JP2009051737A - Brominated porphycene derivative and photodynamic therapeutic agent containing the same - Google Patents
Brominated porphycene derivative and photodynamic therapeutic agent containing the same Download PDFInfo
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Abstract
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本発明は、光により、高い量子収率で一重項酸素を発生するブロモ化ポルフィセン誘導体、該誘導体を含有する、光線力学療法（ＰＤＴ）に用いられる光線力学治療剤、環境浄化のための、有害有機物分解・除去剤、及び有機合成触媒に関する。 The present invention relates to a brominated porphycene derivative that generates singlet oxygen with high quantum yield by light, a photodynamic therapeutic agent used for photodynamic therapy (PDT) containing the derivative, a harmful substance for environmental purification. The present invention relates to an organic matter decomposition / removal agent and an organic synthesis catalyst.
一重項酸素は、種々の不飽和結合を有する分子や電子に富んだ分子を攻撃する活性種であり、精密化学合成、ポリマーサイエンス、光線力学的療法（以下、ＰＤＴという）、汚水や汚泥の処理等、それを利用する種々の応用分野がある。そのため、一重項酸素の発生やそれとの反応に人々の注目が集められている。
一重項酸素を発生する通常の手段は、光増感物質を用いる方法であり、光増感物質が特定の波長の光を吸収し、その結果として形成された励起状態が、基底状態の三重項酸素へのエネルギー移動を誘発することにより、一重項酸素が発生する。
Singlet oxygen is an active species that attacks molecules with various unsaturated bonds and molecules rich in electrons. Fine chemical synthesis, polymer science, photodynamic therapy (hereinafter referred to as PDT), treatment of sewage and sludge There are various application fields that use it. Therefore, people are attracting attention for the generation of singlet oxygen and its reaction.
The usual means of generating singlet oxygen is a method using a photosensitizer, where the photosensitizer absorbs light of a specific wavelength and the resulting excited state is the ground state triplet. Singlet oxygen is generated by inducing energy transfer to oxygen.
ＰＤＴとは、ヒトや動物の疾病組織を処置する方法であって、光を照射することにより一重項酸素等の活性酸素種を発生する光増感物質を含有する光力学治療剤を、例えば静脈注射等で患者に投与した後、疾病組織に局所的に光を照射し、発生した活性酸素種により該疾病組織のみを破壊する、癌及び他の疾患を治療する方法である。 PDT is a method for treating diseased tissues of humans and animals, and is a photodynamic therapeutic agent containing a photosensitizer that generates reactive oxygen species such as singlet oxygen when irradiated with light. This is a method for treating cancer and other diseases in which after administration to a patient by injection or the like, the diseased tissue is irradiated with light locally and only the diseased tissue is destroyed by the generated reactive oxygen species.
光増感物質として色素を含めると膨大な種類の物質が存在するが、ＰＤＴに使用される物質は、腫瘍などの特定組織に選択的親和性を有し、毒性が少なく、発癌性のないことが必要で、現在日本の厚生労働省の認可を受けているものとして、ポルフィリン及びクロリン（ポルフィリン環の１ヵ所が二重結合でないもの）等がある。また、このような光増感剤として、種々の置換基を有するポルフィリン誘導体及びそれらの金属錯体が、また、ポルフィリンの異性体であるポルフィセンがあり、それらがＰＤＴに用いられることが提案されている（特許文献１）。 When dyes are included as photosensitizers, there are a huge variety of substances. Substances used in PDT have selective affinity for specific tissues such as tumors, have low toxicity, and are not carcinogenic. And those that are currently approved by the Japanese Ministry of Health, Labor and Welfare include porphyrins and chlorins (where one part of the porphyrin ring is not a double bond). Further, as such photosensitizers, porphyrin derivatives having various substituents and metal complexes thereof, and porphycene, which is an isomer of porphyrin, are proposed to be used for PDT. (Patent Document 1).
また、光増感物質に光を照射して発生する一重項酸素により、汚水中の有害有機物を分解・除去して環境を浄化する方法も提案されている（特許文献２）。ここでは、高分子粒子に担持された大環状金属錯体化合物である金属フタロシアニン化合物又は金属ポルフィリン化合物が、光増感物質として用いられている。 In addition, a method for purifying the environment by decomposing / removing harmful organic substances in sewage with singlet oxygen generated by irradiating the photosensitizer with light has been proposed (Patent Document 2). Here, a metal phthalocyanine compound or a metal porphyrin compound, which is a macrocyclic metal complex compound supported on polymer particles, is used as a photosensitizer.
このように、一重項酸素を活性種として種々の分野に応用するためには、光増感物質として、安定で、高い量子収率で一重項酸素を発生し、加えて可視部の光吸収が大きい化合物が望まれる。中でも高い量子収率で一重項酸素を発生することが重要であり、２，７，１２，１７−テトラ（ｎ−プロピル）ポルフィセンの一重項酸素の量子収率が、３６％であることが知られている（非特許文献１）。 Thus, in order to apply singlet oxygen as an active species to various fields, as a photosensitizer, singlet oxygen is generated in a stable and high quantum yield, and in addition, light absorption in the visible region is absorbed. Larger compounds are desired. Among them, it is important to generate singlet oxygen with a high quantum yield, and it is known that the quantum yield of singlet oxygen of 2,7,12,17-tetra (n-propyl) porphycene is 36%. (Non-Patent Document 1).
従って、本願発明は、可視部の光吸収が大きく、安定で、高い量子収率で一重項酸素を生成することができる、光増感物質を提供することを課題とする。 Therefore, an object of the present invention is to provide a photosensitizer that has a large visible light absorption, is stable, and can generate singlet oxygen with a high quantum yield.
