換されたアルキル基の具体例としては、トリフルオロメチル基、2,2,2−トリフルオロエチル基、−(CF2)4CF3、−(CF2)5CF3、−(CF2)6CF3、−(CF2)7CF3、−(CF2)8CF3、トリクロロメチル基2,2−ジブロモエチル基等を挙げることができる。
Therefore, the substituted alkyl group means an alkyl group substituted with the above substituents. It may be substituted with one or two or more substituents. For example, specific examples of the alkyl group substituted with a halogen atom, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, - (CF 2) 4 CF 3, - (CF 2) 5 CF 3, - (CF 2) 6 CF 3 , - (CF 2) 7 CF 3, - (CF 2) 8 CF 3, can be exemplified trichloromethyl 2,2-dibromo ethyl group and the like.
また、エステル結合で置換されたアルキル基の具体例としては、−CH2−CH2−CH2−COO−CH2−CH3、−CH2−CH(−CH3)−CH2−COO−CH2−CH3、−CH2−CH2−CH2−OCO−CH2−CH3、−CH2−CH2−CH2−CH2−COO−CH2−CH(CH2−CH3)−CH2−CH2−CH2−CH3、−(CH2)5−COO−(CH2)11−CH3、−CH2−CH2−CH2−CH−(COO−CH2−CH3) 2等を挙げることができる。エステル結合で置換されたアルキル基の炭素数は、2〜30の範囲内であることが好ましい。
Specific examples of the alkyl group substituted by an ester bond, -CH 2 -CH 2 -CH 2 -COO -CH 2 -CH 3, -CH 2 -CH (-CH 3) -CH 2 -COO- CH 2 -CH 3, -CH 2 -CH 2 -CH 2 -OCO-CH 2 -CH 3, -CH 2 -CH 2 -CH 2 -CH 2 -COO-CH 2 -CH (CH 2 -CH 3) -CH 2 -CH 2 -CH 2 -CH 3 , - (CH 2) 5 -COO- (CH 2) 11 -CH 3, -CH 2 -CH 2 -CH 2 -CH- (COO-CH 2 -CH 3 ) 2 etc. can be mentioned. The alkyl group substituted with an ester bond preferably has 2 to 30 carbon atoms.
また、エーテル結合で置換されたアルキル基の具体例としては、−CH2−O−CH3、−CH2−CH2−O−CH2−CH3、−CH2−CH2−CH2−O−CH2−CH3、−(CH2−CH2−O)n−CH3(ここでnは1から8の整数である)、−(CH2−CH2−CH2−O)m−CH3(ここでmは1から5の整数である)、−CH2−CH(CH3)−O−CH2−CH3−、−CH2−CH−(OCH3)2等を挙げることができるが、これらに限定されるものではない。エーテル結合で置換されたアルキル基の炭素数は、2〜30の範囲内であることが好ましい。 Specific examples of the alkyl group substituted with an ether bond, -CH 2 -O-CH 3, -CH 2 -CH 2 -O-CH 2 -CH 3, -CH 2 -CH 2 -CH 2 - O-CH 2 -CH 3, - (CH 2 -CH 2 -O) n -CH 3 ( wherein n is an integer from 1 to 8), - (CH 2 -CH 2 -CH 2 -O) m —CH 3 (where m is an integer of 1 to 5), —CH 2 —CH(CH 3 )—O—CH 2 —CH 3 —, —CH 2 —CH—(OCH 3 ) 2 and the like. However, the present invention is not limited to these. The alkyl group substituted with an ether bond preferably has 2 to 30 carbon atoms.
また、エステル結合(−COO−)およびエーテル結合(−O−)で置換されたアルキル基の具体例としては、−CH2−CH2−COO−CH2−CH2−O−CH2−CH(CH2−CH3)−CH2−CH2−CH2−CH3、−CH2−CH2−COO−CH2−CH2−O−CH2−CH2−O−CH2−CH(CH2−CH3)−CH2−CH2−CH2−CH3を挙げることができる。エステル結合(−COO−)およびエーテル結合で置換されたアルキル基の炭素数は、3〜30の範囲内であることが好ましい。 Further, an ester bond (-COO-) and Specific examples of the alkyl group substituted with an ether bond (-O-), -CH 2 -CH 2 -COO-CH 2 -CH 2 -O-CH 2 -CH (CH 2 -CH 3) -CH 2 -CH 2 -CH 2 -CH 3, -CH 2 -CH 2 -COO-CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 2 -CH ( can be exemplified CH 2 -CH 3) -CH 2 -CH 2 -CH 2 -CH 3. The alkyl group substituted with an ester bond (-COO-) and an ether bond preferably has 3 to 30 carbon atoms.
シクロアルキル基としては、シクロペンチル基、シクロへキシル基、2,5−ジメチルシクロペンチル基、4−tert−プチルシクロヘキシル基等が挙げられる。また、シクロアルキル基の炭素数は5〜12の範囲内であることが好ましい。置換シクロアルキル基の置換基としては、上述したアルキル基における置換基と同じ置換基が挙げられる。 Examples of the cycloalkyl group include a cyclopentyl group, a cyclohexyl group, a 2,5-dimethylcyclopentyl group, a 4-tert-putylcyclohexyl group and the like. Further, the cycloalkyl group preferably has 5 to 12 carbon atoms. Examples of the substituent of the substituted cycloalkyl group include the same substituents as the above-mentioned substituents in the alkyl group.
アリール基としては、単環または縮合多環のアリール基が挙げられる。例えば、フェニル基、1−ナフチル基、2−ナフチル基、p−ビフェニル基、m−ビフェニル基、2−アントリル基、9−アントリル基、2−フェナントリル基、3−フェナントリル基、9−フェナントリル基、2−フルオレニル基、3−フルオレニル基、9−フルオレニル基、1−ピレニル基、2−ピレニル基、3−ペリレニル基、o−トリル基、m−トリル基、p−トリル基、4−メチルビフェニル基、ターフェニル基、4−メチル−1−ナフチル基、4−tert−ブチル−1−ナフチル基、4−ナフチル−1−ナフチル基、6−フェニル−2−ナフチル基、10−フェニル−9−アントリル基、スピロフルオレニル基、2−ベンゾシクロブテニル基等が挙げられる。アリール基の炭素数は6〜18の範囲内であることが好ましい。置換アリール基の置換基としては、上述したアルキル基における置換基と同じ置換基が挙げられる。 Examples of the aryl group include monocyclic or condensed polycyclic aryl groups. For example, phenyl group, 1-naphthyl group, 2-naphthyl group, p-biphenyl group, m-biphenyl group, 2-anthryl group, 9-anthryl group, 2-phenanthryl group, 3-phenanthryl group, 9-phenanthryl group, 2-fluorenyl group, 3-fluorenyl group, 9-fluorenyl group, 1-pyrenyl group, 2-pyrenyl group, 3-perylenyl group, o-tolyl group, m-tolyl group, p-tolyl group, 4-methylbiphenyl group , Terphenyl group, 4-methyl-1-naphthyl group, 4-tert-butyl-1-naphthyl group, 4-naphthyl-1-naphthyl group, 6-phenyl-2-naphthyl group, 10-phenyl-9-anthryl group Group, spirofluorenyl group, 2-benzocyclobutenyl group and the like. The aryl group preferably has 6 to 18 carbon atoms. Examples of the substituent of the substituted aryl group include the same substituents as the above-mentioned substituents in the alkyl group.
アルケニル基としては、直鎖状または分岐鎖状のアルケニル基が挙げられる。それらアルケニル基はその構造中に一つの二重結合を一般的に指すが、本明細書においては複数の二重結合を有するものもアルケニル基に含めるものとする。具体例としては、ビニル基、1−プロペニル基、アリル基、2−ブテニル基、3−ブテニル基、イソプロペニル基、イソブテニル基、1−ペンテニル基、2−ペンテニル基、3−ペンテニル基、4−ペンテニル基、1−ヘキセニル基、2−ヘキセニル基、3−ヘキセニル基、4−ヘキセニル基、1,3−ブタジエニル基等を挙げることができる。アルケニル基の炭素数は2〜18の範囲内であることが好ましい。置換アルケニル基の置換基としては、上述したアルキル基における置換基と同じ置換基が挙げられる。 Examples of the alkenyl group include linear or branched alkenyl groups. The alkenyl groups generally refer to one double bond in the structure, but in the present specification, those having a plurality of double bonds are also included in the alkenyl group. As specific examples, vinyl group, 1-propenyl group, allyl group, 2-butenyl group, 3-butenyl group, isopropenyl group, isobutenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4- Examples thereof include a pentenyl group, a 1-hexenyl group, a 2-hexenyl group, a 3-hexenyl group, a 4-hexenyl group and a 1,3-butadienyl group. The alkenyl group preferably has 2 to 18 carbon atoms. Examples of the substituent of the substituted alkenyl group include the same substituents as the above-mentioned substituents in the alkyl group.
アルコキシル基としては、直鎖状または分岐鎖状のアルコキシル基が挙げられる。具体例としては、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、n−ブトキシ基、イソブトキシ基、tert−ブトキシ基、ネオペンチルオキシ基、2,3−ジメチル−3−ペンチルオキシ基、n−へキシルオキシ基、n−オクチルオキシ基、ステアリルオキシ基、2−エチルへキシルオキシ基等が挙げられる。アルコキシル基の炭素数は1〜6の範囲内であることが好ましい。置換アルコキシル基の置換基としては、上述したアルキル基における置換基と同じ置換基が挙げられる。 Examples of the alkoxyl group include a linear or branched alkoxyl group. Specific examples include methoxy group, ethoxy group, propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, neopentyloxy group, 2,3-dimethyl-3-pentyloxy group, n- Hexyloxy group, n-octyloxy group, stearyloxy group, 2-ethylhexyloxy group and the like can be mentioned. The number of carbon atoms of the alkoxyl group is preferably within the range of 1-6. Examples of the substituent of the substituted alkoxyl group include the same substituents as the above-mentioned substituents in the alkyl group.
置換アルコキシル基の置換基としては、上述したアルキル基における置換基と同じ置換基が挙げられる。具体例としては、トリクロロメトキシ基、トリフルオロメトキシ基、2,2,2−トリフルオロエトキシ基、2,2,3,3−テトラフルオロプロポキシ基、2,2−ビス(トリフルオロメチル)プロポキシ基、2−エトキシエトキシ基、2−ブトキシエトキシ基、2−ニトロプロポキシ基、ベンジルオキシ基等が挙げられる。 Examples of the substituent of the substituted alkoxyl group include the same substituents as the above-mentioned substituents in the alkyl group. Specific examples include a trichloromethoxy group, a trifluoromethoxy group, a 2,2,2-trifluoroethoxy group, a 2,2,3,3-tetrafluoropropoxy group, a 2,2-bis(trifluoromethyl)propoxy group. , 2-ethoxyethoxy group, 2-butoxyethoxy group, 2-nitropropoxy group, benzyloxy group and the like.