そのため、本発明者等は、重原子効果（原子番号の大きな原子や金属イオンなどの元素が化合物の中に含まれると、三重項状態と呼ばれる光励起状態の生成効率が増大する現象）に着目し、可視光領域に強い吸収帯を有する２，７，１２，１７−テトラ−ｎ−プロピルポルフィセンを用いて、三重項状態の生成効率を高め、もって三重項状態が酸素分子にエネルギーを与えることによって生成する一重項酸素の量子収率を向上させることを検討した。 Therefore, the present inventors have focused on the heavy atom effect (a phenomenon in which the generation efficiency of a photoexcited state called a triplet state increases when an element such as an atom having a large atomic number or a metal ion is contained in a compound). By using 2,7,12,17-tetra-n-propylporphycene, which has a strong absorption band in the visible light region, the efficiency of triplet state generation is increased, and the triplet state gives energy to oxygen molecules. We studied to improve the quantum yield of singlet oxygen.
その結果、ポルフィセン骨格に臭素原子を導入した化合物は、原料化合物である臭素原子を導入しない化合物と比較して一重項酸素の量子収率が極度に増大すること及び該化合物が、光照射に対して極めて安定であることを見出し、本発明を完成した。 As a result, the compound in which a bromine atom is introduced into the porphycene skeleton has an extremely increased quantum yield of singlet oxygen compared to the compound that does not introduce a bromine atom as a raw material compound, and the compound has a high The present invention was completed.
従って、本願発明は、以下の（１）〜（４）のとおり特定される。
（１） 光を照射することにより、高い量子収率で一重項酸素を生成する、下記式（１）（化２）のブロモ化ポルフィセン誘導体。
Therefore, this invention is specified as the following (1)-(4).
(1) A brominated porphycene derivative represented by the following formula (1) (Chemical Formula 2) that generates singlet oxygen with high quantum yield by irradiation with light.
（２） （１）のブロモ化ポルフィセン誘導体を含有する光線力学的治療剤。
（３） （１）のブロモ化ポルフィセン誘導体を含有する環境浄化のための、有害有機物分解・除去剤。
（４） （１）のブロモ化ポルフィセン誘導体を含有する物質変換のための、有機合成触媒。
(2) A photodynamic therapeutic agent comprising the brominated porphycene derivative of (1).
(3) A hazardous organic decomposition / removal agent for environmental purification containing the brominated porphycene derivative of (1).
(4) An organic synthesis catalyst for substance conversion containing the brominated porphycene derivative of (1).
本発明において、テトラノルマルプロピルポルフィセンをブロモ化することにより得られたモノブロモ化及びジブロモ化ポルフィセン誘導体（３−ブロモ化体及び３，１８−ジブロモ化体）は、既存のポルフィリン誘導体や、原料テトラノルマルプロピルポルフィセンと比較して、非常に高い量子収率で一重項酸素を生成し、光増感反応における触媒活性が高く、一重項酸素や光に対しても安定である。さらに、ジブロモ化体をパラジウム錯体化した化合物は、更に高い量子収率（ほぼ１００％）で一重項酸素を生成した。 In the present invention, monobrominated and dibrominated porphycene derivatives (3-brominated product and 3,18-dibrominated product) obtained by brominating tetranormal propylporphycene are existing porphyrin derivatives and raw materials tetranormal. Compared with propylporphycene, it produces singlet oxygen with a very high quantum yield, has high catalytic activity in the photosensitization reaction, and is stable against singlet oxygen and light. Furthermore, the compound obtained by complexing the dibrominated compound with palladium produced singlet oxygen with a higher quantum yield (almost 100%).
本発明のブロモ化に用いられた２，７，１２，１７−テトラ−ｎ−プロピルポルフィセン（TPrPcという）は、光照射による一重項酸素の量子収率が公知の化合物であり、公知の方法(Angew. Chem. Int., Ed. Engl. 26(No.9), 928-931(1987)で製造できる。このTPrPcのブロモ化は、下記反応式（化３）に基づいて、反応させる臭素の当量数を変えることにより臭素の置換数を容易に変えることができ、各１〜４ブロモ化体を収率よく合成することができる。 2,7,12,17-tetra-n-propylporphycene (referred to as TPrPc) used for bromination of the present invention is a compound having a known quantum yield of singlet oxygen by light irradiation. Chem. Int., Ed. Engl., 26 (No. 9), 928-931 (1987) This bromination of TPrPc is based on the following reaction formula (Formula 3). By changing the number of equivalents, the number of substitutions of bromine can be easily changed, and each 1-4 brominated product can be synthesized with good yield.
反応は、溶媒に溶かした臭素を約２〜約１０分を要して滴下しながら、室温で行なうことができる。溶媒は、TPrPcと臭素を溶解し、臭素と反応しないものであれば、どのようなものでも良く、例えば、四塩化炭素が好適に用いられる。得られたブロモ化ポルフィセン誘導体は、定法に従って、溶媒中、塩化パラジウムにより、パラジウム錯体化することができる。何れの反応物も、シリカゲルカラムクロマトグラフィーにより精製し、再結晶して、所望の誘導体を得ることができる。 The reaction can be carried out at room temperature while bromine dissolved in a solvent is added dropwise in about 2 to about 10 minutes. The solvent may be any solvent as long as it dissolves TPrPc and bromine and does not react with bromine. For example, carbon tetrachloride is preferably used. The obtained brominated porphycene derivative can be palladium-complexed with palladium chloride in a solvent according to a conventional method. Any reaction product can be purified by silica gel column chromatography and recrystallized to obtain the desired derivative.
得られた各ブロモ化誘導体の光照射による一重項酸素生成量子収率を、本願明細書の実施例の項に記載した方法により、原料TPrPcの公知の一重項酸素生成量子収率を基に、算出した。 Based on the known singlet oxygen generation quantum yield of the raw material TPrPc, the singlet oxygen generation quantum yield of each brominated derivative obtained by light irradiation by the method described in the Examples section of the present specification, Calculated.
原料TPrPcのブロモ化により得られる１〜４の置換数のいずれのブロモ化ポルフィセン誘導体も、光照射により、一重項酸素生成量子収率が３６％である原料TPrPcと比較して、高い量子収率で一重項酸素を生成するが、特に、モノブロモ化体（以下、Br1という）とジブロモ化体（以下、Br2という）が、９０％以上の極めて高い一重項酸素生成量子収率を示す。加えて、それらのブロモ化ポルフィセン誘導体をパラジウム錯体化することにより、光照射による一重項酸素生成量子収率が更に上昇し、ジブロモ化ポルフィセンのパラジウム錯体（以下、PdBr2という）は、ほぼ１００％の一重項酸素生成量子収率を示す。 Any brominated porphycene derivative having a substitution number of 1 to 4 obtained by bromination of the raw material TPrPc is higher in quantum yield than the raw material TPrPc having a singlet oxygen generation quantum yield of 36% by light irradiation. In particular, a monobrominated product (hereinafter referred to as Br1) and a dibrominated product (hereinafter referred to as Br2) exhibit a very high singlet oxygen generation quantum yield of 90% or more. In addition, by complexing these brominated porphycene derivatives with palladium, the singlet oxygen generation quantum yield by light irradiation is further increased, and the palladium complex of dibrominated porphycene (hereinafter referred to as PdBr2) is almost 100%. The singlet oxygen production quantum yield is shown.
また、本発明のブロモ化ポルフィセン誘導体は、原料TPrPcと同等に、光に対して安定であり、光増感反応雰囲気下で分解することがなく、既存のテトラフェニルポルフィリンより、極めて高い耐久性を有する。 In addition, the brominated porphycene derivative of the present invention is as stable as light as the raw material TPrPc, does not decompose in a photosensitized reaction atmosphere, and has extremely higher durability than existing tetraphenylporphyrins. Have.
本発明のブロモ化ポルフィセン誘導体は、可視部の光吸収が大きく、光照射により、高い一重項酸素生成量子収率を有し、光増感反応雰囲気下で高い安定性を有するので、極めてマイルドな条件下（例えば、室温で）で、種々の不飽和結合を有する分子や電子に富んだ分子を攻撃する活性種を生成する光増感物質として、精密化学合成（物質変換のための、有機合成触媒として）、ポリマーサイエンス、光線力学的療法（以下、ＰＤＴという）、汚水や汚泥の処理等、種々の応用分野に有効に利用できる。 The brominated porphycene derivative of the present invention has a large light absorption in the visible region, a high singlet oxygen generation quantum yield upon irradiation with light, and a high stability in a photosensitized reaction atmosphere. Fine chemical synthesis (organic synthesis for material conversion) as a photosensitizer that generates active species that attack molecules with various unsaturated bonds and molecules rich in electrons under conditions (eg, at room temperature) As a catalyst), it can be effectively used in various application fields such as polymer science, photodynamic therapy (hereinafter referred to as PDT), treatment of sewage and sludge.
例えば、精密化学合成分野では、１，５−ヒドロキシナフタレンを、本発明のブロモ化ポルフィセン誘導体の存在下、溶媒中、空気雰囲気下、室温で、光を照射することにより、ジュグロン（１）（Juglone (1)）を高収率で得ることができる。ジュグロン（１）は、生物学的に活性なキノイド化合物を構築・合成する原料として有用である。 For example, in the field of fine chemical synthesis, 1,5-hydroxynaphthalene is irradiated with light in the presence of the brominated porphycene derivative of the present invention in a solvent, in an air atmosphere at room temperature, to form Juglone (1) (Juglone (1)) can be obtained in high yield. Juglone (1) is useful as a raw material for constructing and synthesizing biologically active quinoid compounds.
また、ポリマーサイエンス分野では、例えば、本発明のブロモ化ポルフィセン誘導体を、ポリマーのグラフト化反応での水素引き抜き剤として、利用できる。 In the field of polymer science, for example, the brominated porphycene derivative of the present invention can be used as a hydrogen abstraction agent in a polymer grafting reaction.
光増感物質を動物の全身又は局所に投与し、次いで、酸素供給下に、癌等の罹患標的組織に光照射することにより、一重項酸素を発生させ、それにより標的細胞組織を破壊して、疾患を治療する方法（光線力学的治療：ＰＤＴ）において、前述のとおり、本発明のブロモ化ポルフィセン誘導体は、光照射により、効率的に一重項酸素を生成することができることから、光線力学的治療剤として、使用することができる可能性がある。 A photosensitizer is administered systemically or locally in an animal, and then, under oxygen supply, the target tissue such as cancer is irradiated with light to generate singlet oxygen, thereby destroying the target cell tissue. In the method for treating diseases (photodynamic therapy: PDT), as described above, the brominated porphycene derivative of the present invention can efficiently generate singlet oxygen by light irradiation. It may be possible to use as a therapeutic agent.
さらに、光増感物質存在下に光を照射して、水中又は土中の環境汚染物質、例えば、クロルフェノール類を分解して、最終的には無機物質にまで酸化できることが知られている（Meiqin Hu, et.al., Chem. Letters, Vol.33, No.9 (2004)）。本発明のブロモ化ポルフィセン誘導体は、可視部の光吸収が大きく、光照射により、高い一重項酸素生成量子収率を有し、光増感反応雰囲気下で高い安定性を有するので、環境浄化のための有害有機物分解・除去剤（環境汚染物質除去剤）として、好適に使用することができる。 Furthermore, it is known that light can be irradiated in the presence of a photosensitizer to decompose environmental pollutants in water or soil, such as chlorophenols, and finally be oxidized to inorganic substances ( Meiqin Hu, et.al., Chem. Letters, Vol. 33, No. 9 (2004)). The brominated porphycene derivative of the present invention has a large light absorption in the visible region, has a high singlet oxygen generation quantum yield upon irradiation with light, and has high stability in a photosensitized reaction atmosphere. Therefore, it can be suitably used as a harmful organic substance decomposition / removal agent (environmental pollutant removal agent).
上述のとおり、本発明のブロモ化ポルフィセン誘導体は、種々の用途に応用することができるが、その形態は、懸濁剤、溶液、クリーム、軟膏、ゲル、シロップ等の液体、半固体、固体のいずれであってもよい。また、本発明のブロモ化ポルフィセン誘導体を、ポリスチレン等のポリマーやシリカゲル等の無機固体に固定化して使用することもできる。 As described above, the brominated porphycene derivative of the present invention can be applied to various uses, and the form thereof is a liquid such as a suspension, solution, cream, ointment, gel, syrup, semi-solid, solid Either may be sufficient. Further, the brominated porphycene derivative of the present invention can be used by being immobilized on a polymer such as polystyrene or an inorganic solid such as silica gel.