アリールオキシ基としては、単環または縮合多環のアリールオキシ基が挙げられる。具体例としては、フェノキシ基、p−メチルフェノキシ基、ナフチルオキシ基、アンスリルオキシ基等が挙げられる。アリールオキシ基は、単環のアリールオキシ基が好ましい。また、炭素数6〜12のアリールオキシ基が好ましい。 Examples of the aryloxy group include a monocyclic or condensed polycyclic aryloxy group. Specific examples include phenoxy group, p-methylphenoxy group, naphthyloxy group, anthryloxy group and the like. The aryloxy group is preferably a monocyclic aryloxy group. Further, an aryloxy group having 6 to 12 carbon atoms is preferable.
置換アリールオキシ基の置換基としては、上述したアルキル基における置換基と同じ置換基が挙げられる。例えば、p−ニトロフェノキシ基、p−メトキシフェノキシ基、2,4−ジクロロフェノキシ基、ペンタフルオロフェノキシ基、2−メチル−4−クロロフェノキシ基等が挙げられる。 Examples of the substituent of the substituted aryloxy group include the same substituents as the above-mentioned substituents in the alkyl group. For example, p-nitrophenoxy group, p-methoxyphenoxy group, 2,4-dichlorophenoxy group, pentafluorophenoxy group, 2-methyl-4-chlorophenoxy group and the like can be mentioned.
複素環基としては、脂肪族複素環基や芳香族複素環基が挙げられる。具体例としては、ピリジル基、ピラジル基、ピペリジノ基、ピラニル基、モルホリノ基、アクリジニル基等が挙げられる。また、下記構造式で表される基も挙げられる。複素環基の炭素数は、4〜12であることが好ましい。環員数は、5〜13であることが好ましい。 Examples of the heterocyclic group include an aliphatic heterocyclic group and an aromatic heterocyclic group. Specific examples thereof include a pyridyl group, a pyrazyl group, a piperidino group, a pyranyl group, a morpholino group, and an acridinyl group. Moreover, the group represented by the following structural formula is also mentioned. The heterocyclic group preferably has 4 to 12 carbon atoms. The number of ring members is preferably 5 to 13.
置換複素環基の置換基としては、上述したアルキル基における置換基と同じ置換基が挙げられる。例えば、複素環基3−メチルピリジル基、N−メチルピペリジル基、N−メチルピローリル基等が挙げられる。 Examples of the substituent of the substituted heterocyclic group include the same substituents as the above-mentioned substituents in the alkyl group. For example, a heterocyclic group 3-methylpyridyl group, N-methylpiperidyl group, N-methylpyrrolyl group and the like can be mentioned.
M2のアルカリ金属としては、リチウム、ナトリウム、カリウム、ルビジウム、セシウム等が挙げられる。 Examples of the alkali metal of M 2 include lithium, sodium, potassium, rubidium and cesium.
(蛍光標識剤)
本発明の蛍光標識剤の用途は特に限定されないが、例えば、タンパク質や生体内の低分子化合物を蛍光ラベルすることで、生体内での挙動を可視化することが挙げられる。
この用途の場合、本発明のフタロシアニンと両親媒性物質からなる粒子に、抗原等のターゲット分子に結合する物質を修飾することが好ましい。ターゲット分子に結合する物質としては、ターゲット分子と特異的に結合する一次抗体、その一次抗体に結合する二次抗体、アビジン、ビオチン、あるいは糖鎖等が挙げられる。
(Fluorescent labeling agent)
The use of the fluorescent labeling agent of the present invention is not particularly limited, and examples thereof include visualization of behavior in vivo by fluorescently labeling a protein or a low-molecular compound in vivo.
In the case of this use, it is preferable to modify the particles comprising the phthalocyanine of the present invention and the amphipathic substance with a substance that binds to a target molecule such as an antigen. Examples of the substance that binds to the target molecule include a primary antibody that specifically binds to the target molecule, a secondary antibody that binds to the primary antibody, avidin, biotin, or a sugar chain.
(両親媒性物質)
水系で非水溶性のフタロシアニンを使用する場合、両親媒性物質等で可溶化する方法が知られている。両親媒性物質とは、一つの分子内に親水基と疎水基を有する分子の総称であり、代表的なものとして界面活性剤やリン脂質等がある。両親媒性物質は一種類のみを使用してもよく、二種類以上を混合して使用してもよい。本実施形態に関わる両親媒性物質としては、特に限定されることはなく、本発明のフタロシアニンを可溶化することができればいかなるものでもよい。
(Amphiphile)
When water-insoluble phthalocyanine is used, a method of solubilizing it with an amphipathic substance or the like is known. The amphipathic substance is a generic term for molecules having a hydrophilic group and a hydrophobic group in one molecule, and representative examples thereof include a surfactant and a phospholipid. As for the amphipathic substance, only one kind may be used, or two or more kinds may be mixed and used. The amphipathic substance according to this embodiment is not particularly limited, and any substance can be used as long as it can solubilize the phthalocyanine of the present invention.
界面活性剤としては、非イオン性界面活性剤、カチオン性界面活性剤、アニオン性界面活性剤等を挙げることができる。
非イオン性界面活性剤としては、例えば、Tween(登録商標)20、Tween(登録商標)40、Tween(登録商標)60、およびTween(登録商標)80等のポリオキシエチレンソルビタン系脂肪酸エステル、Cremophor(登録商標)ELおよびCremophor(登録商標)RH60等のポリオキシエチレンヒマシ油誘導体、Solutol(登録商標)HS15等の12−ヒドロキシステアリン酸−ポリエチレングリコールコポリマー、あるいはTriton(登録商標)X−100およびTriton(登録商標)X−114等のオクチルフェノールエトキシレート等を挙げることができる。
Examples of the surfactant include nonionic surfactants, cationic surfactants, anionic surfactants and the like.
Examples of the nonionic surfactant include polyoxyethylene sorbitan fatty acid esters such as Tween (registered trademark) 20, Tween (registered trademark) 40, Tween (registered trademark) 60, and Tween (registered trademark) 80, Cremophor. Polyoxyethylene castor oil derivatives such as (registered trademark) EL and Cremophor (registered trademark) RH60, 12-hydroxystearic acid-polyethylene glycol copolymer such as Solutol (registered trademark) HS15, or Triton (registered trademark) X-100 and Triton. Octylphenol ethoxylates such as (registered trademark) X-114 and the like can be mentioned.
カチオン性界面活性剤としては、例えば、塩化ステアリルトリメチルアンモニウムおよび塩化ラウリルトリメチルアンモニウム等のアルキルトリメチルアンモニウム塩、塩化セチルピリジニウム等のアルキルピリジニウム塩、塩化ジステアリルジメチルアンモニウムジアルキルジメチルアンモニウム塩および塩化ポリ(N,N’−ジメチル−3,5−メチレンピペリジニウム)等のアルキル四級アンモニウム塩、アルキルジメチルベンジルアンモニウム塩、アルキルイソキノリニウム塩、ジアルキルモリホニウム塩、ポリオキシエチレンアルキルアミン、アルキルアミン塩、ポリアミン脂肪酸誘導体、アミルアルコール脂肪酸誘導体、塩化ベンザルコニウム、塩化ベンゼトニウム、ポリビニルアルコール、ポリオキシエチレンポリオキシプロピレングリコール、あるいはポリエチレングリコール−ポリアルキル、ポリエチレングリコール−ポリ乳酸、ポリエチレングリコール−ポリカプロラクトン、ポリエチレングリコール−ポリグリコール酸、およびポリエチレングリコール−ポリ(ラクチド−グリコリド)等のブロック共重合体等を挙げることができる。 Examples of the cationic surfactant include alkyltrimethylammonium salts such as stearyltrimethylammonium chloride and lauryltrimethylammonium chloride, alkylpyridinium salts such as cetylpyridinium chloride, distearyldimethylammonium dialkyldimethylammonium chloride and poly(N, N'-dimethyl-3,5-methylenepiperidinium) and other alkyl quaternary ammonium salts, alkyldimethylbenzylammonium salts, alkylisoquinolinium salts, dialkylmorphonium salts, polyoxyethylene alkylamines, alkylamine salts , Polyamine fatty acid derivative, amyl alcohol fatty acid derivative, benzalkonium chloride, benzethonium chloride, polyvinyl alcohol, polyoxyethylene polyoxypropylene glycol, or polyethylene glycol-polyalkyl, polyethylene glycol-polylactic acid, polyethylene glycol-polycaprolactone, polyethylene glycol Examples thereof include block copolymers such as polyglycolic acid and polyethylene glycol-poly(lactide-glycolide).
アニオン性界面活性剤としては、例えば、ドデシル硫酸ナトリウム、ドデシルベンゼンスルホネート、デシルベンゼンスルホネート、ウンデシルベンゼンスルホネート、トリデシルベンゼンスルホネート、ノニルベンゼンスルホネート並びにこれらのナトリウム、カリウム及びアンモニウム塩等が挙げられる。 Examples of the anionic surfactant include sodium dodecyl sulfate, dodecyl benzene sulfonate, decyl benzene sulfonate, undecyl benzene sulfonate, tridecyl benzene sulfonate, nonyl benzene sulfonate, and their sodium, potassium and ammonium salts.
リン脂質としては、ジステアロイルホスファチジルコリン(DSPC)、ジミリストリルホスファチジルコリン(DMPC)、ジパルミトイルホスファチジルコリン(DPPC)、ジオレイルホスファチジルコリン(DOPC)、およびジパルミトイルホスファチジルグリセロール(DPPG)等の合成リン脂質、あるいはホスファチジルコリン、ホスファチジルセリン、ホスファチジルグリセロール、ホスファチジルイノシトール、ホスファチジルエタノールアミン、ホスファチジン酸、カルジオリピン、スフィンゴミエリン、卵黄レシチン、大豆レシチン、およびリゾレシチン等の天然リン脂質を挙げることができる。 Examples of the phospholipid include synthetic phospholipids such as distearoylphosphatidylcholine (DSPC), dimyristolylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), dioleylphosphatidylcholine (DOPC), and dipalmitoylphosphatidylglycerol (DPPG), or phosphatidylcholine. , Phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidic acid, cardiolipin, sphingomyelin, egg yolk lecithin, soybean lecithin, and lysolecithin.
本発明における蛍光標識剤は、本発明のフタロシアニンを含有していれば、必要に応じてその他の成分を含有していてもよい。その他の成分としては、例えば、水や両親媒性物質等が挙げられる。 The fluorescent labeling agent in the present invention may contain other components as necessary as long as it contains the phthalocyanine of the present invention. Examples of other components include water and amphipathic substances.
本発明のフタロシアニンの濃度は特に限定されないが、例えば、細胞を扱う場合、細胞の機能障害や増殖阻害等への影響を考量すると、濃度は低い方が好ましく、本発明のフタロシアニンの濃度は100μM以下であることが好ましい。また同様に、両親媒性物質の濃度も低い方が好ましく、両親媒性物質の量は本発明のフタロシアニンに対して500倍質量以下が好ましく、200倍質量以下がより好ましく、100倍質量以下がさらに好ましい。ただし、両親媒性物質の量が少な過ぎると、本発明のフタロシアニンの会合や凝集が強く生じるため、フタロシアニンに対して10倍質量以上の量であることが好ましい。 Although the concentration of the phthalocyanine of the present invention is not particularly limited, for example, when dealing with cells, the concentration is preferably lower in consideration of the effects on dysfunction and growth inhibition of cells, and the concentration of the phthalocyanine of the present invention is 100 μM or less. Is preferred. Similarly, the concentration of the amphipathic substance is preferably low, and the amount of the amphipathic substance is preferably 500 times by mass or less, more preferably 200 times by mass or less, and 100 times by mass or less with respect to the phthalocyanine of the present invention. More preferable. However, if the amount of the amphipathic substance is too small, the association and aggregation of the phthalocyanine of the present invention will occur strongly, so the amount is preferably 10 times or more the mass of the phthalocyanine.