［ポルフィセン誘導体の一重項酸素発生量子収率（ΦΔ）の測定方法］
６００ｎｍにおける吸光度（Ａ６００）が０．０５、０．０７及び０．１のポルフィセン誘導体の３種のトルエン溶液を用意した。それらの溶液に励起波長６００ｎｍの光を照射し、測定装置フルオロログ（Fluorolog-3：JOBIN YVON（堀場製作所製））を用いて、発光スペクトルを測定した。このスペクトルから、１２７０ｎｍのピーク面積を算出し、一重項酸素による発光強度とした。
[Measurement method of singlet oxygen generation quantum yield (Φ Δ ) of porphycene derivative]
Three toluene solutions of porphycene derivatives having absorbances (A 600 ) at 600 nm of 0.05, 0.07, and 0.1 were prepared. These solutions were irradiated with light having an excitation wavelength of 600 nm, and an emission spectrum was measured using a measurement apparatus Fluorolog-3 (JOBIN YVON (manufactured by Horiba)). From this spectrum, the peak area at 1270 nm was calculated and used as the emission intensity due to singlet oxygen.
各濃度における一重項酸素による発光強度は、その吸光度（Ａ６００）に比例するので、発光強度を吸光度（Ａ６００）に対してプロットし、その傾きを算出した。
TPrPcの一重項酸素発生の量子収率（ΦΔ）が、文献値より０．３６と報告されている（E.Vogel et al., J. Photochem. Photobiol., B:Biology, 3, 193-207(1989)）ので、その値を基に、測定した上記傾きから一重項酸素発生の量子収率（ΦΔ）を算出した。
Since the emission intensity due to singlet oxygen at each concentration is proportional to the absorbance (A 600 ), the emission intensity was plotted against the absorbance (A 600 ), and the slope was calculated.
The quantum yield (Φ Δ ) of singlet oxygen generation of TPrPc is reported to be 0.36 from literature values (E. Vogel et al., J. Photochem. Photobiol., B: Biology, 3, 193- 207 (1989)), based on the value, the quantum yield (Φ Δ ) of singlet oxygen generation was calculated from the measured slope.
また、以下のＮＭＲ分析、ＭＳ分析及びＵＶ−ＶＩＳ分析に用いられた装置はそれぞれ、AVANCE 500核磁気共鳴装置（（株）ブルカー・バイオスピン社製）、Autoflex質量分析装置（（株）ブルカー・ダルトニクス社製）及びU-3300分光光度計（（株）日立製作所製である。 Moreover, the apparatus used for the following NMR analysis, MS analysis, and UV-VIS analysis is respectively AVANCE 500 nuclear magnetic resonance apparatus (Bruker Biospin Co., Ltd.), Autoflex mass spectrometer (Bruker Co., Ltd.). Dartonics) and U-3300 spectrophotometer (manufactured by Hitachi, Ltd.).
実施例１（ブロモ化ポルフィセン（１置換体）（Br1という）の合成）
５０ｍｇ（１００μｍｏｌ）の２，７，１２，１７−テトラ−ｎ−プロピルポルフィセン（TPrPcという）を四塩化炭素３０ｍｌに溶解し、２．５％酢酸ナトリウム水溶液２０ｍｌを加えた。その後、５μｌ（１００μｍｏｌ）の臭素を１０ｍｌの四塩化炭素希釈した溶液を５分かけて滴下した。滴下後、室温で１時間攪拌し、飽和チオ硫酸ナトリウム溶液を加えて分液した。有機層を蒸留水で３回洗い、硫酸マグネシウムで脱水し、溶媒を減圧留去した。その後、紫色残留物をシリカゲルカラムクロマトグラフィー（塩化メチレン：ｎ−ヘキサン＝１：６ｖ／ｖ、φ５ｃｍ×３０ｃｍ）で精製した。カラム第１成分は２置換体であり、第２成分が１置換体であった。塩化メチレン／ｎ−ヘキサンで再結晶し、下記式（２）（化３）のブロモ化ポルフィセン（１置換体）（Br1）の紫色の針状結晶を得た（３３ｍｇ、５７％）。
Example 1 (Synthesis of brominated porphycene (monosubstituted) (referred to as Br1))
50 mg (100 μmol) of 2,7,12,17-tetra-n-propylporphycene (TPrPc) was dissolved in 30 ml of carbon tetrachloride, and 20 ml of 2.5% aqueous sodium acetate solution was added. Thereafter, a solution of 5 μl (100 μmol) of bromine diluted with 10 ml of carbon tetrachloride was added dropwise over 5 minutes. After the dropwise addition, the mixture was stirred at room temperature for 1 hour, and a saturated sodium thiosulfate solution was added for liquid separation. The organic layer was washed 3 times with distilled water, dehydrated with magnesium sulfate, and the solvent was distilled off under reduced pressure. Thereafter, the purple residue was purified by silica gel column chromatography (methylene chloride: n-hexane = 1: 6 v / v, φ5 cm × 30 cm). The first component of the column was a 2-substituted product, and the second component was a 1-substituted product. Recrystallization from methylene chloride / n-hexane gave purple needle-like crystals of brominated porphycene (monosubstituted) (Br1) of the following formula (2) (Chemical Formula 3) (33 mg, 57%).
1H-NMR(δvalue, CDCl3)： 1.29-1.35(m, 12H), 2.25-2.44(m, 8H), 3.96-4.05(m, 8H), 9.24(s, 1H), 9.35(s, 1H), 9.60-9.73(m, 4H), 10.14(s, 1H)
HRMS(FAB)： Caled.（C32H37BrN4 ＋として）：556.2202
実測値：556.2256
元素分析：Caled.(C32H37BrN4として)： C, 48.93； H, 6.69； N, 10.05
Found： C, 48.02； H, 6.62； N, 9.80
1 H-NMR (δvalue, CDCl 3 ): 1.29-1.35 (m, 12H), 2.25-2.44 (m, 8H), 3.96-4.05 (m, 8H), 9.24 (s, 1H), 9.35 (s, 1H ), 9.60-9.73 (m, 4H), 10.14 (s, 1H)
HRMS (FAB): Caled. (As C 32 H 37 BrN 4 + ): 556.2202
Actual value: 556.2256
Elemental analysis: Caled. (As C 32 H 37 BrN 4 ): C, 48.93; H, 6.69; N, 10.05
Found: C, 48.02; H, 6.62; N, 9.80
実施例２（ブロモ化ポルフィセン（２置換体）（Br2という）の合成）
５０ｍｇ（１００μｍｏｌ）のTPrPcを四塩化炭素３０ｍｌに溶解し、２．５％酢酸ナトリウム水溶液２０ｍｌを加えた。その後、１０μｌ（２００μｍｏｌ）の臭素を１０ｍｌの四塩化炭素希釈した溶液を５分かけて滴下した。滴下後、室温で１時間攪拌し、飽和チオ硫酸ナトリウム溶液を加えて分液した。有機層を蒸留水で３回洗い、硫酸マグネシウムで脱水し、溶媒を減圧留去した。その後、紫色残留物をシリカゲルカラムクロマトグラフィー（塩化メチレン：ｎ−ヘキサン＝１：６ｖ／ｖ、φ５ｃｍ×３０ｃｍ）で精製した。カラム第１成分は２置換体であり、第２成分が１置換体であった。塩化メチレン／ｎ−ヘキサンで再結晶し、下記式（３）（化４）のブロモ化ポルフィセン（２置換体）（Br2）の紫色の針状結晶を得た（４７ｍｇ、７０％）。
Example 2 (Synthesis of brominated porphycene (disubstituted) (referred to as Br2))
50 mg (100 μmol) of TPrPc was dissolved in 30 ml of carbon tetrachloride, and 20 ml of 2.5% aqueous sodium acetate solution was added. Thereafter, 10 μl (200 μmol) of bromine diluted with 10 ml of carbon tetrachloride was added dropwise over 5 minutes. After the dropwise addition, the mixture was stirred at room temperature for 1 hour, and a saturated sodium thiosulfate solution was added for liquid separation. The organic layer was washed 3 times with distilled water, dehydrated with magnesium sulfate, and the solvent was distilled off under reduced pressure. Thereafter, the purple residue was purified by silica gel column chromatography (methylene chloride: n-hexane = 1: 6 v / v, φ5 cm × 30 cm). The first component of the column was a 2-substituted product, and the second component was a 1-substituted product. Recrystallization from methylene chloride / n-hexane gave purple needle-like crystals of brominated porphycene (disubstituted product) (Br2) of the following formula (3) (Chemical Formula 4) (47 mg, 70%).
1H-NMR(δ value(ppm), CDCl3)： 1.29-1.34(m, 12H), 2.26-2.42(m, 8H), 3.92-4.04(m, 8H), 9.67(d, 2H), 9.73(d, 2H), 10.16(s, 2H)
HMRS(FAB)： Caled.（C32H36Br2N4 +として）： 634.1307
Found： 634.1401
元素分析： Caled.（C32H36Br2N4として）： C, 60.39； H, 5.70； N, 8.80
Found： C, 60.04； H, 5.66； N,8.72
1 H-NMR (δ value (ppm), CDCl 3 ): 1.29-1.34 (m, 12H), 2.26-2.42 (m, 8H), 3.92-4.04 (m, 8H), 9.67 (d, 2H), 9.73 (d, 2H), 10.16 (s, 2H)
HMRS (FAB): Caled. (As C 32 H 36 Br 2 N 4 + ): 634.1307
Found: 634.1401
Elemental analysis: Caled. (As C 32 H 36 Br 2 N 4 ): C, 60.39; H, 5.70; N, 8.80
Found: C, 60.04; H, 5.66; N, 8.72
実施例３（ブロモ化ポルフィセン（１置換体）Ｐｄ錯体（PdBr1という）の合成）
実施例１で得られたブロモ化ポルフィセン（１置換体）(Br1)３０ｍｇ（５４μｍｏｌ）とＰｄＣｌ２５２ｍｇ（２９３μｍｏｌ）を無水ＤＭＦ５ｍｌに溶解し、窒素雰囲気下で１時間還流、還流後、溶媒を留去し、シリカゲルカラムで精製（塩化メチレン：ｎ−ヘキサン＝１：６ｖ／ｖ、φ７ｃｍ×１７ｃｍ）、塩化メチレン／ｎ−ヘキサンで再結晶し、下記式（４）（化５）のブロモ化ポルフィセン（１置換体）Ｐｄ錯体（PdBr1という）の紫色の針状結晶を得た（１５．４ｍｇ、４３％）。
Example 3 (Synthesis of brominated porphycene (monosubstituted) Pd complex (referred to as PdBr1))
30 mg (54 μmol) of brominated porphycene (monosubstituted) (Br1) and 52 mg (293 μmol) of PdCl 2 obtained in Example 1 were dissolved in 5 ml of anhydrous DMF and refluxed for 1 hour under a nitrogen atmosphere. And purified with a silica gel column (methylene chloride: n-hexane = 1: 6 v / v, φ7 cm × 17 cm), recrystallized with methylene chloride / n-hexane, and brominated porphycene of the following formula (4) (chemical formula 5) (1 substitution product) Purple needle crystals of Pd complex (referred to as PdBr1) were obtained (15.4 mg, 43%).