(蛍光標識剤の作製方法)
本発明における蛍光標識剤の作製方法は、特に限定されないが、例えば、本発明のフタロシアニンと両親媒性物質を有機溶媒中に溶解した後、有機溶媒を留去し、水に再溶解させる方法、あるいは本発明のフタロシアニンと両親媒性物質を有機溶媒に溶解した溶液に水を注入し、有機溶媒を留去する方法等を挙げることができる。
(Method for producing fluorescent labeling agent)
The method for producing the fluorescent labeling agent in the present invention is not particularly limited, for example, after dissolving the phthalocyanine and the amphipathic substance of the present invention in an organic solvent, the organic solvent is distilled off, and redissolved in water, Alternatively, a method of injecting water into a solution of the phthalocyanine of the present invention and an amphipathic substance dissolved in an organic solvent, and distilling off the organic solvent can be used.
前者の方法では、有機溶媒の留去が容易であり、本発明のフタロシアニンと両親媒性物質の濃度も比較的容易に見積もることができるといった利点がある。有機溶媒の留去には、エバポレーター等による減圧留去装置が好適に用いられる。溶媒留去時の温度は、15℃から有機溶媒の沸点温度の範囲で任意に設定することができる。水に再溶解させるときは、プロペラ撹拌機、タービン撹拌機、ボルテックスミキサー、撹拌子を用いたマグネティックスターラーによる撹拌、あるいは超音波照射装置による分散等が好適に用いられる。また、コロイドミル等を併用してもよい。 The former method has an advantage that the organic solvent can be easily distilled off and the concentrations of the phthalocyanine and the amphipathic substance of the present invention can be estimated relatively easily. A vacuum distillation device such as an evaporator is preferably used for distilling off the organic solvent. The temperature at which the solvent is distilled off can be arbitrarily set within the range of 15° C. to the boiling point temperature of the organic solvent. When re-dissolving in water, a propeller stirrer, a turbine stirrer, a vortex mixer, a magnetic stirrer using a stirrer, or a dispersion using an ultrasonic irradiation device is preferably used. Further, a colloid mill or the like may be used together.
後者の方法では、ミセル粒子を均一に調製し易いといった利点がある。有機溶媒に溶解した溶液に水を注入するとき、溶液は撹拌あるいは超音波照射した状態とし、水を短時間で注入することが好ましい。撹拌は上記と同様の装置で行うことができる。水注入時の温度は、15℃から有機溶媒の沸点より5℃低い温度の範囲で任意に設定することができる。有機溶媒の留去は、撹拌あるいは超音波照射した状態で常圧の下に留去する方法、あるいはエバポレーター等により減圧留去する方法が好ましい。溶媒留去時の温度は、15℃から有機溶媒の沸点温度の範囲で任意に設定することができる。 The latter method has an advantage that it is easy to uniformly prepare micelle particles. When injecting water into a solution dissolved in an organic solvent, it is preferable to inject the water in a short time with stirring or ultrasonic irradiation. The stirring can be performed by the same device as described above. The temperature at the time of water injection can be arbitrarily set within a range of 15° C. to 5° C. lower than the boiling point of the organic solvent. The organic solvent is preferably distilled off under atmospheric pressure under stirring or irradiation with ultrasonic waves, or under reduced pressure by an evaporator or the like. The temperature at which the solvent is distilled off can be arbitrarily set within the range of 15° C. to the boiling point temperature of the organic solvent.
上記の作製方法で使用される有機溶媒としては、ヘキサン、シクロへキサン、およびヘプタン等の炭化水素類、アセトンおよびメチルエチルケトン等のケトン類、ジエチルエーテルおよびテトラヒドロフラン等のエーテル類、ジクロロメタン、クロロホルム、四塩化炭素、ジクロロエタン、およびトリクロロエタン等のハロゲン化炭化水素類、ベンゼンおよびトルエン等の芳香族炭化水素、酢酸エチルおよび酢酸ブチル等のエステル類、N,N−ジメチルホルムアミド、ジメチルスルホキシド、およびN−メチル−2−ピロリドン等の非プロトン性極性溶媒類、あるいはピリジン誘導体を挙げることができる。これらの溶媒は、単独で使用してもよく、混合して使用してもよい。また、上記方法にて作製した蛍光標識剤を透析にかけることで、有機溶媒を完全に除去してもよい。 Examples of the organic solvent used in the above production method include hydrocarbons such as hexane, cyclohexane, and heptane, ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether and tetrahydrofuran, dichloromethane, chloroform, tetrachloride. Carbon, halogenated hydrocarbons such as dichloroethane and trichloroethane, aromatic hydrocarbons such as benzene and toluene, esters such as ethyl acetate and butyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, and N-methyl-2. Aprotic polar solvents such as pyrrolidone, or pyridine derivatives. These solvents may be used alone or as a mixture. The organic solvent may be completely removed by subjecting the fluorescent labeling agent produced by the above method to dialysis.
上記の作製方法で使用される水としては、イオン交換水、蒸留水、あるいは超純水を挙げることができる。細胞を扱う場合は、生理条件に近づけるために水に塩を加えた生理食塩水、さらにリン酸緩衝剤を加えたリン酸緩衝生理食塩水等を好適に用いることができる。 Examples of water used in the above-mentioned production method include ion-exchanged water, distilled water, and ultrapure water. In the case of handling cells, physiological saline containing salt added to water, or phosphate buffered saline containing a phosphate buffer in order to approximate physiological conditions can be preferably used.
(光線力学治療剤)
本発明の光線力学治療剤は、腫瘍、皮膚疾患、眼疾患、加齢黄斑変性等の光線力学治療用として好適であり、本発明のフタロシアニンを有効成分として含有する。光線力学治療剤は、カテーテル、静脈内、筋肉内注射等により投与でき、またその他非経口的な経路で投与できる。また、クリーム状の薬剤組成物としてもよく、これにより経皮的にも投与できる。その他、体内の深部の腫瘍組織へ直接に局所注入できる。
(Photodynamic therapeutic agent)
The photodynamic therapeutic agent of the present invention is suitable for photodynamic treatment of tumors, skin diseases, eye diseases, age-related macular degeneration and the like, and contains the phthalocyanine of the present invention as an active ingredient. The photodynamic therapeutic agent can be administered by a catheter, intravenous injection, intramuscular injection, or the like, or can be administered by other parenteral routes. Further, it may be in the form of a cream-shaped pharmaceutical composition, which enables transdermal administration. In addition, it can be directly injected locally into deep tumor tissue.
また、光線力学治療剤は、本発明のフタロシアニンを含有していれば、必要に応じてその他成分を含有していてもよい。その他成分としては、例えば、賦形剤が挙げられる。 Further, the photodynamic therapeutic agent may contain other components, if necessary, as long as it contains the phthalocyanine of the present invention. Examples of other components include excipients.
賦形剤としては、例えば、固形物として、乳糖、カオリン、ショ糖、結晶セルロース、コーンスターチ、タルク、寒天、ペクチン、ステアリン酸、ステアリン酸マグネシウム、レシチン、および、塩化ナトリウム等が挙げられる。液状物として、グリセリン、落花生油、エタノール、ベンジルアルコール、プロピレングリコール等が挙げられる。 Examples of the excipient include lactose, kaolin, sucrose, crystalline cellulose, corn starch, talc, agar, pectin, stearic acid, magnesium stearate, lecithin, and sodium chloride as a solid substance. Examples of the liquid substance include glycerin, peanut oil, ethanol, benzyl alcohol, propylene glycol and the like.
光線力学治療剤は、賦形剤以外にも、必要に応じて、基材、界面活性剤、保存剤、乳化剤、着色剤、矯臭剤、香料、安定剤、防腐剤、酸化防止剤、潤沢剤、抗菌剤、溶解補助剤、懸濁剤、結合剤、崩壊剤等を含有してもよい。 The photodynamic therapeutic agent may be a base material, a surfactant, a preservative, an emulsifier, a coloring agent, a flavoring agent, a fragrance, a stabilizer, a preservative, an antioxidant, and a lubricant, if necessary, in addition to the excipient. , An antibacterial agent, a solubilizing agent, a suspending agent, a binder, a disintegrating agent and the like may be contained.
光線力学治療剤の使用形態としては、特に制限されず、例えば、錠剤、散財、顆粒剤、カプセル剤、トローチ剤、シロップ剤、乳液、軟ゼラチンカプセル、ゲル、ペースト、注射用製剤、クリーム、ジェル、ローション、貼付剤等の使用形態が挙げられる。 The use form of the photodynamic therapeutic agent is not particularly limited, and examples thereof include tablets, powders, granules, capsules, troches, syrups, emulsions, soft gelatin capsules, gels, pastes, injectable preparations, creams and gels. , Lotions, patches and the like.
注射用製剤として調製する場合、本発明のフタロシアニンを含む水溶液もしくは分散体等の形に製剤化できる。液体担体としては、例えば、水、生理食塩水、エタノール、含水エタノール、グリセロール、プロピレングリコール、植物油等が好ましい。 When prepared as an injectable preparation, it can be prepared in the form of an aqueous solution or dispersion containing the phthalocyanine of the present invention. As the liquid carrier, for example, water, physiological saline, ethanol, hydrous ethanol, glycerol, propylene glycol, vegetable oil and the like are preferable.
光線力学治療剤には、本発明のフタロシアニンとともに、ラクトース、スクロース、第二リン酸カルシウム、カルボキシメチルセルロース等の希釈剤、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク等の滑剤、デンプン、グルコース、糖蜜、ポリビニルピロリドン、セルロースおよびこれらの誘導体等の結合剤を含み得る。 Photodynamic therapeutic agent, together with the phthalocyanine of the present invention, lactose, sucrose, dibasic calcium phosphate, diluents such as carboxymethyl cellulose, magnesium stearate, calcium stearate, lubricants such as talc, starch, glucose, molasses, polyvinylpyrrolidone, cellulose. And binding agents such as their derivatives.
本実施形態における一製剤当たりの有効成分の含量は、治療すべき対象や用法によって適宜とすることができる。 The content of the active ingredient per formulation in the present embodiment can be appropriately determined depending on the subject to be treated and the usage.
腫瘍の治療には、光線力学治療剤を投与した後、治療すべき部位に、本発明のフタロシアニンの吸収帯を含む光線を照射する。具体的には、600nm以上の光線照射により一重項酸素を発生して、目的の細胞毒性を発揮することができるが、好ましくは最大吸収波長の光の割合が高い光線を照射することである。 To treat a tumor, a photodynamic therapeutic agent is administered, and then the region to be treated is irradiated with a light beam containing the phthalocyanine absorption band of the present invention. Specifically, irradiation with light having a wavelength of 600 nm or more can generate singlet oxygen and exert desired cytotoxicity, but irradiation with light having a high ratio of light having a maximum absorption wavelength is preferable.