1H-NMR(δ value(ppm), CDCl3)： 1.23-1.37(m, 12H), 2.21-2.36(m, 8H), 3.83-3.92(m, 8H), 9.08(s, 1H), 9.26-9.33(m, 4H)
MALDI-MS： Obsd.： 661.1
元素分析： Caled.（C32H35N4BrPdとして）： C, 58.06； H,5.33； N, 8.46
Found： C, 58.30； H, 5.38； N, 8.51
1 H-NMR (δ value (ppm), CDCl 3 ): 1.23-1.37 (m, 12H), 2.21-2.36 (m, 8H), 3.83-3.92 (m, 8H), 9.08 (s, 1H), 9.26 -9.33 (m, 4H)
MALDI-MS: Obsd .: 661.1
Elemental analysis: Caled. (As C 32 H 35 N 4 BrPd): C, 58.06; H, 5.33; N, 8.46
Found: C, 58.30; H, 5.38; N, 8.51
実施例４（ブロモ化ポルフィセン（２置換体）Ｐｄ錯体（PdBr2という）の合成）
実施例２で得られたブロモ化ポルフィセン（２置換体）(Br2)３ｍｇ（４．７μｍｏｌ）とＰｄＣｌ２２．１ｍｇ（１１．８μｍｏｌ）を無水ＤＭＦ５ｍｌに溶解し、窒素雰囲気下で１時間還流、還流後、溶媒を留去し、シリカゲルカラムで精製（塩化メチレン：ｎ−ヘキサン＝１：６ｖ／ｖ、φ２ｃｍ×２０ｃｍ）、塩化メチレン／ｎ−ヘキサンで再結晶し、下記式（５）（化６）のブロモ化ポルフィセン（２置換体）Ｐｄ錯体（PdBr2）の紫色の針状結晶を得た（０．３７ｍｇ、１１％）。
Example 4 (Synthesis of brominated porphycene (disubstituted) Pd complex (referred to as PdBr2))
3 mg (4.7 μmol) of brominated porphycene (disubstituted product) (Br2) obtained in Example 2 and 2.1 mg (11.8 μmol) of PdCl 2 were dissolved in 5 ml of anhydrous DMF and refluxed for 1 hour under a nitrogen atmosphere. After refluxing, the solvent was distilled off and the residue was purified with a silica gel column (methylene chloride: n-hexane = 1: 6 v / v, φ2 cm × 20 cm), recrystallized with methylene chloride / n-hexane, 6) Purple needle-like crystals of brominated porphycene (disubstituted) Pd complex (PdBr2) of 6) were obtained (0.37 mg, 11%).
1H-NMR(δ value(ppm), CDCl3)：1.23-1.38(m, 12H), 2.22-2.45(m, 8H), 3.85-4.05(m, 8H), 9.05(s, 2H), 9.33-9.45(m, 4H)
MALDI-MS： Obsd.: 738.98
1 H-NMR (δ value (ppm), CDCl 3 ): 1.23-1.38 (m, 12H), 2.22-2.45 (m, 8H), 3.85-4.05 (m, 8H), 9.05 (s, 2H), 9.33 -9.45 (m, 4H)
MALDI-MS: Obsd .: 738.98
比較例１（ブロモ化ポルフィセン（３置換体：Br3という）の合成）
５０ｍｇ（１００μｍｏｌ）のTPrPcを四塩化炭素３０ｍｌに溶解し、２．５％酢酸ナトリウム水溶液２０ｍｌを加えた。その後、１５μｌ（３００μｍｏｌ）の臭素を１０ｍｌの四塩化炭素で希釈した溶液を５分かけて滴下した。滴下後、室温で１時間攪拌し、飽和チオ硫酸ナトリウム溶液を加えて分液した。有機層を蒸留水で３回洗い、硫酸マグネシウムで脱水し、溶媒を減圧留去した。その後、紫色残留物をシリカゲルカラムクロマトグラフィー（塩化メチレン：ｎ−ヘキサン＝１：６ｖ／ｖ、φ５ｃｍ×１００ｃｍ）で精製した。カラム第１成分は２置換体であり、第２成分が３置換体であった。塩化メチレン／ｎ−ヘキサンで再結晶し、下記式（６）（（化７）のブロモ化ポルフィセン（３置換体）（Br3）の紫色の針状結晶を得た（３２ｍｇ、４０％）。
Comparative Example 1 (Synthesis of brominated porphycene (trisubstituted product: referred to as Br3))
50 mg (100 μmol) of TPrPc was dissolved in 30 ml of carbon tetrachloride, and 20 ml of 2.5% aqueous sodium acetate solution was added. Thereafter, a solution prepared by diluting 15 μl (300 μmol) of bromine with 10 ml of carbon tetrachloride was added dropwise over 5 minutes. After the dropwise addition, the mixture was stirred at room temperature for 1 hour, and a saturated sodium thiosulfate solution was added for liquid separation. The organic layer was washed 3 times with distilled water, dehydrated with magnesium sulfate, and the solvent was distilled off under reduced pressure. Thereafter, the purple residue was purified by silica gel column chromatography (methylene chloride: n-hexane = 1: 6 v / v, φ5 cm × 100 cm). The first component of the column was a disubstituted product, and the second component was a trisubstituted product. Recrystallization from methylene chloride / n-hexane gave purple needle-like crystals of the following formula (6) (brominated porphycene (3-substituted product) (Br3) of (Chem. 7) (32 mg, 40%).