照射光源としては、LED(Light Emitting Diode)、レーザー、ハロゲンランプ等が用いられる。レーザーとしては、色素レーザー、半導体レーザー、アルゴンレーザー等、フタロシアニンの光励起に必要な波長の光線が得られるものであればよい。 As the irradiation light source, an LED (Light Emitting Diode), a laser, a halogen lamp or the like is used. As the laser, a dye laser, a semiconductor laser, an argon laser, or the like may be used as long as it can obtain a light beam having a wavelength necessary for photoexcitation of phthalocyanine.
本発明のフタロシアニンの具体例としては、以下のフタロシアニンが挙げられるが、本発明のフタロシアニンはこれらに限定されない。
表1
Specific examples of the phthalocyanine of the present invention include the following phthalocyanines, but the phthalocyanine of the present invention is not limited to these.
Table 1
本発明のフタロシアニンは、着色材として印刷インキ、IJインキ、プラスチック、塗料、繊維、文具、筆記具、化粧品等の着色に使用することができる。 The phthalocyanine of the present invention can be used as a coloring material for coloring printing inks, IJ inks, plastics, paints, fibers, stationery, writing instruments, cosmetics and the like.
以下に、本発明を実施例に基づいて説明するが、本発明はこれによって限定されるものではない。なお、実施例中「部」とは、「質量部」を表す。 Hereinafter, the present invention will be described based on examples, but the present invention is not limited thereto. In addition, "part" in an Example represents a "mass part."
<フタロニトリル誘導体1の製造方法>
4,5−ジアミノフタロニトリル5部をアセトニトリル480部に溶解させ、ベンズアルデヒド3.4部を添加後、30%過酸化水素水25部と濃塩酸10.9部を続けて添加した。25℃で2時間撹拌し後、水500部に炭酸水素ナトリウム11.9部を溶解した水溶液を添加し、析出した固体をろ取し、水100部で洗浄を行った。80℃で乾燥させ、収率80.4%で6.2部の表2に示すフタロニトリル誘導体1を得た。
<Method for producing phthalonitrile derivative 1>
5 parts of 4,5-diaminophthalonitrile was dissolved in 480 parts of acetonitrile, 3.4 parts of benzaldehyde was added, and then 25 parts of 30% hydrogen peroxide solution and 10.9 parts of concentrated hydrochloric acid were successively added. After stirring at 25° C. for 2 hours, an aqueous solution in which 11.9 parts of sodium hydrogen carbonate was dissolved in 500 parts of water was added, the precipitated solid was collected by filtration, and washed with 100 parts of water. After drying at 80° C., 6.2 parts of phthalonitrile derivative 1 shown in Table 2 was obtained with a yield of 80.4%.
<フタロニトリル誘導体2〜30の製造方法>
フタロニトリル誘導体1の製造方法で使用したベンズアルデヒドを、表2に示すアルデヒド類に変更した以外は、フタロニトリル誘導体1の製造と同様にして、表2に示すフタロニトリル誘導体2〜30をそれぞれ製造した。尚、アルデヒド類は、フタロニトリル誘導体1の製造におけるベンズアルデヒドと同モル量使用した。
表2
<Method for producing phthalonitrile derivative 2 to 30>
The phthalonitrile derivatives 2 to 30 shown in Table 2 were produced in the same manner as the phthalonitrile derivative 1 except that the benzaldehyde used in the method for producing the phthalonitrile derivative 1 was changed to the aldehydes shown in Table 2. .. The aldehydes were used in the same molar amount as benzaldehyde in the production of phthalonitrile derivative 1.
Table 2
<フタロニトリル誘導体31〜41の製造方法> <Method for producing phthalonitrile derivatives 31 to 41>
フタロニトリル誘導体1の製造方法で使用した4,5−ジアミノフタロニトリルおよびベンズアルデヒドを、それぞれ表3に示すフタロニトリル類およびアルデヒド類に変更した以外は、フタロニトリル誘導体1の製造方法と同様にして、表3に示すフタロニトリル誘導体31〜41をそれぞれ製造した。尚、フタロニトリル類およびアルデヒド類は、フタロニトリル誘導体1の製造方法における4,5−ジアミノフタロニトリルおよびベンズアルデヒドと同モル量使用した。
表3
In the same manner as in the method for producing the phthalonitrile derivative 1, except that the 4,5-diaminophthalonitrile and benzaldehyde used in the method for producing the phthalonitrile derivative 1 were changed to the phthalonitriles and the aldehydes shown in Table 3, respectively, The phthalonitrile derivatives 31 to 41 shown in Table 3 were produced. The phthalonitriles and aldehydes were used in the same molar amounts as 4,5-diaminophthalonitrile and benzaldehyde in the method for producing the phthalonitrile derivative 1.
Table 3
<フタロニトリル誘導体42の製造方法>
4,5−ジアミノフタロニトリル1.5部と1,1’−カルボニルジイミダゾール2部、アセトニトリル8部を混合し、90℃で5時間撹拌した。反応液を25℃に冷却後、析出している固体をろ取し、水50部で洗浄を行った。80℃で乾燥させ、収率90%で1.6部の表4に示すフタロニトリル誘導体42を得た。
<Method for producing phthalonitrile derivative 42>
1.5 parts of 4,5-diaminophthalonitrile, 2 parts of 1,1′-carbonyldiimidazole and 8 parts of acetonitrile were mixed and stirred at 90° C. for 5 hours. After cooling the reaction solution to 25° C., the precipitated solid was collected by filtration and washed with 50 parts of water. After drying at 80° C., 1.6 parts of phthalonitrile derivative 42 shown in Table 4 was obtained with a yield of 90%.
<フタロニトリル誘導体43、44の製造方法> <Method for producing phthalonitrile derivative 43, 44>
フタロニトリル誘導体42の製造で使用した4,5−ジアミノフタロニトリルを、表4に示すフタロニトリル類に変更した以外は、フタロニトリル誘導体42と同様にして、表4に示すフタロニトリル誘導体43、44をそれぞれ製造した。尚、表4のフタロニトリル類は、フタロニトリル誘導体42の製造における4,5−ジアミノフタロニトリルと同モル量使用した。
表4
The phthalonitrile derivative 43, 44 shown in Table 4 was obtained in the same manner as the phthalonitrile derivative 42 except that the 4,5-diaminophthalonitrile used in the production of the phthalonitrile derivative 42 was changed to the phthalonitriles shown in Table 4. Were manufactured respectively. The phthalonitriles in Table 4 were used in the same molar amount as 4,5-diaminophthalonitrile in the production of the phthalonitrile derivative 42.
Table 4
<フタロシアニン前駆体1の製造方法>
脱水ジメチルアセトアミド90部に水素化ナトリウム(パラフィン含有、純度60%)1.1部を添加し、25℃で15分間撹拌した。次に、フタロニトリル誘導体1を6部と脱水ジメチルアセトアミド10部の混合物を5℃で添加し、さらにヨウ化エチル7部を添加して、80℃で6時間撹拌を行った。その後、反応物を25℃まで冷却し、水を500部添加し、析出した固体をろ過後、水300部で洗浄を行った。80℃で乾燥し、収率90%で6部の表5に示すフタロシアニン前駆体1を得た。
<Method for producing phthalocyanine precursor 1>
1.1 parts of sodium hydride (containing paraffin, purity 60%) was added to 90 parts of dehydrated dimethylacetamide, and the mixture was stirred at 25°C for 15 minutes. Next, a mixture of 6 parts of the phthalonitrile derivative 1 and 10 parts of dehydrated dimethylacetamide was added at 5°C, 7 parts of ethyl iodide was further added, and the mixture was stirred at 80°C for 6 hours. Then, the reaction product was cooled to 25° C., 500 parts of water was added, the precipitated solid was filtered, and then washed with 300 parts of water. After drying at 80° C., 6 parts of phthalocyanine precursor 1 shown in Table 5 was obtained with a yield of 90%.
<フタロシアニン前駆体2〜49の製造方法> <Method for producing phthalocyanine precursors 2 to 49>
フタロシアニン前駆体1の製造で使用したフタロニトリル誘導体1とヨウ化エチルを、表5に示すフタロニトリル誘導体とハロゲン類にそれぞれ変更した以外は、フタロシアニン前駆体1と同様にして、表5に示すフタロニトリル前駆体2〜49をそれぞれ製造した。尚、表5のフタロニトリル誘導体とハロゲン類は、フタロシアニン前駆体1の製造におけるフタロニトリル誘導体1とヨウ化エチルと同モル量使用した。
表5
The phthalonitrile derivative 1 and the ethyl iodide used in the production of the phthalocyanine precursor 1 were replaced with the phthalonitrile derivative and halogens shown in Table 5, respectively, in the same manner as the phthalocyanine precursor 1, except that the phthalonitrile derivative 1 shown in Table 5 was used. Nitrile precursors 2-49 were prepared respectively. The phthalonitrile derivative and halogens in Table 5 were used in the same molar amounts as the phthalonitrile derivative 1 and ethyl iodide in the production of the phthalocyanine precursor 1.
Table 5
<フタロシアニン前駆体50の製造方法>
脱水ジメチルアセトアミド14部に水素化ナトリウム(パラフィン含有、純度60%)0.7部を添加し、25℃で15分間撹拌した。次に、フタロニトリル誘導体42を1.5部と脱水ジメチルアセトアミド9部の混合物を5℃で添加し、さらにヨウ化エチル2.7部を添加して、80℃で6時間撹拌を行った。その後、反応物を25℃まで冷却し、水を100部添加し、析出した固体をろ過後、100部の水で洗浄を行った。80℃で乾燥し、収率92%で1.8部の表6に示すフタロシアニン前駆体50を得た。
<Method for producing phthalocyanine precursor 50>
0.7 parts of sodium hydride (containing paraffin, purity 60%) was added to 14 parts of dehydrated dimethylacetamide, and the mixture was stirred at 25°C for 15 minutes. Next, a mixture of 1.5 parts of phthalonitrile derivative 42 and 9 parts of dehydrated dimethylacetamide was added at 5° C., 2.7 parts of ethyl iodide was further added, and the mixture was stirred at 80° C. for 6 hours. Then, the reaction product was cooled to 25° C., 100 parts of water was added, and the precipitated solid was filtered and washed with 100 parts of water. After drying at 80° C., 1.8 parts of a phthalocyanine precursor 50 shown in Table 6 was obtained with a yield of 92%.
<フタロシアニン前駆体51〜57の製造方法>
フタロシアニン前駆体50の製造で使用したフタロニトリル誘導体42とヨウ化エチルを表6に示すフタロニトリル誘導体とハロゲン類にそれぞれ変更した以外は、フタロシアニン前駆体50と同様にして、表6に示すフタロニトリル前駆体51〜57をそれぞれ製造した。尚、表6のフタロニトリル誘導体とハロゲン類は、フタロシアニン前駆体50の製造方法におけるフタロニトリル誘導体42とヨウ化エチルと同モル量使用した。
表6
<Method for producing phthalocyanine precursors 51 to 57>
The phthalonitrile precursor 42 shown in Table 6 was obtained in the same manner as the phthalocyanine precursor 50 except that the phthalonitrile derivative 42 and ethyl iodide used in the production of the phthalocyanine precursor 50 were changed to the phthalonitrile derivative and halogens shown in Table 6, respectively. The precursors 51 to 57 were manufactured, respectively. The phthalonitrile derivative and halogens in Table 6 were used in the same molar amounts as the phthalonitrile derivative 42 and ethyl iodide in the method for producing the phthalocyanine precursor 50.
Table 6
<フタロシアニンの製造方法>
[実施例1]<フタロシアニン1の製造方法>
特開平9−217020号公報の合成例1に記載されている方法を参考に製造を行った。フタロシアニン前駆体1を0.4部と1−クロロナフタレン2部、塩化アルミニウム0.06部を混合し、210℃で5時間撹拌を行った。25℃に冷却後、析出した固体をろ過し、熱トルエン5部、アセトン3部で洗浄した後、乾燥した。その後、0.14部の固体を濃硫酸10部に溶解させ、1時間撹拌後、100部の氷に添加し、30分撹拌後、析出した固体をろ取し、50部の水で洗浄した後、乾燥し、収率41%で0.17部のフタロシアニン1を得た。質量分析装置(TOF−MS:ブルカー・ダルトニクス社製 autoflexII)により分析した結果、m/z=1133.65(理論値1132.41)に分子イオンピークが検出され、表1に記載したフタロシアニン1の構造を有することが同定された。
<Method for producing phthalocyanine>
[Example 1] <Method for producing phthalocyanine 1>
The production was carried out with reference to the method described in Synthesis Example 1 of JP-A-9-217020. 0.4 parts of phthalocyanine precursor 1, 2 parts of 1-chloronaphthalene and 0.06 part of aluminum chloride were mixed and stirred at 210° C. for 5 hours. After cooling to 25°C, the precipitated solid was filtered, washed with 5 parts of hot toluene and 3 parts of acetone, and then dried. Then, 0.14 parts of the solid was dissolved in 10 parts of concentrated sulfuric acid, stirred for 1 hour, added to 100 parts of ice, stirred for 30 minutes, and the precipitated solid was collected by filtration and washed with 50 parts of water. Then, it was dried to obtain 0.17 part of phthalocyanine 1 with a yield of 41%. As a result of analysis by a mass spectrometer (TOF-MS: autoflexII manufactured by Bruker Daltonics, Inc.), a molecular ion peak was detected at m/z=1133.65 (theoretical value 1132.41), and phthalocyanine 1 shown in Table 1 was detected. It was identified as having structure.
[実施例2〜57]
<フタロシアニン2〜57の製造方法>
フタロシアニン1の製造方法で使用したフタロシアニン前駆体1を、表7に示すフタロシアニン前駆体にそれぞれ変更して、フタロシアニン1の製造方法と同様にして、表7に示すフタロシアニン2〜57をそれぞれ製造した。表7のフタロシアニン前駆体は、フタロシアニン1の製造方法におけるフタロシアニン前駆体1と同モル量使用した。質量分析装置(TOF−MS:ブルカー・ダルトニクス社製 autoflexII)により分析した結果、表7に示した分子イオンピーク(m/z)が検出され、表1に示したフタロシアニン2〜57の構造を有することが同定された。
表7
[Examples 2 to 57]
<Method for producing phthalocyanines 2 to 57>
The phthalocyanine precursor 1 used in the method for producing phthalocyanine 1 was changed to the phthalocyanine precursor shown in Table 7, and phthalocyanines 2 to 57 shown in Table 7 were produced in the same manner as the method for producing phthalocyanine 1. The phthalocyanine precursor in Table 7 was used in the same molar amount as the phthalocyanine precursor 1 in the method for producing phthalocyanine 1. As a result of analysis by a mass spectrometer (TOF-MS: autoflexII manufactured by Bruker Daltonics, Inc.), the molecular ion peaks (m/z) shown in Table 7 were detected, and the compounds had the structures of phthalocyanines 2 to 57 shown in Table 1. Was identified.
Table 7
[実施例58〜61]
<フタロシアニン58〜61の製造方法>
フタロシアニン1の製造方法で使用したフタロニトリル前駆体1を、表8に示すフタロシアニン誘導体にそれぞれ変更して、フタロシアニン1の製造方法と同様にして、表8に示すフタロシアニン58〜61をそれぞれ製造した。表8のフタロシアニン誘導体は、フタロシアニン1の製造方法におけるフタロシアニン前駆体1と同モル量使用した。質量分析装置(TOF−MS:ブルカー・ダルトニクス社製 autoflexII)により分析した結果、表8に示した分子イオンピーク(m/z)が検出され、表1に示したフタロシアニン58〜61の構造を有することが同定された。
表8
[Examples 58 to 61]
<Method for producing phthalocyanines 58 to 61>
The phthalonitrile precursor 1 used in the method for producing phthalocyanine 1 was changed to the phthalocyanine derivatives shown in Table 8, and phthalocyanines 58 to 61 shown in Table 8 were produced in the same manner as in the method for producing phthalocyanine 1. The phthalocyanine derivative in Table 8 was used in the same molar amount as the phthalocyanine precursor 1 in the method for producing phthalocyanine 1. As a result of analysis by a mass spectrometer (TOF-MS: autoflexII manufactured by Bruker Daltonics, Inc.), the molecular ion peaks (m/z) shown in Table 8 were detected, and the phthalocyanines 58 to 61 had the structures shown in Table 1. Was identified.
Table 8
[実施例62]
<フタロシアニン62の製造方法>
フタロシアニン前駆体1を3部とホルムアミド15部、水酸化ナトリウム1.8部、テトラヒドロフラン15部を混合し、50℃で8時間加熱撹拌した。その後、25℃に冷却した反応液を水300部に添加し、析出した固体をろ過、乾燥し、中間体であるジイミノイソインドリン誘導体を収率73%で2.34部得た。次に、得られた中間体2.25部とn−アミルアルコール15部、四塩化ケイ素0.36部を混合攪拌し、136℃で8時間還流した。攪拌したまま30℃まで冷却した反応溶液を、メタノール75部および水150部からなる混合溶媒中へ攪拌しながら注入し、析出した固体をろ過し、メタノール60部および水120部からなる混合溶媒で洗浄した後、乾燥した。最後に、この乾燥物を濃硫酸10部に溶解させ、1時間撹拌後、氷100部に添加し、30分撹拌後、析出した固体をろ取し、水50部でした後、乾燥し、収率65%で1.55部のフタロシアニン51を得た。質量分析装置(TOF−MS:ブルカー・ダルトニクス社製 autoflexII)により分析した結果、m/z=1151.91(理論値1150.41)に分子イオンピークが検出され、表1に記載したフタロシアニン62の構造を有することが同定された。
Example 62
<Method for producing phthalocyanine 62>
3 parts of phthalocyanine precursor 1 was mixed with 15 parts of formamide, 1.8 parts of sodium hydroxide and 15 parts of tetrahydrofuran, and the mixture was heated and stirred at 50° C. for 8 hours. Then, the reaction liquid cooled to 25° C. was added to 300 parts of water, and the precipitated solid was filtered and dried to obtain 2.34 parts of an intermediate diiminoisoindoline derivative in a yield of 73%. Next, 2.25 parts of the obtained intermediate, 15 parts of n-amyl alcohol, and 0.36 part of silicon tetrachloride were mixed and stirred, and the mixture was refluxed at 136° C. for 8 hours. While stirring, the reaction solution cooled to 30° C. was poured into a mixed solvent consisting of 75 parts of methanol and 150 parts of water while stirring, and the precipitated solid was filtered and washed with a mixed solvent of 60 parts of methanol and 120 parts of water. After washing, it was dried. Finally, the dried product was dissolved in 10 parts of concentrated sulfuric acid, stirred for 1 hour, added to 100 parts of ice, stirred for 30 minutes, the precipitated solid was collected by filtration, dried with 50 parts of water, and then dried. 1.55 parts of phthalocyanine 51 was obtained with a yield of 65%. As a result of analysis by a mass spectrometer (TOF-MS: autoflexII manufactured by Bruker Daltonics, Inc.), a molecular ion peak was detected at m/z=1151.91 (theoretical value 1150.41), and phthalocyanine 62 shown in Table 1 was detected. It was identified as having structure.
[実施例63〜118]
<フタロシアニン63〜118の製造方法>
[Examples 63 to 118]
<Method for producing phthalocyanines 63 to 118>
フタロシアニン62の製造方法で使用したフタロシアニン前駆体1を、表9に示すフタロシアニン前駆体にそれぞれ変更して、フタロシアニン62の製造方法と同様にして、表9に示すフタロシアニン63〜118をそれぞれ製造した。表9のフタロシアニン前駆体は、フタロシアニン62の製造方法におけるフタロシアニン前駆体1と同モル量使用した。質量分析装置(TOF−MS:ブルカー・ダルトニクス社製 autoflexII)により分析した結果、表9に示した分子イオンピーク(m/z)が検出され、表1に示したフタロシアニン63〜118の構造を有することが同定された。
表9
The phthalocyanine precursor 1 used in the method for producing the phthalocyanine 62 was changed to the phthalocyanine precursor shown in Table 9, and phthalocyanines 63 to 118 shown in Table 9 were produced in the same manner as in the method for producing the phthalocyanine 62. The phthalocyanine precursor in Table 9 was used in the same molar amount as the phthalocyanine precursor 1 in the method for producing phthalocyanine 62. As a result of analysis by a mass spectrometer (TOF-MS: autoflexII manufactured by Bruker Daltonics, Inc.), the molecular ion peaks (m/z) shown in Table 9 were detected, and the compounds had the structures of phthalocyanines 63 to 118 shown in Table 1. Was identified.
Table 9
[実施例119〜122]
<フタロシアニン119〜122の製造方法>
[Examples 119 to 122]
<Method for producing phthalocyanines 119 to 122>
フタロシアニン62の製造方法で使用したフタロシアニン前駆体1を、表10に示すフタロニトリル誘導体にそれぞれ変更して、フタロシアニン62の製造方法と同様にして、表10に示すフタロシアニン119〜122をそれぞれ製造した。表10のフタロシアニン誘導体は、フタロシアニン62の製造方法におけるフタロシアニン前駆体1と同モル量使用した。質量分析装置(TOF−MS:ブルカー・ダルトニクス社製 autoflexII)により分析した結果、表10に示した分子イオンピーク(m/z)が検出され、表1に示したフタロシアニン119〜122の構造を有することが同定された。
表10
The phthalocyanine precursor 1 used in the method for producing the phthalocyanine 62 was changed to the phthalonitrile derivative shown in Table 10, and phthalocyanines 119 to 122 shown in Table 10 were produced in the same manner as the method for producing the phthalocyanine 62. The phthalocyanine derivative in Table 10 was used in the same molar amount as the phthalocyanine precursor 1 in the method for producing phthalocyanine 62. As a result of analysis with a mass spectrometer (TOF-MS: autoflexII manufactured by Bruker Daltonics, Inc.), the molecular ion peaks (m/z) shown in Table 10 were detected, and the compounds had the structures of phthalocyanines 119 to 122 shown in Table 1. Was identified.