1H-NMR(δ value(ppm), CDCl3)： 1.25-1.31(m, 12H), 2.10-2.43(m, 8H), 3.79-3.94(m, 8H), 9.48(d, 1H), 9.49(d, 1H), 9.70(d, 1H), 10.04(s, 2H)
HMRS(FAB)： Caled.（C32H37BrN4 +として）： 712.0412
Found: 712.0252
元素分析： Caled.（C32H35N4Br3として）： C, 53.73； H,4.93； N, 7.83
Found： C, 53.73； H, 4.93； N, 7.83
1 H-NMR (δ value (ppm), CDCl 3 ): 1.25-1.31 (m, 12H), 2.10-2.43 (m, 8H), 3.79-3.94 (m, 8H), 9.48 (d, 1H), 9.49 (d, 1H), 9.70 (d, 1H), 10.04 (s, 2H)
HMRS (FAB): Caled. (As C 32 H 37 BrN 4 + ): 712.0412
Found: 712.0252
Elemental analysis: Caled. (As C 32 H 35 N 4 Br 3 ): C, 53.73; H, 4.93; N, 7.83
Found: C, 53.73; H, 4.93; N, 7.83
比較例２（ブロモ化ポルフィセン（４置換体）（Br４という）の合成）
５０ｍｇ（１００μｍｏｌ）のTPrPcを四塩化炭素３０ｍｌに溶解し、２．５％酢酸ナトリウム水溶液２０ｍｌを加えた。その後、３０μｌ（６００μｍｏｌ）の臭素を１０ｍｌの四塩化炭素で希釈した溶液を５分かけて滴下した。滴下後、室温で１時間攪拌し、飽和チオ硫酸ナトリウム溶液を加えて分液した。有機層を蒸留水で３回洗い、硫酸マグネシウムで脱水し、溶媒を減圧留去した。その後、紫色残留物をシリカゲルカラムクロマトグラフィー（塩化メチレン：ｎ−ヘキサン＝１：６ｖ／ｖ、φ５ｃｍ×１００ｃｍ）で精製した。カラム第３成分は５置換体であり、第４成分が３置換体であり、第５成分が４置換体であった。塩化メチレン／ｎ−ヘキサンで再結晶し、下記式（７）（化８）のブロモ化ポルフィセン（４置換体）（Br4）の紫色の針状結晶を得た（２５ｍｇ、３０％）。
Comparative Example 2 (Synthesis of brominated porphycene (4-substituted product) (referred to as Br4))
50 mg (100 μmol) of TPrPc was dissolved in 30 ml of carbon tetrachloride, and 20 ml of 2.5% aqueous sodium acetate solution was added. Thereafter, a solution prepared by diluting 30 μl (600 μmol) of bromine with 10 ml of carbon tetrachloride was added dropwise over 5 minutes. After the dropwise addition, the mixture was stirred at room temperature for 1 hour, and a saturated sodium thiosulfate solution was added for liquid separation. The organic layer was washed 3 times with distilled water, dehydrated with magnesium sulfate, and the solvent was distilled off under reduced pressure. Thereafter, the purple residue was purified by silica gel column chromatography (methylene chloride: n-hexane = 1: 6 v / v, φ5 cm × 100 cm). The third component of the column was a 5-substituted product, the fourth component was a 3-substituted product, and the fifth component was a 4-substituted product. Recrystallization from methylene chloride / n-hexane gave purple needle-like crystals of brominated porphycene (4-substituted product) (Br4) of the following formula (7) (Chemical Formula 8) (25 mg, 30%).
1H-NMR(δvalue(ppm), CDCl3)： 1.21(t, 12H), 2.06(m, 8H), 3.76(t, 8H), 9.48(s, 4H)
TOF-MS(MALDI)： m/z=795.7(M+H)+
元素分析： Caled.（C32H34N4Br4として）： C, 48.39； H,4.31； N, 7.05
Found： C, 48.22； H, 4.31； N, 7.05
1 H-NMR (δvalue (ppm), CDCl 3 ): 1.21 (t, 12H), 2.06 (m, 8H), 3.76 (t, 8H), 9.48 (s, 4H)
TOF-MS (MALDI): m / z = 795.7 (M + H) +
Elemental analysis: Caled. (As C 32 H 34 N 4 Br 4 ): C, 48.39; H, 4.31; N, 7.05
Found: C, 48.22; H, 4.31; N, 7.05
比較例３（テトラプロピルポルフィセンＰｄ錯体（PdTPrPcという）の合成）
TPrPc３０ｍｇ（６３μｍｏｌ）とＰｄＣｌ２６０ｍｇ（３４０μｍｏｌ）を無水ＤＭＦ５ｍｌに溶かし、窒素雰囲気下で１時間還流。還流後、溶媒を留去し、シリカゲルカラム（塩化メチレン, φ４ｃｍ×１０ｃｍ）で精製した。塩化メチレン/ｎ-ヘキサンで再結晶し、紫色の下記式８（化９）の針状結晶のテトラプロピルポルフィセンＰｄ錯体（PdTPrPc）を得た。（３５．２ｍｇ，９６％）
Comparative Example 3 (Synthesis of tetrapropylporphycene Pd complex (referred to as PdTPrPc))
TPrPc 30 mg (63 μmol) and PdCl 2 60 mg (340 μmol) were dissolved in
1H-NMR(δvalue(ppm), CDCl3)： 1.35(t, 12H), 2.39(m, 8H), 4.01(t, 8H), 8.95(s, 4H), 9.63(s, 4H)
元素分析： Calcd.（C32H36N4Pdとして）： C 65.92； H, 6.22； N, 9.61
Found： C, 65.86； H, 6.21； N, 9.64
MALDI-MS： Obsd.： 581.08(M+H)
1 H-NMR (δvalue (ppm), CDCl 3 ): 1.35 (t, 12H), 2.39 (m, 8H), 4.01 (t, 8H), 8.95 (s, 4H), 9.63 (s, 4H)
Elemental analysis: Calcd. (As C 32 H 36 N 4 Pd): C 65.92; H, 6.22; N, 9.61
Found: C, 65.86; H, 6.21; N, 9.64
MALDI-MS: Obsd .: 581.08 (M + H)
［ポルフィセン誘導体の一重項酸素発生量子収率（ΦΔ）の測定］
前記測定方法にしたがって、実施例１〜４及び比較例１〜４のポルフィセン誘導体の一重項酸素発生量子収率（ΦΔ）を測定した。各スペクトルの例を図１（図１）に、また、各誘導体の一重項酸素の発生の量子収率（ΦΔ）を表１（表１）に示す。
[Measurement of singlet oxygen generation quantum yield (Φ Δ ) of porphycene derivative]
According to the measurement method, singlet oxygen generation quantum yields (Φ Δ ) of the porphycene derivatives of Examples 1 to 4 and Comparative Examples 1 to 4 were measured. An example of each spectrum is shown in FIG. 1 (FIG. 1), and the quantum yield (Φ Δ ) of singlet oxygen generation of each derivative is shown in Table 1 (Table 1).
この結果から、TPrPcをブロモ化した誘導体は、原料であるブロモ化しないTPrPcと比較して、一重項酸素の発生の量子収率が高くなり、特に１ブロモ体及び２ブロモ体は、極めて高い一重項酸素の生成の量子収率を示した。 From this result, the derivative obtained by brominating TPrPc has a higher quantum yield of generation of singlet oxygen than TPrPc which is not brominated as a raw material, and especially the 1 bromo and 2 bromo forms are extremely high singlet. The quantum yield of the production of term oxygen is shown.