Table 10
[実施例123]
<フタロシアニン123の製造方法>
フタロシアニン1を2部とリン酸ジフェニル0.6部、ジメチルスルホキシド40部を混合し、85℃で3時間反応させた後、反応溶液を水40部に添加した。析出物をろ過し、水20部で洗浄後、乾燥し、収率70%で1.7部のフタロシアニン101を得た。質量分析装置(TOF−MS:ブルカー・ダルトニクス社製 autoflexII)により分析した結果、m/z=1365.69(理論値1364.44)に分子イオンピークが検出され、表1に記載したフタロシアニン123の構造を有することが同定された。
[Example 123]
<Method for producing phthalocyanine 123>
After mixing 2 parts of phthalocyanine 1 with 0.6 part of diphenyl phosphate and 40 parts of dimethyl sulfoxide and reacting at 85° C. for 3 hours, the reaction solution was added to 40 parts of water. The precipitate was filtered, washed with 20 parts of water and dried to obtain 1.7 parts of phthalocyanine 101 with a yield of 70%. As a result of analysis using a mass spectrometer (TOF-MS: autoflexII manufactured by Bruker Daltonics, Inc.), a molecular ion peak was detected at m/z=1365.69 (theoretical value 1364.44), and phthalocyanine 123 shown in Table 1 was detected. It was identified as having structure.
[実施例124〜141]
<フタロシアニン124〜141の製造方法>
フタロシアニン123の製造方法で使用したフタロシアニン1とリン酸ジフェニルを、表11に示す原料と酸性化合物にそれぞれ変更して、フタロシアニン123と同様にして、表11に示すフタロシアニン124〜141をそれぞれ製造した。ただし、表11の酸性化合物は、原料にフタロシアニン1を用いた場合は、フタロシアニン123の製造方法のリン酸ジフェニルと同モル量を、原料にフタロシアニン62を用いた場合は、フタロシアニン123の製造方法のリン酸ジフェニルの2倍モル量を使用した。質量分析装置(TOF−MS:ブルカー・ダルトニクス社製 autoflexII)により分析した結果、表11に示した分子イオンピーク(m/z)が検出され、表1に示したフタロシアニン124〜141の構造を有することが同定された。
表11
[Examples 124 to 141]
<The manufacturing method of phthalocyanine 124-141>
Phthalocyanine 1 and diphenyl phosphate used in the method for producing phthalocyanine 123 were changed to the raw materials and acidic compounds shown in Table 11, respectively, and phthalocyanines 124 to 141 shown in Table 11 were produced in the same manner as phthalocyanine 123. However, when the phthalocyanine 1 was used as the raw material, the acidic compounds in Table 11 had the same molar amount as the diphenyl phosphate used in the production method of the phthalocyanine 123, and when phthalocyanine 62 was used as the raw material, the acidic compound of the production method of the phthalocyanine 123 was used. Twice the molar amount of diphenyl phosphate was used. As a result of analysis by a mass spectrometer (TOF-MS: autoflexII manufactured by Bruker Daltonics, Inc.), the molecular ion peaks (m/z) shown in Table 11 were detected, and the phthalocyanines 124 to 141 shown in Table 1 were formed. Was identified.
Table 11
[比較例1]
インドシアニングリーン(東京化成製)を用いた。
[Comparative Example 1]
Indocyanine green (manufactured by Tokyo Kasei) was used.
[比較例2]
フタロシアニン142を用いた。
[Comparative Example 2]
Phthalocyanine 142 was used.
フタロシアニン142
<フタロシアニン142の製造方法>
フタロシアニン前駆体1を0.4部とn−アミルアルコール10部、塩化マグネシウム0.04部、1,8−ジアザビシクロ[5.4.0]−7−ウンデセン0.26部を混合し、136℃で6時間還流した。攪拌したまま30℃まで冷却した反応溶液にメタノール16部を添加し、析出した固体をろ過し、メタノール16部で洗浄した後、乾燥した。収率63%で0.26部のフタロシアニン142を得た。質量分析装置(TOF−MS:ブルカー・ダルトニクス社製 autoflexII)により分析した結果、m/z=1113.74(理論値1112.41)に分子イオンピークが検出され、上記フタロシアニン142の構造を有することが同定された。
<Method for producing phthalocyanine 142>
Phthalocyanine precursor 1 (0.4 parts), n-amyl alcohol (10 parts), magnesium chloride (0.04 parts) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.26 parts) were mixed, and the mixture was heated to 136°C. At reflux for 6 hours. 16 parts of methanol was added to the reaction solution cooled to 30° C. with stirring, the precipitated solid was filtered, washed with 16 parts of methanol, and then dried. 0.26 parts of phthalocyanine 142 was obtained with a yield of 63%. As a result of analysis with a mass spectrometer (TOF-MS: autoflexII manufactured by Bruker Daltonics, Inc.), a molecular ion peak was detected at m/z=1113.74 (theoretical value 112.41), and the compound had the above-mentioned phthalocyanine 142 structure. Was identified.
[実施例142]
<分散体K−1の作製>
フタロシアニン1を1部、両親媒性物質としてポリエチレングリコール(PEG)・ポリカプロラクトン(PCL)ブロック共重合体(シグマアルドリッチ社製、PEG分子量5000、PCL分子量5000)100部をアセトン20000部に溶解した。得られたアセトン溶液を25℃で撹拌下、水25000部を滴下した。さらに、25℃で12時間撹拌することでアセトンを留去した後、0.45μmナイロン製メンブレンフィルターで濾過して、フタロシアニン1がPEG−PCLミセル内に可溶化された分散体を作製した。
[Example 142]
<Production of Dispersion K-1>
1 part of phthalocyanine 1 and 100 parts of polyethylene glycol (PEG)/polycaprolactone (PCL) block copolymer (manufactured by Sigma-Aldrich, PEG molecular weight 5000, PCL molecular weight 5000) as an amphipathic substance were dissolved in 20000 parts of acetone. 25,000 parts of water was added dropwise to the obtained acetone solution with stirring at 25°C. Further, the mixture was stirred at 25° C. for 12 hours to remove acetone, and then filtered through a 0.45 μm nylon membrane filter to prepare a dispersion in which phthalocyanine 1 was solubilized in PEG-PCL micelles.
[実施例143]
<分散体K−2の作製>
分散体K−1の作製で使用した両親媒性物質のかわりに、ポリエチレングリコール(PEG)・ポリ乳酸(PLGA)ブロック共重合体(シグマアルドリッチ社製、PEG分子量5000、PLGA分子量7000)に変更した以外は、分散体K−1の作製と同様にして、分散体K−2を作製した。
[Example 143]
<Preparation of Dispersion K-2>
Instead of the amphipathic substance used in the preparation of the dispersion K-1, a polyethylene glycol (PEG)/polylactic acid (PLGA) block copolymer (manufactured by Sigma-Aldrich, PEG molecular weight 5000, PLGA molecular weight 7000) was used. Dispersion K-2 was prepared in the same manner as dispersion K-1 except for the above.
[実施例144〜283、比較例3]
<分散体K−3〜143の作製>
分散体K−1の作製で使用したフタロシアニン1のかわりに、表12に示すフタロシアニンに変更した以外は、分散体K−1の作製と同様にして、分散体K−3〜143をそれぞれ作製した。ただし、各フタロシアニンは、フタロシアニン1と同モル量使用した。
[Examples 144 to 283, Comparative Example 3]
<Production of Dispersions K-3 to 143>
Dispersions K-3 to 143 were prepared in the same manner as the dispersion K-1 except that the phthalocyanine shown in Table 12 was used instead of the phthalocyanine 1 used in the preparation of the dispersion K-1. .. However, each phthalocyanine was used in the same molar amount as phthalocyanine 1.
[比較例4]
<分散体144の作製>
分散体K−1の作製で使用したフタロシアニン1のかわりに、インドシアニングリーンに変更した以外は、分散体K−1の作製と同様にして、分散体K−144を作成した。インドシアニングリーンは、フタロシアニン1と同モル量使用した。
[Comparative Example 4]
<Production of Dispersion 144>
Dispersion K-144 was prepared in the same manner as dispersion K-1 except that indocyanine green was used instead of phthalocyanine 1 used in the preparation of dispersion K-1. Indocyanine green was used in the same molar amount as phthalocyanine 1.
[比較例5]
<分散体K−145の作製>
蛍光標識剤K−1の作製で使用したフタロシアニン1のかわりに、LI−COR社製IRDye(登録商標)800CW NHS Esterに変更した以外は、分散体K−1の作製と同様にして、分散体K−145を作製した。IRDye(登録商標)800CW NHS Esterは、フタロシアニン1と同モル量使用した。
[Comparative Example 5]
<Production of Dispersion K-145>
The phthalocyanine 1 used in the preparation of the fluorescent labeling agent K-1 was replaced with an IRDye (registered trademark) 800CW NHS Ester manufactured by LI-COR in the same manner as in the preparation of the dispersion K-1 except that the dispersion was changed. K-145 was produced. IRDye (registered trademark) 800CW NHS Ester was used in the same molar amount as phthalocyanine 1.
<蛍光強度評価>
各々の分散体について、蛍光光度計(日本分光株式会社製、FP−6500)を用いて蛍光スペクトルを測定し、蛍光波長780〜840nmの範囲内での最大蛍光強度を求めた。比較例5の分散体の最大蛍光強度を1とした時の、各々の分散体の蛍光強度の相対値を算出し、下記の基準に基づいて評価した。蛍光強度の相対値が4以上である場合、各フタロシアニンは蛍光標識剤としての特性が良好であるといえる。
△:蛍光強度1以上、4未満(不良)
〇:蛍光強度4以上、8未満(良好)
◎:蛍光強度8以上(極めて良好)
<Evaluation of fluorescence intensity>
For each dispersion, the fluorescence spectrum was measured using a fluorescence photometer (FP-6500, manufactured by JASCO Corporation), and the maximum fluorescence intensity in the fluorescence wavelength range of 780 to 840 nm was obtained. When the maximum fluorescence intensity of the dispersion of Comparative Example 5 was set to 1, the relative value of the fluorescence intensity of each dispersion was calculated and evaluated based on the following criteria. When the relative value of the fluorescence intensity is 4 or more, it can be said that each phthalocyanine has excellent characteristics as a fluorescent labeling agent.
Δ: Fluorescence intensity 1 or more and less than 4 (poor)
◯: Fluorescence intensity of 4 or more and less than 8 (good)
⊚: Fluorescence intensity of 8 or more (very good)
<耐光性評価>
各々の分散体について、蛍光測定時の励起波長の光を、蛍光光度計(日本分光株式会社製、FP−6500)を用いて1時間照射し、励起光の照射前後の吸収スペクトルを分光光度計(株式会社日立ハイテクノロジーズ社製、U−4100)を用いてそれぞれ測定した。光照射前の最大吸収波長の吸光度をI0、光照射後の最大吸収波長の吸光度をI1を記録し、I1/I0値を耐光性の指標とした。
〇:I1/I0が0.9以上(良好)
×:I1/I0が0.9未満(不良)
<Light resistance evaluation>
Each of the dispersions was irradiated with light having an excitation wavelength at the time of measuring fluorescence for 1 hour using a fluorescence photometer (FP-6500 manufactured by JASCO Corporation), and the absorption spectrum before and after the irradiation of the excitation light was measured by a spectrophotometer. (U-4100 manufactured by Hitachi High-Technologies Corporation) was used for the measurement. The absorbance of the maximum absorption wavelength before irradiation I 0, the absorbance at the maximum absorption wavelength after the light irradiation to record I 1, was used as an index of light resistance of I 1 / I 0 values.
◯: I 1 /I 0 is 0.9 or more (good)
X: I 1 /I 0 is less than 0.9 (poor)
<細胞の視認性評価>
HeLa細胞を96ウェルプレートに播種(5×103cell/well)し、10%Fetal Bovine Serum(FBS)および1%ペニシリン―ストレプトマイシンを含ませたMinimum Essential Media(MEM)を用いて、インキュベーター(37℃、5%CO2含有Air、加湿環境)内で24時間培養した。その後、培地を取り除き、作製した各分散体を水で10倍希釈したものを添加し、インキュベーター内に24時間静置した後、リン酸緩衝食塩水(PBS)で洗浄した。適切な波長の励起フィルターおよび蛍光フィルターを設置した蛍光顕微鏡(キーエンス社製、BZ−X800)を用いて、細胞の暗視野像と蛍光像を観察した。細胞の像が、明瞭に観察されれば良好であり、不明瞭であれば不良である。
<Evaluation of cell visibility>
HeLa cells were seeded in a 96-well plate (5×10 3 cells/well), and an incubator (37) was used using a Minimum Essential Media (MEM) containing 10% Fetal Bovine Serum (FBS) and 1% penicillin-streptomycin. ℃, 5% CO 2 containing Air, and cultured for 24 hours in a humidified environment) within. After that, the medium was removed, each of the prepared dispersions diluted 10-fold with water was added, the mixture was allowed to stand in an incubator for 24 hours, and then washed with phosphate buffered saline (PBS). Using a fluorescence microscope (BZ-X800, manufactured by KEYENCE CORPORATION) equipped with an excitation filter and a fluorescence filter having appropriate wavelengths, the dark field image and the fluorescence image of the cells were observed. If the image of cells is clearly observed, it is good, and if it is unclear, it is bad.
以下、各励起波長における評価結果を示す。図に分散体K−1、K−124、K−143、K−144の蛍光スペクトルを示す。
表12
The evaluation results at each excitation wavelength are shown below. The fluorescence spectra of Dispersions K-1, K-124, K-143 and K-144 are shown in the figure.
Table 12
本発明のフタロシアニンを用いて作製した分散体K−1〜142(実施例142〜283)は、分散体K−144、145(比較例4、5)よりも蛍光強度、耐光性が良好であった。さらに、これらが向上したことで細胞の視認性も明瞭であった。また、フタロシアニンの中心金属がAlやSiである蛍光標識剤K−1〜142(実施例142〜283)は、同じフタロシアニン骨格であるが中心金属がMgであるK−143(比較例3)よりも耐光性が良好であった。このことから、本発明のフタロシアニンは、優れた蛍光標識剤としての特性を有することが明らかとなった。 Dispersions K-1 to 142 (Examples 142 to 283) produced using the phthalocyanine of the present invention have better fluorescence intensity and light resistance than Dispersions K-144 and 145 (Comparative Examples 4 and 5). It was Furthermore, the visibility of cells was clear due to these improvements. Further, the fluorescent labeling agents K-1 to 142 (Examples 142 to 283) in which the central metal of phthalocyanine is Al or Si are more than those of K-143 (Comparative Example 3) having the same phthalocyanine skeleton but the central metal is Mg. Also had good light resistance. From this, it became clear that the phthalocyanine of the present invention has excellent properties as a fluorescent labeling agent.
[実施例284〜424、比較例6]<一重項酸素発生量の評価>
各々のフタロシアニンについて、光線力学治療剤の基本特性である一重項酸素発生量について評価を実施した。評価は、J.Am.Chem.Soc.,2017,139,13713−13719に記載されている方法を基にした。すなわち、フタロシアニンへの光照射により発生した一重項酸素が、3−Diphenylisobenzofuran(DPBF)と反応し、DPBFが消失する際の吸光度変化により一重項酸素発生能を評価した。500mlのN−メチル―2−ピロリドン(NMP)に2滴の水を入れ均一にし、このNMP溶液を用いて各々のフタロシアニンの濃度2.00×10−5MのNMP溶液とDPBFの濃度2.00×10−4MのNMP溶液をそれぞれ作製した。吸収スペクトルの測定直前に両者を同量(体積)混合し、その吸収スペクトルを分光光度計(株式会社日立ハイテクノロジーズ社製、U−4100)を用いて測定した。次に、蛍光光度計(日本分光株式会社製、FP−6500)に吸収スペクトルを測定した石英セルを入れ、表12に示した励起波長の光を3分30秒間照射し、光照射後の吸収スペクトルを分光光度計にて測定した。光照射前後のDPBFの吸光度の変化より発生した一重項酸素濃度(OD)を算出した。また、リファレンスとしてローズベンガルの一重項酸素濃度(OR)を測定した(励起波長として554nmの光を使用)。そして、ODをORで割った値(OD/OR)を一重項酸素発生能とした。また、The Journal of Japan Society for Laser Surgery and Medicine,2017,28,122−128に記載されているインドシアニングリーンとPDTの光感受性物質Laserphyrinの一重項発生量と上記のインドシアニングリーンを用いた測定結果(励起波長として680nmの光を使用)からPDTの光感受性物質Laserphyrinの一重項発生能を算出し、本発明のフタロシアニンの一重項発生能と比較を行った。
△:一重項酸素発生能0.3未満(不良)
〇:一重項酸素発生能0.3以上、0.5未満(良好)
◎:一重項酸素発生能0.5以上(極めて良好)
[Examples 284 to 424, Comparative Example 6] <Evaluation of singlet oxygen generation amount>
For each phthalocyanine, the singlet oxygen generation amount, which is a basic characteristic of the photodynamic therapeutic agent, was evaluated. The evaluation is based on J. Am. Chem. Soc. , 2017, 139, 13713-13719. That is, singlet oxygen generated by irradiating phthalocyanine with light was reacted with 3-Diphenylisobenzofuran (DPBF), and the singlet oxygen generating ability was evaluated by the change in absorbance when DPBF disappeared. Two drops of water were uniformly added to 500 ml of N-methyl-2-pyrrolidone (NMP), and the NMP solution was used to make the concentration of each phthalocyanine 2.00×10 −5 M NMP and DPBF 2. A 00×10 −4 M NMP solution was prepared. Immediately before the measurement of the absorption spectrum, both were mixed in the same amount (volume), and the absorption spectrum was measured using a spectrophotometer (U-4100 manufactured by Hitachi High-Technologies Corporation). Next, a quartz cell whose absorption spectrum was measured was placed in a fluorescence photometer (FP-6500 manufactured by JASCO Corporation), and the light having the excitation wavelength shown in Table 12 was irradiated for 3 minutes and 30 seconds, and absorption after light irradiation The spectrum was measured with a spectrophotometer. It was calculated singlet oxygen generated from the change in absorbance before and after the light irradiation DPBF (O D). It was also measured Rose singlet oxygen concentration of Bengal (O R) as a reference (using light of 554nm as the excitation wavelength). The value obtained by dividing O D by O R (O D /O R ) was defined as the singlet oxygen generating ability. Also, the singlet abundance of the indocyanine green described in The Journal of Japan Society for Laser Surgery and Medicine, 2017, 28, 122-128 and the singlet generation amount of the laser sensitizer Laserpyrin and the above-mentioned indocyanine green were used. From the results (using light of 680 nm as an excitation wavelength), the singlet generating ability of PDT photosensitizer Laserphyrin was calculated and compared with the singlet generating ability of the phthalocyanine of the present invention.
Δ: Singlet oxygen generation capacity of less than 0.3 (poor)
◯: Singlet oxygen generation capacity of 0.3 or more and less than 0.5 (good)
⊚: Singlet oxygen generation capacity of 0.5 or more (extremely good)
以下、表13にその結果を示す。
表13
The results are shown in Table 13 below.
Table 13
本発明のフタロシアニン1〜141(実施例284〜424)は、文献値より算出したLaserphyrinの一重項酸素発生能より高い一重項酸素発生能を有することが認められた。このことから、本発明のフタロシアニンは、優れた光線力学治療剤としての特性を有することが明らかとなった。 It was confirmed that the phthalocyanines 1 to 141 (Examples 284 to 424) of the present invention have a singlet oxygen generating ability higher than that of Laserphyrin calculated from literature values. From this, it became clear that the phthalocyanine of the present invention has excellent properties as a photodynamic therapeutic agent.
Claims (4)
一般式(1)
(式中、X1〜X8は、それぞれ独立に、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、−O−R21、−S−R22を表し、R21およびR22は、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基を表す。R1〜R20は、それぞれ独立に、水素原子、ハロゲン原子、水酸基、ニトロ基、ホルミル基、シアノ基、−COOM2、−SO3M2、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアルケニル基、置換もしくは無置換のアリール基、−O−R23、−S−R24を表し、M2は、水素原子、アルカリ金属を、R23およびR24は、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基を表す。R1〜R20は、隣接する基同士が互いに連結して環を形成してもよい。Y1〜Y4は、それぞれ独立に、N−H、N−R25、O、Sを表し、R25は、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基を表す。M1は、AlまたはSiを表し、Alの場合はnが1であり、Siの場合はnが2である。Z1は、水酸基、−OP(=O)R26R27、−OC(=O)R28、−OS(=O)2R29、−SiR30R31R32を表す。R26およびR27は、それぞれ独立に、水素原子、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換のアルコキシル基、置換もしくは無置換のアリールオキシ基を表す。R28は、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換の複素環基を表す。R29は、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換の複素環基を表す。R30〜R32は、それぞれ独立に、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基を表す。)
一般式(2)
(式中、X9〜X16は、それぞれ独立に、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、−O−R41、−S−R42を表し、R41およびR42は、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基を表す。R33〜R40は、それぞれ独立に、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基を表す。M3は、H2、Mg、Zn、Al、Siを表し、M3が、H2、Mg、Znの場合はnが0であり、Alの場合はnが1であり、Siの場合はnが2である。Z2は、水酸基、−OP(=O)R43R44、−OC(=O)R45、−OS(=O)2R46、−SiR47R48R49を表す。R43およびR44は、それぞれ独立に、水素原子、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換のアルコキシル基、置換もしくは無置換のアリールオキシ基を表す。R45は、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基または置換基を有してもよい複素環基を表す。R46は、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換の複素環基を表す。R47〜R49は、それぞれ独立に、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基を表す。) A fluorescent labeling agent comprising a phthalocyanine represented by the following general formula (1) or general formula (2).