［光増感反応］
１，５−ジヒドロキシナフタレンを基質とした下記スキーム（化１０）の光増感反応を行った。
[Photosensitized reaction]
The photosensitization reaction of the following scheme (Chemical Formula 10) using 1,5-dihydroxynaphthalene as a substrate was performed.
基質として、１，５−ジヒドロキシナフタレン２０ｍｇ（０．１２５ｍｍｏｌ）を２５ｍｌのメスフラスコに入れ、ＣＨ２Ｃｌ２／ＭｅＯＨ =９／１（Ｖ／Ｖ）の溶媒に溶かしメスアップし、基質溶液を調製した。また、３．８３×１０−６Ｍの各ポルフィセン誘導体の溶液を調製し、基質溶液２ｍｌと各ポルフィセン誘導体の溶液１ｍｌを反応容器（石英セル）に入れ、反応溶液の調製を行った。空気下、室温で、５００Ｗのタングステンランプを用い、カットフィルターで４６０ｎｍ以上の光を反応溶液に照射し、ＵＶvisスペクトルで反応を追跡した。
反応３時間後の反応溶液を３１倍希釈した溶液のＵＶvisスペクトルを測定し、生成物のモル吸光係数（ε427＝３３９２）から、生成物濃度を算出した。その生成物濃度を触媒濃度で割ってターンオーバー数（ＴＯＮ）を得た。結果を表２（表２）に示す。
As a substrate, 20 mg (0.125 mmol) of 1,5-dihydroxynaphthalene is placed in a 25 ml volumetric flask, dissolved in a solvent of CH 2 Cl 2 / MeOH = 9/1 (V / V) and made up to prepare a substrate solution. did. A 3.83 × 10 −6 M solution of each porphycene derivative was prepared, and 2 ml of the substrate solution and 1 ml of each porphycene derivative were placed in a reaction vessel (quartz cell) to prepare a reaction solution. Using a 500 W tungsten lamp at room temperature under air, the reaction solution was irradiated with light of 460 nm or more with a cut filter, and the reaction was followed by UVvis spectrum.
The UVvis spectrum of a solution obtained by diluting the reaction solution 31 times after 3 hours of reaction was measured, and the product concentration was calculated from the molar extinction coefficient (ε 427 = 3392) of the product. The product concentration was divided by the catalyst concentration to obtain the turnover number (TON). The results are shown in Table 2 (Table 2).
従って、本発明のブロモ化ポルフィセン誘導体は、基質として、１，５−ジヒドロキシナフタレンを用いた光増感反応において、高い触媒活性を示し、特に２ブロモ体（Br2）の活性は極めて高かった。 Therefore, the brominated porphycene derivative of the present invention showed high catalytic activity in the photosensitization reaction using 1,5-dihydroxynaphthalene as a substrate, and particularly the activity of the 2-bromo form (Br2) was extremely high.
［ブロモ化プロフィセン誘導体の耐久性］
ブロモ化プロフィセン誘導体の溶液（４．０×１０−６Ｍ，ＣＨ２Ｃｌ２／ＭｅＯＨ）＝９／１ ｖ／ｖ）に５００Ｗタングステンランプを用いて、空気下、室温にて、カットフィルターを用いて４６０ｎｍ以上の光を、１０時間照射し、ＵＶvisスペクトルで追跡を行った。
１０時間後のＵＶvisスペクトルから、各プロフィセン誘導体のＳｏｒｅｔ帯に由来するピークの吸光度変化より、下記式（数１）に従い、プロフィセン誘導体の生存率を算出した。結果を表３（表３）に示す。
[Durability of brominated prophycene derivatives]
Using a 500 W tungsten lamp in a brominated prophycene derivative solution (4.0 × 10 −6 M, CH 2 Cl 2 / MeOH) = 9/1 v / v), the cut filter was used at room temperature under air. It was used and irradiated with light of 460 nm or more for 10 hours, followed by UVvis spectrum.
From the UVvis spectrum after 10 hours, the viability of the prophycene derivative was calculated from the absorbance change of the peak derived from the Soret band of each prophycene derivative according to the following formula (Equation 1). The results are shown in Table 3 (Table 3).
本発明のブロモ化ポルフィセン誘導体は、光照射により、可視部の光吸収が大きく、高い量子収率で一重項酸素を生成し、安定であるので、光線力学療法（ＰＤＴ）に用いられる光線力学治療剤、環境浄化のための有害有機物分解・除去剤（環境汚染物質除去剤）、及び酸化反応等の有機合成触媒として、好適に用いられる。 Since the brominated porphycene derivative of the present invention has a large light absorption in the visible region upon irradiation with light, and generates singlet oxygen with a high quantum yield and is stable, photodynamic therapy used for photodynamic therapy (PDT). It is preferably used as an agent, a decomposition / removal agent of harmful organic substances (environmental pollutant removal agent) for environmental purification, and an organic synthesis catalyst such as an oxidation reaction.
TPrPcは、原料の２，７，１２，１７−テトラ−ｎ−プロピルポルフィセンの発光スペクトルである。
Br1は、TPrPcを、モノブロモ化した化合物の発光スペクトルである。
Br2は、TPrPcを、ジブロモ化した化合物の発光スペクトルである。
Br3は、TPrPcを、トリブロモ化した化合物の発光スペクトルである。
Br4は、TPrPcを、テトラブロモ化した化合物の発光スペクトルである。
TPrPc is an emission spectrum of the
Br1 is an emission spectrum of a compound obtained by monobromination of TPrPc.
Br2 is an emission spectrum of a compound obtained by dibromination of TPrPc.
Br3 is an emission spectrum of a compound obtained by tribromolating TPrPc.
Br4 is an emission spectrum of a compound obtained by tetrabromolation of TPrPc.
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| WO2017033557A1 (en) * | 2015-08-21 | 2017-03-02 | アグロカネショウ株式会社 | Method for producing 2-hydroxy-1,4-naphthoquinone |
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| EP3773561A4 (en) * | 2018-03-26 | 2021-11-24 | Zamadar, Matibur Rahaman | Multifunctional treatment and diagnostic compositions and methods |
| US11324826B2 (en) | 2018-03-26 | 2022-05-10 | Matibur Rahaman Zamadar | Multifunctional treatment and diagnostic compositions and methods |
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