General formula (1)
(In the formula, X 1 to X 8 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —O—R 21 , or —S—R 22 , and R 21 And R 22 represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group, and R 1 to R 20 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a formyl group or a cyano group. , -COOM 2, -SO 3 M 2 , substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aryl group, -O-R 23, Represents —S—R 24 , M 2 represents a hydrogen atom or an alkali metal, R 23 and R 24 represent a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group. R< 1 > to R< 20 > may form a ring by connecting adjacent groups to each other, and Y< 1 > to Y< 4 > are each independently N-H, N-R< 25 > , O, S. R 25 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, M 1 represents Al or Si, and in the case of Al, n is In the case of Si, n is 2. Z 1 is a hydroxyl group, -OP(=O)R 26 R 27 , -OC(=O)R 28 , -OS(=O) 2 R 29 , -SiR 30 R 31 R 32. R 26 and R 27 are each independently a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkoxyl group, Represents a substituted or unsubstituted aryloxy group, R 28 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle .R 29 representing the group, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, .R 30 to R 32 to represent a substituted or unsubstituted heterocyclic group, each independently represent a substituted or It represents an unsubstituted alkyl group or a substituted or unsubstituted aryl group.)
General formula (2)
(In the formula, X 9 to X 16 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —O—R 41 , or —S—R 42 , and R 41 And R 42 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, and R 33 to R 40 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyl group. Represents a cycloalkyl group or a substituted or unsubstituted aryl group, M 3 represents H 2 , Mg, Zn, Al or Si, and when M 3 is H 2 , Mg or Zn, n is 0, In the case of Al, n is 1. In the case of Si, n is 2. Z 2 is a hydroxyl group, -OP(=O)R 43 R 44 , -OC(=O)R 45 , -OS(= O) 2 R 46 , —SiR 47 R 48 R 49. R 43 and R 44 are each independently a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or R 45 represents an unsubstituted alkoxyl group, a substituted or unsubstituted aryloxy group, R 45 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group or a substituted represents a heterocyclic group which may have a group .R 46 represents a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, .R 47 to R representing a substituted or unsubstituted heterocyclic group 49 independently represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group.)
一般式(1)
(式中、X1〜X8は、それぞれ独立に、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、−O−R21、−S−R22を表し、R21およびR22は、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基を表す。R1〜R20は、それぞれ独立に、水素原子、ハロゲン原子、水酸基、ニトロ基、ホルミル基、シアノ基、−COOM2、−SO3M2、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアルケニル基、置換もしくは無置換のアリール基、−O−R23、−S−R24を表し、M2は、水素原子、アルカリ金属を、R23およびR24は、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基を表す。R1〜R20は、隣接する基同士が互いに連結して環を形成してもよい。Y1〜Y4は、それぞれ独立に、N−H、N−R25、O、Sを表し、R25は、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基を表す。M1は、AlまたはSiを表し、Alの場合はnが1であり、Siの場合はnが2である。Z1は、水酸基、−OP(=O)R26R27、−OC(=O)R28、−OS(=O)2R29、−SiR30R31R32を表す。R26およびR27は、それぞれ独立に、水素原子、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換のアルコキシル基、置換もしくは無置換のアリールオキシ基を表す。R28は、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換の複素環基を表す。R29は、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換の複素環基を表す。R30〜R32は、それぞれ独立に、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基を表す。)
一般式(2)
(式中、X9〜X16は、それぞれ独立に、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、−O−R41、−S−R42を表し、R41およびR42は、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基を表す。R33〜R40は、それぞれ独立に、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基を表す。M3は、H2、Mg、Zn、Al、Siを表し、M3が、H2、Mg、Znの場合はnが0であり、Alの場合はnが1であり、Siの場合はnが2である。Z2は、水酸基、−OP(=O)R43R44、−OC(=O)R45、−OS(=O)2R46、−SiR47R48R49を表す。R43およびR44は、それぞれ独立に、水素原子、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換のアルコキシル基、置換もしくは無置換のアリールオキシ基を表す。R45は、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基または置換基を有してもよい複素環基を表す。R46は、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換の複素環基を表す。R47〜R49は、それぞれ独立に、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基を表す。) A photodynamic therapeutic agent comprising a phthalocyanine represented by the following general formula (1) or general formula (2).
General formula (1)
(In the formula, X 1 to X 8 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —O—R 21 , or —S—R 22 , and R 21 And R 22 represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group, and R 1 to R 20 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a formyl group or a cyano group. , -COOM 2, -SO 3 M 2 , substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aryl group, -O-R 23, Represents —S—R 24 , M 2 represents a hydrogen atom or an alkali metal, R 23 and R 24 represent a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group. R< 1 > to R< 20 > may form a ring by connecting adjacent groups to each other, and Y< 1 > to Y< 4 > are each independently N-H, N-R< 25 > , O, S. R 25 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, M 1 represents Al or Si, and in the case of Al, n is In the case of Si, n is 2. Z 1 is a hydroxyl group, -OP(=O)R 26 R 27 , -OC(=O)R 28 , -OS(=O) 2 R 29 , -SiR 30 R 31 R 32. R 26 and R 27 are each independently a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkoxyl group, Represents a substituted or unsubstituted aryloxy group, R 28 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle .R 29 representing the group, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, .R 30 to R 32 to represent a substituted or unsubstituted heterocyclic group, each independently represent a substituted or It represents an unsubstituted alkyl group or a substituted or unsubstituted aryl group.)
General formula (2)
(In the formula, X 9 to X 16 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —O—R 41 , or —S—R 42 , and R 41 And R 42 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, and R 33 to R 40 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyl group. Represents a cycloalkyl group or a substituted or unsubstituted aryl group, M 3 represents H 2 , Mg, Zn, Al or Si, and when M 3 is H 2 , Mg or Zn, n is 0, In the case of Al, n is 1. In the case of Si, n is 2. Z 2 is a hydroxyl group, -OP(=O)R 43 R 44 , -OC(=O)R 45 , -OS(= O) 2 R 46 , —SiR 47 R 48 R 49. R 43 and R 44 are each independently a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or R 45 represents an unsubstituted alkoxyl group, a substituted or unsubstituted aryloxy group, R 45 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group or a substituted represents a heterocyclic group which may have a group .R 46 represents a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, .R 47 to R representing a substituted or unsubstituted heterocyclic group 49 independently represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group.)
一般式(1)
(式中、X1〜X8は、それぞれ独立に、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、−O−R21、−S−R22を表し、R21およびR22は、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基を表す。R1〜R20は、それぞれ独立に、水素原子、ハロゲン原子、水酸基、ニトロ基、ホルミル基、シアノ基、−COOM2、−SO3M2、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアルケニル基、置換もしくは無置換のアリール基、−O−R23、−S−R24を表し、M2は、水素原子、アルカリ金属を、R23およびR24は、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基を表す。R1〜R20は、隣接する基同士が互いに連結して環を形成してもよい。Y1〜Y4は、それぞれ独立に、N−H、N−R25、O、Sを表し、R25は、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基を表す。M1は、AlまたはSiを表し、Alの場合はnが1であり、Siの場合はnが2である。Z1は、水酸基、−OP(=O)R26R27、−OC(=O)R28、−OS(=O)2R29、−SiR30R31R32を表す。R26およびR27は、それぞれ独立に、水素原子、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換のアルコキシル基、置換もしくは無置換のアリールオキシ基を表す。R28は、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換の複素環基を表す。R29は、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換の複素環基を表す。R30〜R32は、それぞれ独立に、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基を表す。) Phthalocyanine represented by the following general formula (1).
General formula (1)
(In the formula, X 1 to X 8 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —O—R 21 , or —S—R 22 , and R 21 And R 22 represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group, and R 1 to R 20 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a formyl group or a cyano group. , -COOM 2, -SO 3 M 2 , substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aryl group, -O-R 23, Represents —S—R 24 , M 2 represents a hydrogen atom or an alkali metal, R 23 and R 24 represent a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group. R< 1 > to R< 20 > may form a ring by connecting adjacent groups to each other, and Y< 1 > to Y< 4 > are each independently N-H, N-R< 25 > , O, S. R 25 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, M 1 represents Al or Si, and in the case of Al, n is In the case of Si, n is 2. Z 1 is a hydroxyl group, -OP(=O)R 26 R 27 , -OC(=O)R 28 , -OS(=O) 2 R 29 , -SiR 30 R 31 R 32. R 26 and R 27 are each independently a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkoxyl group, Represents a substituted or unsubstituted aryloxy group, R 28 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocycle .R 29 representing the group, hydroxyl group, substituted or non substituted alkyl group, an unsubstituted or substituted aryl group, .R 30 to R 32 representing a substituted or unsubstituted heterocyclic group, each independently, a substituted or It represents an unsubstituted alkyl group or a substituted or unsubstituted aryl group.)
一般式(3)
(式中、X17〜X24は、それぞれ独立に、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、−O−R58、−S−R59を表し、R58およびR59は、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基を表す。R50〜R57は、それぞれ独立に、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基を表す。M4は、Al、Siを表し、M4が、Alの場合はnが1であり、Siの場合はnが2である。Z3は、水酸基、−OP(=O)R60R61、−OC(=O)R62、−OS(=O)2R63、−SiR64R65R66を表す。R60およびR61は、それぞれ独立に、水素原子、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換のアルコキシル基、置換もしくは無置換のアリールオキシ基を表す。R62は、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換の複素環基を表す。R63は、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換の複素環基を表す。R64〜R66はそれぞれ独立に置換基を有してもよいアルキル基、置換もしくは無置換のアリール基を表す。) A phthalocyanine represented by the following general formula (3).
General formula (3)
(In the formula, X 17 to X 24 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, —O—R 58 , or —S—R 59 , and R 58 And R 59 represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group, and R 50 to R 57 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyl group. .M 4 representing an cycloalkyl group, a substituted or unsubstituted aryl groups, Al, represents Si, M 4 is in the case of Al and n is 1, .Z for Si is n 2 3 Represents a hydroxyl group, -OP(=O)R 60 R 61 , -OC(=O)R 62 , -OS(=O) 2 R 63 , -SiR 64 R 65 R 66. R 60 and R 61 are each. Each independently represents a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkoxyl group, or a substituted or unsubstituted aryloxy group, and R 62 represents hydrogen. An atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, R 63 represents a hydroxyl group, a substituted or unsubstituted alkyl group Represents a group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, and R 64 to R 66 each independently represent an alkyl group which may have a substituent, a substituted or unsubstituted aryl group. .)
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WO2011018994A1 (en) * | 2009-08-13 | 2011-02-17 | Dic株式会社 | Phthalocyanine compound, preparation method therefor, and coloring composition including said phthalocyanine compound |
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WO2006088140A1 (en) * | 2005-02-18 | 2006-08-24 | Dainippon Ink And Chemicals, Inc. | Phthalocyanine compound, process for producing the same, and colored composition containing the phthalocyanine compound |
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WO2011018994A1 (en) * | 2009-08-13 | 2011-02-17 | Dic株式会社 | Phthalocyanine compound, preparation method therefor, and coloring composition including said phthalocyanine compound |
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